CN1443182A - 一种可降低二聚体杂质水平的提纯洛伐他汀和辛伐他汀的方法 - Google Patents
一种可降低二聚体杂质水平的提纯洛伐他汀和辛伐他汀的方法 Download PDFInfo
- Publication number
- CN1443182A CN1443182A CN01808689A CN01808689A CN1443182A CN 1443182 A CN1443182 A CN 1443182A CN 01808689 A CN01808689 A CN 01808689A CN 01808689 A CN01808689 A CN 01808689A CN 1443182 A CN1443182 A CN 1443182A
- Authority
- CN
- China
- Prior art keywords
- mixture
- lovastatin
- solvent
- simvastatin
- alcohol
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims abstract description 63
- 239000012535 impurity Substances 0.000 title claims abstract description 26
- 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 title claims description 57
- 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 title claims description 56
- 229960004844 lovastatin Drugs 0.000 title claims description 54
- 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 title claims description 54
- 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 title claims description 42
- 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 title claims description 40
- 229960002855 simvastatin Drugs 0.000 title claims description 40
- 239000011877 solvent mixture Substances 0.000 claims abstract description 25
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 57
- 239000000203 mixture Substances 0.000 claims description 39
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- 239000000539 dimer Substances 0.000 claims description 25
- 239000002904 solvent Substances 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 13
- 230000008025 crystallization Effects 0.000 claims description 13
- -1 methyl-formiate Natural products 0.000 claims description 13
- 150000002148 esters Chemical class 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 10
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 10
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 10
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 10
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 9
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical group CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 8
- 239000000908 ammonium hydroxide Substances 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- 229910021529 ammonia Inorganic materials 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 5
- 125000001931 aliphatic group Chemical group 0.000 claims description 5
- 150000004982 aromatic amines Chemical class 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 claims description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 4
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- 229940090181 propyl acetate Drugs 0.000 claims description 4
