WO2002072566A1 - A lactonization process - Google Patents
A lactonization process Download PDFInfo
- Publication number
- WO2002072566A1 WO2002072566A1 PCT/NL2002/000161 NL0200161W WO02072566A1 WO 2002072566 A1 WO2002072566 A1 WO 2002072566A1 NL 0200161 W NL0200161 W NL 0200161W WO 02072566 A1 WO02072566 A1 WO 02072566A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- process according
- compound
- lactonization
- solvent
- reaction medium
- Prior art date
Links
- 0 CC[C@@](C)(*)C(O[C@@]1C(C(CC[C@](C[C@](C2)O)OC2=O)[C@@](C)C=C2)C2=C[C@@](C)C1)=O Chemical compound CC[C@@](C)(*)C(O[C@@]1C(C(CC[C@](C[C@](C2)O)OC2=O)[C@@](C)C=C2)C2=C[C@@](C)C1)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- 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
Definitions
- Antihypercholesterolemic compounds lovastatin and simvastatin are widely used in medicine for the lowering of levels of blood cholesterol.
- Both compounds may be produced by the fermentation of various microorganisms or they may be lOprepared synthetically or semi-synthetically by methods known in the art.
- Fermentation or synthetic methods for preparing lovastatin or simvastatin usually lead to the formation of a dihydroxyacid form (B) or a salt thereof 15
- Ammonium salts of the dihydroxyacid form (B) are often used as intermediates in production methods as 5these salts are nicely crystalline. Acid and lactone forms may also be formed in the mixture.
- dihydroxyacid form (B) of compounds of formula (1) may be denoted as the * statin acid” or, if appropriate, * lovastatin acid” or ⁇ simvastatin acid” of formula (2) :
- Lactonization is a process wherein a hydroxy lOacid loses one molecule of water to form an intramolecular ester - a lactone. This reaction is generally catalysed by an acid; the necessary acidity arises either through the ambient acidity of the substrate itself or by addition of a stronger acid, i.e.
- Lactonization is an equilibrium process characterized, in the case of statins, by the following equation:
- statin acid is the 5physical removal of water produced from the reaction mixture, e.g. by means of azeotropic distillation.
- the statin acid and/or ammonium salt thereof is heated in a suitable solvent, for example toluene, butyl acetate, ethyl acetate, cyclohexane to a lOboiling point thereof, whereby the azeotropic mixture of the solvent and water having a lower boiling point distills off first and the reaction equilibrium is thus shifted to the formation of the lactone.
- a suitable solvent for example toluene, butyl acetate, ethyl acetate, cyclohexane to a lOboiling point thereof, whereby the azeotropic mixture of the solvent and water having a lower boiling point distills off first and the reaction equilibrium is thus shifted to the formation of the lactone.
- the speed of water and, optionally, ammonia removal may be increased 15by passing a stream of in
- 35simvastatin of pharmaceutically acceptable quality e.g. the quality of Ph.Eur. monograph
- statin acid or its salt is dissolved in a water-miscible solvent in the presence of an acidic catalyst and water is added to the reaction mixture, after a certain reaction period, as an antisolvent.
- reaction medium lO wherein R is a hydrogen atom or a lower alkyl group, preferably a methyl group and X is a hydrogen atom or a cation, wherein the lactonization agent forms a hydrated complex with water, released on the lactonization of compound (2) 15into compound (1) , which hydrated complex is substantially insoluble in the solvent.
- the process also comprises the steps of removal of the hydrated complex after the reaction from the reaction mixture and isolation of the 20compound (1) from the reaction medium, preferably without an aid of an antisolvent.
- the starting acid form of simvastatin or lovastatin may be employed in a crude or purified state.
- a preferred precursor is the ammonium salt of lovastatin or simvastatin acid as this compound may be isolated from reaction mixtures of preceding reaction steps, by methods known per se, in a stable crystalline form. Also this
- 5salt form may be used in the crude or purified state.
- reaction solvent employed in the process may be any inert, preferably water immiscible, solvent in which the lactone form is sufficiently soluble.
- the starting compound e.g. the ammonium salt lOof the statin acid, may, however be only sparingly soluble in the solvent.
- the acidic compound and the chemically converted acidic compound i.e. the stable hydrated complex, are also 15essentially insoluble in the solvent and may thus be easily removed from the reaction mixture by filtration after termination of the lactonization reaction.
- the solvent employed is preferably anhydrous.
