WO2004096789A1 - Method of preparing statins intermediates - Google Patents
Method of preparing statins intermediates Download PDFInfo
- Publication number
- WO2004096789A1 WO2004096789A1 PCT/KR2004/000974 KR2004000974W WO2004096789A1 WO 2004096789 A1 WO2004096789 A1 WO 2004096789A1 KR 2004000974 W KR2004000974 W KR 2004000974W WO 2004096789 A1 WO2004096789 A1 WO 2004096789A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formula
- lovastatin
- water
- mixed solvent
- simvastatin
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 42
- 239000000543 intermediate Substances 0.000 title description 30
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 title description 2
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 title description 2
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 claims abstract description 44
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims abstract description 24
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims abstract description 24
- 229960002855 simvastatin Drugs 0.000 claims abstract description 24
- QLJODMDSTUBWDW-BXMDZJJMSA-N mevinolinic acid Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C=C21 QLJODMDSTUBWDW-BXMDZJJMSA-N 0.000 claims abstract description 18
- 238000007273 lactonization reaction Methods 0.000 claims abstract description 16
- 230000007062 hydrolysis Effects 0.000 claims abstract description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 13
- 150000002596 lactones Chemical group 0.000 claims abstract description 12
- 239000007858 starting material Substances 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000012046 mixed solvent Substances 0.000 claims description 17
- 238000002425 crystallisation Methods 0.000 claims description 15
- 230000008025 crystallization Effects 0.000 claims description 15
- 150000002009 diols Chemical class 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 8
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 27
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 26
- 229960004844 lovastatin Drugs 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 238000002360 preparation method Methods 0.000 description 13
- 230000011987 methylation Effects 0.000 description 10
- 238000007069 methylation reaction Methods 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 9
- 239000012535 impurity Substances 0.000 description 8
- 238000000855 fermentation Methods 0.000 description 7
- 230000004151 fermentation Effects 0.000 description 7
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical group CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000000605 extraction Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- -1 diol lactone Chemical class 0.000 description 3
- 229940093499 ethyl acetate Drugs 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 2
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical group O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- ONXPBYKPLPARFU-VCLQVUGCSA-N C[C@H](C[C@@H]([C@@H](C)C=C1)[C@@H]2C1=CCC[C@@H]2O)[C@H](C[C@H](CC(O)=O)O)O Chemical compound C[C@H](C[C@@H]([C@@H](C)C=C1)[C@@H]2C1=CCC[C@@H]2O)[C@H](C[C@H](CC(O)=O)O)O ONXPBYKPLPARFU-VCLQVUGCSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- IFIFFBWHLKGTMO-SJIDJMGWSA-N [(1s,3s,4ar,7s,8s,8as)-8-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 IFIFFBWHLKGTMO-SJIDJMGWSA-N 0.000 description 1
- GZGUDHDMNATZDU-CRMSOXFQSA-N [(4r)-2-[2-[(1s,2s,6r,8s,8ar)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]ethyl]-6-oxooxan-4-yl] (3r,5r)-7-[(1s,2s,6r,8s,8ar)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydrox Chemical compound C([C@@H]1C)=CC2=C[C@H](C)C[C@H](OC(=O)[C@@H](C)CC)[C@@H]2[C@H]1CCC(OC(=O)C1)C[C@H]1OC(=O)C[C@H](O)C[C@H](O)CC[C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@H](OC(=O)[C@@H](C)CC)[C@H]12 GZGUDHDMNATZDU-CRMSOXFQSA-N 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
-
- 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
Definitions
- the present invention relates to a method for preparing a simvastatin intermediate. More particularly, the present invention relates to a method for preparing a simvastatin intermediate, which includes hydrolysis of mevinolinic acid as a starting material, lactonization, and protection of a hydroxy group of a lactone ring.
- the method of the present invention has advantages in that process steps are reduced and the simvastatin intermediate is produced in high yield, relative to a conventional method.
- simvastatin of Formula 1 is prepared using lovastatin of Formula 2 as a starting material.
- lovastatin is hydrolyzed to its inorganic salt, followed by lactonization, to obtain a diol lactone.
- a 3 -hydroxy group of a lactone ring is then selectively protected with t-butyldimethylsilyl (TBDMS) group, followed by acylation and deprotection.
