WO2008130638A2 - A process for preparing intermediates of hmg-coa reductase inhibitors - Google Patents
A process for preparing intermediates of hmg-coa reductase inhibitors Download PDFInfo
- Publication number
- WO2008130638A2 WO2008130638A2 PCT/US2008/005034 US2008005034W WO2008130638A2 WO 2008130638 A2 WO2008130638 A2 WO 2008130638A2 US 2008005034 W US2008005034 W US 2008005034W WO 2008130638 A2 WO2008130638 A2 WO 2008130638A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- group
- formula
- tert
- butyldimethylsilyl
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 38
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 title claims description 12
- 239000000543 intermediate Substances 0.000 title abstract description 7
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 title description 8
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 title description 3
- 238000000034 method Methods 0.000 claims abstract description 80
- 229960000672 rosuvastatin Drugs 0.000 claims abstract description 12
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims abstract description 12
- 150000001875 compounds Chemical class 0.000 claims description 244
- -1 triethylsilyl Chemical group 0.000 claims description 74
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 72
- 238000006243 chemical reaction Methods 0.000 claims description 55
- 125000006239 protecting group Chemical group 0.000 claims description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 51
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 44
- 125000003118 aryl group Chemical group 0.000 claims description 44
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical group CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 39
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims description 38
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 31
- 235000019441 ethanol Nutrition 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 27
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 27
- 239000000203 mixture Substances 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 23
- 150000003512 tertiary amines Chemical group 0.000 claims description 22
- 239000003054 catalyst Substances 0.000 claims description 18
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 125000001931 aliphatic group Chemical group 0.000 claims description 16
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 16
- 229910052760 oxygen Inorganic materials 0.000 claims description 16
- 239000001301 oxygen Substances 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 claims description 15
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 15
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- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 13
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 10
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- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 9
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- 230000003301 hydrolyzing effect Effects 0.000 claims description 7
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- 238000011003 system suitability test Methods 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/535—Organo-phosphoranes
- C07F9/5352—Phosphoranes containing the structure P=C-
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
Definitions
- the invention relates to rosuvastatin intermediates and processes for their preparation thereof.
- Rosuvastatin (7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino) pyrimidin-5-yl]-(3R, 5S)-dihydroxy-(E)-6-heptenoic acid) calcium is an HMG-CoA reductase inhibitor, developed by Shionogi for the once daily oral treatment of hyperlipidaemia (Ann Rep, Shionogi, 1996; Direct communications, Shionogi, 8 Feb 1999 & 25 Feb 2000). Rosuvastatin calcium has the following chemical formula:
- Rosuvastatin calcium is marketed under the name CRESTOR for treatment of a mammal such as a human. According to the maker of CRESTOR, it is administered in a daily dose of from about 5mg to about 40 mg for LDL cholesterol reduction.
- PCT publication No. WO 03/087112 discloses the synthesis of rosuvastatin from a different intermediate, (3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5- oxohexanate (TSPH), which was synthesized from 3-hydroxy diethyl glutarate via partial hydrolysis by a microorganism to obtain enantiomerically pure glutaric acid derivative according to Scheme 1 :
- US publication No. 2005/0070605 Al discloses the enantioselective opening of 3- hydroxyprotected glutaric anhydride by phenyl ethylamine to form an amide bond, and further converting it to HMG-CoA reductase inhibitor.
- the process may have problems such as breaking of the phenyl ethyl amide bond in the final step of producing cerivastatin and the problematic removal of phenyl ethylamine after breaking of the amide linkage in the synthesis of pitavastatin.
- PCT publication No. WO 2006/021326 discloses the opening of 3-hydroxy protected glutaric anhydride by methanol to yield racemic methyl 3( ⁇ )-3-(t-butyl dimethylsilyloxy)-6- dimethoxy-phosphinyl-5-oxohexante, and the preparation of racemic methyl (3R)-3-(t-butyl dimethylsilyloxy)-6-dimethoxy-phosphinyl-5-oxohexante.
- the disclosed process employs explosive and toxic materials, such as diazomethane, during the preparation ofmethyl-(3R)-3-(t-butyl dimethylsilyloxy)-6-dimethoxy-phosphinyl-5- oxohexante(esterification). Moreover, the yield of the above steps is low, and thus the process may not suitable for industrial and commercial use.
- J.Org.Chem. (1991) 56:3744-47 discloses the preparation of (3R)-3-(t-butyl dimethylsilyloxy)-6-dimethoxy-phosphinyl-5-oxohexante from 3-hydroxy protected glutaric anhydride.
- the disclosed process which involves using hazardous reactions, such as use of N 2 O 4 oxidation, followed by a hydrogenation reaction to cleave the amino group of the resolving agent, and use of diazomethane.
- hazardous reactions such as use of N 2 O 4 oxidation
- hydrogenation reaction to cleave the amino group of the resolving agent
- diazomethane use of diazomethane.
- the process also uses an expensive palladium catalyst which could remain as an impurity in the final product.
- the present invention provides a process for preparing a compound of formula 4, having the following structure:
- Ci-C 5 alcohol in the presence of alkaloid, wherein Ri is Ci-C 5 alkyl preferably C]-C 4 ; and Z is a hydroxy protecting group.
- the protecting group is preferably a silyl group, including trialkylsilysl group having the formula-Si(A) 3 where each A is independently selected from a Ci-C 6 linear or branched aliphatic or aromatic group. Examples of silyl
- EV 079444 136 US groups include triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl.
- the silyl group is tert-butyldimethylsilyl.
- the present invention further provides a process for preparing the compound of formula 5 having the following structure:
- the compound of formula 6 may be used to prepare the compound of formula 2, having the following structure:
- the present invention provides a process for preparing a compound of formula 7, having the following structure:
- R 4 is Ci to C 6 alkyl, e.g., methyl or ethyl, and Ar is phenyl or substituted phenyl, and Z is a hydroxy protecting group as above.
- the present invention provides a compound of formula 7 having the following structure:
- R 4 is Ci to C 6 alkyl, e.g., methyl or ethyl
- Ax is phenyl or substituted phenyl
- Z is a hydroxy protecting group as above.
- a compound of formula 7 which is at least 50% chiral pure.
- the compound of formula 7 can be purified by HPLC.
- the enriched enantiomer has the following structure;
- the present invention provides a compound of formula 8 having the following structure:
- R 4 is Ci to C 6 alkyl, e.g., methyl or ethyl, and Ar is phenyl or substituted phenyl.
- a compound of formula 8 which is at least 50% chiral pure.
- the compound of formula 8 can be purified by HPLC.
- the enriched enantiomer has the following structure;
- the present invention further provides a process for the preparation of the compound of formula 8, described above, by combining a compound of formula 7, described above, with BOC anhydride.
- the present invention provides a process for preparing a compound of formula 6, having the following structure:
- the present invention provides a process for preparing the compound of formula 4a, having the following structure:
- the enriched enantiomer has the following structure;
- the present invention provides a process for preparing compound of formula 5a, having the following structure:
- the enriched enantiomer has the following structure;
- the present invention provides a process for preparing compound of formula 6a, having the following structure:
- the enriched enantiomer has the following structure;
- the present invention provides a compound of formula 7 having the following structure:
- R 4 is Ci to C 6 alkyl, e.g., methyl or ethyl
- Ar is phenyl or substituted phenyl
- Z is a hydroxy protecting group as above.
- the present invention also provides a process for preparing the compound of formula 7a by enantioselectively opening the prochiral anhydride of formula 3, described above with chiral alcohols of the formula 3a, described above, wherein R 4 is Ci to C 6 alkyl, e.g., methyl or ethyl, Ar is phenyl or substituted phenyl, and Z is a hydroxy protecting group as above.
- the enriched enantiomer of formula 7 has the following structure;
- the invention provides a compound of formula 8 having the following structure:
- the enriched enantiomer of formula 8 has the following structure;
- the present invention also provides a process for preparing the compound of formula 8a by combining the compound of formula 7a, described above, with BOC anhydride in the presence of a base.
- the present invention also provides a process for preparing compound of formula 6a having the following structure:
- the enriched enantiomer of formula 6a has the following structure;
- the present invention also provides a process for preparing the chiral pure R-isomer compound of formula 6, described above, by an optical resolution process by combining the compound of formula 6a, described above, a compound (R)-(+)- phenylethylamine of formula 9a, having the following structure:
- the present invention provides a compound of formula 9, having the following structure:
- the present invention also provides a process for preparing the compound of formula 9 by combining the compound of formula 6, described above, with at least one organic solvent, preferably selected from the group consisting of: C 5- Ci 2 aromatic hydrocarbons optionally substituted with halogen, -SH, -OH, -NO 2 , or -NH 2 ; C 5- Ci 2 aromatic hydrocarbons where one or more ring carbons is substituted with N, S, or O; C 6- Ci O aliphatic hydrocarbons, halogenated Ci-Ci 2 hydrocarbons, ethers and ketones, an amidation reagent selected from the group consisting of: Ci -4 alkyl and C 6-8 aryl haloformates and acid halides, and at least one base; and adding N,O-dimethyl hydroxyl amine.
- organic solvent preferably selected from the group consisting of: C 5- Ci 2 aromatic hydrocarbons optionally substituted with halogen, -SH, -OH, -NO 2 , or -NH 2 ; C
- the present invention provides a novel process for the preparation of a chirally pure compound of the general formula A, having the following structure:
- Ri is H, Ci-C 5 alkyl, or a Ci to C 5 carbonyl
- R 2 is C]-C 6 alkyl, e.g., methyl, ethyl, or t- butyl group
- Z is a hydroxy protecting group.
- the protecting group is preferably a silyl group, including trialkylsilysl group having the formula-Si(A) 3 where each A is independently selected from a Ci-C 6 linear or branched aliphatic or C 5- Ci 2 aromatic group.
- silyl groups include trimethylsilyl, triethylsilyl, triisopropylsilyl, tert- butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl.
- the silyl group is tert-butyldimethylsilyl.
- R 2 is t-butyl group.
- the present invention provides a process for preparing a compound of formula 2, having the following structure:
- substituents in the "substituted alkyl” or “substituted aryl or phenyl” may be selected from the groups such as hydroxy, carboxyl, alkyl (such as Ci-C 4 ), alkoxy (such as
- the invention provides a process for producing chirally pure (more than 50% enrichment) compounds of formulas A and 2 in high yield, making the process economically attractive by using less toxic chemicals and fewer reaction steps.
- the invention provides a process for preparing a compound of formula 4, having the following structure:
- Ri is Cj-C 5 alkyl, preferably Cl to C4 alkyl, more preferably R 1 is a methyl group and Z is a hydroxy protecting group.
- the protecting group is preferably a silyl group, including trialkylsilysl group having the formula-Si(A) 3 where each A is independently selected from a C]-C 6 linear or branched aliphatic or aromatic group.
- silyl groups include trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl, preferably tert-butyldimethylsilyl.
- a Ci-C 5 alkyl alcohol is used in the presence of an alkaloid.
- alkaloids include a) Indole alkaloids such as 5 -MeO-DMT, dimethyltryptamine, Harmala alkaloids, psilocin, psilocybin, reserpine, serotonin, tryptamine, yohimbine; b) phenethylamine alkaloids such as amphetamine, cathinone, ephedrine, mescaline, methamphetamine, phenethylamine, tyramine; c) purine alkaloids such as caffeine, theobromine, theophylline, d) pyridine alkaloids such as Coniine; d) pyrrolidine alkaloids such as nicotine e) quinoline alkaloids such as quinine or quinidin; and f) terpenoids such as aconitine and solanine. More preferably the alkaloids
- the reaction temperature is between about -35 0 C to about -60 0 C, more preferably, between about -40 0 C to about -50 0 C.
- the reaction is maintained for about 5 to about 30 hours, more preferably for about 12 to about 24 hours.
- the compound of formula 4 obtained is in enantiomeric excess of about 80% to about 98%, more preferably about 85% to about 90% as measured by chiral HPLC.
- the present invention further provides a process for preparing the compound of formula 5 having the following structure:
- the basic catalyst is preferably a tertiary amine such N-methyl morpholine, N 5 N- dimethylaminopyridine, and mixtures thereof.
- the tertiary amine base is of the formula
- N(A1)(A2)(A3) contains C 3 -Ci 5 carbon atoms wherein Al, A2, and A3 are each independently selected from a Ci-Cio alkyl group and a C 5 -Ci 2 aromatic group, wherein Al,
- A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like
- Al and A2 are methyl groups
- A3 is a C 5 -Ci 2 aromatic group containing a nitrogen or an oxygen (such as cyclic structures like morpholino and pyridine groups).
- the protecting group is preferably a silyl group, including trialkylsilysl group having the formula-Si(A) 3 where each A is independently selected from a Ci-C 6 linear or branched aliphatic or C 5 -Ci 2 aromatic group.
- silyl groups include trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl.
- the silyl group is tert- butyldimethylsilyl.
- the combination of compound of formula 4 with BOC anhydride in the presence of a base catalyst can be maintained at a temperature of about 5 0 C to about 50 0 C, more preferably, at about 10 0 C to about 30 0 C.
- the combination can be maintained for a period of about 2 to about 10 hours, more preferably about 2 to about 5 hours.
- the hydrolysis is carried out under basic conditions in an alcohol.
- the concentration of the alkaline solution can be about 0.5 to about 2N.
- the alcohol is can be a C1-C4 alcohol, preferably selected from the group consisting of: methyl alcohol, ethyl alcohol, and mixtures thereof, more preferably ethyl alcohol.
- the reaction can be maintained for a period of about 2 to about 12 hours, such as about 6 to about 8 hours, hi one embodiment, the reaction is maintained at a temperature of about 20 0 C to about 60 0 C, such as at about 45 0 C to about 55 0 C.
- suitable bases include alkali metal and alkaline earth metal bases, particularly hydroxide bases such as sodium and potassium hydroxide.
- the reaction mixture can be acidified.
- Compound of 6 can then be extracted into a water immiscible solvent such as toluene, followed by evaporation of the toluene, such as at a pressure of less than one atmosphere.