- Suitable solvents are e.g. hydrocarbons such as benzene 20or chlorinated hydrocarbons such as dichloromethane .
- the lactonization agent is, in general, an organic or inorganic compound, preferably of acid nature, which is able to bind water and, if applicable, the cation or ammonia. 25
- a preferred lactonization agent is anhydrous methane sulfonic acid. Methane sulfonic acid is able to bind water to form a hydrate and is also able to bind ammonia if the ammonium salt of a statin is used.
- the hydrated complex carrying the entrapped 30water and ammonia is preferably substantially insoluble in the reaction solvent.
- Phosphorous pentoxide, a strongly acidic ion- exchange resin (such as Dowex 50X2 - 400), molecular sieves, acid clay or acidic silica gel are further 35examples of suitable acidic lactonization agents to bind water and/or ammonia into insoluble compounds.
- Ion exchange acidic resins are particularly advantageous as they may work in various types of solvents, including polar solvents such as actonitrile, are easily removable from the reaction mixture after the reaction and may be easily regenerated by conventional procedures. Care is to be taken that the resins are sufficiently dry prior to use . If the lactonization agent, e.g.
- ion-exchange resin, molecular sieve, clay or silica gel is not sufficiently acidic by its nature, it may be combined with necessary amount of an acid directly in the reaction mixture .
- the amount of the lactonization agent to be employed may vary depending on the nature of the lactonization agent and the starting material. If the ammonium (or another) salt of the statin acid is used, one acid equivalent of the agent is spent to bind the salt cation; the same or next equivalent is necessary to bind water. Preferably, slightly more than the stoechiometric equivalent of the agent is required, as the molar excess of the acidic compound serves for catalysis of the reaction.
- a suitable amount of methane sulfonic acid in relation to simvastatin or lovastatin acid ammonium salt is 1-50% molar excess (1.01-1.5 equivalents), while phosphorous pentoxide requires about 50% stoechiometric excess.
- the reaction temperature of the process is essentially ambient.
- the mixture of the starting acid or salt is stirred, preferably under a nitrogen atmosphere, together with the lactonization agent without heating or cooling. No control of the reaction temperature is generally required.
- Progress of the reaction may be monitored by any suitable method allowing separation and determination of the amounts of the starting and formed product in the reaction mixture.
- Such a suitable method is high performance liquid chromatography (HPLC) .
- HPLC high performance liquid chromatography
- the lactonization process proceeds with a high conversion rate; whereby a sufficient conversion (more than 90% and more preferably than 95%) at ambient temperature may be obtained in 15-60 minutes.
- the complete conversion may be reached in 3 hours at ambient temperature .
- a strongly acidic ion exchange resin requires lOthe same and sometimes longer reaction times at ambient temperature.
- Dowex 50X2-400 resin provided 95% conversion in 2 hours in acetonitrile, while in dichloromethane the reaction required about 24 hours for obtaining complete conversion at ambient temperature.
- 15shorter reaction time may be obtained by increasing the reaction temperature, e.g. up to 50°C, whereby the amounts of the undesired by-products, particularly the dirtier, are still negligible.
- Insoluble polymeric lactonization agents e.g. acidic ion-exchange resins may also be employed within the process of our invention in a continual or semicontinual reactor. For instance, the solution of the
- 30substrate may be passed or circulated through a column filled with the resin until the sufficient conversion is obtained.
- the solution comprising the lactonized statin is then elaborated to isolate the statin. This may lead to economic use of the resin and, as well, regeneration
- the resin may be simple.
- Isolation of the statin from the reaction medium after lactonization is also simple and does not require any contrasolvent to precipitate the statin.
- insoluble acidic lactonization agents such as ion-exchange resin
- its excess incl. the spent part of such compound that binds water and /or ammonia
- the remaining excess of the acidic compound can be firstly neutralized by a suitable amount of a base, whereby preferably, organic amines such as triethylamine or pyridine are employed, as such compounds do not react with the acid catalyst with formation of water .
- a suitable amount of a base whereby preferably, organic amines such as triethylamine or pyridine are employed, as such compounds do not react with the acid catalyst with formation of water .
- the insoluble neutralized acidic compound is subsequently removed from the reaction mixture by filtration or centrifugation.
- Water soluble co-products carrying the bound water or ammonia may alternately be removed from the reaction mixture by extraction with alkalinized water.
- the remaining solution comprises the formed lactone.
- the desired statin may be obtained by crystallization after cooling, optionally after concentration of the solution, or by evaporation of the solution to dryness, yielding the corresponding statin in a solid state.
