US20070043241A1 - Optical resolution of 3-carbamoylmethyl-5-methylhexanoic acid - Google Patents
Optical resolution of 3-carbamoylmethyl-5-methylhexanoic acid Download PDFInfo
- Publication number
- US20070043241A1 US20070043241A1 US11/432,010 US43201006A US2007043241A1 US 20070043241 A1 US20070043241 A1 US 20070043241A1 US 43201006 A US43201006 A US 43201006A US 2007043241 A1 US2007043241 A1 US 2007043241A1
- Authority
- US
- United States
- Prior art keywords
- cmh
- precipitate
- salt
- ephedrine
- ketone
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 230000003287 optical effect Effects 0.000 title claims abstract description 42
- NPDKTSLVWGFPQG-UHFFFAOYSA-N 3-(2-amino-2-oxoethyl)-5-methylhexanoic acid Chemical compound CC(C)CC(CC(N)=O)CC(O)=O NPDKTSLVWGFPQG-UHFFFAOYSA-N 0.000 title claims description 10
- 238000000034 method Methods 0.000 claims abstract description 119
- 229960001233 pregabalin Drugs 0.000 claims abstract description 28
- 239000012452 mother liquor Substances 0.000 claims abstract description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 75
- 239000000203 mixture Substances 0.000 claims description 73
- 239000002244 precipitate Substances 0.000 claims description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 57
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 45
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 34
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 30
- 150000002576 ketones Chemical class 0.000 claims description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 27
- 239000003153 chemical reaction reagent Substances 0.000 claims description 23
- 239000002904 solvent Substances 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 22
- 239000002002 slurry Substances 0.000 claims description 22
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 20
- 239000011707 mineral Substances 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 150000002148 esters Chemical class 0.000 claims description 18
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000011541 reaction mixture Substances 0.000 claims description 15
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 claims description 12
- 229960002179 ephedrine Drugs 0.000 claims description 12
- AYXYPKUFHZROOJ-SSDOTTSWSA-N pregabalin Chemical compound CC(C)C[C@@H](CN)CC(O)=O AYXYPKUFHZROOJ-SSDOTTSWSA-N 0.000 claims description 12
- -1 alkali metal hydrogen carbonates Chemical class 0.000 claims description 11
- 150000002825 nitriles Chemical class 0.000 claims description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 150000001414 amino alcohols Chemical class 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 claims description 8
- 229960000395 phenylpropanolamine Drugs 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
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- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 150000003335 secondary amines Chemical class 0.000 claims description 4
- 230000002378 acidificating effect Effects 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- 229910002651 NO3 Inorganic materials 0.000 claims description 2
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims description 2
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- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 229940043232 butyl acetate Drugs 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical compound CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 abstract description 26
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
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- 235000002639 sodium chloride Nutrition 0.000 description 18
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- 235000010755 mineral Nutrition 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- NPDKTSLVWGFPQG-SSDOTTSWSA-N (3r)-3-(2-amino-2-oxoethyl)-5-methylhexanoic acid Chemical compound CC(C)C[C@H](CC(N)=O)CC(O)=O NPDKTSLVWGFPQG-SSDOTTSWSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
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- 238000004090 dissolution Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- 108010010803 Gelatin Proteins 0.000 description 4
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 3
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
- C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
- C07C215/30—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings containing hydroxy groups and carbon atoms of six-membered aromatic rings bound to the same carbon atom of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/16—Preparation of optical isomers
- C07C231/20—Preparation of optical isomers by separation of optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
Definitions
- the present invention is directed to pure (R)—CMH, the optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid-racemate (CMH-racemate), the process for optically purifying (R)—CMH and the process for isolating (S)—CMH from the mother liquor.
- (S)-Pregabalin (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, a compound having the chemical structure, is also known as ⁇ -amino butyric acid or (S)-3-isobutyl GABA.
- (S)-Pregabalin has been found to activate GAD (L-glutamic acid decarboxylase).
- GAD L-glutamic acid decarboxylase
- (S)-Pregabalin has a dose dependent protective effect on-seizure, and is a CNS-active compound.
- (S)-Pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses.
- (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity.
- (S)-Pregabalin is obtained after optical resolution of the ( ⁇ )-3-(carbamoylmethyl)-5-methylhexanoic acid racemate (referred to as CMH-racemate), which is accomplished by reaction of the CMH-racemate with chiral phenylethylamine in a solvent mixture of CHCl 3 and ethanol to obtain the desired R-enantiomer of CMH according to the following scheme: However, according to Chemical Development of CI -1008. An Enantiomerically Pure Anticonvulsant, O RGANIC P ROCESS R ESEARCH & D EVELOPMENT, 1997, 1, 26-38, this synthetic method was avoided because it requires the use of chloroform.
- Optical resolution of a racemic mixture is performed via a diastereomeric salt.
- An example of this method is depicted in the following scheme, The salt is formed by reacting the racemic mixture with a chiral resolving reagent. Then, a selective crystallization of only one of the diastereomers is done to isolate the desired diastereomer salt, while the undesired remains in the solution. The crystalline salt is then isolated and the chiral resolving reagent is removed to give the desired enantiomer.
- CMH which has a carboxylic acid function can be reacted with an appropriate chiral amine to obtain the salt of the desirable enantiomer (R-enantiomer), which is then isolated followed by removing the chiral amine to give (R)—CMH.
- the present invention provides (R)—CMH containing less than about 0.2% area by HPLC of (S)—CMH.
- the present invention provides (R)—CMH containing less than about 0.1% area by HPLC of (S)—CMH.
- the present invention provides a process for the optical resolution of ( ⁇ )-3-(carbamoylmethyl)-5-methylhexanoic acid (referred to as CMH-racemate), comprising combining CMH-racemate, a solvent selected from the group consisting of ketone, ester, nitrile, C 1-4 alcohol, water, or mixtures thereof, a chiral resolving reagent of amino alcohol and salts thereof; recovering; and adding a solvent selected from the group consisting of ketone, C 1-8 alcohol, water or mixtures thereof, and a strong mineral acid, wherein; any individual stereoisomer of the chiral resolving reagent may be used.
- the present invention also provides a process for the optical resolution CMH-racemate that comprises two steps: the first is the preparation of the (R)—CMH amine salt and the second, recovering (R)—CMH from the salt.