- TDMS t-butyldimethylsilyl
- lovastatin is converted to its potassium salt followed by direct methylation of the alpha-carbon of the potassium salt.
- U.S. Patent No. 4,820,850 discloses a method involving direct methylation of the alpha-carbon of lovastatin monoalkylamide .
- the above methods can be largely classified into a method involving removal of a 2-methylbutyrate side chain by de-esterification and a method involving methylation of the side chain.
- the method involving the methylation can be subdivided into two methods: direct methylation of the 2-methylbutyrate side chain and methylation of protected lovastatin.
- the two methylation-based methods may produce unreacted lovastatin and several impurities of methylation, in spite of a relatively high yield of simvastatin. Therefore, a further purification process is required, which causes a yield reduction, thereby decreasing production efficiency.
- the methylation requires the use of a strong base, such as organic lithium, which is a very dangerous reagent that is not applicable industrially.
- the method involving the removal of the 2-methylbutyrate side chain is disadvantageous in that the duration of the hydrolysis is lengthy.
- complete removal of the side chain enables production of high purity simvastatin and removal of unreacted lovastatin and impurities is easy.
- the method involving the side chain removal is industrially more preferable, relative to the method involving the direct methylation.
- lovastatin is used as a starting material for preparation of simvastatin.
- Lovastatin can be prepared by lactonizing mevinolinic acid obtained by fermentation of Aspergillus terrreus (Korean Patent Publication No. 83-2438 and U.S. Patent No. 4,231,938) followed by crystallization.
- the preparation of lovastatin by the fermentation method is summarized as the following Scheme 2: [Scheme 2] 1) Broth
- a fermentation broth is acidified and extracted with an organic solvent to obtain mevinolinic acid.
- the mevinolinic acid is filtrated, concentrated, lactonized, and crystallized to obtain lovastatin (Korean Patent Application Laid-Open Publication No: 97-0001545).
- a fermentation broth is acidified and directly lactonized under reflux, followed by extraction with an organic solvent, purification, and crystallization, to obtain lovastatin (Korean Patent Application Laid-Open Publication No: 99-0047622).
- these two methods produce new impurities such as lovastatin dimers after the lactonization.
- an organic solvent such as ethylacetate, anhydrous methanol, and anhydrous ethanol, which increases solubility of lovastatin, is used in the crystallization of lovastatin, a yield loss of 15-20% may be caused.
- the organic solvent is used in large amount, there are problems such as cost ineffectiveness and environmental contamination.
- the present invention provides a method for preparing a simvastatin intermediate, which includes hydrolysis of mevinolinic acid as a starting material, lactonization, and protection of a hydroxy group of a lactone ring.
- mevinolinic acid encompasses its salts.
- the mevinolinic acid of Formula 3 may be converted to a triol acid of Formula 4 using water as a reaction solvent in the presence of a strong base.
- the triol acid may be directly lactonized to a diol intermediate of Formula 6.
- the method may further include crystallization after the protection of the hydroxy group of the lactone ring.
- the crystallization may be carried out in the presence of a mixed solvent of water and methanol.
- the water and the methanol may be used in a ratio of 1:1 to 2:1.
- the crystallization may be carried out in the presence of a mixed solvent of water and ethanol.
- the water and the ethanol may be used in a ratio of 1:1 to 2:1.
- a 2-methylbutyrate side chain of the mevinolinic acid of Formula 3 is directly removed by de-esterification. Therefore, generation of impurities and a yield loss of 15-20% that may be caused by lactonization and crystallization in a conventional lovastatin preparation method by fermentation can be prevented. Furthermore, process steps after selective protection of the 3-hydroxy group are simplified, which enables economical and industrial application.
- the simvastatin intermediate of Formula 5 is industrially prepared by a simplified four-step process including preparation of a fermentation broth, hydrolysis, lactonization, and selective protection of the 3-hydroxy group of the lactone ring.
- This is in contrast to a conventional lengthy and uneconomical preparation method including six steps, i.e., preparation of a fermentation broth, lactonization, production of lovastatin, hydrolysis, lactonization, and protection of the 3-hydroxy group of the lactone ring.