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 3
- 239000000725 suspension Substances 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims 3
- 238000003756 stirring Methods 0.000 claims 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims 1
- 150000002596 lactones Chemical group 0.000 description 25
- 239000002253 acid Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- 238000007273 lactonization reaction Methods 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 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 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000006460 hydrolysis reaction Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
- 239000003377 acid catalyst Substances 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 238000000855 fermentation Methods 0.000 description 4
- 230000004151 fermentation Effects 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000001888 Peptone Substances 0.000 description 3
- 108010080698 Peptones Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 230000003570 biosynthesizing effect Effects 0.000 description 3
- 230000001851 biosynthetic effect Effects 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 235000013372 meat Nutrition 0.000 description 3
- 244000005700 microbiome Species 0.000 description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 3
- 235000019319 peptone Nutrition 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 235000014347 soups Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 2
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 2
- 241000228347 Monascus <ascomycete fungus> Species 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 240000001462 Pleurotus ostreatus Species 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 240000008042 Zea mays Species 0.000 description 2
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 2
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 229940043376 ammonium acetate Drugs 0.000 description 2
- 239000012296 anti-solvent Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 235000019628 coolness Nutrition 0.000 description 2
- 235000005822 corn Nutrition 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical compound OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 1
- NPOAOTPXWNWTSH-UHFFFAOYSA-N 3-hydroxy-3-methylglutaric acid Chemical compound OC(=O)CC(O)(C)CC(O)=O NPOAOTPXWNWTSH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- 239000004382 Amylase Substances 0.000 description 1
- 102000013142 Amylases Human genes 0.000 description 1
- 108010065511 Amylases Proteins 0.000 description 1
- 241000228212 Aspergillus Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- 238000009631 Broth culture Methods 0.000 description 1