- the process comprises combining CMH-racemate, a solvent selected from the group consisting of ketone, ester, nitrile, C 1-4 alcohol, water, or mixtures thereof, a chiral resolving reagent selected from ephedrine, ephedrine salt, norephedrine, and norephedrine salt to obtain a precipitate, wherein the precipitate is of (R)—CMH-ephedrine salt of the following structure: or of (R)—CMH-norephedrine salt of the following structure:
- the precipitate is further isolated and thereafter combined with a solvent selected from the group consisting of ketone, C 1-8 alcohol, water, or mixtures thereof, and with a strong mineral acid to obtain a precipitate of (R)—CMH of the following structure
- the present invention provides a process for the optical resolution of ( ⁇ )-3-(carbamoylmethyl)-5-methylhexanoic acid (referred to as CMH-racemate) comprising combining CMH-racemate, a solvent selected from ketone, ester, nitrile, C 1-4 alcohol, water, or mixtures thereof, and 1R, 2S-( ⁇ )-ephedrine to obtain a reaction mixture.
- the obtained reaction mixture is then heated to a temperature of about 50° C. to about 140° C.
- the reaction mixture is then cooled to a temperature of about ambient to about 2° C. to obtain a precipitate, wherein the precipitate is of (R)—CMH-ephedrine salt of the following structure: or of (R)—CMH-norephedrine salt of the following structure:
- the precipitate is further isolated and thereafter combined with a solvent selected from the group consisting of ketone, C 1-8 alcohol, water or mixtures thereof, and with a strong mineral acid to obtain a slurry and the slurry is then cooled to a temperature of about 10° C. to about 2° C. to obtain a precipitate of (R)—CMH of the following structure
- the present invention provides (R)—CMH-Ephedrine salt.
- the present invention provides a process for improving the optical purity of (R)—CMH comprising combining (R)—CMH with water.
- the present invention provides a process for isolating (S)—CMH from the remaining mother liquor comprising combining the mother liquor obtained after the filtration of (R)—CMH with water, and heating to dissolution.
- the solution is then cooled and combined with an acid to obtain a precipitate of CMH containing about a specific amount of (S)—CMH.
- the precipitate is then filtered and resolved again with acetone, and ephedrine as a chiral resolving reagent to obtain a second precipitate of R—CMH-ephedrine salt that is then removed.
- the remaining mother liquor, which contains (S)—CMH-ephedrine salt is then evaporated to dryness, and the residue is treated with an acid to obtain (S)—CMH, which is further recovered
- the present invention provides a process for preparing (S)-Pregabalin comprising preparing (R)—CMH by the process of the present invention, and converting it to (S)-Pregabalin.
- chiral resolving reagent refers to an acidic or basic structure re that can lead to the precipitation of the diastereomer containing the desired enantiomer in high chemical and optical yields.
- racemate refers to a mixture that contains an equal amount of enantiomers.
- the present invention provides (R)—CMH containing less than about 0.2% area by HPLC of (S)—CMH.
- the present invention provides (R)—CMH containing less than about 0.1% area by HPLC of (S)—CMH.
- the process of the present invention performs resolution at the stage of CMH-racemate, of the following structure without using carcinogenic solvents as chloroform, while also recycling the undesired enantiomer.
- some processes of the prior art perform the optical resolution on Pregabalin itself while, recycling (R)-Pregabalin is very difficult, thus leading to a non-efficient and non-economical process.
- the present invention provides a process for the optical resolution of ( ⁇ )-3-(carbamoylmethyl)-5-methylhexanoic acid (referred to as CMH-racemate), comprising combining CMH-racemate, a solvent selected from the group consisting of ketone, ester, nitrile, C 1-4 alcohol, water, or mixtures thereof, a chiral resolving reagent of amino alcohol and salts thereof to obtain a precipitate; isolating the precipitate; and adding a solvent selected from the group consisting of ketone, C 1-8 alcohol, water or mixtures thereof, and a strong mineral acid, wherein; any individual stereoisomer of the chiral resolving reagent may be used.
- the present invention also provides a process for the optical resolution CMH-racemate that comprises two steps: the first is the preparation of the (R)—CMH amine salt and the second, recovering (R)—CMH from the salt.
- the process comprises combining CMH-racemate, a solvent selected from the group consisting of ketone, ester, nitrile, C 1-4 alcohol, water, or mixtures thereof, a chiral resolving reagent selected from ephedrine, ephedrine salt, norephedrine, and norephedrine salt to obtain a precipitate, wherein the precipitate is of (R)—CMH-ephedrine salt of the following structure: or of (R)—CMH-norephedrine salt of the following structure:
- the precipitate is further isolated and thereafter combined with a solvent selected from the group consisting of ketone, C 1-8 alcohol, water, or mixtures thereof, and with a strong mineral acid to obtain a precipitate of (R)—CMH of the following structure
- the present invention provides a process for the optical resolution of CMH-racemate comprising combining CMH-racemate, a solvent selected from ketone, ester, nitrile, C 1-4 alcohol, water, or mixtures thereof, and 1R, 2S-( ⁇ )-ephedrine to obtain a reaction mixture.
- the obtained reaction mixture is then heated to a temperature of about 50° C. to about 140° C.
- the reaction mixture is then cooled to a temperature of about 20° C. to about ⁇ 20° C. to obtain a precipitate, wherein the precipitate is of (R)—CMH-ephedrine salt of the following structure: or of (R)—CMH-norephedrine salt of the following structure:
- the precipitate is further isolated and thereafter combined with a solvent selected from the group consisting of ketone, C 1-8 alcohol, water or mixtures thereof, and with a strong mineral acid to obtain a slurry and the slurry is then cooled to a temperature of about 10° C. to about 2° C. to obtain a precipitate of (R)—CMH of the following structure
- the chiral resolving reagent of amino alcohol and salts thereof is selected from the group consisting of ephedrine, ephedrine salt, norephedrine, and norephedrine salt. More preferably, the chiral resolving reagent is ephedrine or ephedrine salt. Most preferably, the chiral resolving reagent is 1R,2S-( ⁇ )-ephedrine.
- the salt of ephedrine or norephedrine is a hydrochloride, nitrate, or sulfate. More preferably, the salt is a hydrochloride.
- a base is further added with the resolving reagent.
- the chiral resolving reagent is the salt of ephedrine or of norephedrine
- a base must also be used.
- the base is either an organic base or an inorganic base.
- the organic base is an amine.
- the amine is tertiary or secondary amine.
- the tertiary amine is triethylamine or tributylamine.
- the secondary amine is diisopropylamine or n-dipropylamine.
- the more preferred organic base is triethylamine.
- the inorganic base is alkali metal hydrogen carbonates, alkali hydroxide or alkali carbonate.
- the alkali hydroxide is either NaOH or KOH.
- the alkali carbonate is either K 2 CO 3 or Na 2 CO 3 .
- the more preferred inorganic base is NaOH.