- Crude statin obtained by this process may optionally be subsequently purified to a desired degree of purity by any suitable conventional purification method known per se. E.g., it may be crystallized from a solvent system or may be chromatographed on a suitable carrier.
- Statins produced by the process of the present invention may further be used in the production of pharmaceutical compositions useful in treatment of various types of hypercholesterolemia. They may be formulated into e.g. tablets or capsules comprising therapeutically effective amounts of the active substance together with pharmaceutically acceptable carriers or diluents.
- the formulation methods may comprise various techniques of blending, filing and/or compressing known in the art. Examples
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP02705606A EP1368332A1 (en) | 2001-03-09 | 2002-03-11 | A lactonization process |
NZ525972A NZ525972A (en) | 2001-03-09 | 2002-03-11 | A lactonization process |
NO20032227A NO20032227L (en) | 2001-03-09 | 2003-05-16 | A lactonization method |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
NL1017548 | 2001-03-09 | ||
NL1017548A NL1017548C2 (en) | 2001-03-09 | 2001-03-09 | A lactonization process. |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2002072566A1 true WO2002072566A1 (en) | 2002-09-19 |
Family
ID=19773028
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/NL2002/000161 WO2002072566A1 (en) | 2001-03-09 | 2002-03-11 | A lactonization process |
Country Status (7)
Country | Link |
---|---|
US (1) | US6562984B2 (en) |
EP (1) | EP1368332A1 (en) |
CN (1) | CN1476440A (en) |
NL (1) | NL1017548C2 (en) |
NO (1) | NO20032227L (en) |
NZ (1) | NZ525972A (en) |
WO (1) | WO2002072566A1 (en) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7511140B2 (en) | 2002-08-13 | 2009-03-31 | Astrazeneca Ab | Process for preparing the calcium salt of rosuvastatin |
US8063213B2 (en) | 2003-06-05 | 2011-11-22 | Astrazeneca Uk Limited | Production of rosuvastatin calcium salt |
EP2502923A1 (en) * | 2009-11-20 | 2012-09-26 | Peking University Founder Group Co., Ltd | Methods for preparing statin compounds by lactonization |
US8436167B2 (en) | 2003-09-10 | 2013-05-07 | Astrazeneca Uk Limited | Chemical compounds |
US9371291B2 (en) | 2003-10-24 | 2016-06-21 | Astrazeneca Uk Limited | Process for the manufacture of the calcium salt of rosuvastatin (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-Dihydroxyhept-6-enoic acid and crystalline intermediates thereof |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005095374A1 (en) * | 2004-03-30 | 2005-10-13 | Lupin Ltd. | An improved method for manufacture of 4-hydroxy pyran-2-one derivatives |
ATE441629T1 (en) * | 2004-09-08 | 2009-09-15 | Jubilant Organosys Ltd | IMPROVED PROCESS FOR LACTONIZATION IN THE PRODUCTION OF STATINS |
US7678928B2 (en) | 2005-02-04 | 2010-03-16 | Lupin Limited | Process for manufacture of simvastatin |
CN104098537A (en) * | 2009-11-20 | 2014-10-15 | 北大医药股份有限公司 | Lactonization method for preparation of statin compound |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0351918A1 (en) * | 1988-07-19 | 1990-01-24 | Merck & Co. Inc. | Process for the lactonization of mevinic acids and analogs thereof |
EP0511867A1 (en) * | 1991-05-01 | 1992-11-04 | Merck & Co. Inc. | Process for the preparation of simvastatin |
WO2001000606A1 (en) * | 1999-06-29 | 2001-01-04 | Kaneka Corporation | Process for selective lactonization |
WO2001044144A2 (en) * | 1999-12-17 | 2001-06-21 | Ranbaxy Laboratories Limited | Process for the preparation of sodium salts of statins |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4444784A (en) | 1980-08-05 | 1984-04-24 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
US4582915A (en) | 1983-10-11 | 1986-04-15 | Merck & Co., Inc. | Process for C-methylation of 2-methylbutyrates |