- 108010076119 Caseins Proteins 0.000 description 1
- KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 240000004859 Gamochaeta purpurea Species 0.000 description 1
- AGPKZVBTJJNPAG-UHNVWZDZSA-N L-allo-Isoleucine Chemical compound CC[C@@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-UHNVWZDZSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- 229930182844 L-isoleucine Natural products 0.000 description 1
- 238000008214 LDL Cholesterol Methods 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 241001330696 Leptosphaeria coniothyrium Species 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 241000031003 Monascus ruber Species 0.000 description 1
- 241000222350 Pleurotus Species 0.000 description 1
- 244000158441 Pleurotus sajor caju Species 0.000 description 1
- 235000004116 Pleurotus sajor caju Nutrition 0.000 description 1
- 241000392433 Pleurotus sapidus Species 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- PCZOHLXUXFIOCF-KVVRZSONSA-N [(1s,3r,7s,8s,8ar)-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] (2s)-2-methylbutanoate 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)CC1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-KVVRZSONSA-N 0.000 description 1
- GUEULYYYHDURDF-CWZAOXTASA-N [(2r,4r)-2-[2-[(1s,2s,6r,8s,8ar)-8-(2,2-dimethylbutanoyloxy)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]ethyl]-6-oxooxan-4-yl] (3r,5r)-7-[(1s,2s,6r,8s,8ar)-8-(2,2-dimethylbutanoyloxy)-2,6-dimethyl-1,2,6,7,8,8a-hexahydronaphthalen-1-yl]-3,5-dihydro Chemical class C([C@@H]1C)=CC2=C[C@H](C)C[C@H](OC(=O)C(C)(C)CC)[C@@H]2[C@H]1CC[C@@H](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(C)(C)CC)[C@H]12 GUEULYYYHDURDF-CWZAOXTASA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical group 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000005233 alkylalcohol group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 235000019418 amylase Nutrition 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- 108010079058 casein hydrolysate Proteins 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000002288 cocrystallisation Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 230000020176 deacylation Effects 0.000 description 1
- 238000005947 deacylation reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000013530 defoamer Substances 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000012262 fermentative production Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 150000002696 manganese Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940099246 mevacor Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 150000003431 steroids Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 229940072168 zocor Drugs 0.000 description 1