- the ketone is a C 2 to C 6 ketone, more preferably a C 2 to C 5 ketone, more preferably, acetone or methylisobutyl ketone, most preferably, aetone.
- the C 1-4 alcohol is selected from the group consisting of methanol, ethanol, isopropanol, or isobutanol. More preferably, the C 1-4 alcohol is methanol.
- the ester is selected from a C 3 to C 8 , more preferably a C 4 to C 6 ester, such as a C 2 to C 4 alkylacetate.
- the ester is selected from the group consisting of ethyl acetate, butylacetate and isopropyl acetate. Most preferably, the ester is Ethylacetate.
- the nitrile is acetonitrile.
- the most preferred solvent is acetone or a mixture of acetone and water.
- the mixture is heated to a temperature of about 50° C. to about 100° C. obtain a reaction mixture, which is maintained at this temperature for about 0.5 hour to about 5 hours, more preferably, for about 0.5 hour to about 2 hours.
- the reaction mixture is a solution.
- the obtained reaction mixture is cooled to a temperature of about 20° C. to about ⁇ 20° C., and is preferably maintained for about an hour to about 24 hours, more preferably, for an hour to about 12 hours.
- the isolation is by recovering.
- the strong mineral acid is HCl, HBr, H 2 SO 4 , or H 2 PO 3 .
- the more preferred strong mineral acid is HCl.
- a pH of about 0 to about 4 is obtained, more preferably, a pH of about 1 to about 3 is obtained.
- the slurry is cooled to a temperature of about 2° C.
- the slurry is maintained at a temperature of about 2° C. to about ambient temperature, more preferably, of about 2° C. to about 10° C., for about 0.5 hours to about 24 hours, more preferably, for about 0.5 hours to about 2 hours.
- the (R)—CMH is further recovered.
- (R)—CMH, (R)—CMH-ephedrine salt and (R)—CMH-norephedrine salt may be recovered by known methods in the art, such as filtering, washing, and drying in a vacuum oven. After the filtration step, the remaining mother liquor is obtained.
- the (R)—CMH obtained by the process of the invention contains less than about 7% area by HPLC, more preferably, less than about 4% area by HPLC, most preferably, less than about 0.2% area by HPLC and even most preferably, less than 0.1% area by HPLC of (S)—CMH.
- the present invention provides (R)—CMH-Ephedrine salt.
- the present invention provides a process for optically purifying (R)—CMH comprising combining (R)—CMH with water.
- the water is in an amount of 8-15 vol.
- the (R)—CMH has a specific optical purity as measured by HPLC.
- the combination of (R)—CMH and water results in a slurry.
- the obtained slurry is stirred to obtain a precipitate of (R)—CMH.
- the obtained slurry is stirred at a temperature of about 2° C. to about 30° C. for about one hour to about 24 hours, more preferably, at a temperature of about 15° C. to about 20° C. for about 0.5 hour to about 24 hours, most preferably, at a temperature of about 20° C. for about one hour to about 2 hours.
- the starting (R)—CMH may be obtained by the processes described before, having a purity of about 90% to about 99% area by HPLC, more preferably, of about 96.5% to about 99% area by HPLC.
- (R)—CMH obtained by the above process contains less than about 1% area by HPLC, more preferably, less than about 0.2% area by HPLC, most preferably, less than 0.1% area by HPLC of (S)—CMH.
- the precipitate is recovered.
- the precipitate may be recovered by any method known in the art, such as filtering, washing, and drying.
- the present invention provides a process for isolating (S)—CMH from the remaining mother liquor comprising combining the mother liquor obtained after the flirtation of (R)—CMH with water, and heating to dissolution.
- the solution is then cooled and combined with an acid to obtain a precipitate of CMH containing about a specific amount of (S)—CMH.
- the precipitate is then filtered and resolved again with acetone, and 1R, 2S-( ⁇ )-ephedrine to obtain a second precipitate of R—CMH-ephedrine salt that is then removed.
- the remaining mother liquor, which contains (S)—CMH-ephedrine salt is then evaporated to dryness, and the residue is treated with an acid to obtain (S)—CMH, which is further recovered.
- the precipitate of (S)—CMH may be recovered by known methods in the art, such as filtering, washing and drying in a vacuum oven.
- the present invention provides a process for preparing (S)-Pregabalin comprising preparing (R)—CMH by the process of the present invention, and converting it to (S)-Pregabalin.
- the conversion of (R)—CMH to (S)-Pregabalin comprises reacting (R)—CMH with bromine in a Hoffman reaction under basic conditions at a temperature of about 60° C. to about 85° C., to obtain a basic mixture, followed by an addition of a strong mineral acid, to obtain an acidic mixture containing a complex of (S)-Pregabalin with the strong mineral acid, as disclosed in Co-application No. 60/689,699, or by any other process known to one skilled in the art.
- the (S)-Pregabalin contains less than about 0.2% area by HPLC of (R)-Pregabalin. More preferably, (S)-Pregabalin contains less than about 0.1% area by HPLC of (R)-Pregabalin.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising (S)-Pregabalin made by the process of the present invention and at least one pharmaceutically acceptable excipient.
- the present invention provides a process for preparing a pharmaceutical formulation comprising combining (S)-Pregabalin made by the process of the present invention, with at least one pharmaceutically acceptable excipient.
- the present invention provides the use of (S)-Pregabalin made by the process of the present invention for the manufacture of a pharmaceutical composition.
- compositions of the present invention can be administered in various preparations depending on the age, sex, and symptoms of the patient.
- the pharmaceutical compositions can be administered, for example, as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injection preparations (solutions and suspensions), and the like.
- compositions of the present invention can optionally be mixed with (S)-Pregabalin obtained in the present invention and other active ingredients.
- pharmaceutical compositions of the present invention can contain inactive ingredients such as diluents, carriers, fillers, bulking agents, binders, disintegrants, disintegration inhibitors, absorption accelerators, wetting agents, lubricants, glidants, surface active agents, flavoring agents, and the like.
- Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle.
- Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. AVICEL®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
- microcrystalline cellulose e.g. AVICEL®
- microfine cellulose lactose
- starch pregelatinized starch
- calcium carbonate calcium sulfate
- sugar dextrates
- Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
- Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL®), hydroxypropyl methyl cellulose (e.g. METHOCEL®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. KOLLIDON®, PLASDONE®), pregelatinized starch, sodium alginate and starch.
- carbomer e.g. carbopol
- carboxymethylcellulose sodium, dextrin ethyl cellulose
- the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
- Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. AC-DI-SOL®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. KOLLIDON®, POLYPLASDONE®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. EXPLOTAB®) and starch.
- Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
- Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
- a dosage form such as a tablet
- the composition is subjected to pressure from a punch and dye.
- Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
- a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
- Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
- Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
- Common flavoring agents and flavor enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
- Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
- liquid pharmaceutical compositions of the present invention the (S)-Pregabalin and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
- a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
- Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
- Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
- Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
- a viscosity enhancing agent include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
- Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
- Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
- a liquid composition may also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
- a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate.
- injectable (parenteral) pharmaceutical compositions When preparing injectable (parenteral) pharmaceutical compositions, solutions and suspensions are sterilized and are preferably made isotonic to blood.
- Injection preparations may use carriers commonly known in the art.
- carriers for injectable preparations include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyoxyethylene sorbitan.
- One of ordinary skill in the art can easily determine with little or no experimentation the amount of sodium chloride, glucose, or glycerin necessary to make the injectable preparation isotonic. Additional ingredients, such as dissolving agents, buffer agents, and analgesic agents may be added.
- the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
- the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
- the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
- Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and elixirs.
- the dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell.
- the shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
- compositions and dosage forms may be formulated into compositions and dosage forms according to methods known in the art.
- a composition for tableting or capsule filling may be prepared by wet granulation.
- wet granulation some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
- the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
- the granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
- a tableting composition may be prepared conventionally by dry blending.
- the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
- a blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
- Direct compression produces a more uniform tablet without granules.
- Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
- a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
- the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
- the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
- the dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
Abstract
Description
- This application claims the benefit of U.S. provisional application Nos. 60/679,784, filed May 10, 2005, 60/689,699, filed Jun. 9, 2005, 60/733,009, filed Nov. 2, 2005, 60/735,634, filed Nov. 9, 2005, and 60/740,950, filed Nov. 29, 2005, the contents of which are incorporated herein by reference in their entirety.
- The present invention is directed to pure (R)—CMH, the optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid-racemate (CMH-racemate), the process for optically purifying (R)—CMH and the process for isolating (S)—CMH from the mother liquor.
- (S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, a compound having the chemical structure,
is also known as γ-amino butyric acid or (S)-3-isobutyl GABA. (S)-Pregabalin has been found to activate GAD (L-glutamic acid decarboxylase). (S)-Pregabalin has a dose dependent protective effect on-seizure, and is a CNS-active compound. (S)-Pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity. - In the synthesis disclosed in U.S. Pat. No. 5,616,793, (S)-Pregabalin is obtained after optical resolution of the (±)-3-(carbamoylmethyl)-5-methylhexanoic acid racemate (referred to as CMH-racemate), which is accomplished by reaction of the CMH-racemate with chiral phenylethylamine in a solvent mixture of CHCl3 and ethanol to obtain the desired R-enantiomer of CMH according to the following scheme:
However, according to Chemical Development of CI-1008. An Enantiomerically Pure Anticonvulsant, ORGANIC PROCESS RESEARCH & DEVELOPMENT, 1997, 1, 26-38, this synthetic method was avoided because it requires the use of chloroform. - In the synthesis disclosed in D
RUGS OF THE FUTURE, 24 (8), 862-870 (1999), CMH-racemate is also resolved with (R)-1-phenylethylamine, yielding the (R)-phenylethylamine salt of (R)—CMH. Combining the salt with an acid liberates the R enantiomer. Finally, Hoffmann degradation with Br2/NaOH provides (S)-Pregabalin. However, the optical resolution is done using a mixture of EtOH and chloroform, and therefore is problematic. - Optical resolution of a racemic mixture, particularly of carboxylic acids and amines, is performed via a diastereomeric salt. An example of this method is depicted in the following scheme,
The salt is formed by reacting the racemic mixture with a chiral resolving reagent. Then, a selective crystallization of only one of the diastereomers is done to isolate the desired diastereomer salt, while the undesired remains in the solution. The crystalline salt is then isolated and the chiral resolving reagent is removed to give the desired enantiomer. Accordingly, CMH which has a carboxylic acid function can be reacted with an appropriate chiral amine to obtain the salt of the desirable enantiomer (R-enantiomer), which is then isolated followed by removing the chiral amine to give (R)—CMH. - Thus, there is a need for an optical resolution process that overcomes the limitations of the above resolution procedures.
- In one embodiment, the present invention provides (R)—CMH containing less than about 0.2% area by HPLC of (S)—CMH. Preferably, the present invention provides (R)—CMH containing less than about 0.1% area by HPLC of (S)—CMH.
- In another embodiment, the present invention provides a process for the optical resolution of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (referred to as CMH-racemate),
comprising combining CMH-racemate, a solvent selected from the group consisting of ketone, ester, nitrile, C1-4 alcohol, water, or mixtures thereof, a chiral resolving reagent of amino alcohol and salts thereof; recovering; and adding a solvent selected from the group consisting of ketone, C1-8 alcohol, water or mixtures thereof, and a strong mineral acid, wherein; any individual stereoisomer of the chiral resolving reagent may be used. - In yet another embodiment the present invention also provides a process for the optical resolution CMH-racemate that comprises two steps: the first is the preparation of the (R)—CMH amine salt and the second, recovering (R)—CMH from the salt. The process comprises combining CMH-racemate, a solvent selected from the group consisting of ketone, ester, nitrile, C1-4 alcohol, water, or mixtures thereof, a chiral resolving reagent selected from ephedrine, ephedrine salt, norephedrine, and norephedrine salt to obtain a precipitate, wherein the precipitate is of (R)—CMH-ephedrine salt of the following structure:
or of (R)—CMH-norephedrine salt of the following structure: -
- In one embodiment the present invention provides a process for the optical resolution of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (referred to as CMH-racemate) comprising combining CMH-racemate, a solvent selected from ketone, ester, nitrile, C1-4 alcohol, water, or mixtures thereof, and 1R, 2S-(−)-ephedrine to obtain a reaction mixture. The obtained reaction mixture is then heated to a temperature of about 50° C. to about 140° C. The reaction mixture is then cooled to a temperature of about ambient to about 2° C. to obtain a precipitate, wherein the precipitate is of (R)—CMH-ephedrine salt of the following structure:
or of (R)—CMH-norephedrine salt of the following structure: - The precipitate is further isolated and thereafter combined with a solvent selected from the group consisting of ketone, C1-8 alcohol, water or mixtures thereof, and with a strong mineral acid to obtain a slurry and the slurry is then cooled to a temperature of about 10° C. to about 2° C. to obtain a precipitate of (R)—CMH of the following structure
- In another embodiment, the present invention provides (R)—CMH-Ephedrine salt.
- In yet another embodiment, the present invention provides a process for improving the optical purity of (R)—CMH comprising combining (R)—CMH with water.