- R 4 is Ci-C 6 alkyl, e.g., methyl or ethyl, and Ax is phenyl or substituted phenyl as defined above, and Z is a hydroxy protecting group as above.
- the enriched enantiomer of formula 7 has the following structure;
- the reaction can be carried out in the presence of a catalyst
- the catalyst can be a base.
- the base is N,N-dimethylamino- pyridine.
- the basic catalyst is preferably a tertiary amine such N-methyl morpholine, N,N-dimethylaminopyridine, and mixtures thereof.
- the tertiary amine base is of the formula N(A1)(A2)(A3), contains C 3 -Ci 5 carbon atoms wherein Al, A2, and A3 are each independently selected from a Cj-Cio alkyl group and a C 5 -Ci 2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like morpholino and pyridine groups).
- N(A1)(A2)(A3) contains C 3 -Ci 5 carbon atoms wherein Al, A2, and A3 are each independently selected from a Cj-Cio alkyl group and a C 5 -Ci 2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like morpholino and pyridine groups).
- EV 079 444 136 US Al and A2 are methyl groups, and A3 is a C 5 -Ci 2 aromatic group containing a nitrogen or an oxygen atom (such as cyclic structures like morpholino and pyridine groups).
- the compound of formula 3 Prior to the combining step with the compound of formula 3 a, the compound of formula 3 can be dissolved in an organic solvent.
- the organic solvent can be a C1-C4 chlorinated hydrocarbon, such as methylene dichloride.
- the compound of formula 3a and the catalyst are mixed with a solution of the compound of formula 3 in an organic solvent, to obtain a reaction mixture.
- the reaction mixture can be at a temperature of about - 20 0 C to about -60 0 C, such as at about -30 0 C to about -50 0 C.
- the reaction mixture can be maintained for a period of about 10 to about 30 hours, such as about 15 to about 25 hours.
- the invention provides a compound of formula 7 having the following structure:
- R 4 is C 1 -C 6 alkyl, e.g., methyl or ethyl
- Ar is phenyl or substituted phenyl as defined above
- Z is a hydroxy protecting group as above.
- a compound of formula 7 which is at least 50% chiral pure as determined by chiral HPLC.
- the compound of formula 7 can be purified by HPLC.
- the enriched enantiomer of formula 7 has the following structure;
- the invention provides a compound of formula 8 having the following structure:
- R 4 is Ci-C 6 alkyl, preferably Ci -C 4 alkyl e.g., methyl or ethyl, and Ar is phenyl or substituted phenyl as defined above. Also provided
- EV 079444 136 US is a compound of formula 8 which is at least 50% chiral pure as measured by an HPLC chiral column.
- the compound of formula 8 can be purified by HPLC.
- the enriched enantiomer of formula 8 has the following structure;
- the present invention further provides a process for the preparation of the compound of formula 8, described above, by combining a compound of formula 7, described above, with BOC anhydride.
- a C5-C 12 aromatic hydrocarbon such as toluene can be used as a solvent.
- the process is done in the presence of a basic catalyst.
- the basic catalyst can be selected from the group of tertiary amines consisting of: N-methyl morpholine, N 9 N- dimethylaminopyridine, and mixtures thereof.
- the tertiary amine base is of the formula N(A1)(A2)(A3), contains C 3 -Ci 5 carbon atoms wherein Al, A2, and A3 are each independently selected from a C 1 -Ci 0 alkyl group and a C 5 -C 12 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like morpholino and pyridine groups).
- Al and A2 are methyl groups
- A3 is a C 5 -Ci 2 aromatic group containing a nitrogen or an oxygen atom (such as cyclic structures like morpholino and pyridine groups).
- the combination of the compound of formula 7 with BOC anhydride is maintained at a temperature of about 5 0 C to about 5O 0 C, more preferably at about 10 0 C to about 30 0 C.
- the combination is maintained for a period of about 2 to about 10 hours, more preferably for about 2 to about 5 hours.
- the invention provides a process for preparing a compound of formula 6, having the following structure:
- the hydrolysis is carried out under basic conditions in an alcohol.
- concentration of the alkaline solution can be about 1 to about 2N.
- the alcohol is can be a C1-C4 alcohol, preferably selected from the group consisting of: methyl alcohol, ethyl alcohol, and mixtures thereof, more preferably ethyl alcohol.
- EV 079444 136 US solution and the alcoholic mixture of the compound of formula 8 is maintained for a period of about 10 to about 30 hours, more preferably for about 15 to about 25 hours.
- the combination is maintained at a temperature of about 20 0 C to about 60 0 C, more preferably at about 40 0 C to about 55 0 C.
- suitable bases include alkali metal and alkaline earth metal bases, particularly hydroxide bases such as sodium and potassium hydroxide.
- the reaction mixture can be acidified.
- Compound of 6 can then be extracted into a water immiscible solvent such as toluene, followed by evaporation of the toluene, such as at a pressure of less than one atmosphere.
- the invention provides a process for preparing a compound of formula 6, having the following structure:
- the hydrolysis comprises combining an alkaline solution with the alcoholic mixture of the compound of formula 8.
- the concentration of the alkaline solution is about 1 to about 2N.
- the alcohol is selected from the group consisting of: C 1 - C5 alcohol (preferably Cj-C 4 ) such as methyl alcohol, ethyl alcohol, and mixtures thereof.
- the present invention provides a process for preparing the compound of formula 4a, having the following structure:
- the compound of formula 4a is obtained in the enantiomeric ratio of about 85:15 to about 95:5.
- the compound of formula 4a is combined with an organic solvent.
- the organic solvent may be C 6 -Ci 2 aromatic hydrocarbon, Ci-C 4 chlorinated hydrocarbon, C 4 -C 8 ether and or C 3 -C 8 ether. Examples of these solvents include methylene dichloride, toluene, methyl t-butyl ether, n-heptane, methyl ethyl ketone, tetrahydrofuran, and
- the more preferred solvents are methylene dichloride and toluene.
- the reaction temperature is about -30 0 C to about -60 0 C, and more preferably, about -40 0 C to about -50 0 C.
- the reaction is maintained for about 5 to about 30 hours, more preferably, for about 8 to about 15 hours.
- the present invention provides a process for preparing compound of formula 5a, having the following structure:
- the base can be selected from the group consisting of: tertiary amines like N-methyl morpholine, N,N-dimethyl amino pyridine and mixtures thereof.
- the tertiary amine base is of the formula N(A1)(A2)(A3), contains C 3 -Ci 5 carbon atoms wherein Al, A2, and A3 are each independently selected from a Ci-Ci 0 alkyl group and a C 5 -Ci 2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like morpholino and pyridine groups).
- Al and A2 are methyl groups
- A3 is a C 5 -Ci 2 aromatic group containing a nitrogen or an oxygen atom (such as cyclic structures like morpholino and pyridine groups).
- the temperature is of about -10 0 C to about 50 0 C, more preferably about 10 0 C to 30 0 C.
- the combination of the compound of formula 4a, BOC anhydride and the base is maintained for about 2 to 10 hours, more preferably for 2 to about 5 hours.
- the present invention provides a process for preparing compound of formula 6a, having the following structure:
- the compound of formula 6a is obtained in the enantiomeric ratio of about 85:15 to about 95:5.
- the hydrolysis comprises adding about 0.5 to about 2N alkaline solution to the alcoholic mixture of the compound of formula 5a.
- the alcohol may be selected from the group consisting of: methyl, ethyl alcohol, and mixtures thereof.
- the hydrolyzation is for about 2 to about 12 hours at a temperature of about 20 0 C to about 60 0 C, more preferably for about 6 to about 8 hours at a temperature of about 45-55 0 C.
- the base can be selected from the group consisting of: tertiary amines like N-methyl morpholine, N,N-dimethyl amino pyridine and mixtures thereof.
- the tertiary amine base is of the formula N(A1)(A2)(A3), contains C 3 -C 15 carbon atoms wherein Al, A2, and A3 are each independently selected from a C 1 -C I0 alkyl group and a C 5 -Ci 2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like morpholino and pyridine groups).
- Al and A2 are methyl groups
- A3 is a C 5 -C] 2 aromatic group containing a nitrogen or an oxygen atom (such as cyclic structures like morpholino and pyridine groups).
- the present invention provides a compound of formula 7 having the following structure:
- R 4 is Ci-C 6 alkyl, e.g., methyl or ethyl
- Ar is phenyl or substituted phenyl as defined above
- Z is a hydroxy protecting group as above.
- the present invention also provides a process for preparing the compound of formula 7a by enantioselectively opening the prochiral anhydride of formula 3, described above with chiral alcohols of the formula 3a, described above.
- the compound of formula 7a is in the enantiomeric ratio of about 80:20 to about 85:15.
- the reaction comprises combining a solution of a compound of formula 3a with a mixture of a compound of formula 3 and a base in an organic solvent.
- the temperature during the process is of about -20 0 C to about -60 0 C and more preferably, of about -30 0 C to about -50 0 C.
- combination of the compound of formula 3a, the compound of formula 3, the base and the organic solvent is maintained for about 10 to about 30 hours, more preferably for about 15 to about 25 hours.
- the base can be selected from the group consisting of: tertiary amines like N-methyl morpholine, N,N-dimethyl amino pyridine and mixtures thereof.
- the tertiary amine base is of the formula N(A1)(A2)(A3), contains C 3 - Ci 5 carbon atoms wherein Al, A2, and A3 are each independently selected from a Ci-Cio alkyl group and a C 5 -Ci 2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like morpholino and pyridine groups), hi one embodiment Al and A2 are methyl groups, and A3 is a C 5 -C] 2 aromatic group containing a nitrogen or an oxygen atom (such as cyclic structures like morpholino and pyridine groups).
- the organic solvent is a C 6 -Ci 2 aromatic hydrocarbon or C 1 -C 4 chlorinated hydrocarbon. Specific examples of these solvents include methylene di chloride, toluene and mixtures thereof.
- the present invention provides a compound of formula 8 having the following structure:
- the present invention also provides a process for preparing the compound of formula 8a by combining the compound of formula 7a, described above, with BOC anhydride in the presence of a base, wherein Z is a hydroxy protecting group as above and R 4 is alky 1 of Cj to C 6 carbon group, preferably C1-C4 group.
- the base can be selected from the group consisting of: tertiary amines like N-methyl morpholine, N,N-dimethyl amino pyridine and mixtures thereof.
- the tertiary amine base is of the formula N(A1)(A2)(A3), contains C 3 -Ci 5 carbon atoms wherein Al, A2, and A3 are each independently selected from a Ci-Ci 0 alkyl group and a C 5 -Ci 2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like morpholino and pyridine groups).
- Al and A2 are methyl groups
- A3 is a C 5 -Ci 2 aromatic group containing a nitrogen or an oxygen atom (such as cyclic structures like morpholino and pyridine groups).
- the temperature during the process is of about -10 0 C to about 50 0 C, more preferably about 10 0 C to 30 0 C.
- the combination of the compound of formula 7a with BOC anhydride in the presence of a base is maintained for about 2 to about 10 hours, more preferably for about 2 to about 5 hours.
- the present invention also provides a process for preparing compound of formula 6a having the following structure:
- the compound of formula 6a is obtained in an enantiomeric ratio of about 80:20 to about 85:15.
- the enantiomeric enriched formula 6 has the following structure;
- the hydrolysis comprises combining about 0.5 to about 2N alkaline solution with an alcoholic mixture of the compound of formula 8a.
- the alcohol may be selected from the group consisting of: Ci-C 4 alcohol such as methanol, ethanol and mixtures thereof.
- EV 079 444 136 US combination of the alkaline solution and the an alcoholic mixture of the compound of formula 8a is preferably maintained for about 10 to about 30 hours, preferably at a temperature of about 20 0 C to about 60 0 C, more preferably for a period of about 15 to about 25 hours at a temperature of about 40 0 C to about 55 0 C.
- the compound of formula 6 may be used to prepare the compound of formula 2, having the following structure:
- R 2 is aCi-C 4 alcohol such as methyl, ethyl, or t- butyl; Z is a hydroxy protecting group; and R 3 is Ci to C 3 alkoxy, aryloxy, or substituted aryloxy group.
- the protecting group is preferably a silyl group, including trialkylsilysl group having the formula-Si(A) 3 where each A is independently selected from a C1-C6 linear or branched aliphatic or aromatic group.
- silyl groups include trimethylsilyl, triethylsilyl, triisopropylsilyl, tert- butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl.
- the present invention also provides a process for preparing the chiral pure R-isomer compound of formula 6, described above, by an optical resolution process by combining the compound of formula 6a, described above, a compound (R)-(+)-phenylethylamine of formula 9a, having the following structure:
- the resolution comprises combining the compound of formula 6a with chiral ratio of about 80:20 to about 85:15 with compound of formula 9a or 9b to get a salt of formula 8b, having the following structure:
- a Ci-C 4 alcohol selected from the group consisting of: as methanol, ethanol, isopropyl alcohol, n-butyl alcohol and t-butyl alcohol, more preferably isopropyl alcohol.
- the compound of formula 9a is used in a molar ratio of about 1 to about 2 to the compound of formula 6a at a temperature of about O 0 C to about 70 0 C.
- the obtained product is crystallized to get chirally pure salt of formula 8c having the following structure:
- the salt of formula 8c is hydrolyzed in aqueous medium using a mineral acid to get the compound of formula 6 with chiral purity of about 99 to about 100%, more preferably about 99.5 to about 99.8%.
- the mineral acid may be: a dilute hydrochloric acid or dilute sulfuric acid.
- dilute hydrochloric acid is used.
- Hydrochloric acid is added in an amount of about 1 to about 2 equivalents with regard to the compound of formula 8c, at a temperature of about O 0 C to about 50 0 C, preferably at about O 0 C to about 30 0 C.
- the present invention provides a compound of formula 9, having the following structure:
- the compound of formula 9 may be used to prepare the compound of formula 2, having the following structure:
- R 2j and R 3 are, independently, an optionally substituted alkyl of 1-4 carbon atoms
- X is an alkoxy group of Ci to C 5 carbon atoms or an optionally substituted alkyl group of Cr C 5 carbons.