- 238000011911 α-alkylation Methods 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pyrane Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
一种将抑制素中二聚体杂质含量降低到低于0.08％的方法，通过在一种合适的溶剂混合物中用一种温和碱处理含有多于0.08％二聚体杂质的抑制素。
Description
相关申请的交叉参考
本申请要求2000年3月3日提交的美国临时申请No.60/186868的优先权，其内容在此引入作为参考。
发明领域
本发明涉及一种提纯洛伐他汀或辛伐他汀的方法，其降低了终产品中二聚体杂质的水平。
发明背景
洛伐他汀及其类似物，例如辛伐他汀，是有效的抗高胆固醇血症的试剂，通过限制胆固醇的生物合成发挥作用。洛伐他汀是已知的降胆固醇试剂中最重要的一种。洛伐他汀(CAS注册号75330-75-5)也被称作美维诺林或莫纳可林K，其化学名称是β，β-二羟基-7-[1，2，6，7，8，8a-六氢-2，6-二甲基-8-(2-甲基-丁酰氧基)-1-萘-1-基]-庚酸β-内酯，分子式：
洛伐他汀
洛伐他汀，是一类化合物中的一种，其通常被称为抑制素，已知以开环羟基酸和内酯形式存在。洛伐他汀的内酯形式如上所示。
洛伐他汀及其类似物抑制3-羟基-3-甲基-戊二酸辅酶A还原酶(“HMG-CoA还原酶”)。HMG-CoA还原酶催化甲羟戊酸，一种胆固醇生物合成的早期中间体，的形成。洛伐他汀是非常有利的，这是由于应用它的结果是，形成于生物合成后期的具有有毒的类固醇骨架的生物合成中间体不能积累。洛伐他汀也可以增加细胞膜表面上的LDL受体的数量，其可以去除血液循环中的LDL胆固醇，因此降低了血浆中胆固醇的含量。
洛伐他汀常规地通过发酵生产。GB 2,046,737公开了洛伐他汀可以用一些属于红曲霉菌属的菌株，例如，通过在7到40℃培养红色红曲霉菌(M.ruber)1005生产。作为培养基，使用葡萄糖，蛋白胨，玉米浆和氯化铵的水溶液。在需氧状态下发酵10天，从5升肉汤培养基滤液中得到87毫克洛伐他汀。
美国专利4,294,926公开了洛伐他汀优选地生物合成的方法：在包含碳水化合物，例如，葡萄糖，果糖，麦芽糖作为碳源；氮源，例如，酵母，水解酵母，水解酪蛋白，玉米浆，和无机盐，例如，碳酸钙，硫酸镁，钴，铁，和锰盐的培养基上，在20-37℃下使用属于土曲霉菌种的保藏号为ATCC20541或20542的微生物。类似的方法在美国专利4,420,491；4,342,767；4,319,039和4,294,846中也有描述，其中，在包含1-6％碳水化合物和0.2-6％氮源的培养基上发酵3-5天。
德国专利4,402,591公开了洛伐他汀的生物合成方法：通过在25-35℃表面或浸没培养属于侧耳属的微生物，例如，糙皮侧耳(P.ostreatus)，紫孢侧耳(P.sapidus)和凤尾菇(P.saca)，培养时间为7-14天。
加拿大专利2,129,416公开了洛伐他汀的制备方法：用属于盾壳霉菌属的微生物，例如，保藏号为蔷薇盾壳霉菌(Coniothyriumfuckelii)ATCC 74227在包含3-15％葡萄糖，0.5-4％蛋白胨，0.5-5％淀粉酶，0.2-1％硫酸铵，0.01-0.1％硫酸镁，0.05-0.2％消泡剂，0.2-1.5％L-异亮氨酸，0.2-1.5％天冬氨酸的培养基上，在pH值为5-6之间培养。根据实施例，肉汤中活性成分的浓度为19-430毫克/升。
匈牙利专利HU 208,997公开了编号为MV-1，保藏号为NCAIM(P)F001189的主模式标本(holotype)菌株黑曲霉菌(Aspergillus obscurus)的应用。发酵优选在包含酵母浸出物和/或蛋白胨和/或酪蛋白作为氮源和葡萄糖和/或麦芽糖或蔗糖作为碳源的培养基上进行。在实验室规模培养的最后，肉汤的活性为400-850毫克/升。
辛伐他汀是洛伐他汀的一种合成类似物，其中8-酰基部分是2，2-二甲基丁酰。辛伐他汀是一种甚至比洛伐他汀更加有效的HMG-CoA还原酶抑制剂。辛伐他汀的化学名称是2，2-二甲基丁酸(4R，6R)-6-[2(1S，2S，6R，8S，8aR)-1，2，6，7，8，8a-六氢-2，6-二甲基-1-[2-(四氢-4-羟基-6-氧代-2H-吡喃-2-基)乙基]-1-萘基酯(CAS注册号79902-63-9)。辛伐他汀的化学结构如下：
辛伐他汀
注册号79902-63-9
辛伐他汀现在在一些市场上可以ZOCOR商品化得到。辛伐他汀的制备最初描述于美国专利4,444,784中。方法包括洛伐他汀的脱酰基化及随后用2，2-二甲基丁酰部分酰基化。如美国专利4,582,915和4,820,850所述，辛伐他汀也已经通过洛伐他汀酯部分的α烷基化来制备。
发酵完毕之后，洛伐他汀以内酯和酸的形式存在于肉汤中。抑制素的开环羟基酸形式是其有生物活性的形式。然而，抑制素一般是以内酯的形式给病人用药，其在体内被转化为它的活性代谢物羟基酸形式。因此，因为只有内酯形式才是有商业利益的，酸形式就通过一种叫做内酯化的过程转化为内酯形式。内酯化过程是一个平衡反应，由此开环的二羟基酸形式被转化为闭环的内酯形式。因为内酯化是一个平衡过程，为了达到内酯产物高的产率，必须采用一些方法使平衡向内酯方向移动。该平衡方程可以描述如下：
内酯化是一种分子内的酯化。导致二聚体形成和更高的寡聚体种类的分子间酯化与内酯化相竞争：
内酯化的方法为本领域所熟知并且许多这样的方法将在下面讨论。在洛伐他汀的内酯化或合成辛伐他汀之后，应用本领域熟知的结晶技术分离抑制素。
文献报道的游离羟基酸或其盐的内酯化方法或者在高温条件下进行，即用惰性溶剂回流，或者当内酯化在环境温度下进行时用强酸催化。美国专利4,820,850公开的方法包括：在高沸点烃类化合物溶剂如甲苯中加热游离酸或其盐，例如铵盐，至回流温度(通常100-110℃)7-8小时。在此高温下，酸的环境酸性据信是内酯化反应的主要因素。另外，作为反应副产物形成的水用共沸蒸馏不断的除去可以迫使反应接近完全(平衡向内酯方向移动)。在加热回流条件下的内酯化过程由于形成二聚体杂质而复杂化，这会降低最终内酯产物的质量。一旦形成，该二聚体杂质很难除去并且其经常占产物的0.4到0.08％。为了使二聚体形成最小化，在内酯化反应中经常采用高稀释度，代价是反应和过程的效率，这对工业化规模生产是不利的。