- In one embodiment, the present invention provides a process for isolating (S)—CMH from the remaining mother liquor comprising combining the mother liquor obtained after the filtration of (R)—CMH with water, and heating to dissolution. The solution is then cooled and combined with an acid to obtain a precipitate of CMH containing about a specific amount of (S)—CMH. The precipitate is then filtered and resolved again with acetone, and ephedrine as a chiral resolving reagent to obtain a second precipitate of R—CMH-ephedrine salt that is then removed. The remaining mother liquor, which contains (S)—CMH-ephedrine salt, is then evaporated to dryness, and the residue is treated with an acid to obtain (S)—CMH, which is further recovered
- In another embodiment, the present invention provides a process for preparing (S)-Pregabalin comprising preparing (R)—CMH by the process of the present invention, and converting it to (S)-Pregabalin.
- As used herein, the term “chiral resolving reagent” refers to an acidic or basic structure re that can lead to the precipitation of the diastereomer containing the desired enantiomer in high chemical and optical yields.
- As used herein, the term “racemate” refers to a mixture that contains an equal amount of enantiomers.
- The present invention provides (R)—CMH containing less than about 0.2% area by HPLC of (S)—CMH. Preferably, the present invention provides (R)—CMH containing less than about 0.1% area by HPLC of (S)—CMH.
- The process of the present invention performs resolution at the stage of CMH-racemate, of the following structure
without using carcinogenic solvents as chloroform, while also recycling the undesired enantiomer. However, some processes of the prior art perform the optical resolution on Pregabalin itself while, recycling (R)-Pregabalin is very difficult, thus leading to a non-efficient and non-economical process. - The present invention provides a process for the optical resolution of (±)-3-(carbamoylmethyl)-5-methylhexanoic acid (referred to as CMH-racemate),
comprising combining CMH-racemate, a solvent selected from the group consisting of ketone, ester, nitrile, C1-4 alcohol, water, or mixtures thereof, a chiral resolving reagent of amino alcohol and salts thereof to obtain a precipitate; isolating the precipitate; and adding a solvent selected from the group consisting of ketone, C1-8 alcohol, water or mixtures thereof, and a strong mineral acid, wherein; any individual stereoisomer of the chiral resolving reagent may be used. - The present invention also provides a process for the optical resolution CMH-racemate that comprises two steps: the first is the preparation of the (R)—CMH amine salt and the second, recovering (R)—CMH from the salt. The process comprises combining CMH-racemate, a solvent selected from the group consisting of ketone, ester, nitrile, C1-4 alcohol, water, or mixtures thereof, a chiral resolving reagent selected from ephedrine, ephedrine salt, norephedrine, and norephedrine salt to obtain a precipitate, wherein the precipitate is of (R)—CMH-ephedrine salt of the following structure:
or of (R)—CMH-norephedrine salt of the following structure: -
- The present invention provides a process for the optical resolution of CMH-racemate comprising combining CMH-racemate, a solvent selected from ketone, ester, nitrile, C1-4 alcohol, water, or mixtures thereof, and 1R, 2S-(−)-ephedrine to obtain a reaction mixture. The obtained reaction mixture is then heated to a temperature of about 50° C. to about 140° C. The reaction mixture is then cooled to a temperature of about 20° C. to about −20° C. to obtain a precipitate, wherein the precipitate is of (R)—CMH-ephedrine salt of the following structure:
or of (R)—CMH-norephedrine salt of the following structure: - The precipitate is further isolated and thereafter combined with a solvent selected from the group consisting of ketone, C1-8 alcohol, water or mixtures thereof, and with a strong mineral acid to obtain a slurry and the slurry is then cooled to a temperature of about 10° C. to about 2° C. to obtain a precipitate of (R)—CMH of the following structure
- Preferably, the chiral resolving reagent of amino alcohol and salts thereof is selected from the group consisting of ephedrine, ephedrine salt, norephedrine, and norephedrine salt. More preferably, the chiral resolving reagent is ephedrine or ephedrine salt. Most preferably, the chiral resolving reagent is 1R,2S-(−)-ephedrine.
- Preferably, the salt of ephedrine or norephedrine is a hydrochloride, nitrate, or sulfate. More preferably, the salt is a hydrochloride.
- Optionally, a base is further added with the resolving reagent. When the chiral resolving reagent is the salt of ephedrine or of norephedrine, a base must also be used. Preferably, the base is either an organic base or an inorganic base. Preferably, the organic base is an amine. Preferably, the amine is tertiary or secondary amine. Preferably, the tertiary amine is triethylamine or tributylamine. Preferably, the secondary amine is diisopropylamine or n-dipropylamine. The more preferred organic base is triethylamine. Preferably, the inorganic base is alkali metal hydrogen carbonates, alkali hydroxide or alkali carbonate. Preferably, the alkali hydroxide is either NaOH or KOH. Preferably, the alkali carbonate is either K2CO3 or Na2CO3. The more preferred inorganic base is NaOH.
- Preferably, the ketone is a C2 to C6 ketone, more preferably a C2 to C5 ketone, more preferably, acetone or methylisobutyl ketone, most preferably, aetone. Preferably, the C1-4 alcohol is selected from the group consisting of methanol, ethanol, isopropanol, or isobutanol. More preferably, the C1-4 alcohol is methanol. Preferably, the ester is selected from a C3 to C8, more preferably a C4 to C6 ester, such as a C2 to C4 alkylacetate. More preferably, the ester is selected from the group consisting of ethyl acetate, butylacetate and isopropyl acetate. Most preferably, the ester is Ethylacetate. Preferably, the nitrile is acetonitrile. The most preferred solvent is acetone or a mixture of acetone and water.
- Preferably, the mixture is heated to a temperature of about 50° C. to about 100° C. obtain a reaction mixture, which is maintained at this temperature for about 0.5 hour to about 5 hours, more preferably, for about 0.5 hour to about 2 hours. Preferably, the reaction mixture is a solution.
- The obtained reaction mixture is cooled to a temperature of about 20° C. to about −20° C., and is preferably maintained for about an hour to about 24 hours, more preferably, for an hour to about 12 hours.
- Preferably, the isolation is by recovering.
- Preferably, the strong mineral acid is HCl, HBr, H2SO4, or H2PO3. The more preferred strong mineral acid is HCl.
- Preferably, after the addition of the acid, a pH of about 0 to about 4 is obtained, more preferably, a pH of about 1 to about 3 is obtained.
- Preferably, the slurry is cooled to a temperature of about 2° C.
- Preferably, the slurry is maintained at a temperature of about 2° C. to about ambient temperature, more preferably, of about 2° C. to about 10° C., for about 0.5 hours to about 24 hours, more preferably, for about 0.5 hours to about 2 hours.