- the mevinolinic acid of Formula 3 which is a precursor of lovastatin having a pyranone ring opening structure, is directly subjected to hydrolysis of its 2-methylbutyrate side chain, to obtain the triol acid of Formula 4, instead of being converted to lovastatin by lactonization and crystallization.
- the triol acid is converted to the diol intermediate of Formula 6 by lactonization and the 3-hydroxy group of the lactone ring is selectively protected with t-butyldimethylsilyl (TBDMS) group followed by crystallization
- TDMS t-butyldimethylsilyl
- the protected diol intermediate is directly crystallized without undergoing industrially unfavorable extraction and concentration, thereby resulting in economical and industrial production of the simvastatin intermediate in high yield.
- the mevinolinic acid of Formula 3 is hydrolyzed in an aqueous solution at 90-100 °C for 50 hours in the presence of a strong inorganic base such as lithium hydroxide and potassium hydroxide and then lactonized in toluene to obtain the diol intermediate of Formula 6 in high yield.
- the strong base may be used in an amount of 6-10 equivalents (eq), and preferably 7-8 eq, based on the mevinolinic acid of Formula 3.
- the hydrolysis is preferably carried out for 45-55 hours, and more preferably 50 hours.
- simvastatin intermediate of Formula 5 in which the 3-hydroxy group is selectively protected, is isolated using a mixed solvent of methanol and water considering the fact that N,N-dimethylformamide is well mixed with water and the simvastatin intermediate of Formula 5 is insoluble in water. As a result, the simvastatin intermediate (purity 97% or more) is obtained in high yield of 97%.
- a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile may be used. N,N-dimethylformamide is preferable.
- the diol intermediate of Formula 6 reacts with 1.0-3.0 eq, preferably 1.3 eq of t-butyldimethylsilyl chloride in the presence of a base.
- the base as used in the protection may be imidazole, triethylamine, or pyridine. Imidazole is preferable.
- the protection may be carried out at 20-70 ° C, preferably 55-60°C .
- a solvent for the crystallization may be a mixed solvent of water and one selected from methanol, ethanol, and isopropanol, and preferably a mixed solvent of water and methanol.
- water and methanol are used in a ratio of 1.0:1.0 to 2.0:1.0, and preferably 1.25:1.0.
- N,N-dimethylformamide are used in a ratio of 1.5:1.0 to 3.0:1.0, and preferably 2.4:1.0.
- the total yield of the simvastatin intermediate of Formula 5 produced from the mevinolinic acid of Formula 3 as a starting material is 79% or more.
- the total yield of the simvastatin intermediate of the present invention may reach 90% or more, which is very economical and industrially excellent.
- Example 1 Preparation of ⁇ fR ⁇ - ⁇ -r ⁇ SVhvdroxy ⁇ S ⁇ . ⁇ 'fRVdimethyl- r ⁇ '. ⁇ ' '- ⁇ '. ⁇ a ⁇ RVhexahvdronaphthalene-lYS ⁇ -yll-ethyll ⁇ fRVhvdroxy-S ⁇ .S. 6-tetrahvdro-2H-pyran-2-one (Formula 6.
- Example 2 Preparation of e D- ⁇ -r ⁇ 'rS ⁇ -hvdroxy ⁇ SV ⁇ R dimethyl- r ⁇ '.e' '. ⁇ '. ⁇ a ⁇ RVhexahvdronaphthalene-l ⁇ SVyll-ethyll ⁇ nD-fdimeth yl-tert-butylsilyloxyV3 A5,6-tetr_thvdro-2H-pyran-2-one (Formula 5)
- a simvastatin intermediate of the present invention can be produced in a high yield of 97% or more by crystallization using commercially available mixed solvent without extraction and filtration. This is in contrast to a conventional method in that the yield of a simvastatin intermediate of Formula
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrane Compounds (AREA)
Abstract
Provided is a method for preparing a simvastatin intermediate. The method includes hydrolysis of mevinolinic acid as a starting material, lactonization, and protection of a hydroxy group of a lactone ring. Therefore, process steps are reduced and the simvastatin intermediate is produced in high yield.