美国专利4,916,239公开了在室温下进行内酯化的方法：在强酸催化剂存在下，在乙酸和水的混合物中处理莫维诺林酸的游离铵盐。在游离羟基酸-内酯平衡建立之后(反应进行到50％转化率)，逐渐加入水，其用量足以将内酯从反应介质中结晶出来。从溶液中取出内酯有利于内酯的形成并因此促使内酯化作用完全。由于内酯不断从溶液中取出，二聚体的形成也最小化。该方法的缺点在于在大规模合成中不便使用强酸催化剂。强酸催化剂(例如，甲酸，磷酸，三氟乙酸，硫酸，盐酸，对-甲苯酸，磺酸，甲磺酸)的用量经常在1.2到1.5摩尔当量之间变化，难以操作并且造成环境不接受的处理问题，尤其是在工业化规模。此外，所使用的过量酸催化剂需要在过滤产物之前通过加入强碱中和掉。另外，内酯化反应在达到平衡后仅仅完成了大约50％。任何过快或过早地加入水都会导致严重的结晶和过滤问题。此外，反应及随后的处理工作需要大约9-12个小时才能完成，因此降低了方法的效率。
美国专利5,917,058公开了一种不用强腐蚀性酸和剧烈加热条件的内酯化方法。该方法包括：在惰性的无水环境中在室温或适度温度下用乙酸处理抑制素的开环羟基酸形式，优选其铵盐形式。乙酸既是溶剂又是催化剂。内酯化过程无需加入强酸催化剂。反应结束后通过加入反溶剂将内酯化的产物结晶分离出来。公开的反溶剂是水，己烷，庚烷，或环己烷。因为内酯化是一个平衡反应，反应副产物-水和氨必须被除去以使平衡向内酯方向移动。该方法中使用的乙酸原位消耗氨，导致形成乙酸铵。乙酸铵吸收另外一种副产物-水，因为它本质是吸湿的。据报道该方法产率达85-95％且纯度达95-98％。
美国专利5,939,564也公开了一种不用强腐蚀性酸的内酯化方法。在有机溶剂中无水条件下，盐形式的开环羟基酸被加热至从室温到溶剂回流的温度。该混合物随后在从室温到50℃的温度下用温和的催化剂处理。温和的催化剂是有机碱和无机或有机酸的盐，例如吡啶氢溴化物，吡啶盐酸盐，或吡啶对甲苯磺酸盐。内酯化产物然后通过加入水沉淀，最后从混合物中收集结晶的产物。该方法最多可制得98.7％纯度的洛伐他汀。
尽管上述各种内酯化方法降低了环境负担并提高了产率和纯度，但是这些方法仍然导致明显产生洛伐他汀二聚体。另外，在从洛伐他汀合成辛伐他汀的过程中，在内酯化过程中形成二聚体杂质。因此，仍然需要一种可以降低二聚体杂质水平的纯化方法。本发明正是解决这种需要的。
发明简述
目前已经发现通过用温和碱处理可以将二聚体杂质从洛伐他汀或辛伐他汀中除去，碱可以选择性地水解该二聚体但不会同时打开辛伐他汀或洛伐他汀的内酯环。
优选的温和碱包括脂肪族单或双或三胺，芳香族胺，氢氧化铵，氨气和上述试剂的水溶液。
使用本发明的纯化方法，可以得到包含低于约0.08％二聚体杂质的洛伐他汀或辛伐他汀。因此，本发明的另一个方面是提供化合物，含有低于约0.08％二聚体杂质的洛伐他汀和辛伐他汀。
发明详述
如上面所讨论，已知的合成辛伐他汀的方法或洛伐他汀的内酯化方法都会形成不想要的二聚体杂质。由于它们会和洛伐他汀及辛伐他汀共结晶，因此二聚体杂质很难去除。本发明提供一种洛伐他汀或辛伐他汀的纯化方法，其可以降低这些二聚体杂质的水平。本发明提供一种得到基本上纯内酯形式的纯化洛伐他汀或辛伐他汀的方法。本发明的方法可生产具有低于0.08％二聚体杂质的洛伐他汀或辛伐他汀。
本发明方法利用包含洛伐他汀或辛伐他汀的溶剂混合物在微碱性条件可以水解洛伐他汀二聚体或辛伐他汀二聚体和其他酯类杂质，而不会同时使内酯开环。一种0.4摩尔当量或更少的温和碱试剂被加到溶剂混合物中以得到碱性条件。优选的温和碱试剂包括脂肪族单或双或三胺，芳香族胺，氢氧化铵，氨气和上述试剂的水溶液和它们的混合物。最优选的温和碱试剂是氢氧化铵。
辛伐他汀或洛伐他汀的内酯形式(“抑制素内酯”)与羟基酸形式的溶解度有很大不同，因此可以被分开。洛伐他汀二聚体可被水解为洛伐他汀羟基酸，脱水洛伐他汀，和洛伐他汀内酯。脱水洛伐他汀与洛伐他汀的测定比例取决于水的量。水的量是受到限制的因为它有助于内酯形式的开环。抑制素内酯从溶剂混合物中回收。回收抑制素内酯可以用本领域熟知的方法通过从一种合适的溶剂中结晶出来。结晶可通过冷却用于水解内酯的溶剂混合物实现。或者，水解用溶剂混合物可以被蒸发，固体重新悬浮于结晶溶液中。优选结晶用溶剂包括乙酸异丁酯，乙醇，乙酸丁酯，乙腈，上述溶剂的混合物，乙醇和水的混合物，甲醇和水的混合物。优选的混合溶剂是乙酸异丁酯与乙醇以约3∶1混合。用乙醇和水结晶时，优选比例是0.8∶1.1。用甲醇和水结晶时，优选比例是0.7∶1.0。结晶优选在大约-20℃到大约+25℃之间进行。结晶更优选在大约-15℃到大约+15℃之间进行，最优选在大约-15℃到大约+5℃之间进行。
本发明另外的一个方面涉及用来纯化洛伐他汀或辛伐他汀的溶剂混合物。在本发明的一个方面，溶剂混合物包括一种醇和另一种或多种溶剂成分。溶剂混合物中的醇可以是任何一种烷基醇，芳香族醇，或这些醇的混合物。优选的醇包括，但不限于，甲醇，乙醇，异丙醇，正丙醇，异丁醇，正丁醇，叔丁醇或它们的混合物。最优选的醇是甲醇和乙醇。本发明优选的溶剂混合物包含1-70v/v％的醇。更优选包含5-50v/v％的醇，最优选10-30v/v％的醇。
混合物中另外一种溶剂成分据信可以防止洛伐他汀或辛伐他汀水解或内酯开环。优选的溶剂成分，除了溶剂混合物中的醇以外，包括烷烃，烷基衍生物溶剂，和酯衍生物溶剂。优选的溶剂包括：二氯甲烷，二氯乙烷，氯仿，四氯化碳，乙腈，石油醚，庚烷，己烷，环己烷，丙酮，和丁基-甲基酮，乙酸甲酯，乙酸乙酯，乙酸丙酯，乙酸异丁酯，乙酸正丁酯，乙酸叔丁酯，甲酸甲酯，甲酸乙酯，甲酸丙酯和它们的混合物。最优选的溶剂是醇类，例如甲醇和乙醇和乙酸酯，例如乙酸异丁酯，和乙酸乙酯。
本发明的另外一个优点是溶剂混合物比纯溶剂更容易溶解洛伐他汀和辛伐他汀并且也可以用于结晶。因此，本方法与本领域已知的以前的方法相比可以提高洛伐他汀和辛伐他汀的产率。
本发明的方法制备的洛伐他汀和辛伐他汀包含低于约0.08％的二聚体杂质。因此，本发明另外一个方面就是关于二聚体杂质含量低于0.08％的洛伐他汀和辛伐他汀化合物。
实施例买施例1