- Preferably, the (R)—CMH is further recovered.
- (R)—CMH, (R)—CMH-ephedrine salt and (R)—CMH-norephedrine salt may be recovered by known methods in the art, such as filtering, washing, and drying in a vacuum oven. After the filtration step, the remaining mother liquor is obtained.
- The (R)—CMH obtained by the process of the invention contains less than about 7% area by HPLC, more preferably, less than about 4% area by HPLC, most preferably, less than about 0.2% area by HPLC and even most preferably, less than 0.1% area by HPLC of (S)—CMH.
- The present invention provides (R)—CMH-Ephedrine salt.
- The present invention provides a process for optically purifying (R)—CMH comprising combining (R)—CMH with water. Preferably, the water is in an amount of 8-15 vol.
- Preferably, the (R)—CMH has a specific optical purity as measured by HPLC. The combination of (R)—CMH and water results in a slurry. Preferably, the obtained slurry is stirred to obtain a precipitate of (R)—CMH. Preferably, the obtained slurry is stirred at a temperature of about 2° C. to about 30° C. for about one hour to about 24 hours, more preferably, at a temperature of about 15° C. to about 20° C. for about 0.5 hour to about 24 hours, most preferably, at a temperature of about 20° C. for about one hour to about 2 hours.
- The starting (R)—CMH may be obtained by the processes described before, having a purity of about 90% to about 99% area by HPLC, more preferably, of about 96.5% to about 99% area by HPLC.
- (R)—CMH obtained by the above process contains less than about 1% area by HPLC, more preferably, less than about 0.2% area by HPLC, most preferably, less than 0.1% area by HPLC of (S)—CMH.
- Preferably, the precipitate is recovered. The precipitate may be recovered by any method known in the art, such as filtering, washing, and drying.
- The present invention provides a process for isolating (S)—CMH from the remaining mother liquor comprising combining the mother liquor obtained after the flirtation of (R)—CMH with water, and heating to dissolution. The solution is then cooled and combined with an acid to obtain a precipitate of CMH containing about a specific amount of (S)—CMH. The precipitate is then filtered and resolved again with acetone, and 1R, 2S-(−)-ephedrine to obtain a second precipitate of R—CMH-ephedrine salt that is then removed. The remaining mother liquor, which contains (S)—CMH-ephedrine salt, is then evaporated to dryness, and the residue is treated with an acid to obtain (S)—CMH, which is further recovered.
- Preferably, when the precipitate is resolved again with acetone and ephedrine a base is also added.
- The precipitate of (S)—CMH may be recovered by known methods in the art, such as filtering, washing and drying in a vacuum oven.
- The present invention provides a process for preparing (S)-Pregabalin comprising preparing (R)—CMH by the process of the present invention, and converting it to (S)-Pregabalin. Preferably, the conversion of (R)—CMH to (S)-Pregabalin comprises reacting (R)—CMH with bromine in a Hoffman reaction under basic conditions at a temperature of about 60° C. to about 85° C., to obtain a basic mixture, followed by an addition of a strong mineral acid, to obtain an acidic mixture containing a complex of (S)-Pregabalin with the strong mineral acid, as disclosed in Co-application No. 60/689,699, or by any other process known to one skilled in the art.
- Preferably, the (S)-Pregabalin contains less than about 0.2% area by HPLC of (R)-Pregabalin. More preferably, (S)-Pregabalin contains less than about 0.1% area by HPLC of (R)-Pregabalin.
- The present invention provides a pharmaceutical composition comprising (S)-Pregabalin made by the process of the present invention and at least one pharmaceutically acceptable excipient.
- The present invention provides a process for preparing a pharmaceutical formulation comprising combining (S)-Pregabalin made by the process of the present invention, with at least one pharmaceutically acceptable excipient.
- The present invention provides the use of (S)-Pregabalin made by the process of the present invention for the manufacture of a pharmaceutical composition.
- Methods of administration of a pharmaceutical composition of the present invention can be administered in various preparations depending on the age, sex, and symptoms of the patient. The pharmaceutical compositions can be administered, for example, as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injection preparations (solutions and suspensions), and the like.
- Pharmaceutical compositions of the present invention can optionally be mixed with (S)-Pregabalin obtained in the present invention and other active ingredients. In addition, pharmaceutical compositions of the present invention can contain inactive ingredients such as diluents, carriers, fillers, bulking agents, binders, disintegrants, disintegration inhibitors, absorption accelerators, wetting agents, lubricants, glidants, surface active agents, flavoring agents, and the like.
- Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g. AVICEL®), microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. EUDRAGIT®), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
- Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. KLUCEL®), hydroxypropyl methyl cellulose (e.g. METHOCEL®), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g. KOLLIDON®, PLASDONE®), pregelatinized starch, sodium alginate and starch.
- The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g. AC-DI-SOL®, PRIMELLOSE®), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. KOLLIDON®, POLYPLASDONE®), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. EXPLOTAB®) and starch.
- Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
- When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
- Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
- Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
- In liquid pharmaceutical compositions of the present invention, the (S)-Pregabalin and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerin.
- Liquid pharmaceutical compositions may contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier. Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol, and cetyl alcohol.
- Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, carbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
- Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
- Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
- According to the present invention, a liquid composition may also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
- When preparing injectable (parenteral) pharmaceutical compositions, solutions and suspensions are sterilized and are preferably made isotonic to blood. Injection preparations may use carriers commonly known in the art. For example, carriers for injectable preparations include, but are not limited to, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyoxyethylene sorbitan. One of ordinary skill in the art can easily determine with little or no experimentation the amount of sodium chloride, glucose, or glycerin necessary to make the injectable preparation isotonic. Additional ingredients, such as dissolving agents, buffer agents, and analgesic agents may be added.
- The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
- Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and losenges, as well as liquid syrups, suspensions and elixirs.
- The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin and optionally contain a plasticizer such as glycerin and sorbitol, and an opacifying agent or colorant.
- The active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
- A composition for tableting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
- A tableting composition may be prepared conventionally by dry blending. For example, the blended composition of the actives and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
- As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. Direct compression produces a more uniform tablet without granules. Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate, and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
- A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
- The solid compositions of the present invention include powders, granulates, aggregates and compacted compositions. The dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable route in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral. The dosages can be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
- While the present invention is described with respect to particular examples and preferred embodiments, it is understood that the present invention is not limited to these examples and embodiments. The present invention as claimed therefore includes variations from the particular examples and preferred embodiments described herein, as will be apparent to one of skill in the art.