- R 3 groups are methyl groups.
- the phosphonium salt depicted above is suspended in a solvent such as diethyl ether or THF (tetrahydrofuran) and a strong base, preferably a Cr C 8 aryl or alkyl metal base, such as the organolithium reagents phenyllithium or n-butyllithium is added.
- a strong base preferably a Cr C 8 aryl or alkyl metal base, such as the organolithium reagents phenyllithium or n-butyllithium is added.
- the lithium salt has the following structure:
- Ci-C 4 dialkyl phosphonate is used, and more preferably dimethyl methylphosphonate is used in the process of the invention.
- the solvent is selected from Ci- C 4 aliphatic alcoholic solvent, a C 6 - Cio aromatic and C 5 -C 8 aliphatic hydrocarbon, a C 2 - C 8 aliphatic ester, a C 4 -C 8 ether (including cyclic compounds), and a C1-C6 aliphatic solvent with one, two or three chlorine atoms.
- solvents include toluene, benzene, xylene, cyclohexane; ethers, methyl t-butyl ether, tetrahydrofuran and tetrahydrofuran.
- the solvent is tetrahydrofuran.
- Suitable bases include alkyl lithium bases, such as n-butyl lithium and Cr
- dimethylmethylphosphonate is combined with a suitable solvent such as a C 4 -C 8 ether such as tetrahydrofuran.
- a suitable solvent such as a C 4 -C 8 ether such as tetrahydrofuran.
- the reaction mixture is then cooled before addition of a strong base such an organolithium reagent such as phenyllithium or n- butyllithium.
- the reaction is maintained to obtain anion formation.
- Compound of formula 9 is then added to the reaction mixture, preferably in the same solvent.
- the reaction mixture is obtained to complete the reaction.
- the reaction can be quenched by addition of ammonium chloride.
- the reaction can be carried out at a preferred temperature of about -70 0 C to about - 90 0 C. Afterwards, the reaction mixture can be warmed, such as to about 25 0 C.
- the product, compound of formula one can be extracted into a water immiscible solvent such as hexane.
- the hexane can then be evaporated to obtain the product.
- the present invention also provides a process for preparing the compound of formula 9, by combining the compound of formula 6, described above, with at least one organic solvent selected from the group consisting of: C 5 -Ci 2 aromatic hydrocarbons (including substituted), C 6- C] 0 aliphatic hydrocarbons, halogenated C 6- Ci O hydrocarbons, ethers having from 2 to 20 carbon atoms and ketones having from 2 to 20 carbon atoms , an amidation reagent selected from the group consisting of: Ci -4 alkyl and C 6-8 aryl haloformates and acid halides, and at least one base; and adding N,O-dimethyl hydroxyl amine.
- the Ci -4 alkyl halo formate is ethyl or methyl derivative of chloro or bromo formate.
- the C 6-8 aryl haloformate is a benzyl chloro or bromo formate.
- Preferred acid halides are acetyl, pivaloyl, oxaloyl or benzoyl chlorides and bromides.
- the most preferred haloformate is either ethyl chloroformate or methyl chloroformate.
- the more preferred acid halide is acetyl or pivaloyl chlorides.
- the substituted aromatic hydrocarbon is either toluene or xylene.
- a preferred C 6- Ci O aliphatic hydrocarbon is either hexane or heptane.
- Preferred ketones are
- the base is an organic base selected from the group consisting of: diethyl amine, triethyl amine, di-n-propyl amine, diisopropyl amine, tri-n-butyl amine, morpholine, piperidine, pyridine, N, N-dimethyl aminopyridine.
- the base is either N, N- dimethylaminopyridine or triethyl amine.
- the compound of formula 6 and an organic solvent first combined, and thereafter are combined with the amidation reagent and a base at a temperature of about 20 0 C to about -30 0 C, more preferably of about -10 0 C to about -20 0 C, to obtain a reaction mixture.
- the reaction mixture is maintained at a temperature of about -10 to -20 0 C for a period of about 0 to about 4 hours.
- reaction mixture is maintained for about 0.5 to about 2 hours after the addition of N, O-dimethyl hydroxyl amine at a temperature of about -10 0 C to about 35 0 C, more preferably at about O 0 C to about 20 0 C.
- the invention provides a process for the preparation of a chirally pure compound of the general formula A, having the following structure:
- R 1 is H, C 1 -C 5 alkyl
- R 2 is C]-C 6 alkyl, e.g., methyl, ethyl, or t- butyl group
- Z is a hydroxy protecting group, optionally a trimethylsilyl, t-butyldimethylsilyl, diphenylmethylsilyl, or dimethyl phenylsilyl group.
- the silyl group is tert- butyldimethylsilyl.
- R 2 is t-butyl group.
- the compound of formula A is an intermediate used for the synthesis of the compound of formula 2, having the following structure:
- R 2 is methyl, ethyl, or t- butyl group
- Z is hydroxy protecting group such as trimethylsilyl, t-butyldimethylsilyl, diphenylmethylsilyl, or dimethyl phenylsilyl group
- R 3 is C] to C 3 alkyloxy, aryloxy, or substituted aryloxy group, which can be used for the preparation of HMG-CoA reductase inhibitors.
- the present invention provides a process for preparing a compound of formula 2a, having the following structure:
- R 3 is lower Ci to C 3 alkyloxy, C 5 -Cj 2 aryloxy, C 5 -Ci 2 aryloxy (optionally substituted) and Z is a hydroxy protecting group, such as trimethylsilyl, t- butyldimethylsilyl, or diphenyl methylsilyl, dimethylphenylsilyl.
- the dialkyl phosphonate is Ci-C 3 dialkyl phosphonate.
- the lithiated salt of dialkyl phosphonate is prepared at a temperature of about -50 0 C to about -HO 0 C using n- butyl lithium and dialkyl phosphonate in the molar ratios of about 1.3 to about 4.5 and about 1.5 to about 5, respectively, in relation to compound of formula 9. More preferably, the molar ratios are about 1.4 to about 2 and about 1.5 to about 2.2, respectively.
- the reaction is maintained preferably at a temperature of about -75 0 C to about -85 0 C for about 2 to about 6 hours.
- the reaction is maintained preferably at a temperature of about -75 0 C to about -85 0 C for about 0 to about 4 hours.
- the reaction is done preferably using toluene, xylene, cyclohexane, methyl t-butyl ether, tetrahydrofuran ,or mixtures thereof. More preferably the solvent is selected from methyl t-butyl ether and tetrahydrofuran.
- the group Ri is preferably Ci-C 4 group, more preferably methyl;
- R 2 is preferably a Ci-C 4 group, more preferably t-butyl;
- Z is preferably a silyl group, more preferably tert-butyldimethylsilyl.
- the compounds prepared by the process of the invention may be used to prepare statins for treatment of hyperlipidemia.
- Statins can be combined with a pharmaceutically acceptable excipient to prepare pharmaceutical compositions.
- statins that can be prepared include the following:
- TBDMS-OH, DMMP, MBSG and 19TBPO into 10ml volumetric flask, dissolve and brought to volume with diluent. Transferred ImI of the stock solution into 10ml volumetric flask and brought to volume with diluent. System suitability test Injected system suitability solution.
- Typical retention times are about 4minutes for TNDMS-OH peak, about 6.5 minutes for the DMMP peak, About 14.5minutes for the MBSG peak and 31.5minutes for the 19TBPO peak.
- a four neck round bottom flask fitted with a mechanical stirrer, condenser, and charging tube was charged with methylene dichloride (75 ml) and the compound of formula 3 ( 25 g, 0.1 mole) under inert atmosphere at 25 to 30 0 C.
- the reaction mass was cooled to -35 to -4O 0 C, followed by addition of a solution of quinidine (35.68 g, 0.11 mole) in methylene dichloride (125 ml).
- the methanol (28.3 ml) was slowly added into the reaction mass at -35 to -40 0 C and it was maintained for 15-20 hours.
- a catalytic amount of N,N-dimethylaminopyridine was added at 20 to 30 0 C, and the mass was maintained at 25-3O 0 C for 3-5 hours.
- Silica gel (2.5 g) was added and then removed.
- Water (10 ml) was added to the mass, and the pH was adjusted to 4-4.5 using hydrochloric acid.
- the aqueous phase was separated.
- the organic phase was washed with water, followed by removal of toluene under vacuum, giving the compound of formula 8 in 62 % yield.
- the reaction mass was cooled to -15 to -25 0 C followed by addition of tri ethyl amine (13.34 g) and ethyl chloro formate (13.13 g) and it was maintained for 30-60 minutes at 0 to -15 0 C followed by addition of a solution of N,O- dimethyl hydroxyl amine ( 13.95 g) in methylene dichloride (30 ml).
- Reaction mass was maintained for 1-3 hours at -75 to -90 0 C followed by quenching of the mass with ammonium chloride solution. The temperature of the reaction mixture was allowed to 20- 30 C. Phases were separated and aq. layer was extracted with hexane. Combined organic phase was washed with brine followed by stripping of hexane to get 85% yield of compound of formula 2 with GC purity of 87.1%.
- Example 16 Conversion of Compound 22TB into rosuvastatin Ca with extraction in ethyl acetate A l L reactor equipped with a mechanical stirrer was charged with EtOH (3 L), water
- reaction mixture (1800 mL), and TBRE (600 g), forming a reaction mixture.
- NaOH (47%, 1.2 eq, 114 g) was slowly added to the reaction mixture, at RT.
- the reaction mixture was stirred at about RT for two hours.
- the reaction mixture was filtered under reduced pressure with Synter and Hyflo to eliminate the small particles present.
- the reaction mixture was concentrated under reduced pressure at about 40°C until half the volume of the reaction mixture remained.
Abstract
The present invention relates to intermediates of rosuvastatin and processes for the production thereof.
Description
A PROCESS FOR PREPARING INTERMEDIATES
OF HMG-CoA REDUCTASE INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No. 60/925,216, filed April 18, 2007; 60/931,926, filed May 24, 2007; 61/066,678, filed February 21, 2008, and 61/069,099, filed March 11, 2008. The contents of which are incorporated herein by reference.
FIELD OF THE INVENTION
The invention relates to rosuvastatin intermediates and processes for their preparation thereof.
BACKGROUND OF THE INVENTION
Rosuvastatin (7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino) pyrimidin-5-yl]-(3R, 5S)-dihydroxy-(E)-6-heptenoic acid) calcium is an HMG-CoA reductase inhibitor, developed by Shionogi for the once daily oral treatment of hyperlipidaemia (Ann Rep, Shionogi, 1996; Direct communications, Shionogi, 8 Feb 1999 & 25 Feb 2000). Rosuvastatin calcium has the following chemical formula:
Rosuvastatin calcium is marketed under the name CRESTOR for treatment of a mammal such as a human. According to the maker of CRESTOR, it is administered in a daily dose of from about 5mg to about 40 mg for LDL cholesterol reduction.
U.S. Patent application No. 5,260,440 (EP0521471 Al) (US '440), discloses the synthesis of rosuvastatin from the intermediate 3(R)-3(tert-butyldimethylsilyloxy)-5-oxo-6-
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triphenyl-phoporanylidene hexanoate. PCT publication No. WO 03/097614 discloses the synthesis of rosuvastatin from the intermediate (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6- triphenyl-phosphoralydene hexanoate, disclosed in US '440 patent.
PCT publication No. WO 03/087112 discloses the synthesis of rosuvastatin from a different intermediate, (3R)-3-(t-butyldimethylsilyloxy)-6-dimethoxyphosphinyl-5- oxohexanate (TSPH), which was synthesized from 3-hydroxy diethyl glutarate via partial hydrolysis by a microorganism to obtain enantiomerically pure glutaric acid derivative according to Scheme 1 :
Scheme 1 9 Il ? I H o Il o iϊ O IH o Ti o OH o
11 1 11 Esterase Jl ! JJ lsobutene Il I Il
Imidazole TBDMS Chloride
The process of PCT publication No. WO 03/087112 may not be desirable on an industrial scale. For example, it requires the use of an expensive microorganism such as CLS-BC-
14011 during the partial hydrolysis of 3-hydroxy diethyl glutarate. Additionally, the process uses a hazardous reaction, such as isobutylene gas during esterification of ethyl-(3S)-3- hydroxyglutaric acid in the presence of sulphuric acid, and the purification of TSPH by column chromatography is commercially difficult.
US publication No. 2005/0070605 Al discloses the enantioselective opening of 3- hydroxyprotected glutaric anhydride by phenyl ethylamine to form an amide bond, and further converting it to HMG-CoA reductase inhibitor. The process may have problems such as breaking of the phenyl ethyl amide bond in the final step of producing cerivastatin and the problematic removal of phenyl ethylamine after breaking of the amide linkage in the synthesis of pitavastatin.
PCT publication No. WO 2006/021326 discloses the opening of 3-hydroxy protected glutaric anhydride by methanol to yield racemic methyl 3(±)-3-(t-butyl dimethylsilyloxy)-6- dimethoxy-phosphinyl-5-oxohexante, and the preparation of racemic methyl (3R)-3-(t-butyl dimethylsilyloxy)-6-dimethoxy-phosphinyl-5-oxohexante.