Description
METHOD OF PREPARING STATINS INTERMEDIATES
Technical Field
The present invention relates to a method for preparing a simvastatin intermediate. More particularly, the present invention relates to a method for preparing a simvastatin intermediate, which includes hydrolysis of mevinolinic acid as a starting material, lactonization, and protection of a hydroxy group of a lactone ring. The method of the present invention has advantages in that process steps are reduced and the simvastatin intermediate is produced in high yield, relative to a conventional method.
Background Art
Conventionally, simvastatin of Formula 1 is prepared using lovastatin of Formula 2 as a starting material. [Formula 1]
[Formula 2]
[Formula 4]
[Formula 5]
Various methods for preparing simvastatin from lovastatin are known.
According to a method disclosed in U.S. Patent No. 4,444,784, lovastatin is hydrolyzed to its inorganic salt, followed by lactonization, to obtain a diol lactone. A 3 -hydroxy group of a lactone ring is then selectively protected with t-butyldimethylsilyl (TBDMS) group, followed by acylation and deprotection.
According to a method disclosed in U.S. Patent No. 4,582,915, lovastatin is converted to its potassium salt followed by direct methylation of the alpha-carbon of the potassium salt. U.S. Patent No. 4,820,850 discloses a method involving direct methylation of the alpha-carbon of lovastatin monoalkylamide .
The above methods can be largely classified into a method involving removal of a 2-methylbutyrate side chain by de-esterification and a method involving methylation of the side chain. The method involving the methylation can be subdivided into two methods: direct methylation of the 2-methylbutyrate side chain and methylation of protected lovastatin.
However, the two methylation-based methods may produce unreacted lovastatin and several impurities of methylation, in spite of a relatively high yield of simvastatin. Therefore, a further purification process is required, which causes a yield reduction, thereby decreasing production efficiency. Furthermore, the methylation requires the use of a strong base, such as organic lithium, which is a very dangerous reagent that is not applicable industrially.
The method involving the removal of the 2-methylbutyrate side chain is disadvantageous in that the duration of the hydrolysis is lengthy. However, there are advantages in that complete removal of the side chain enables
production of high purity simvastatin and removal of unreacted lovastatin and impurities is easy.
The method involving the side chain removal is industrially more preferable, relative to the method involving the direct methylation.
The above two methods are summarized as the following Scheme 1 :
[Scheme 1]
In the above-described methods, lovastatin is used as a starting material for preparation of simvastatin. Lovastatin can be prepared by lactonizing mevinolinic acid obtained by fermentation of Aspergillus terrreus (Korean Patent Publication No. 83-2438 and U.S. Patent No. 4,231,938) followed by crystallization. The preparation of lovastatin by the fermentation method is summarized as the following Scheme 2: [Scheme 2]
1) Broth
In Scheme 2, according to the first method, a fermentation broth is acidified and extracted with an organic solvent to obtain mevinolinic acid. The mevinolinic acid is filtrated, concentrated, lactonized, and crystallized to obtain lovastatin (Korean Patent Application Laid-Open Publication No: 97-0001545). According to the second method, a fermentation broth is acidified and directly lactonized under reflux, followed by extraction with an organic solvent, purification, and crystallization, to obtain lovastatin (Korean Patent Application Laid-Open Publication No: 99-0047622). However, these two methods produce new impurities such as lovastatin dimers after the lactonization. Furthermore, since an organic solvent, such as ethylacetate, anhydrous methanol, and anhydrous ethanol, which increases solubility of lovastatin, is used in the crystallization of lovastatin, a yield loss of 15-20% may be caused. In particular, since the organic solvent is used in large amount, there are problems such as cost ineffectiveness and environmental contamination.
Disclosure of the Invention
In view of these problems, the present invention provides a method for preparing a simvastatin intermediate, which includes hydrolysis of mevinolinic acid as a starting material, lactonization, and protection of a hydroxy group of a lactone ring.
The above and other objects of the present invention can be accomplished by embodiments of the present invention as will be described hereinafter.
Therefore, according to an aspect of the present invention, there is provided a method for preparing a simvastatin intermediate represented by Formula 5, which includes hydrolysis of mevinolinic acid represented by Formula 3 as a starting material, lactonization, and protection of a hydroxy group of a lactone ring:
[Formula 3]
[Formula 5]
As used herein, the term "mevinolinic acid" encompasses its salts. In the hydrolysis, the mevinolinic acid of Formula 3 may be converted to a triol acid of Formula 4 using water as a reaction solvent in the presence of a strong base.