100-220克洛伐他汀(以其内酯形式)溶于1升以3∶1比例混合的乙酸异丁酯和乙醇的溶剂混合物中。该混合物加热到40-70℃。浓氢氧化铵溶液以1.0-2.0％(以活性物质计算)的比例加到该溶液中。溶液在40-85℃混合1-6小时，然后在1-3小时内冷却到20-30℃。在-5到+10℃悬浮液进一步冷却2-10小时。最后在-5到-20℃冷却15-24小时。产率为90％。HPLC分析显示洛伐他汀二聚体降低到了低于0.08％。
实施例2
100-220克辛伐他汀(以其内酯形式)溶于1升以3∶1比例混合的乙酸异丁酯和乙醇的溶剂混合物中。该混合物加热到40-70℃。浓氢氧化铵溶液(0.1-3.0％，以活性物质计算)被加到该溶液中。溶液在40-70℃混合1-6小时，然后在1-3小时内冷却到20-30℃。在-5到+10℃悬浮液进一步冷却2-10小时。最后在-5到-20℃冷却15-24小时。产率为90％。HPLC分析显示洛伐他汀二聚体降低到了低于0.08％。
实施例3
如上进行实施例1或2的方法，只是溶剂混合物改变如下。乙酸异丁酯被以下溶剂之一或其混合物代替：二氯甲烷，二氯乙烷，氯仿，四氯化碳，乙腈，石油醚，庚烷，己烷，环己烷，丙酮，环己酮和丁基-甲基酮，乙酸甲酯，乙酸乙酯，乙酸丙酯，乙酸异丁酯，乙酸正丁酯，乙酸叔丁酯，甲酸甲酯，甲酸乙酯，甲酸丙酯或另一种酯。另外，乙醇被下面的一种醇或其混合物代替：烷基和芳香族醇，包括甲醇，乙醇，异丙醇，正丙醇，异丁醇，正丁醇，叔丁醇。在40-85℃混合后真空蒸发掉水解用溶剂混合物。固体溶解于加热到50℃的20倍乙醇中。通过冷却到10-25℃并加入28倍水沉淀出抑制素。晶体被过滤并干燥。
实施例4
作如下修改进行实施例1或2的方法：氢氧化铵被一种脂肪族单-或二-或三胺或者芳香族胺或者上述胺的水溶液或者氨气代替。
实施例5
进行实施例1或2的方法，只是醇在溶剂混合物中占1-70v/v％。在5％乙醇含量时，产率是94％。HPLC分析显示洛伐他汀二聚体低于0.08％。
Claims (19)
1.一种降低洛伐他汀或辛伐他汀中二聚体杂质的方法，包括：
a)在一种溶剂混合物中溶解或悬浮含大于0.08％二聚体杂质的洛伐他汀或辛伐他汀；
b)用一种温和碱处理所述的溶液或悬浮液；和
c)分离包含低于约0.08％二聚体杂质的洛伐他汀或辛伐他汀。
2.权利要求1的方法，其中通过搅拌所述溶剂混合物或者混合所述溶液将所述温和碱加到所述溶剂混合物中。
3.权利要求1的方法，进一步包括通过结晶从所述溶剂混合物中分离洛伐他汀或辛伐他汀的步骤。
4.权利要求2的方法，其中所述搅拌或混合步骤在从约5℃到所述溶剂混合物的沸点温度下进行。
5.权利要求2的方法，其中所述搅拌或混合步骤进行1到10个小时。
6.权利要求3的方法，其中所述结晶在大约-20℃到+25℃温度下进行。
7.权利要求1的方法，其中溶剂混合物包含一种醇和另外一种溶剂成分。
8.权利要求7的方法，其中溶剂混合物包含醇的量为大约1-大约70v/v％。
9.权利要求7的方法，其中所述醇选自链烷醇，芳族醇或所述醇的混合物。
10.权利要求7的方法，其中所述醇选自甲醇，乙醇，异丙醇，正丙醇，异丁醇，正丁醇，叔丁醇或它们的混合物。
11.权利要求7的方法，其中所述溶剂成分选自酯或酯混合物，乙腈，一种酯和其它溶剂成分的混合物，乙腈和其它溶剂成分的混合物，一种酯和乙腈的混合物，多种酯和乙腈的混合物，或酯和其它溶剂成分的混合物。
12.权利要求11的方法，其中酯选自乙酸甲酯，乙酸乙酯，乙酸丙酯，乙酸异丁酯，乙酸正丁酯，乙酸叔丁酯，甲酸甲酯，甲酸乙酯，和甲酸丙酯及其混合物。
13.权利要求11的方法，其中溶剂成分选自二氯甲烷，二氯乙烷，氯仿，四氯化碳，乙腈，石油醚，庚烷，己烷，环己烷，丙酮，和丁基-甲基酮及其混合物。
14.权利要求1的方法，其中所述碱性试剂选自脂肪族单-或二-或三胺，芳香族胺，氢氧化铵，氨气，上述任何一种的水溶液，和它们的混合物。
15.包含低于约0.08％二聚体杂质的洛伐他汀，用权利要求1的方法制备。
16.包含低于约0.08％二聚体杂质的辛伐他汀，用权利要求1的方法制备。
17.一种制备选自洛伐他汀或辛伐他汀的抑制素的方法，包括：
a)将抑制素溶解或悬浮在一种溶剂中，该溶剂包含1-70％的醇，选自甲醇，乙醇，异丙醇，正丙醇，异丁醇，正丁醇，叔丁醇和它们的混合物；和第二溶剂，选自二氯甲烷，二氯乙烷，氯仿，四氯化碳，乙腈，石油醚，庚烷，己烷，环己烷，丙酮，丁基-甲基酮，乙酸甲酯，乙酸乙酯，乙酸丙酯，乙酸异丁酯，乙酸正丁酯，乙酸叔丁酯，甲酸甲酯，甲酸乙酯，甲酸丙酯；和所述溶剂的混合物；
b)添加一种温和碱，选自脂肪族单-或二-或三胺，芳香族胺，氢氧化铵，氨气，上述任何一种的水溶液，和它们的混合物；
c)处理该溶液；和
d)通过结晶或沉淀从所述溶剂混合物中分离洛伐他汀或辛伐他汀，在大约-20℃到+25℃。
18.用权利要求17的方法制备的洛伐他汀，含有低于约0.08％二聚体杂质。
19.用权利要求17的方法制备的辛伐他汀，含有低于约0.08％二聚体杂质。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US18686800P | 2000-03-03 | 2000-03-03 | |
| US60/186,868 | 2000-03-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1443182A true CN1443182A (zh) | 2003-09-17 |
Family
ID=22686591
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN01808689A Pending CN1443182A (zh) | 2000-03-03 | 2001-02-27 | 一种可降低二聚体杂质水平的提纯洛伐他汀和辛伐他汀的方法 |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US6521762B2 (zh) |
| EP (1) | EP1265884A4 (zh) |
| JP (1) | JP2003525935A (zh) |
| KR (1) | KR20030069790A (zh) |
| CN (1) | CN1443182A (zh) |
| AU (1) | AU4183301A (zh) |