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US patent No. 5,354,879 discloses the preparation of both methyl (3R)-3-(t-butyl dimethylsilyloxy)-6-dimethoxy-phosphinyl-5-oxohexante and 3(R)-3(tert- butyldimethylsilyloxy)-5-oxo-6-triphenyl-phoporanylidene hexanoate from (3R) 3-[(tert- butyldimethylsilyl)oxy]-glutaric acid 1 -(R)-(-)-mandelate and (3S) 3-[(tert- butyldimethylsilyl)oxy]-glutaric acid l-(S)-(+)-mandelate, respectively. The disclosed process employs explosive and toxic materials, such as diazomethane, during the preparation ofmethyl-(3R)-3-(t-butyl dimethylsilyloxy)-6-dimethoxy-phosphinyl-5- oxohexante(esterification). Moreover, the yield of the above steps is low, and thus the process may not suitable for industrial and commercial use. J.Org.Chem. (1991) 56:3744-47 discloses the preparation of (3R)-3-(t-butyl dimethylsilyloxy)-6-dimethoxy-phosphinyl-5-oxohexante from 3-hydroxy protected glutaric anhydride. The disclosed process which involves using hazardous reactions, such as use of N2O4 oxidation, followed by a hydrogenation reaction to cleave the amino group of the resolving agent, and use of diazomethane. The process also uses an expensive palladium catalyst which could remain as an impurity in the final product.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for preparing a compound of formula 4, having the following structure:
using Ci-C5 alcohol in the presence of alkaloid, wherein Ri is Ci-C5 alkyl preferably C]-C4; and Z is a hydroxy protecting group. The protecting group is preferably a silyl group, including trialkylsilysl group having the formula-Si(A)3 where each A is independently selected from a Ci-C6 linear or branched aliphatic or aromatic group. Examples of silyl
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groups include triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl. Preferably the silyl group is tert-butyldimethylsilyl.
In another embodiment, the present invention further provides a process for preparing the compound of formula 5 having the following structure:
5
by combining the compound of formula 4, described above, with BOC anhydride in the presence of a basic catalyst, wherein R1 is Ci-C5 alkyl, preferably Ci-C4; and Z is a hydroxy protecting group as above.
The compound of formula 5, described above, is selectively hydrolyzed to obtain the compound of formula 6.
, wherein Z is a hydroxy protecting group as above.
The compound of formula 6 may be used to prepare the compound of formula 2, having the following structure:
2
,wherein R2 is methyl, ethyl, or t- butyl; Z is a hydroxy protecting group as above; and R3 is Ci to C3 alkoxy, C6 to Ci2 aryloxy, or substituted aryloxy. In yet another embodiment, the present invention provides a process for preparing a compound of formula 7, having the following structure:
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, by enantioselectively opening the prochiral anhydride of formula 3, having the following structure:
using a chiral alcohol of the formula 3a, having the following structure:
R4
Ar^^OH 3a wherein R4 is Ci to C6 alkyl, e.g., methyl or ethyl, and Ar is phenyl or substituted phenyl, and Z is a hydroxy protecting group as above.
In one embodiment, the present invention provides a compound of formula 7 having the following structure:
7
wherein R4 is Ci to C6 alkyl, e.g., methyl or ethyl, Ax is phenyl or substituted phenyl, and Z is a hydroxy protecting group as above. Also provided is a compound of formula 7 which is at least 50% chiral pure. Optionally, the compound of formula 7 can be purified by HPLC. The enriched enantiomer has the following structure;
7a
In another embodiment, the present invention provides a compound of formula 8 having the following structure:
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8
, wherein Z is a hydroxy protecting group as above, R4 is Ci to C6 alkyl, e.g., methyl or ethyl, and Ar is phenyl or substituted phenyl. Also provided is a compound of formula 8 which is at least 50% chiral pure. Optionally, the compound of formula 8 can be purified by HPLC. The enriched enantiomer has the following structure;
In yet another embodiment, the present invention further provides a process for the preparation of the compound of formula 8, described above, by combining a compound of formula 7, described above, with BOC anhydride. hi one embodiment, the present invention provides a process for preparing a compound of formula 6, having the following structure:
by selectively hydrolyzing the compound of formula 8, wherein Z is a hydroxy protecting group as above. In another embodiment, the present invention provides a process for preparing the compound of formula 4a, having the following structure:
, by enantioselectively opening the prochiral anhydride compound of formula 3, described above, by combining it with CpC5 alkyl alcohols in the presence of alkaloids, wherein Z is a hydroxy protecting group as above and Ri is lower alkyl, preferably Ci to C4 carbon. The enriched enantiomer has the following structure;
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In yet another embodiment, the present invention provides a process for preparing compound of formula 5a, having the following structure:
by combining the compound of formula 4a, described above with BOC anhydride in the presence of a base, wherein Z is a hydroxy protecting group as above and R1 is Q to C5 alkyl, preferably Ci to C4 alkyl. The enriched enantiomer has the following structure;
In one embodiment, the present invention provides a process for preparing compound of formula 6a, having the following structure:
by selectively hydrolyzing the compound of formula 5a, described above, wherein Z is a hydroxy protecting group as above. The enriched enantiomer has the following structure;
6
hi another embodiment, the present invention provides a compound of formula 7 having the following structure:
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, wherein R4 is Ci to C6 alkyl, e.g., methyl or ethyl, Ar is phenyl or substituted phenyl, and Z is a hydroxy protecting group as above.
In yet another embodiment, the present invention also provides a process for preparing the compound of formula 7a by enantioselectively opening the prochiral anhydride of formula 3, described above with chiral alcohols of the formula 3a, described above, wherein R4 is Ci to C6 alkyl, e.g., methyl or ethyl, Ar is phenyl or substituted phenyl, and Z is a hydroxy protecting group as above. The enriched enantiomer of formula 7 has the following structure;
7a
In one embodiment, the invention provides a compound of formula 8 having the following structure:
, wherein Z is a hydroxy protecting group as above and R4 is Ci to C6 alkyl. The enriched enantiomer of formula 8 has the following structure;
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In another embodiment, the present invention also provides a process for preparing the compound of formula 8a by combining the compound of formula 7a, described above, with BOC anhydride in the presence of a base.
In yet another embodiment, the present invention also provides a process for preparing compound of formula 6a having the following structure:
by selectively hydrolyzing the compound of formula 8a, described above, wherein Z is a hydroxy protecting group as above. The enriched enantiomer of formula 6a has the following structure;
6
In one embodiment, the present invention also provides a process for preparing the chiral pure R-isomer compound of formula 6, described above, by an optical resolution process by combining the compound of formula 6a, described above, a compound (R)-(+)- phenylethylamine of formula 9a, having the following structure:
Me
Ar Λ. NH2 9a
, or a compound (S)-(-)-phenylethylamine of formula 9b, having the following structure:
Me
Ar^^NH2 9b
In another embodiment, the present invention provides a compound of formula 9, having the following structure:
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, wherein Z is a hydroxy protecting group as above.
In yet another embodiment, the present invention also provides a process for preparing the compound of formula 9 by combining the compound of formula 6, described above, with at least one organic solvent, preferably selected from the group consisting of: C5-Ci2 aromatic hydrocarbons optionally substituted with halogen, -SH, -OH, -NO2, or -NH2; C5-Ci2 aromatic hydrocarbons where one or more ring carbons is substituted with N, S, or O; C6-CiO aliphatic hydrocarbons, halogenated Ci-Ci2 hydrocarbons, ethers and ketones, an amidation reagent selected from the group consisting of: Ci-4 alkyl and C6-8 aryl haloformates and acid halides, and at least one base; and adding N,O-dimethyl hydroxyl amine.
In one embodiment, the present invention provides a novel process for the preparation of a chirally pure compound of the general formula A, having the following structure:
wherein Ri is H, Ci-C5 alkyl, or a Ci to C5 carbonyl; R2 is C]-C6 alkyl, e.g., methyl, ethyl, or t- butyl group; and Z is a hydroxy protecting group. The protecting group is preferably a silyl group, including trialkylsilysl group having the formula-Si(A)3 where each A is independently selected from a Ci-C6 linear or branched aliphatic or C5-Ci2 aromatic group. Examples of silyl groups include trimethylsilyl, triethylsilyl, triisopropylsilyl, tert- butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl. Preferably the silyl group is tert-butyldimethylsilyl. Preferably, R2 is t-butyl group.
In another embodiment, the present invention provides a process for preparing a compound of formula 2, having the following structure:
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by combining the compound of formula 9, described above with a lithiated salt of dialkyl phosphonate, wherein R3 is C1 to C3 alkyloxy, C5-Ci2 aryloxy, substituted C5-Ci2 aryloxy and Z is a hydroxy protecting group as above
DETAILED DESCRIPTION OF THE INVENTION
The substituents in the "substituted alkyl" or "substituted aryl or phenyl" may be selected from the groups such as hydroxy, carboxyl, alkyl (such as Ci-C4), alkoxy (such as
C6-Ci2), aryl (such as C6-C]2), arylalkyl (such as C6-Ci2), cycloalkyl (such as C6-Ci2) and amino. When an aromatic solvent is used, the solvent can be substituted with halogen (such
as chlorine), -SH, -OH, -NO2, or -NH2.
The invention provides a process for producing chirally pure (more than 50% enrichment) compounds of formulas A and 2 in high yield, making the process economically attractive by using less toxic chemicals and fewer reaction steps.
The invention provides a process for preparing a compound of formula 4, having the following structure:
by enantioselectively opening the prochiral anhydride compound of formula 3, having the following structure:
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using C1-C5 alcohol of the formula R)-OH in the presence of alkaloid, wherein Ri is Cj-C5 alkyl, preferably Cl to C4 alkyl, more preferably R1 is a methyl group and Z is a hydroxy protecting group. The protecting group is preferably a silyl group, including trialkylsilysl group having the formula-Si(A)3 where each A is independently selected from a C]-C6 linear or branched aliphatic or aromatic group. Examples of silyl groups include trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl, preferably tert-butyldimethylsilyl.
Preferably, a Ci-C5 alkyl alcohol is used in the presence of an alkaloid. Examples of alkaloids include a) Indole alkaloids such as 5 -MeO-DMT, dimethyltryptamine, Harmala alkaloids, psilocin, psilocybin, reserpine, serotonin, tryptamine, yohimbine; b) phenethylamine alkaloids such as amphetamine, cathinone, ephedrine, mescaline, methamphetamine, phenethylamine, tyramine; c) purine alkaloids such as caffeine, theobromine, theophylline, d) pyridine alkaloids such as Coniine; d) pyrrolidine alkaloids such as nicotine e) quinoline alkaloids such as quinine or quinidin; and f) terpenoids such as aconitine and solanine. More preferably the akaloid is quinine or quinidine.
Preferably, the reaction temperature is between about -350C to about -600C, more preferably, between about -400C to about -500C. Preferably, the reaction is maintained for about 5 to about 30 hours, more preferably for about 12 to about 24 hours. Preferably the compound of formula 4 obtained is in enantiomeric excess of about 80% to about 98%, more preferably about 85% to about 90% as measured by chiral HPLC.
The present invention further provides a process for preparing the compound of formula 5 having the following structure:
by combining the compound of formula 4, described above, with BOC anhydride (Di-tert- butyl dicarbonate) in the presence of a basic catalyst, wherein R] is C)-C5 alkyl group as described above; and Z is a hydroxy protecting group as described above.
The basic catalyst is preferably a tertiary amine such N-methyl morpholine, N5N- dimethylaminopyridine, and mixtures thereof. The tertiary amine base is of the formula
N(A1)(A2)(A3), contains C3-Ci5 carbon atoms wherein Al, A2, and A3 are each independently selected from a Ci-Cio alkyl group and a C5-Ci2 aromatic group, wherein Al,
A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like
EV 079444 136 US
morpholino and pyridine groups). In one embodiment Al and A2 are methyl groups, and A3 is a C5-Ci2 aromatic group containing a nitrogen or an oxygen (such as cyclic structures like morpholino and pyridine groups).
The protecting group is preferably a silyl group, including trialkylsilysl group having the formula-Si(A)3 where each A is independently selected from a Ci-C6 linear or branched aliphatic or C5-Ci2 aromatic group. Examples of silyl groups include trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl. Preferably the silyl group is tert- butyldimethylsilyl. The combination of compound of formula 4 with BOC anhydride in the presence of a base catalyst can be maintained at a temperature of about 50C to about 500C, more preferably, at about 100C to about 300C. The combination can be maintained for a period of about 2 to about 10 hours, more preferably about 2 to about 5 hours.
The compound of formula 5, described above, is selectively hydrolyzed to obtain the compound of formula 6.
, wherein Z is a hydroxy protecting group as described above.
The hydrolysis is carried out under basic conditions in an alcohol.. The concentration of the alkaline solution can be about 0.5 to about 2N. The alcohol is can be a C1-C4 alcohol, preferably selected from the group consisting of: methyl alcohol, ethyl alcohol, and mixtures thereof, more preferably ethyl alcohol. The reaction can be maintained for a period of about 2 to about 12 hours, such as about 6 to about 8 hours, hi one embodiment, the reaction is maintained at a temperature of about 200C to about 600C, such as at about 450C to about 550C. Examples of suitable bases include alkali metal and alkaline earth metal bases, particularly hydroxide bases such as sodium and potassium hydroxide. After the hydrolysis, the reaction mixture can be acidified. Compound of 6 can then be extracted into a water immiscible solvent such as toluene, followed by evaporation of the toluene, such as at a pressure of less than one atmosphere.
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The invention provides a process for preparing a compound of formula 7, having the following structure:
, by enantioselectively opening the prochiral anhydride of formula 3, having the following structure:
using a chiral alcohol of the formula 3a, having the following structure:
R4
3a wherein R4 is Ci-C6 alkyl, e.g., methyl or ethyl, and Ax is phenyl or substituted phenyl as defined above, and Z is a hydroxy protecting group as above. The enriched enantiomer of formula 7 has the following structure;
7a
The reaction can be carried out in the presence of a catalyst The catalyst can be a base. Preferably, the base is N,N-dimethylamino- pyridine. The basic catalyst is preferably a tertiary amine such N-methyl morpholine, N,N-dimethylaminopyridine, and mixtures thereof. The tertiary amine base is of the formula N(A1)(A2)(A3), contains C3-Ci5 carbon atoms wherein Al, A2, and A3 are each independently selected from a Cj-Cio alkyl group and a C5-Ci2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like morpholino and pyridine groups). In one embodiment
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Al and A2 are methyl groups, and A3 is a C5-Ci2 aromatic group containing a nitrogen or an oxygen atom (such as cyclic structures like morpholino and pyridine groups).