The triol acid may be directly lactonized to a diol intermediate of Formula 6.
The method may further include crystallization after the protection of the hydroxy group of the lactone ring. The crystallization may be carried out in the presence of a mixed solvent
of water and methanol.
In the mixed solvent, the water and the methanol may be used in a ratio of 1:1 to 2:1.
The crystallization may be carried out in the presence of a mixed solvent of water and ethanol.
In the mixed solvent, the water and the ethanol may be used in a ratio of 1:1 to 2:1.
Hereinafter, the present invention will be described in detail. In the method for preparing a simvastatin intermediate of the present invention, a 2-methylbutyrate side chain of the mevinolinic acid of Formula 3 is directly removed by de-esterification. Therefore, generation of impurities and a yield loss of 15-20% that may be caused by lactonization and crystallization in a conventional lovastatin preparation method by fermentation can be prevented. Furthermore, process steps after selective protection of the 3-hydroxy group are simplified, which enables economical and industrial application.
In addition, according to the present invention, the simvastatin intermediate of Formula 5 is industrially prepared by a simplified four-step process including preparation of a fermentation broth, hydrolysis, lactonization, and selective protection of the 3-hydroxy group of the lactone ring. This is in contrast to a conventional lengthy and uneconomical preparation method including six steps, i.e., preparation of a fermentation broth, lactonization, production of lovastatin, hydrolysis, lactonization, and protection of the 3-hydroxy group of the lactone ring. According to the present invention, the mevinolinic acid of Formula 3, which is a precursor of lovastatin having a pyranone ring opening structure, is directly subjected to hydrolysis of its 2-methylbutyrate side chain, to obtain the triol acid of Formula 4, instead of being converted to lovastatin by lactonization and crystallization. When the triol acid is converted to the diol intermediate of Formula 6 by lactonization and the 3-hydroxy group of the lactone ring is selectively protected
with t-butyldimethylsilyl (TBDMS) group followed by crystallization, the simvastatin intermediate of Formula 5 can be produced in high yield.
The above-described preparation method of the present invention is summarized as the following Scheme 3:
[Scheme 3]
TBDMS-CI
While paying attention to the fact that in preparation of lovastatin, impurities such as dihydrolovastatin and lovastatin dimer are generated during lactonization and a large yield loss of lovastatin is caused during purification of the impurities, the present inventors found a method for producing the diol intermediate of Formula 6 without yielding lovastatin.
With respect to the selective protection of the 3-hydroxy group of the diol intermediate, a conventional method involves extraction with an organic solvent and concentration of the diol intermediate after the protection, which is uneconomical and production inefficient. On the other hand, in the present invention, the protected diol intermediate is directly crystallized without undergoing industrially unfavorable extraction and concentration, thereby resulting in economical and industrial production of the simvastatin intermediate in high yield. The mevinolinic acid of Formula 3 is hydrolyzed in an aqueous solution at 90-100 °C for 50 hours in the presence of a strong inorganic base such as
lithium hydroxide and potassium hydroxide and then lactonized in toluene to obtain the diol intermediate of Formula 6 in high yield.
In the hydrolysis, the strong base may be used in an amount of 6-10 equivalents (eq), and preferably 7-8 eq, based on the mevinolinic acid of Formula 3. The hydrolysis is preferably carried out for 45-55 hours, and more preferably 50 hours.
The simvastatin intermediate of Formula 5, in which the 3-hydroxy group is selectively protected, is isolated using a mixed solvent of methanol and water considering the fact that N,N-dimethylformamide is well mixed with water and the simvastatin intermediate of Formula 5 is insoluble in water. As a result, the simvastatin intermediate (purity 97% or more) is obtained in high yield of 97%.
In the protection of the hydroxy group of the lactone ring of the diol intermediate of Formula 6, a solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, and acetonitrile may be used. N,N-dimethylformamide is preferable. For the protection, the diol intermediate of Formula 6 reacts with 1.0-3.0 eq, preferably 1.3 eq of t-butyldimethylsilyl chloride in the presence of a base. The base as used in the protection may be imidazole, triethylamine, or pyridine. Imidazole is preferable. The protection may be carried out at 20-70 °C, preferably 55-60°C . A solvent for the crystallization may be a mixed solvent of water and one selected from methanol, ethanol, and isopropanol, and preferably a mixed solvent of water and methanol.