US4855481A (en) | 1984-11-19 | 1989-08-08 | Merck Frosst Canada, Inc. | Process for the preparation of HMG-CoA reductase inhibitors and intermediate compounds employed therein |
US4820850A (en) | 1987-07-10 | 1989-04-11 | Merck & Co., Inc. | Process for α-C-alkylation of the 8-acyl group on mevinolin and analogs thereof |
US5223415A (en) | 1990-10-15 | 1993-06-29 | Merck & Co., Inc. | Biosynthetic production of 7-[1',2',6',7',8',8a'(R)-hexahydro-2'(S),6'(R)-dimethyl-8'(S)-hydroxy-1'(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoic acid (triol acid) |
US5393893A (en) | 1993-11-08 | 1995-02-28 | Apotex, Inc. | Process for producing simvastatin and analogs thereof |
CA2185961A1 (en) | 1996-09-19 | 1998-03-20 | K.S. Keshava Murthy | Process for producing simvastatin |
ATE323689T1 (en) | 1997-01-28 | 2006-05-15 | Plus Chemicals Bv | METHOD FOR PRODUCING SEMI-SYNTHETIC STATINS VIA NEW INTERMEDIATE PRODUCTS |
IN186880B (en) | 1997-10-28 | 2001-12-01 | Ranbaxy Lab Ltd | |
IN186879B (en) | 1997-10-28 | 2001-12-01 | Ranbaxy Lab Ltd | |
SI20070A (en) | 1998-09-18 | 2000-04-30 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | NOVEL SALTS OF INHIBITORS OF HMG-CoA REDUCTASE |
-
2001
- 2001-03-09 NL NL1017548A patent/NL1017548C2/en not_active IP Right Cessation
-
2002
- 2002-03-11 US US10/094,132 patent/US6562984B2/en not_active Expired - Fee Related
- 2002-03-11 WO PCT/NL2002/000161 patent/WO2002072566A1/en not_active Application Discontinuation
- 2002-03-11 CN CNA02803158XA patent/CN1476440A/en active Pending
- 2002-03-11 NZ NZ525972A patent/NZ525972A/en unknown
- 2002-03-11 EP EP02705606A patent/EP1368332A1/en not_active Withdrawn
-
2003
- 2003-05-16 NO NO20032227A patent/NO20032227L/en not_active Application Discontinuation
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0351918A1 (en) * | 1988-07-19 | 1990-01-24 | Merck & Co. Inc. | Process for the lactonization of mevinic acids and analogs thereof |
EP0511867A1 (en) * | 1991-05-01 | 1992-11-04 | Merck & Co. Inc. | Process for the preparation of simvastatin |
WO2001000606A1 (en) * | 1999-06-29 | 2001-01-04 | Kaneka Corporation | Process for selective lactonization |
EP1110959A1 (en) * | 1999-06-29 | 2001-06-27 | Kaneka Corporation | Process for selective lactonization |
WO2001044144A2 (en) * | 1999-12-17 | 2001-06-21 | Ranbaxy Laboratories Limited | Process for the preparation of sodium salts of statins |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7511140B2 (en) | 2002-08-13 | 2009-03-31 | Astrazeneca Ab | Process for preparing the calcium salt of rosuvastatin |
US7842807B2 (en) | 2002-08-13 | 2010-11-30 | Astrazeneca Uk Limited | Process for preparing the calcium salt of rosuvastatin |
US8063213B2 (en) | 2003-06-05 | 2011-11-22 | Astrazeneca Uk Limited | Production of rosuvastatin calcium salt |
US8436167B2 (en) | 2003-09-10 | 2013-05-07 | Astrazeneca Uk Limited | Chemical compounds |
US9371291B2 (en) | 2003-10-24 | 2016-06-21 | Astrazeneca Uk Limited | Process for the manufacture of the calcium salt of rosuvastatin (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl](3R,5S)-3,5-Dihydroxyhept-6-enoic acid and crystalline intermediates thereof |
EP2502923A1 (en) * | 2009-11-20 | 2012-09-26 | Peking University Founder Group Co., Ltd | Methods for preparing statin compounds by lactonization |
EP2502923A4 (en) * | 2009-11-20 | 2013-04-10 | Univ Peking Founder Group Co | Methods for preparing statin compounds by lactonization |
US8779167B2 (en) | 2009-11-20 | 2014-07-15 | Peking University Founder Group Co., Ltd. | Method for preparing a statin compound by lactonization |
Also Published As
Publication number | Publication date |
---|---|
US20020147351A1 (en) | 2002-10-10 |
EP1368332A1 (en) | 2003-12-10 |
NL1017548C2 (en) | 2002-09-10 |
CN1476440A (en) | 2004-02-18 |
NO20032227D0 (en) | 2003-05-16 |
US6562984B2 (en) | 2003-05-13 |
NO20032227L (en) | 2003-09-08 |
NZ525972A (en) | 2005-09-30 |
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