Prior to the combining step with the compound of formula 3 a, the compound of formula 3 can be dissolved in an organic solvent. The organic solvent can be a C1-C4 chlorinated hydrocarbon, such as methylene dichloride. Typically, the compound of formula 3a and the catalyst are mixed with a solution of the compound of formula 3 in an organic solvent, to obtain a reaction mixture. The reaction mixture can be at a temperature of about - 200C to about -600C, such as at about -300C to about -500C. The reaction mixture can be maintained for a period of about 10 to about 30 hours, such as about 15 to about 25 hours. The invention provides a compound of formula 7 having the following structure:
wherein R4 is C1-C6 alkyl, e.g., methyl or ethyl, Ar is phenyl or substituted phenyl as defined above, and Z is a hydroxy protecting group as above. Also provided is a compound of formula 7 which is at least 50% chiral pure as determined by chiral HPLC. The compound of formula 7 can be purified by HPLC. The enriched enantiomer of formula 7 has the following structure;
7a
The invention provides a compound of formula 8 having the following structure:
, wherein Z is a hydroxy protecting group as above, R4 is Ci-C6 alkyl, preferably Ci -C4 alkyl e.g., methyl or ethyl, and Ar is phenyl or substituted phenyl as defined above. Also provided
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is a compound of formula 8 which is at least 50% chiral pure as measured by an HPLC chiral column. The compound of formula 8 can be purified by HPLC. The enriched enantiomer of formula 8 has the following structure;
8a
The present invention further provides a process for the preparation of the compound of formula 8, described above, by combining a compound of formula 7, described above, with BOC anhydride. A C5-C12 aromatic hydrocarbon such as toluene can be used as a solvent. Preferably, the process is done in the presence of a basic catalyst. The basic catalyst can be selected from the group of tertiary amines consisting of: N-methyl morpholine, N9N- dimethylaminopyridine, and mixtures thereof. The tertiary amine base is of the formula N(A1)(A2)(A3), contains C3-Ci5 carbon atoms wherein Al, A2, and A3 are each independently selected from a C1-Ci0 alkyl group and a C5-C12 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like morpholino and pyridine groups). In one embodiment Al and A2 are methyl groups, and A3 is a C5-Ci2 aromatic group containing a nitrogen or an oxygen atom (such as cyclic structures like morpholino and pyridine groups). Preferably, the combination of the compound of formula 7 with BOC anhydride, is maintained at a temperature of about 50C to about 5O0C, more preferably at about 100C to about 300C. Preferably, the combination is maintained for a period of about 2 to about 10 hours, more preferably for about 2 to about 5 hours.
The invention provides a process for preparing a compound of formula 6, having the following structure:
The hydrolysis is carried out under basic conditions in an alcohol.. The concentration of the alkaline solution can be about 1 to about 2N. The alcohol is can be a C1-C4 alcohol, preferably selected from the group consisting of: methyl alcohol, ethyl alcohol, and mixtures thereof, more preferably ethyl alcohol. Preferably, the combination of the an alkaline
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solution and the alcoholic mixture of the compound of formula 8, is maintained for a period of about 10 to about 30 hours, more preferably for about 15 to about 25 hours. Preferably, the combination is maintained at a temperature of about 200C to about 600C, more preferably at about 400C to about 550C. Examples of suitable bases include alkali metal and alkaline earth metal bases, particularly hydroxide bases such as sodium and potassium hydroxide. After the hydrolysis, the reaction mixture can be acidified. Compound of 6 can then be extracted into a water immiscible solvent such as toluene, followed by evaporation of the toluene, such as at a pressure of less than one atmosphere.
The invention provides a process for preparing a compound of formula 6, having the following structure:
by selectively hydrolyzing the compound of formula 8, wherein Z is a hydroxy protecting group as above. The hydrolysis comprises combining an alkaline solution with the alcoholic mixture of the compound of formula 8. Preferably, the concentration of the alkaline solution is about 1 to about 2N. Optionally, the alcohol is selected from the group consisting of: C1- C5 alcohol (preferably Cj-C4) such as methyl alcohol, ethyl alcohol, and mixtures thereof. The present invention provides a process for preparing the compound of formula 4a, having the following structure:
by enantioselectively opening the prochiral anhydride compound of formula 3, described above, by combining it with C]-C5 alkyl alcohols (Rl-OH) in the presence of alkaloids, wherein Z is a hydroxy protecting group as above.
Preferably, the compound of formula 4a is obtained in the enantiomeric ratio of about 85:15 to about 95:5. Preferably, the compound of formula 4a is combined with an organic solvent. The organic solvent may be C6-Ci2 aromatic hydrocarbon, Ci-C4 chlorinated hydrocarbon, C4-C8 ether and or C3-C8 ether. Examples of these solvents include methylene dichloride, toluene, methyl t-butyl ether, n-heptane, methyl ethyl ketone, tetrahydrofuran, and
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mixtures thereof. The more preferred solvents are methylene dichloride and toluene. Typically, the reaction temperature is about -300C to about -600C, and more preferably, about -400C to about -500C. Typically, the reaction is maintained for about 5 to about 30 hours, more preferably, for about 8 to about 15 hours.
The present invention provides a process for preparing compound of formula 5a, having the following structure:
by combining the compound of formula 4a, described above with BOC anhydride in the presence of a catalyst (in the form of a base), wherein Z is a hydroxy protecting group as above and Ri is Ci-C6 alkyl, preferably C1-C4 group. .
The base can be selected from the group consisting of: tertiary amines like N-methyl morpholine, N,N-dimethyl amino pyridine and mixtures thereof. The tertiary amine base is of the formula N(A1)(A2)(A3), contains C3-Ci5 carbon atoms wherein Al, A2, and A3 are each independently selected from a Ci-Ci0 alkyl group and a C5-Ci2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like morpholino and pyridine groups). In one embodiment Al and A2 are methyl groups, and A3 is a C5-Ci2 aromatic group containing a nitrogen or an oxygen atom (such as cyclic structures like morpholino and pyridine groups). . Preferably, the temperature is of about -100C to about 500C, more preferably about 100C to 300C. Preferably, the combination of the compound of formula 4a, BOC anhydride and the base is maintained for about 2 to 10 hours, more preferably for 2 to about 5 hours.
The present invention provides a process for preparing compound of formula 6a, having the following structure:
by selectively hydrolyzing the compound of formula 5a, described above, wherein Z is a hydroxy protecting group.
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Preferably, the compound of formula 6a is obtained in the enantiomeric ratio of about 85:15 to about 95:5.
The hydrolysis comprises adding about 0.5 to about 2N alkaline solution to the alcoholic mixture of the compound of formula 5a. The alcohol may be selected from the group consisting of: methyl, ethyl alcohol, and mixtures thereof. The hydrolyzation is for about 2 to about 12 hours at a temperature of about 200C to about 600C, more preferably for about 6 to about 8 hours at a temperature of about 45-550C. The base can be selected from the group consisting of: tertiary amines like N-methyl morpholine, N,N-dimethyl amino pyridine and mixtures thereof. The tertiary amine base is of the formula N(A1)(A2)(A3), contains C3-C15 carbon atoms wherein Al, A2, and A3 are each independently selected from a C1-CI0 alkyl group and a C5-Ci2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like morpholino and pyridine groups). In one embodiment Al and A2 are methyl groups, and A3 is a C5-C]2 aromatic group containing a nitrogen or an oxygen atom (such as cyclic structures like morpholino and pyridine groups). . The present invention provides a compound of formula 7 having the following structure:
R4 O OZ O
, wherein R4 is Ci-C6 alkyl, e.g., methyl or ethyl, Ar is phenyl or substituted phenyl as defined above, and Z is a hydroxy protecting group as above. The present invention also provides a process for preparing the compound of formula 7a by enantioselectively opening the prochiral anhydride of formula 3, described above with chiral alcohols of the formula 3a, described above.
Preferably, the compound of formula 7a is in the enantiomeric ratio of about 80:20 to about 85:15.
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7a
The reaction comprises combining a solution of a compound of formula 3a with a mixture of a compound of formula 3 and a base in an organic solvent. Preferably, the temperature during the process is of about -200C to about -600C and more preferably, of about -300C to about -500C. Preferably, combination of the compound of formula 3a, the compound of formula 3, the base and the organic solvent, is maintained for about 10 to about 30 hours, more preferably for about 15 to about 25 hours. The base can be selected from the group consisting of: tertiary amines like N-methyl morpholine, N,N-dimethyl amino pyridine and mixtures thereof. The tertiary amine base is of the formula N(A1)(A2)(A3), contains C3- Ci5 carbon atoms wherein Al, A2, and A3 are each independently selected from a Ci-Cio alkyl group and a C5-Ci2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like morpholino and pyridine groups), hi one embodiment Al and A2 are methyl groups, and A3 is a C5-C]2 aromatic group containing a nitrogen or an oxygen atom (such as cyclic structures like morpholino and pyridine groups). . Preferably, the organic solvent is a C6-Ci2 aromatic hydrocarbon or C1-C4 chlorinated hydrocarbon. Specific examples of these solvents include methylene di chloride, toluene and mixtures thereof.
The present invention provides a compound of formula 8 having the following structure:
8
, wherein Z is a hydroxy protecting group as above and R4 is Ci-C6 alkyl, or a Ci to C6 carbon The enantiomeric enriched form of formula 8 has the following structure;
8a
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The present invention also provides a process for preparing the compound of formula 8a by combining the compound of formula 7a, described above, with BOC anhydride in the presence of a base, wherein Z is a hydroxy protecting group as above and R4 is alky 1 of Cj to C6 carbon group, preferably C1-C4 group. . The base can be selected from the group consisting of: tertiary amines like N-methyl morpholine, N,N-dimethyl amino pyridine and mixtures thereof. The tertiary amine base is of the formula N(A1)(A2)(A3), contains C3-Ci5 carbon atoms wherein Al, A2, and A3 are each independently selected from a Ci-Ci0 alkyl group and a C5-Ci2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen (such as cyclic structures like morpholino and pyridine groups). In one embodiment Al and A2 are methyl groups, and A3 is a C5-Ci2 aromatic group containing a nitrogen or an oxygen atom (such as cyclic structures like morpholino and pyridine groups). Preferably, the temperature during the process is of about -100C to about 500C, more preferably about 100C to 300C. Preferably, the combination of the compound of formula 7a with BOC anhydride in the presence of a base is maintained for about 2 to about 10 hours, more preferably for about 2 to about 5 hours.
The present invention also provides a process for preparing compound of formula 6a having the following structure:
by selectively hydrolyzing the compound of formula 8a, described above, wherein Z is a hydroxy protecting group as above.
Preferably, the compound of formula 6a is obtained in an enantiomeric ratio of about 80:20 to about 85:15. The enantiomeric enriched formula 6 has the following structure;
The hydrolysis comprises combining about 0.5 to about 2N alkaline solution with an alcoholic mixture of the compound of formula 8a. The alcohol may be selected from the group consisting of: Ci-C4 alcohol such as methanol, ethanol and mixtures thereof. The
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combination of the alkaline solution and the an alcoholic mixture of the compound of formula 8a is preferably maintained for about 10 to about 30 hours, preferably at a temperature of about 200C to about 600C, more preferably for a period of about 15 to about 25 hours at a temperature of about 400C to about 550C.
The compound of formula 6 may be used to prepare the compound of formula 2, having the following structure:
.wherein R2 is aCi-C4 alcohol such as methyl, ethyl, or t- butyl; Z is a hydroxy protecting group; and R3 is Ci to C3 alkoxy, aryloxy, or substituted aryloxy group. The protecting group is preferably a silyl group, including trialkylsilysl group having the formula-Si(A)3 where each A is independently selected from a C1-C6 linear or branched aliphatic or aromatic group. Examples of silyl groups include trimethylsilyl, triethylsilyl, triisopropylsilyl, tert- butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl.
The present invention also provides a process for preparing the chiral pure R-isomer compound of formula 6, described above, by an optical resolution process by combining the compound of formula 6a, described above, a compound (R)-(+)-phenylethylamine of formula 9a, having the following structure:
Me
Ar ^NH2 9a
, or a compound (S)-(-)-phenylethylamine of formula 9b, having the following structure:
Me
Ar^^NH2 9b
The resolution comprises combining the compound of formula 6a with chiral ratio of about 80:20 to about 85:15 with compound of formula 9a or 9b to get a salt of formula 8b, having the following structure:
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8b
in an aliphatic alcoholic solvent is a Ci-C4 alcohol selected from the group consisting of: as methanol, ethanol, isopropyl alcohol, n-butyl alcohol and t-butyl alcohol, more preferably isopropyl alcohol. The compound of formula 9a is used in a molar ratio of about 1 to about 2 to the compound of formula 6a at a temperature of about O0C to about 700C. The obtained product is crystallized to get chirally pure salt of formula 8c having the following structure:
The salt of formula 8c is hydrolyzed in aqueous medium using a mineral acid to get the compound of formula 6 with chiral purity of about 99 to about 100%, more preferably about 99.5 to about 99.8%. The mineral acid may be: a dilute hydrochloric acid or dilute sulfuric acid. Preferably dilute hydrochloric acid is used. Hydrochloric acid is added in an amount of about 1 to about 2 equivalents with regard to the compound of formula 8c, at a temperature of about O0C to about 500C, preferably at about O0C to about 300C.
The present invention provides a compound of formula 9, having the following structure:
, wherein Z is a hydroxy protecting group.
The compound of formula 9 may be used to prepare the compound of formula 2, having the following structure:
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by reaction of compound 9 with a metal salt of dialkyl alkylphosphonate of the general formula:
, wherein Z is a hydroxy protecting group, as described above; R2j and R3 are, independently, an optionally substituted alkyl of 1-4 carbon atoms; X is an alkoxy group of Ci to C5 carbon atoms or an optionally substituted alkyl group of Cr C5 carbons. Preferably all R3 groups (including R3 prime) are methyl groups. To form the Wittig reagent (ylide), the phosphonium salt depicted above is suspended in a solvent such as diethyl ether or THF (tetrahydrofuran) and a strong base, preferably a Cr C8 aryl or alkyl metal base, such as the organolithium reagents phenyllithium or n-butyllithium is added. The lithium salt has the following structure:
Preferably, the solvent is selected from Ci- C4 aliphatic alcoholic solvent, a C6- Cio aromatic and C5-C8 aliphatic hydrocarbon, a C2- C8 aliphatic ester, a C4-C8 ether (including cyclic compounds), and a C1-C6 aliphatic solvent with one, two or three chlorine atoms. Examples of such solvents include toluene, benzene, xylene, cyclohexane; ethers, methyl t-butyl ether, tetrahydrofuran and tetrahydrofuran. Preferably the solvent is tetrahydrofuran. Suitable bases include alkyl lithium bases, such as n-butyl lithium and Cr
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C8 alkyl metals, preferably in the amount of 1-5 equivalents based on the compound of formula (XII), more preferably in the amount of 3-4 equivalents.