In the mixed solvent of water and methanol, water and methanol are used in a ratio of 1.0:1.0 to 2.0:1.0, and preferably 1.25:1.0. The mixed solvent and
N,N-dimethylformamide are used in a ratio of 1.5:1.0 to 3.0:1.0, and preferably 2.4:1.0.
The total yield of the simvastatin intermediate of Formula 5 produced from the mevinolinic acid of Formula 3 as a starting material is 79% or more. This i s i n c ontrast t o 63% yield o f t he s imvastatin i ntermediate o f Formula 5 produced from lovastatin of Formula 2 by a conventional preparation method. Considering a yield loss of 15-20% that may be caused during crystallization of lovastatin in the conventional preparation method, the total yield of the
simvastatin intermediate of the present invention may reach 90% or more, which is very economical and industrially excellent.
Best mode for carrying out the Invention Hereinafter, the present invention will be described more specifically by
Examples. However, the following Examples are provided only for illustrations and thus the present invention is not limited to or by them.
Example 1: Preparation of όfR^-^-rδϊSVhvdroxy^ΥS^.ό'fRVdimethyl- r^'.β' '-δ'.δaϊRVhexahvdronaphthalene-lYS^-yll-ethyll^fRVhvdroxy-S^.S. 6-tetrahvdro-2H-pyran-2-one (Formula 6.
1L of a purified ethylacetate solution containing mevinolinic acid (20.84 g/L) was concentrated in vacuum and 520.9 ml of water and 9.90 g of lithium hydroxide were added thereto. Mevinolinic acid of Formula 3 was then added thereto. The reaction solution was heated under reflux for 50 hours and cooled to 10°C. The resultant solution was adjusted to pH 3 with concentrated hydrochloric acid and extracted with ethylacetate, followed by concentration, to obtain
3(R),5(R)-dihydroxy-7-[8'(S)-hydroxy-2'(S),6'(R)-dimethyl-l',2',6',8',8a' (R)-hexahydronaphthalene-l'(S)-yl]heptanic acid (Formula 4). 100.3 ml of toluene was added to the compound of Formula 4 to obtain a suspension. The suspension was refluxed for lactonization and concentrated to give 12.8 g (yield 81.0%) of the diol intermediate of Formula 6. m.p.: 128 °C 1H-NMR (CDC-3, 400 MHz):d 0.89 (d, J= 7.0 Hz, 3H), 1.18 (d, J= 7.5 Hz, 3H), 1.40-2.75 (m, 14H), 4.24(s, IH), 4.34-4.38(m, IH), 4.68-4.73(m, IH), 5.54(s, IH), 5.77-5.97 (d, J= 9.60 Hz, IH).
Example 2: Preparation of e D-^-rδ'rS^-hvdroxy^ϊSVόϊR dimethyl- r^'.e' '.δ'.δaϊRVhexahvdronaphthalene-lϊSVyll-ethyll^nD-fdimeth yl-tert-butylsilyloxyV3 A5,6-tetr_thvdro-2H-pyran-2-one (Formula 5)
12.8 g of the diol intermediate of Example 1 was added to 100 ml of
N,N-dimethylformamide and heated at 60 °C . 10.0 g of imidazole and 7.85 g of t-butyldimethylsilyl chloride were added thereto and stirred at 60 °C for 3 hours. A mixed solvent of 128.5 ml of water and 102.8 ml of methanol was separately prepared. The previously prepared reaction mixture was dropwise added to the mixed solvent and stirred at 4 °C for 1 hour, followed by filtration, washing with a mixed solvent of water and methanol (2:1), and drying, to give 16.9 g (yield 97.4%) of a white title compound. m.p.: 134°C
1H-NMR (CDCI3, 400 MHz): d 0.06(s, 3H), 0.07(t, 3H), 0.88(s, 9H), 0.89(d, J= 7.22 Hz, 3H), 1.18 (d, J= 7.51 Hz, 3H), 1.48-2.60 (m, 14H), 4.24(s, IH), 4.28-4.30(m, IH), 4.66-4.69(m, IH), 5.54(s, IH), 5.77-5.82(d, IH), 5.97 (d, J= 9.64 Hz, IH).