- Instruments
- HPLC
Enantiomeric purity of R-3-(Carbamoylmethyl)-5-methylhexanoic acid (CMH) by chiral HPLC HPLC Column & packing DAICEL Chiralpak AD-H 250*4.6 mm 5 μm P.N. 19325 Eluent: n-Heptane:Ethanol:TFA 850:150:1 TFA from J. T. Baker 9470-01 recommended Stop time: 25 min Flow: 0.5 ml/min Detector: 208 nm. Injection volume: 50 μl. Diluent 85:15 n-Heptane:Ethanol Column temperature 10° C. Autosampler temperature 15° C.
Typical relative retention times are:
R-CMH-R-(+)-3-(Carbamoylmethyl)-5-methylhexanoic acid RRT = 1.00
S-CMH-S-(−)-3-(Carbamoylmethyl)-5-methylhexanoic acid RRT = 1.14
- A 250 ml flask was charged with 100 ml of acetone, 10 ml of methanol, 10 g of CMH-racemate, and 4.4 g of 1R, 2S-(−)-ephedrine. The resulting clear solution was evaporated to dryness, and 100 ml of acetone was added to the residue. After stirring for 1 hour at room temperature, the precipitate was filtered, washed with 40 ml of acetone, and dried at 45° C. at a pressure of 10 mm Hg. The (R)—CMH-ephedrine salt was found to have an optical purity of 99.3% area by HPLC.
- A 100 ml flask was charged with 40 ml of acetone, 5 g of CMH-racemate, and 4.4 g of 1R, 2S-(−)-ephedrine. The mixture was heated to dissolution, and then cooled to 10° C. After stirring for 1 hour at 10° C., the resulting precipitate was filtered, washed with 10 ml of acetone, and dried at 45° C. at a pressure of 10 mm Hg. The (R)—CMH-ephedrine salt was found to have an optical purity of 97% area by HPLC.
- A 100 ml flask was charged with acetone (80 ml), CMH-racemate (10 gr), Triethylamine (5.4 gr) and 1R, 2S-(−)-Ephedrine hydrochloride (10.79 gr). The mixture was heated to reflux and stirred at reflux for 2 h. The mixture was cooled to 10° C., and after stirring for 1 h at 10° C. the precipitate was filtered, washed with acetone (10 ml) and dried at 45° C. under 10 mm Hg. (R)—CMH-ephedrine salt was obtained (9.95 gr), 90.2% optical pure.
- A 100 ml flask was charged with water (22 ml), HCl—32% (2 ml) and CMH-ephedrine salt (GP-4328, 6 gr). The mixture was stirred at room temperature for 15 min, then was cooled to 2° C., and stirred for 2 h. The precipitate was filtered, washed with water (5 ml) and dried at 45° C. under 10 mm Hg. (R)—CMH was obtained (1 gr), 93.6% optical pure.
- A 100 ml flask was charged with acetone (80 ml), CMH-racemate (10 gr), NaOH (2.14 gr) and 1R, 2S-(−)-Ephedrine hydrochloride (10.79 gr). The mixture was heated to reflux and stirred at reflux for 2 h. The mixture was cooled to 10° C., and after stirring (1 h) at 10° C. the precipitate was filtered, washed with acetone (10 ml) and dried at 45° C. under 10 mm Hg. (R)—CMH-ephedrine salt was obtained (9.65 gr), 94.6% optical pure.
- A 100 ml flask was charged with water (22 ml), HCl—32% (2 ml) and (R)—CMH-ephedrine salt (6 gr, optical purity of 94.6%).). The mixture was stirred at RT for 15 min, then was cooled to 2° C., and stirred for 2 h. The precipitate was filtered, washed with water (5 ml) and dried at 45° C. under 10 mm Hg. (R)—CMH was obtained (2.1 gr), 98.5% optical pure.
- A 1 L flask was charged with acetone (480 ml), CMH-racemate (60 gr), NaOH (12.84 gr) and 1R, 2S-(−)-Ephedrine hydrochloride (64.74 gr). The mixture was heated to reflux and stirred at reflux for 2 h. The mixture was cooled to 10° C., and after stirring (1 h) at 10° C. the precipitate was filtered, washed with acetone (60 ml) and dried at 45° C. under 10 mm Hg. (R)—CMH-ephedrine salt was obtained (56 gr), 98.8% optical pure.
- A 0.5 L flask was charged with water (216 ml), and (R)—CMH-ephedrine salt (54 gr, optical purity of 99.7%). The mixture was stirred at RT until dissolution, and HCl—32% (15 ml) was added to obtain pH=1. The solution was cooled to 2° C., stirred for 1 h, after which the precipitate was filtered, washed with water (54 ml) and dried at 45° C. under 10 mm Hg. (R)—CMH was obtained (20 gr), 99.7% optical pure.
- A mixture of (R)—CMH (40 gr, 96.5% optical pure) in water (400 ml) was stirred for 1 h at RT. The solid was filtered, washed with water (80 ml) and dried at 45° C. under 10 mm Hg. (R)—CMH was obtained (34.5 gr), 99.7% optical pure.
- A 1 L flask was charged with acetone (320 ml), CMH-racemate (40 gr), NaOH (8.56 gr) and 1R, 2S-(−)-Ephedrine hydrochloride (43.16 gr). The mixture was heated to reflux and stirred at reflux for 1 h. The mixture was cooled to 2° C., and after stirring (1 h) at 2° C. the precipitate was filtered. Water (320 ml) was added to the wet solid and the mixture was heated until dissolution. After cooling to RT, HCl—32% (10 ml) was added. The solution was cooled to 2° C., stirred for 1 h, after which the precipitate was filtered. Water (320 ml) was added to the cake and the mixture was stirred at 20° C. for 1 h. The precipitate was filtered, washed with water (20 ml) and dried at 45° C. under 10 mm Hg. (R)—CMH was obtained (12.5 gr), 98.4% optical pure.
- 1 l flask was charged with acetone (1600 ml), water (40 ml), CMH-racemate (200 gr), and 1R, 2S-(−)-Ephedrine (186.1 gr). The mixture was heated to reflux and stirred at reflux for 1 h. The solution was cooled to 2° C. (during a period of 6 h), and after stirring (10 h) at 2° C. the precipitate was filtered and washed with acetone (400 ml).
- Water (800 ml) was added to the wet solid and then HCl—32% (50 ml) was added dropwise to pH 2. The mixture was cooled to 2° C., stirred for 2 h, after which the precipitate was filtered and washed with water (100 ml).
- Water (1000 ml) was added to the cake and the mixture was stirred at 25° C. for 1 h. The precipitate was filtered, washed with water (100 ml) and dried at 45° C. under 10 mm Hg. R—CMH was obtained (72 gr), 99.94% optical pure.