As exemplified, a compound of formula:
Preferably, the Ci-4 alkyl halo formate is ethyl or methyl derivative of chloro or bromo formate. Preferably, the C6-8 aryl haloformate is a benzyl chloro or bromo formate. Preferred acid halides are acetyl, pivaloyl, oxaloyl or benzoyl chlorides and bromides. The most preferred haloformate is either ethyl chloroformate or methyl chloroformate. The more preferred acid halide is acetyl or pivaloyl chlorides.
Preferably the substituted aromatic hydrocarbon is either toluene or xylene. A preferred C6-CiO aliphatic hydrocarbon is either hexane or heptane. Preferred ketones are
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acetone, methyl ethyl ketone or methyl isobutyl ketone. Preferably the ethers are diethyl ether, diisopropyl ether or t-butyl methyl ether. Preferably the halogenated hydrocarbon is methylene dichloride. The more preferred organic solvent is either acetone or methylene dichloride. Preferably the base is an organic base selected from the group consisting of: diethyl amine, triethyl amine, di-n-propyl amine, diisopropyl amine, tri-n-butyl amine, morpholine, piperidine, pyridine, N, N-dimethyl aminopyridine. Preferably, the base is either N, N- dimethylaminopyridine or triethyl amine.
Preferably, the compound of formula 6 and an organic solvent first combined, and thereafter are combined with the amidation reagent and a base at a temperature of about 200C to about -300C, more preferably of about -100C to about -200C, to obtain a reaction mixture. Preferably, prior to the addition of the solution of N,O-dimethyl hydroxyl amine, the reaction mixture is maintained at a temperature of about -10 to -200C for a period of about 0 to about 4 hours. Preferably the reaction mixture is maintained for about 0.5 to about 2 hours after the addition of N, O-dimethyl hydroxyl amine at a temperature of about -100C to about 350C, more preferably at about O0C to about 200C.
The invention provides a process for the preparation of a chirally pure compound of the general formula A, having the following structure:
wherein R1 is H, C1-C5 alkyl; R2 is C]-C6 alkyl, e.g., methyl, ethyl, or t- butyl group; and Z is a hydroxy protecting group, optionally a trimethylsilyl, t-butyldimethylsilyl, diphenylmethylsilyl, or dimethyl phenylsilyl group. Preferably the silyl group is tert- butyldimethylsilyl. Preferably, R2 is t-butyl group. The compound of formula A is an intermediate used for the synthesis of the compound of formula 2, having the following structure:
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, wherein R2 is methyl, ethyl, or t- butyl group; Z is hydroxy protecting group such as trimethylsilyl, t-butyldimethylsilyl, diphenylmethylsilyl, or dimethyl phenylsilyl group, and R3 is C] to C3 alkyloxy, aryloxy, or substituted aryloxy group, which can be used for the preparation of HMG-CoA reductase inhibitors.
The present invention provides a process for preparing a compound of formula 2a, having the following structure:
by combining the compound of formula 9, described above with a lithiated salt of dialkyl phosphonate, wherein R3 is lower Ci to C3 alkyloxy, C5-Cj2 aryloxy, C5-Ci2 aryloxy (optionally substituted) and Z is a hydroxy protecting group, such as trimethylsilyl, t- butyldimethylsilyl, or diphenyl methylsilyl, dimethylphenylsilyl.
Preferably, the dialkyl phosphonate is Ci-C3 dialkyl phosphonate. The lithiated salt of dialkyl phosphonate is prepared at a temperature of about -500C to about -HO0C using n- butyl lithium and dialkyl phosphonate in the molar ratios of about 1.3 to about 4.5 and about 1.5 to about 5, respectively, in relation to compound of formula 9. More preferably, the molar ratios are about 1.4 to about 2 and about 1.5 to about 2.2, respectively. The reaction is maintained preferably at a temperature of about -750C to about -850C for about 2 to about 6 hours. After the addition of solution of compound of formula 9, the reaction is maintained preferably at a temperature of about -750C to about -850C for about 0 to about 4 hours. The reaction is done preferably using toluene, xylene, cyclohexane, methyl t-butyl ether, tetrahydrofuran ,or mixtures thereof. More preferably the solvent is selected from methyl t-butyl ether and tetrahydrofuran.
In any of the embodiments of the above process, and compounds, the group Ri is preferably Ci-C4 group, more preferably methyl; R2 is preferably a Ci-C4 group, more preferably t-butyl; Z is preferably a silyl group, more preferably tert-butyldimethylsilyl.
The compounds prepared by the process of the invention may be used to prepare statins for treatment of hyperlipidemia. Statins can be combined with a pharmaceutically acceptable excipient to prepare pharmaceutical compositions.
The statins that can be prepared include the following
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Lo vas latin Simvastatin
Atorvastalm
For example, Helvetica Chemica Acta, vol. 90 (2007), which is incorporated herein by reference, discloses a pitavastatin aldehyde precursor having the structure:
WO2007/041666 and WO2006/091771, incorporated herein by reference, further disclose preparation of rosuvastatin through the Wittig reaction. After the Wittig reaction, the protecting group (Z) is removed, followed by reduction to obtain a diol, followed by hydrolysis of the ester to obtain a pharmaceutically acceptable salt. NMR Data for Compound VII: 0.07 (d, 3H) ; 0.76 (d, 3H) ; 1.47 (d, 3H) ; 2.5 (q, 4H) ; 4.87 (p, IH) ; 5.82 (q, IH) ; 7.29 (m, 5H)
NMR Data for Compound IX:
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0.10 (s, 6H) ; 0.87 (s, 9H), 2.63-2.44 (m,3H) ; 2.848 (q,lH), 3.18 (s, 2H) ; 3.71 (s, 2H) ; 4.23 (q, 2H), 4.59 (q, IH)
for Rosuvastatin Ca
BUFFER: -0.05% v/v Acetic acid glasial pH 3.5 with 5% Ammonium hydroxide.
ELUENT (A): - Mix.60% buffer 35% acetonitrile 5% ethanol.
ELUENT (B): -55% buffer 45% ethanol.
ELUENT (C): - ETHANOL.
COLUMN: -Discovery HS C18,3μm(150x4.6)mm
FLOW: -0.5ml/min, INJ. VOL.: -10μl,WAVELENGTH:-243nm.
COLUMN TEMP.: - 200C, AUTOS AMPLER TEMP.: -4°C
RUN TIME:-25.0 MIN, EQUILIBRATION TIME: -7.0 MIN
GRADIENT:-
Instrument
Gas Chromatograph equipped with Flame Ionisation Detector.
Column
DB 17, 30 m x 0.53 mm x 1.0 μm film thickness, Agilent C/N: 125-1732 or equivalent.
Chromatographic Conditions a.) Initial oven temperature 400C b.) Initial hold time 3.0 minute c.) Initial- 1 ramp rate 200C / minute d.) Intermediate- 1 oven temperature 1600C e.) Intermediate- 1 hold time 10.0 minute f.) Initial-2 ramp rate 100C / minute g.) Intermediate-2 oven temperature 210°C h.) Intermediate-2 hold time 10.0 minute i.) Final ramp rate 200C / minute j.) Final oven temperature 2700C k.) Final hold time 10.0 minute
1.) Injector temperature 1800C m.) Detector temperature 3000C n.) Carrier gas (He) flow lO.Oml/min o.) Mode Constant flow p.) Injection volume 1.0 μl q.) Split ratio Splitless
Temperature and flow rate may be varied in order to achieve the required system suitability. Diluent
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Acetonitrile
Preparation of system suitability solution
Weighed accurately about 20mg of each: TBDMS-OH, DMMP, MBSG and 19TBPO into 10ml volumetric flask, dissolve and brought to volume with diluent. Transferred ImI of the stock solution into 10ml volumetric flask and brought to volume with diluent. System suitability test Injected system suitability solution.
Typical retention times are about 4minutes for TNDMS-OH peak, about 6.5 minutes for the DMMP peak, About 14.5minutes for the MBSG peak and 31.5minutes for the 19TBPO peak.
Preparation of sample solution
Weighed accurately 20mg of sample into 10ml volumetric flask, dissolved and brought to volume with diluent.
EXAMPLES
General Preparation of 3-hvdroxy protected glutaric acid A four-neck round bottom flask fitted with a mechanical stirrer, condenser and charging tube, was charged with methylene dichloride (675 ml) followed by charging of imidazole (187.2 g), t-butyldimethylsilyl chloride (248.3 g) under nitrogen atmosphere. Reaction mass was maintained for 1-2 hours at 20-300C followed by addition of a solution of 3-hydroxy diethyl glutarate in methylene chloride (225 g). The mass was maintained for 4-6 hours followed by water and brine washing of the reaction mass. Methylene dichloride under vacuum at 30- 350C was distilled out and residue was charged into a solution of 30-40% aq. methyl alcohol (1850 ml), sodium hydroxide (96.8 g) at 25-350C and mixed for 20-30 hours. Solvent is distilled out under vacuum at 40-450C, mass was further diluted with water and 1-12N hydrochloric acid was added to bring pH to 2.5-4 and the product was extracted with t-butyl methyl ether and concentrated to give 71 % of 3-hydroxy protected glutaric acid.
Example 1
Preparation of 3-hvdroxy protected glutaric anhydride, compound of formula 3
A four-neck round bottom flask fitted with a mechanical stirrer, condenser, and charging tube was charged with acetic anhydride (609 ml) followed by charging of 3-hydroxy protected
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glutaric acid at 25 to 300C. The reaction mass was refluxed for 2-3 hours at 130-1350C. The unreacted acetic anhydride, along with acetic acid, was completely distilled under vacuum at 60-950C. The product was crystallized from cyclohexane, and dried to obtain 90-95 % of a brown crystalline solid with GC purity of 97.2 %.
Example 2
Preparation of 3-(t-butyldimethylsiIanyloxy)-l, 5-pentane dioic acid monomethyl ester, compound of formula 4
A four neck round bottom flask fitted with a mechanical stirrer, condenser, and charging tube was charged with methylene dichloride (75 ml) and the compound of formula 3 ( 25 g, 0.1 mole) under inert atmosphere at 25 to 300C. The reaction mass was cooled to -35 to -4O0C, followed by addition of a solution of quinidine (35.68 g, 0.11 mole) in methylene dichloride (125 ml). The methanol (28.3 ml) was slowly added into the reaction mass at -35 to -400C and it was maintained for 15-20 hours. Methylene dichloride was distilled off under vacuum at 25-35°C, followed by addition of sufficient amount of methyl t-butyl ether and water (25 ml). The pH of the reaction mass was adjusted to 4-5 using hydrochloric acid. The aqueous phase was separated. The organic phase was washed with acidic water to remove quinidine, followed by removal of methyl t-butyl ether under vacuum, to give the compound of formula 4 in 96 % yield, with chiral purity of 93:7 and GC purity of 99.25 %.
Example 3
Preparation of 3-(t-butvIdimethylsiIanyloxy)-l, 5-pentane dioic acid monomethyl ester, compound of formula 4
A four neck round bottom flask fitted with a mechanical stirrer, condenser and charging tube, was charged with toluene (500 ml), followed by charging of the compound of formula 3 (
50g, 0.181 mole) under inert atmosphere at 25 to 300C. The reaction mass was cooled to -30 to -550C, followed by addition of quinidine (76.33g, 0.235 mole). The methanol (55 ml) was slowly added into the reaction mass at -30 to -550C and it was maintained for 10-20 hours. Water (25 ml) was added and the pH was adjusted to 4-5 using hydrochloric acid. The aqueous phase was separated. The organic phase was washed with acidic water to remove quinidine, followed by removal of toluene under vacuum, giving the compound of formula 4a in 83.5 % yields, with chiral purity of 93.2: 6.8 and GC purity of 96.6 %.
Example 4
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Preparation of compound of formula 5
A four neck round bottom flask fitted with a mechanical stirrer, condenser and charging tube, was charged with methylene dichloride (40 ml), followed by charging of the compound of formula 4 ( 1O g, 0.036 mole) at -5 to 00C. N-methyl morpholine (4.3g, 0.043 mole) was added to the reaction mass at -5 to O0C and the reaction was maintained for 15-30 minutes, followed by slow addition of BOC anhydride (11.8 g, 0.055 mole) in methylene dichloride (40 ml) at -5 to O0C. The reaction was maintained for 15-30 minutes. A catalytic amount of N,N-dimethylaminopyridine was added at -5 to 0°C, and the mass was maintained at 25-3O0C for 3-5 hours. Silica gel (2.5 g) was added, followed by removal of silica gel. Water (30 ml) was added to the reaction mass and the pH was adjusted to 4-4.5 using hydrochloric acid. The aqueous phase was separated and the organic phase was washed with water, followed by removal of methylene dichloride under vacuum, giving the compound of formula 5 in 97.6 % yield with GC purity of 92.9 %.
Example 5
Preparation of compound of formula 6
A four neck round bottom flask fitted with a mechanical stirrer, condenser and charging tube, was charged with ethanol (50ml), followed by charging with the compound of formula 5 (10 g, 0.03 mole) at 20 to 3O0C. 1-2N Sodium hydroxide solution (40 ml) was added into the reaction mass at 45 to 5O0C and it was maintained for 5-8 hours, followed by removal of ethanol under vacuum. Water (50 ml) was added to the reaction mass and the pH was adjusted to 5-6 using hydrochloric acid. Toluene (25 ml) was added and the aq. phase was separated, followed by removal of toluene under vacuum to give the compound of formula 6 in 93 % yield.