Industrial Applicability As apparent from the above descriptions, the present invention has the following advantages.
First, since mevionlinic acid is used as a starting material instead of lovastatin, lactonization involved in preparation of lovastatin is not required, thereby preventing the production of impurities. Furthermore, since a 2-methylbutyrate side chain is completely removed, a diol intermediate of 98% or more impurity can be produced in high yield of 81.0% without side reaction. Second, a simvastatin intermediate of the present invention can be produced in a high yield of 97% or more by crystallization using commercially available mixed solvent without extraction and filtration. This is in contrast to a conventional method in that the yield of a simvastatin intermediate of Formula
5 is as low as 69% due to extraction and concentration carried out after the selective protection.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it will be understood by those of ordinary skill in the art that various changes in form and details may be made
therein without departing from the spirit and scope of the present invention as defined by the following claims.
Claims
1. A method for preparing a simvastatin intermediate represented by Formula 5, which comprises hydrolysis of mevinolinic acid represented by Formula 3 or its salt as a starting material, lactonization, and protection of a hydroxy group of a lactone ring:
[Formula 3]
[Formula 5]
2. The method of claim 1, wherein in the hydrolysis, the mevinolinic acid or its salt is converted to a triol acid of Formula 4 using water as a reaction solvent in the presence of a strong base.
3. The method of claim 1, wherein the triol acid is directly lactonized to a diol intermediate of Formula 6.
4. The method of claim 1 , further comprising crystallization after the protection of the hydroxy group of the lactone ring.
5. The method of claim 4, wherein the crystallization is carried out in the presence of a mixed solvent of water and methanol.
6. The method of claim 5, wherein in the mixed solvent, the water and the methanol are used in a ratio of 1 : 1 to 2 : 1.
7. The method of claim 4, wherein the crystallization is carried out in the presence of a mixed solvent of water and ethanol.
8. The method of claim 7, wherein in the mixed solvent, the water and the ethanol are used in a ratio of 1 : 1 to 2: 1.
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0033538A2 (en) * | 1980-02-04 | 1981-08-12 | Merck & Co. Inc. | 6(R)-(2-(8'-acyloxy-2'-methyl-6'-methyl (or hydrogen)-polyhydronaphthyl-1')-ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones, the hydroxy acid form of said pyranones, the pharmaceutically acceptable salts of said hydroxy acids, and the lower alkyl, and phenyl, dimethylamino or acetylamino substituted lower alkyl esters of said hydroxy acid, processes for preparing the same, and a pharmaceutical antihypercholesterolemic composition containing the same |
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 |
EP0864560A1 (en) * | 1997-03-13 | 1998-09-16 | Ranbaxy Laboratories, Ltd. | Key intermediates in the manufacture of sinvastatin |
-
2003
- 2003-04-29 KR KR1020030027106A patent/KR20040092790A/en not_active Application Discontinuation
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2004
- 2004-04-28 WO PCT/KR2004/000974 patent/WO2004096789A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0033538A2 (en) * | 1980-02-04 | 1981-08-12 | Merck & Co. Inc. | 6(R)-(2-(8'-acyloxy-2'-methyl-6'-methyl (or hydrogen)-polyhydronaphthyl-1')-ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-ones, the hydroxy acid form of said pyranones, the pharmaceutically acceptable salts of said hydroxy acids, and the lower alkyl, and phenyl, dimethylamino or acetylamino substituted lower alkyl esters of said hydroxy acid, processes for preparing the same, and a pharmaceutical antihypercholesterolemic composition containing the same |
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 |
EP0864560A1 (en) * | 1997-03-13 | 1998-09-16 | Ranbaxy Laboratories, Ltd. | Key intermediates in the manufacture of sinvastatin |
Non-Patent Citations (1)
Title |
---|
THAPER, R.K. ET AL.: "A cost-efficient synthesis of simvastatin via high conversion methylation of an alkoxide ester enolate", IN ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 3, no. 6, 1999, pages 476 - 479 * |
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