| CA (1) | CA2402061A1 (zh) |
| CZ (1) | CZ20023201A3 (zh) |
| DE (1) | DE01913139T1 (zh) |
| HR (1) | HRP20020730A2 (zh) |
| HU (1) | HUP0301214A2 (zh) |
| IL (1) | IL151583A0 (zh) |
| IS (1) | IS6533A (zh) |
| PL (1) | PL357533A1 (zh) |
| SK (1) | SK13782002A3 (zh) |
| TR (1) | TR200403001T3 (zh) |
| WO (1) | WO2001066538A1 (zh) |
| ZA (1) | ZA200207023B (zh) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100435078B1 (ko) * | 2002-02-08 | 2004-06-09 | 종근당바이오 주식회사 | 심바스타틴의 정제방법 |
| CA2548297C (en) * | 2003-12-05 | 2011-06-14 | Biocon Limited | Process for the purification of macrolides |
| US7183285B2 (en) * | 2004-04-29 | 2007-02-27 | Pharmix Corp. | Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase |
| US20050282883A1 (en) * | 2004-04-29 | 2005-12-22 | John Griffin | Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase |
| US7199126B2 (en) * | 2004-04-29 | 2007-04-03 | Pharmix Corporation | Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase |
| US20050272770A1 (en) * | 2004-04-29 | 2005-12-08 | John Griffin | Compositions and treatments for inhibiting kinase and/or HMG-CoA reductase |
| US8158139B2 (en) * | 2004-07-12 | 2012-04-17 | Taro Pharmaceuticals North America, Inc. | Topical gel formulation comprising organophosphate insecticide and preparation thereof |
| WO2006017263A1 (en) | 2004-07-12 | 2006-02-16 | Taro Pharmaceutical Industries Ltd. | Topical gel formulation comprising organophosphate insecticide and its preparation thereof |
| US20070015779A1 (en) * | 2005-04-29 | 2007-01-18 | John Griffin | Compositions and treatments for inhibiting kinase and/or hmg-coa reductase |
| US7560445B2 (en) | 2005-07-06 | 2009-07-14 | Taro Pharmaceuticals North America, Inc. | Process for preparing malathion for pharmaceutical use |
| EP1954653A4 (en) * | 2005-11-23 | 2010-11-03 | Merck Sharp & Dohme | METHOD FOR PRODUCING AN AMORPHANT SOLID FOR WATER-INSOLUBLE PHARMACEUTICALS |
| WO2008147807A2 (en) | 2007-05-23 | 2008-12-04 | Amcol International Corporation | Cholesterol-interacting layered phyllosilicates and methods of reducing hypercholesteremia in a mammal |
Family Cites Families (20)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5925599B2 (ja) | 1979-02-20 | 1984-06-19 | 三共株式会社 | 新生理活性物質モナコリンｋおよびその製造法 |
| US4294926A (en) | 1979-06-15 | 1981-10-13 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
| US4319039A (en) | 1979-06-15 | 1982-03-09 | Merck & Co., Inc. | Preparation of ammonium salt of hypocholesteremic fermentation product |
| US4294846A (en) | 1979-09-21 | 1981-10-13 | Merck & Co., Inc. | Hypocholesteremic fermentation products and products of preparation |