Example 6
Preparation of compound of formula 7
A four neck round bottom flask fitted with a mechanical stirrer, condenser and charging tube, was charged with methylene dichloride (50 ml) followed by charging with the compound of formula 3 (10 g, 0.041 mole) under inert atmosphere at 25 to 30°C. The mass was cooled to - 30 to -35°C followed by addition of the compound of formula 3a (7.5 g, 0.0615mole). N,N- Dimethylaminopyridine (7.5 g, 0.0615 mole) in methylene dichloride (30 ml) was slowly added into the reaction mass at -30 to -35°C and it was maintained for 15-20 hours. Water
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(50 ml) was added to the reaction mass and the pH was adjusted to 4-5 using hydrochloric acid. The aqueous phase was separated, and the organic phase was washed with water, followed by removal of methylene dichloride under vacuum, giving the compound of formula 7 in 96 % yield with chiral purity of 80.5:19.5.
Example 7
Preparation of compound of formula 8
A four neck round bottom flask fitted with a mechanical stirrer, condenser and charging tube, was charged with toluene (6 ml) followed by charging with the compound of formula 7 (1 g, 0.0027 mole) at 20 to 300C. N-methyl morpholine (0.327 g, 0.034 mole) was added to the reaction mass at 20 to 300C and it was maintained for 15-30 minutes. BOC anhydride (0.884 g, 0.004 mole) in toluene (3 ml) was slowly added to the reaction mass and it was maintained for 15-30 minutes. A catalytic amount of N,N-dimethylaminopyridine was added at 20 to 300C, and the mass was maintained at 25-3O0C for 3-5 hours. Silica gel (2.5 g) was added and then removed. Water (10 ml) was added to the mass, and the pH was adjusted to 4-4.5 using hydrochloric acid. The aqueous phase was separated. The organic phase was washed with water, followed by removal of toluene under vacuum, giving the compound of formula 8 in 62 % yield.
Example 8
Preparation of compound of formula 6a
A four neck round bottom flask fitted with a mechanical stirrer, condenser and charging tube, was charged with methanol (8 ml), followed by charging with the compound of formula 8 (1 g, 0.0024 mole) at 20 to 300C. 1-2N Sodium hydroxide solution (8 ml) was added into the reaction mass at 45 to 5O0C and it was maintained for 5-8 hours. Methanol was removed under vacuum at 45 to 500C. Water (15 ml) was added to the mass and the pH was adjusted to 4-4.5 using hydrochloric acid. Toluene (15 ml) was added and the aqueous phase was separated, followed by removal of toluene under vacuum, giving the compound of formula 6 in 46 % yield.
Example 9
Preparation of compound of formula 6
A four neck round bottom flask fitted with a mechanical stirrer, condenser and charging tube, was charged with isopropyl alcohol (50 ml), followed by charging with the compound of
EV 079444 136 US
formula 6a (10 g, 0.031 mole) at 20 to 300C. (RH+)-phenylethyl amine (4.18 g, 0.034 mole) was added over a period of 1-2 hours followed by heating the mass to get a clear solution. Mass was mixed for 2-4 hours at 15-250C, filtered, and the solid mass was dissolved into water (110 ml). Sodium chloride (33 g) was added to the mass followed by addition of 1.3 mole equivalent of 10% hydrochloric acid. Reaction mass was mixed for 2-4 hours and extracted with sufficient volume of methylene dichloride followed by stripping of methylene dichloride under vacuum to get 76% of the compound of formula 6 with chiral purity of 99.5%
Example 10
Preparation of compound of formula 9
A four neck round bottom flask fitted with a mechanical stirrer, condenser and charging tube, was charged with methylene dichloride (210 ml), followed by charging with the compound of formula 6 (35 g, 0.11 mole) at 20 to 300C. The reaction mass was cooled to -15 to -250C followed by addition of tri ethyl amine (13.34 g) and ethyl chloro formate (13.13 g) and it was maintained for 30-60 minutes at 0 to -150C followed by addition of a solution of N,O- dimethyl hydroxyl amine ( 13.95 g) in methylene dichloride (30 ml). Reaction mass was maintained for 1-3 hours at 20-300C followed by washing the mass with sufficient quantity of dilute hydrochloric acid, saturated sodium bicarbonate and brine. Stripping of methylene dichloride resulted into 95% yield of compound of formula 9 with GC purity of 95.4%
Example 11
Preparation of compound of formula 2
A four neck round bottom flask fitted with a mechanical stirrer, condenser and charging tube, was charged with tetrahydrofuran (25 ml), followed by charging with dimethyl methyl phosphonate (4.3 g, 0.035 mole) at 20 to 300C. The reaction mass was cooled to -80 to -900C followed by addition of 1.6 M n-butyl lithium solution in hexane (2.08 g, 0.033 mole). The reaction mass was maintained for 2-4 hours at -80 to -900C followed by addition of a solution of compound of formula 9 ( 5 g, 0.014 mole) in tetrahydrofuran (5 ml). Reaction mass was maintained for 1-3 hours at -75 to -900C followed by quenching of the mass with ammonium chloride solution. The temperature of the reaction mixture was allowed to 20- 30 C. Phases were separated and aq. layer was extracted with hexane. Combined organic phase was washed with brine followed by stripping of hexane to get 85% yield of compound of formula 2 with GC purity of 87.1%.
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(Examples 12-16 are copied form WO2006/091771)
Example 12- Preparation of Compound 20TB by Wittig reaction from 19TBPH
A 100 ml flask, protected from light and provided with N2 flow was charged with Compound 14 (3.6 g, 10.5 mmol), Compound 19TBPH (9.05 g, 15.7 mmol), and dry toluene (36 ml, 10 vol relative to Compound 14). The reaction mixture was heated to about 1000C for 19.5 hrs. A sample of the reaction mixture was analyzed by HPLC, and contained 1.7% of Compound 14.
Anhydrous MgCl2 (2 g, 2 equivalents relative to Compound 19TBPH) was added to the reaction mixture and the reaction mixture was stirred at 1000C for 2 hrs. The reaction mixture was cooled to O0C for 2 hours, and filtered without washing the solid. A filtrate was obtained and was washed twice with H2O (100 ml each) and the solvent was evaporated, yielding 7.56 g of a brown solid.
Example 13 : Preparation of Compound 2OM by Wittig Reaction
14 19M 2OM
A 250 ml flask, protected from light and provided with N2 flow was charged with Compound-14 (4.38 g, 12.5 mmol), Compound 19M (10 g, 18.7 mmol), and extra dry toluene (100 ml). The reaction mixture was heated to about 1000C for 15 hrs. After the completion
EV 079444 136 US
of the reaction, anhydrous MgCl2 (4.8 g, 2.7 eq.) was added to the reaction mixture and the reaction mixture was heated for 2 hours at about 1000C. The reaction mixture was cooled to O0C over a period of about 2 hours, filtered, and washed with 45ml of toluene, yielding 12.73g of a viscous oil. Example 14: Preparation of Compound 21TB in HC1/THF
A mixture of HCl (32% in water, 0.57 g), water (2 mL), and THF (17.5 mL) was prepared. 5.4 mL of this mixture were added dropwise to a solution of Compound 20TB (2.7g) in THF (8.1 mL). The reaction mixture was stirred at ambient temperature overnight, until monitoring of the reaction by TLC indicated completion of the reaction.
Ethyl acetate (20 mL) was added to the reaction mixture and the reaction mixture was washed with water (20 mL). An aqueous layer formed, and was extracted with ethyl acetate (20 mL). The organic layers were combined and washed with an aqueous solution OfEt3N (2 x 5 mL) at a pH of about 10.5. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure, yielding an oil of Compound 21TB (2.03 g).
Example 15: Preparation of Compound 22TB (TBRE)
21TB 22TB
To a solution of 21TB (1 g) in dry THF (26 mL) and dry methanol (7 mL), a solution of diethylmethoxyborane (IM) in THF (2 mL) was added at about -78°C, forming a reaction mixture. The reaction mixture was stirred for 0.5 hour, NaBH4 was added, and the stirring was continued for 3 hours. Acetic acid (1.2 mL) was added to the reaction mixture and the reaction mixture was warmed to ambient temperature.
Ethyl acetate (150 mL) was added to the reaction mixture and the pH was adjusted to 8 by addition of concentrated NaHCO3 water solution. The layers were separated, and water was extracted by adding an additional amount of ethyl acetate (50 mL). The organic layers were combined and dried over MgSO4. The solvents were then evaporated under reduced pressure, leaving a residue. The residue was treated with methanol and then the methanol
EV 079444 136 US
was evaporated. Methanol treatment and evaporation was performed two more times, yielding crude Compound 22TB (TBRE) (0.87 g, 86%).
Example 16: Conversion of Compound 22TB into rosuvastatin Ca with extraction in ethyl acetate A l L reactor equipped with a mechanical stirrer was charged with EtOH (3 L), water
(1800 mL), and TBRE (600 g), forming a reaction mixture. NaOH (47%, 1.2 eq, 114 g) was slowly added to the reaction mixture, at RT. The reaction mixture was stirred at about RT for two hours. The reaction mixture was filtered under reduced pressure with Synter and Hyflo to eliminate the small particles present. The reaction mixture was concentrated under reduced pressure at about 40°C until half the volume of the reaction mixture remained.
Water (2000 mL) was added to the reaction mixture and the reaction mixture was stirred at about RT for 5 minutes. An aqueous phase and an organic phase formed. The phases were separated, and the aqueous phase was washed with ethyl acetate (3000 mL) and stirred at RT for half an hour. The organic phase was discarded. The aqueous phase was concentrated under reduced pressure at about 40°C until half the volume remained. Water (2800 mL) was added to the aqueous phase and the aqueous phase was stirred at about RT for 5 minutes. CaCl2 (124 g) was added to the aqueous phase in portions over a period of about 10 minutes at a temperature of about RT. The aqueous phase was then stirred at about RT for about 1 hour, filtered, and washed with 1200 mL of water, yielding a powdery compound (491 g, 88%).
EV 079444 136 US
Claims
What is claimed is: 1. A compound of the formula:
7a
wherein R4 is Ci-C4 alkly, Ar is phenyl, and Z is a hydroxy protecting group.
2. The compound of claim 1, wherein R4 is methyl or ethyl.
3. The compound of claim 1-2, wherein Z is a silyl group.
4. The compound of claim 1-3 or claim 2 wherein Z is a trialkylsilysl group having the formula-Si(A)3 where each A is independently selected from a Ci-C6 linear or branched aliphatic group or a C5-Ci2 aromatic group.
5. The compound of claim 1-4 wherein Z is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl.
6. The compound of claim 3-5, wherein the silyl group is tert-butyldimethylsilyl.
7. The compound of claim 1-6, wherein the phenyl group is substituted with hydroxy, carboxyl, Ci-C4 alkyl, C6-Ci2 alkoxy, C6-C]2 aryl, C6-Ci2 arylalkyl, C6-Ci2 cycloalkyl and amino.
8. The compound of claim 1-7, wherein the compound has the following stereochemistry:
7a
9. The compound of claim 8 wherein the compound has enantiomeric purity of about 80% to about 98%.
10. The compound of claim 9, wherein the compound has enantiomeric purityof about 85% to about 90%.
11. A compound of the formula:
EV 079 444 136 US 
8
wherein R4 is CpC4 alkyl, Ar is phenyl, Z is a hydroxy protecting group.
12. The compound of claim 11, wherein the compound has the following stereochemistry:
13. The compound of claim 11-12 wherein the compound has enantiomeric purity of about 80% to about 98%,
14. The compound of claim 11-13, wherein the compound has enantiomeric excess of about 85% to about 90%.
15. The compound of claim 11-14, wherein R4 is methyl or ethyl.
16. The compound of claim 11-15, wherein Z is a silyl group.
17. The compound of claim 11-16, wherein Z is a trialkylsilyl group having the formula- Si(A)3 where each A is independently selected from a Ci-C6 linear or branched aliphatic group or a C5-Ci2 aromatic group.
18. The compound of calims 11-17, wherein Z is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl, preferably tert-butyldimethylsilyl.
19. The compound of calims 11-18, wherein the phenyl group is substituted with hydroxy, carboxyl, Ci-C4 alkyl, C6-Ci2 alkoxy, C6-Ci2 aryl, C6-Cj2 arylalkyl, C6-Ci2 cycloalkyl and amino.
20. A compound of the formula:
21. The compound of claim 19, wherein the compound has the following stereochemistry:
EV 079444 136 US 
22. The compound of claim 20-21 wherein the compound has enantiomeric purity of about 80% to about 98%,
23. The compound of claim 20-22, wherein the compound has enantiomeric excess of about 85% to about 90%.
24. The compound of claim 20-23, wherein Z is a silyl group.
25. The compound of claim 20-23, wherein Z is a trialkylsilysl group having the formula- Si(A)3 where each A is independently selected from a Ci-C6 linear or branched aliphatic group or a C5-Ci2 aromatic group.
26. The compound of claim 20-23, wherein Z is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl, preferably tert-butyldimethylsilyl.
27. The compounds of any of the preceding claims, wherein the compounds are isolated.
28. A process for preparing a compound of formula 4a, having the following structure:
comprising enantioselectively opening the prochiral anhydride compound of formula 3, having the following structure:
by reacting compound 3 with a Ci-C5 alcohol in the presence of alkaloid, wherein Ri is a Cj- C5 alkyl group; and Z is a hydroxy protecting group.
29. The process of claim 26 wherein the product of formula 4a is enriched in the , compound having the following structure:
EV 079 444 136 US 
30. The compound of claim 28-29 wherein the compound has enantiomeric purity of about 80% to about 98%,
31. The compound of claim 28-30 where in the compound has enantiomeric purity of about 85% to about 90%.
32. The process of claim 28-31 wherein Z is a silyl group.
33. The process of claim 32 wherein Z is a trialkylsilysl group having the formula-Si(A)3 where each A is independently selected from a Ci-C6 linear or branched aliphatic group or C5-Ci2 aromatic group.