- The mother liquor residue of example 10, containing (S)—CMH and a residue of (R)—CMH, was dissolved in water and was heated to dissolution. After cooling to RT, HCl—32% (12 ml) was added and mixture was stirred for 30 min at RT. The precipitate, of (R)—CMH was filtered and washed with water (20 ml), while the (S)—CMH remained in the filtrate.
- A 0.5 L flask was charged with the later cake of the filtered (R)—CMH, acetone (150 ml), NaOH (4.3 gr) and 1R, 2S-(−)-Ephedrine hydrochloride (21.5 gr). The mixture was stirred at RT for 1 h and the precipitate, of (R)—CMH-ephedrine salt, was filtered. The filtrate containing the remaining (S)—CMH-ephedrine salt, was evaporated to dryness. The residue (44 gr) was dissolved in water (100 ml) and HCl—32% was added until pH=1. The mixture was stirred for 30 min at RT, then the precipitate was filtered, washed with water (20 ml) and dried at 45 ° C. under 10 mm Hg. (S)—CMH was obtained (11.4 gr), 99.0% optical pure.
Claims (79)
Priority Applications (4)
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US11/432,010 US20070043241A1 (en) | 2005-05-10 | 2006-05-10 | Optical resolution of 3-carbamoylmethyl-5-methylhexanoic acid |
US11/893,235 US7678938B2 (en) | 2005-05-10 | 2007-08-14 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
US11/893,300 US20070287860A1 (en) | 2005-05-10 | 2007-08-14 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
US11/893,216 US7619112B2 (en) | 2005-05-10 | 2007-08-14 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
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US67978405P | 2005-05-10 | 2005-05-10 | |
US68969905P | 2005-06-09 | 2005-06-09 | |
US73300905P | 2005-11-02 | 2005-11-02 | |
US73563405P | 2005-11-09 | 2005-11-09 | |
US74095005P | 2005-11-29 | 2005-11-29 | |
US11/432,010 US20070043241A1 (en) | 2005-05-10 | 2006-05-10 | Optical resolution of 3-carbamoylmethyl-5-methylhexanoic acid |
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US11/893,300 Division US20070287860A1 (en) | 2005-05-10 | 2007-08-14 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
US11/893,216 Division US7619112B2 (en) | 2005-05-10 | 2007-08-14 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
US11/893,235 Division US7678938B2 (en) | 2005-05-10 | 2007-08-14 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
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US11/432,010 Abandoned US20070043241A1 (en) | 2005-05-10 | 2006-05-10 | Optical resolution of 3-carbamoylmethyl-5-methylhexanoic acid |
US11/893,300 Abandoned US20070287860A1 (en) | 2005-05-10 | 2007-08-14 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
US11/893,216 Expired - Fee Related US7619112B2 (en) | 2005-05-10 | 2007-08-14 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
US11/893,235 Expired - Fee Related US7678938B2 (en) | 2005-05-10 | 2007-08-14 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
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US11/893,300 Abandoned US20070287860A1 (en) | 2005-05-10 | 2007-08-14 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
US11/893,216 Expired - Fee Related US7619112B2 (en) | 2005-05-10 | 2007-08-14 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
US11/893,235 Expired - Fee Related US7678938B2 (en) | 2005-05-10 | 2007-08-14 | Optical resolution of 3-carbamoylmethyl-5-methyl hexanoic acid |
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US (4) | US20070043241A1 (en) |
EP (1) | EP1879854B1 (en) |
KR (2) | KR20090019016A (en) |
AT (1) | ATE523484T1 (en) |
CA (1) | CA2604624A1 (en) |
ES (1) | ES2372700T3 (en) |
IL (1) | IL185032A0 (en) |
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WO2009004643A2 (en) * | 2007-05-08 | 2009-01-08 | Cadila Healthcare Limited | An improved process for preparation of (s)-pregabalin and intermediates thereof |
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WO2009125427A2 (en) * | 2008-02-18 | 2009-10-15 | Matrix Laboratories Limited | Process for preparing (s)-3-(aminomethyl)-5-methylhexanoic acid |
US8546112B2 (en) | 2008-05-21 | 2013-10-01 | Sandoz Ag | Process for the stereoselective enzymatic hydrolysis of 5-methyl-3-nitromethyl-hexanoic acid ester |
WO2016075082A1 (en) | 2014-11-10 | 2016-05-19 | Sandoz Ag | Stereoselective reductive amination of alpha-chiral aldehydes using omega-transaminases for the synthesis of precursors of pregabalin and brivaracetam |
CN113801031B (en) * | 2021-10-26 | 2023-12-26 | 浙江华海药业股份有限公司 | Purification method of pregabalin |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009004643A2 (en) * | 2007-05-08 | 2009-01-08 | Cadila Healthcare Limited | An improved process for preparation of (s)-pregabalin and intermediates thereof |
WO2009004643A3 (en) * | 2007-05-08 | 2009-04-30 | Cadila Healthcare Ltd | An improved process for preparation of (s)-pregabalin and intermediates thereof |
Also Published As
Publication number | Publication date |
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ATE523484T1 (en) | 2011-09-15 |
US20070287748A1 (en) | 2007-12-13 |
IL185032A0 (en) | 2007-12-03 |
EP1879854A1 (en) | 2008-01-23 |
MX2007014129A (en) | 2008-01-11 |
US7619112B2 (en) | 2009-11-17 |
WO2006122259A1 (en) | 2006-11-16 |
US20070287860A1 (en) | 2007-12-13 |
KR20090019016A (en) | 2009-02-24 |
ES2372700T3 (en) | 2012-01-25 |
KR20070118305A (en) | 2007-12-14 |
US7678938B2 (en) | 2010-03-16 |
CA2604624A1 (en) | 2006-11-16 |
EP1879854B1 (en) | 2011-09-07 |
US20070287859A1 (en) | 2007-12-13 |
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Owner name: TEVA PHARMACEUTICALS USA, INC., PENNSYLVANIA Free format text: ASSIGNMENT OF RIGHTS IN BARBADOS;ASSIGNOR:TEVA PHARMACEUTICAL INDUSTRIES LTD.;REEL/FRAME:018464/0146 Effective date: 20060911 Owner name: TEVA PHARMACEUTICAL INDUSTRIES LTD., ISRAEL Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:HEDVATI, LILACH;DEE-NOOR, ZIV;SINGER, CLAUDE;AND OTHERS;REEL/FRAME:018464/0359;SIGNING DATES FROM 20060724 TO 20060807 |
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STCB | Information on status: application discontinuation |
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