34. The process of claim 32 wherein Z is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl, preferably tert-butyldimethylsilyl.
35. The process of claim 28-34 wherein the alkaloid is selected from the group consisting of 5 -MeO-DMT, dimethyltryptamine, harmala alkaloids, psilocin, psilocybin, reserpine, serotonin, tryptamine, yohimbine, amphetamine, cathinone, ephedrine, mescaline, methamphetamine, phenethylamine, tyramine, caffeine, theobromine, theophylline, coniine, nicotine, quinine, quinidine, aconitine and solanine.
36. The process of claim 28-35, wherein the akaloid is quinine or quinidine.
37. A process for preparing the compound of formula 5a having the following structure:
5a
comprising combining the compound of formula 4a:
EV 079 444 136 US with BOC anhydride (Di-tert-butyl dicarbonate) in the presence of a basic catalyst, wherein Ri is C1-C5 alkyl group; and Z is a hydroxy protecting group
38. The product of the process of claim 37 where in the compound has the following structure:
5
39. The process of claim 37-38 wherein the compound is obtained in enantiomeric purity of about 80% to about 98%,
40. The process of claim 37-40 wherein the compound is obtained in an enantiomeric purity of about 85% to about 90%.
41. The process of claim 37-40 wherein the basic catalyst is a tertiary amine base is of the formula N(A 1)(A2)(A3), contains C3-Ci5 carbon atoms and Al, A2, and A3 are each independently selected from a C1-C10 alkyl group and a C5-Ci2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen.
40 The process of claim 41 wherein Al and A2 are methyl groups, and A3 is a C5-Ci2 aromatic group containing a nitrogen or an oxygen.
41. The process of claim 41 , where the tertiary amine base is N-methyl morpholine or N,N-dimethylaminopyridine.
42. The process of claim 37-41, wherein Z is a silyl group.
43. The compound of claim 42, wherein Z is a trialkylsilysl group having the formula- Si(A)3 where each A is independently selected from a Ci-C6 linear or branched aliphatic group or a C5-Ci2 aromatic group.
44. The process of claim 42, wherein Z is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl.
45. The process of claim 42, wherein the silyl group is tert-butyldimethylsilyl.
46. The process of claim 37-45 wherein the reaction of formula 4a with BOC anhydride is maintained at a temperature of about 50C to about 500C.
47. The process of claim 37-46 wherein the reaction is maintained for a period of about 2 to about 10 hours.
48. A process for preparing a compound of formula 7, having the following structure:
EV 079 444 136 US 
, comprising enantioselectively opening the prochiral anhydride of formula 3, having the following structure:
With a chiral alcohol of the formula 3a, having the following structure:
R4
Ar^^OH 3a wherein R4 is C1-C6 alkyl, and Ar is phenyl and Z is a hydroxy protecting group as above.
49. The process of claim 48 wherein the compound has the following stereochemistry:
7a
50. The process of claims 48-49, wherein the compound of formula 7 obtained with enantiomeric purity of about 80% to about 98%,
51. The process of claims 48-49, wherein the compound of formula 7 obtained is obtained with enantiomeric purity of about 85% to about 90%,
50. The process of claim 47-51 wherein the basic catalyst is a tertiary amine base is of the formula N(A1)(A2)(A3), contains C3-C15 carbon atoms and Al, A2, and A3 are each independently selected from a Ci-Cio alkyl group and a C5-Ci2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen.
51. The process of claim 50. wherein Al and A2 are methyl groups, and A3 is a C5-Ci2 aromatic group containing a nitrogen or an oxygen.
EV 079 444 136 US
52. The process of claim 50, where the tertiary amine base is N-methyl morpholine or N,N-dimethylaminopyridine.
53. The process of claim 49-52, wherein Z is a silyl group.
54. The compound of claim 49-53, wherein Z is a trialkylsilysl group having the formula- Si(A)3 where each A is independently selected from a Ci-C6 linear or branched aliphatic group or a C5-C]2 aromatic group.
55. The process of claim 54, wherein Z is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl.
56. The process of claim 54, wherein the silyl group is tert-butyldimethylsilyl.
57. The process of claim 48-56, wherein the solvent is a C1-C4 chlorinated hydrocarbon.
58. The process of claim 57, wherein the solvent is methylene dichloride.
59. The process of claim 48-59 wherein the reaction is conducted at a reaction temperature of about -200C to about -600C.
60. The process of claim 49, wherein the phenyl group is substituted with hydroxy, carboxyl, Cj-C4 alkyl, C6-C]2 alkoxy, C6-C]2 aryl, C6-Ci2 arylalkyl, C6-Ci2 cycloalkyl and amino.
61. A process for preparing a compound of formula 8, having the following structure:
comprising combining the compound of formula 7a:
7a
with BOC anhydride (Di-/er/-butyl dicarbonate) in the presence of a basic catalyst, wherein R4 is Ci-C6 alkyl, e.g., methyl or ethyl, and Ar is phenyl; and Z is a hydroxy protecting group
62. The process of claim 60 wherein the compound has the following structure:
EV 079444 136 US 
8a
63. The process of claims 60-61, wherein the compound of formula 7 obtained has enantiomeric purity of about 80% to about 98%.
63. The process of claims 60-63, wherein the compound of formula 7 obtained has enantiomeric purity of about 85% to about 90%.
64. The process of claims 60-63, wherein the reaction is carried out at a temperature of about 50C to about 500C
65. The process of claim 60-65, wherein the basic catalyst is a tertiary amine base is of the formula N(A1)(A2)(A3), contains C3-Ci5 carbon atoms and Al, A2, and A3 are each independently selected from a Ci-Cio alkyl group and a C5-Ci2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen.
66. The process of claim 65, wherein Al and A2 are methyl groups, and A3 is a C5-C]2 aromatic group containing a nitrogen or an oxygen.
67. The process of claim 61-66, wherein the tertiary amine base is N-methyl morpholine or N,N-dimethylaminopyridine.
68. The process of claim 61-67, wherein Z is a silyl group.
69. The process of claim 68, wherein Z is a trialkylsilysl group having the formula-Si(A)3 where each A is independently selected from a Ci-C6 linear or branched aliphatic group or a C5-Ci2 aromatic group.
70. The process of claim 68, wherein Z is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl.
71. The process of claim 68, wherein the silyl group is tert-butyldimethylsilyl.
72. The process of claim 61-71, wherein the phenyl group is substituted with hydroxy, carboxyl, Ci-C4 alkyl, C6-Ci2 alkoxy, C6-Ci2 aryl, C6-Ci2 arylalkyl, C6-Ci2 cycloalkyl and amino.
73. A process for preparing compound of formula 6a, having the following structure:
EV 079444 136 US 
6a
Comprising selectively hydrolyzing the compound of formula 5a:
wherein Z is a hydroxy protecting group as above and Ri is Ci-C6 alkyl, preferably C1-C4 group.
74. The process of claim 73, wherein the compounds have the following stereochemistry:
and
75. The process of claim 73-74, wherein the compound of formula 7 obtained has enantiomeric purity of about 80% to about 98%.
76. The process of claim 73-75, wherein the compound of formula 7 obtained has enantiomeric purity of about 85% to about 90%.
77. The process of claims 73-76, wherein the hydrolyzation is carried out in a C1-C5 alcohol.
78. The process of claims 73-77, wherein the hydrolyzation is carried out in methyl, ethyl alcohol, and mixtures thereof.
79. The process of claims 73-78, wherein the hydrolyzation is carried out for about 2 to about 12 hours at a temperature of about 200C to about 600C
EV 079 444 136 US
80. The process of claim 73-79, wherein the basic catalyst is a tertiary amine base is of the formula N(A1)(A2)(A3), contains C3-Ci5 carbon atoms and Al, A2, and A3 are each independently selected from a Ci-Ci0 alkyl group and a C5-Ci2 aromatic group, wherein Al, A2, and A3 can further include an oxygen or a nitrogen.
81. The process of claim 80, wherein Al and A2 are methyl groups, and A3 is a C5-Ci2 aromatic group containing a nitrogen or an oxygen.
82. The process of claim 80, wherein the tertiary amine base is N-methyl morpholine or N,N-dimethylaminopyridine.
83. The process of claim 73-82, wherein Z is a silyl group.
84. The compound of claim 83, wherein Z is a trialkylsilysl group having the formula- Si(A)3 where each A is independently selected from a Ci-C6 linear or branched aliphatic group or a C5-Cj2 aromatic group.
85. The process of claim 83, wherein Z is selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldimethylsilyl, methyldiphenylsilyl, and dimethylphenylsilyl.
86. The process of claim 83, wherein the silyl group is tert-butyldimethylsilyl.
87. A process for preparing a compound of formula 2a, having the following structure:
2a
wherein R3 is Ci to C3 alkyloxy, C5-C12 aryloxy, C5-Ci2 aryloxy substituted with and Z is a hydroxy protecting group comprising combining the compound of formula 9
with a lithiated salt of dialkyl phosphonate,
88. The process of claim 87, wherein the dialkyl phosphonate is a Ci-C3 dialkyl phosphonate.
89. The process of claim 87-88, wherein the reaction is carried out in toluene, xylene, cyclohexane, methyl t-butyl ether, tetrahydrofuran ,or mixtures thereof.
EV 079444 136 US
90. The process of any one of claim 87-89, wherein the reaction is carried out in methyl t- butyl ether or tetrahydrofuran.
91. A process for preparing a statin further comprising converting the compound obtained in any of the preceding claims to the stain.
92. 
wherein the statin compound is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin and pitavastatin, preferably rosuvastatin.
93. Use of a compound of any of the preceding claims in the manufacture of a statin compound, preferably wherein the statin compound is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, cerivastatin, atorvastatin, rosuvastatin and pitavastatin, preferably rosuvastatin.
EV 079444 136 US
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| BRPI0803112-6A BRPI0803112A2 (en) | 2007-04-18 | 2008-04-18 | a process for preparing hkg-coa reductase inhibitor intermediates |
| MX2008016244A MX2008016244A (en) | 2007-04-18 | 2008-04-18 | A process for preparing intermediates of hmg-coa reductase inhibitors. |
| JP2009511271A JP2009531466A (en) | 2007-04-18 | 2008-04-18 | Method for producing intermediate of HMG-CoA reductase inhibitor |
| EP08743067A EP2032586A2 (en) | 2007-04-18 | 2008-04-18 | A process for preparing intermediates of hmg-coa reductase inhibitors |
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| US60/931,926 | 2007-05-24 | ||
| US6667808P | 2008-02-21 | 2008-02-21 | |
| US61/066,678 | 2008-02-21 | ||
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| PCT/US2008/005034 WO2008130638A2 (en) | 2007-04-18 | 2008-04-18 | A process for preparing intermediates of hmg-coa reductase inhibitors |
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| WO2011106546A1 (en) * | 2010-02-25 | 2011-09-01 | Teva Pharmaceutical Industries Ltd. | A process for the preparation of rosuvastatin intermediate |
| CN102212081A (en) * | 2010-12-30 | 2011-10-12 | 北京双鹤药业股份有限公司 | Preparation method of chiral intermediate product for synthesis of statins |
| WO2011141934A1 (en) * | 2010-05-13 | 2011-11-17 | Matrix Laboratories Ltd. | An improved process for the preparation of an intermediate of hmg-coa reductase inhibitors |
| WO2013080219A3 (en) * | 2011-11-28 | 2014-01-30 | Mylan Laboratories Ltd | Process for producing chiral statin side chain intermediates employing candida|antarctica lipase b |
| WO2015008294A1 (en) * | 2013-07-16 | 2015-01-22 | Suven Life Sciences Limited | Process for the preparation of rosuvastatin calcium and preparation of its novel intermediates |
| US10519175B2 (en) | 2017-10-09 | 2019-12-31 | Compass Pathways Limited | Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use |
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| PL2172471T3 (en) * | 2007-04-18 | 2013-08-30 | Teva Pharma | A process for preparing intermediates of HMG-CoA reductase inhibitors |
| CN104744215B (en) * | 2010-03-03 | 2019-03-15 | 尼昂克技术公司 | Pharmaceutical composition comprising monoterpene |
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| WO2011141934A1 (en) * | 2010-05-13 | 2011-11-17 | Matrix Laboratories Ltd. | An improved process for the preparation of an intermediate of hmg-coa reductase inhibitors |
| CN102212081A (en) * | 2010-12-30 | 2011-10-12 | 北京双鹤药业股份有限公司 | Preparation method of chiral intermediate product for synthesis of statins |
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| WO2013080219A3 (en) * | 2011-11-28 | 2014-01-30 | Mylan Laboratories Ltd | Process for producing chiral statin side chain intermediates employing candida|antarctica lipase b |
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Also Published As
| Publication number | Publication date |
|---|---|
| KR20090018964A (en) | 2009-02-24 |
| ES2415206T3 (en) | 2013-07-24 |
| EP2093230A1 (en) | 2009-08-26 |
| PL2172471T3 (en) | 2013-08-30 |
| JP2009538831A (en) | 2009-11-12 |
| EP2172471B1 (en) | 2013-03-27 |
| WO2008130678A2 (en) | 2008-10-30 |
| WO2008130678A3 (en) | 2008-12-11 |
| KR20090033183A (en) | 2009-04-01 |
| EP2032586A2 (en) | 2009-03-11 |
| US7964748B2 (en) | 2011-06-21 |
| EP2032587A2 (en) | 2009-03-11 |
| EP2062903A1 (en) | 2009-05-27 |
| JP2009531466A (en) | 2009-09-03 |
| EP2172471A2 (en) | 2010-04-07 |
| US7687660B2 (en) | 2010-03-30 |
| US20100160663A1 (en) | 2010-06-24 |
| MX2008016244A (en) | 2009-04-17 |
| EP2172471A3 (en) | 2010-07-07 |
| US20090076271A1 (en) | 2009-03-19 |
| US20090076292A1 (en) | 2009-03-19 |
| US20090209779A1 (en) | 2009-08-20 |
| WO2008130638A3 (en) | 2008-12-18 |
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