| US4342767A (en) | 1980-01-23 | 1982-08-03 | Merck & Co., Inc. | Hypocholesteremic fermentation products |
| US4444784A (en) | 1980-08-05 | 1984-04-24 | Merck & Co., Inc. | Antihypercholesterolemic compounds |
| US4420491A (en) | 1980-05-28 | 1983-12-13 | Merck & Co., Inc. | Hypocholesteremic fermentation products and process of preparation |
| US4582915A (en) | 1983-10-11 | 1986-04-15 | Merck & Co., Inc. | Process for C-methylation of 2-methylbutyrates |
| 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 |
| US4916239A (en) | 1988-07-19 | 1990-04-10 | Merck & Co., Inc. | Process for the lactonization of mevinic acids and analogs thereof |
| US5202029A (en) | 1991-03-13 | 1993-04-13 | Caron Kabushiki Kaisha | Process for purification of hmg-coa reductase inhibitors |
| HU210867B (en) * | 1992-11-04 | 1995-10-30 | Biogal Gyogyszergyar | Method for extraction and purification of mevinolin from culture medium |
| SI9300047A (en) | 1993-01-29 | 1994-09-30 | Krka | Microbiological method for preparation of lovostatin and/or mevinoline acid |
| US5409820A (en) | 1993-08-06 | 1995-04-25 | Apotex, Inc. | Process for the production of lovastatin using Coniothyrium fuckelii |
| UA44922C2 (uk) | 1995-12-06 | 2002-03-15 | Балканфарма-Разград Ад | Спосіб одержання ловастатину |
| IN186879B (zh) | 1997-10-28 | 2001-12-01 | Ranbaxy Lab Ltd | |
| IN186880B (zh) | 1997-10-28 | 2001-12-01 | Ranbaxy Lab Ltd | |
| SI9800046A (sl) | 1998-02-18 | 1999-08-31 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Postopek za pridobivanje inhibitorjev HMG-CoA reduktaze visoke čistosti |
| SI20072A (sl) | 1998-09-18 | 2000-04-30 | LEK, tovarna farmacevtskih in kemi�nih izdelkov, d.d. | Postopek za pridobivanje inhibitorjev HMG-CoA reduktaze |
| AU8030900A (en) | 1999-10-27 | 2001-05-08 | Merck & Co., Inc. | Lactonization process |
-
2001
- 2001-02-27 DE DE01913139T patent/DE01913139T1/de active Pending
- 2001-02-27 PL PL01357533A patent/PL357533A1/xx not_active Application Discontinuation
- 2001-02-27 CZ CZ20023201A patent/CZ20023201A3/cs unknown
- 2001-02-27 HU HU0301214A patent/HUP0301214A2/hu unknown
- 2001-02-27 WO PCT/US2001/006334 patent/WO2001066538A1/en not_active Application Discontinuation
- 2001-02-27 EP EP01913139A patent/EP1265884A4/en not_active Withdrawn
- 2001-02-27 AU AU4183301A patent/AU4183301A/xx active Pending
- 2001-02-27 IL IL15158301A patent/IL151583A0/xx unknown
- 2001-02-27 US US09/793,946 patent/US6521762B2/en not_active Expired - Fee Related
- 2001-02-27 CA CA002402061A patent/CA2402061A1/en not_active Abandoned
- 2001-02-27 CN CN01808689A patent/CN1443182A/zh active Pending
- 2001-02-27 KR KR1020027011541A patent/KR20030069790A/ko not_active Application Discontinuation
- 2001-02-27 TR TR2004/03001T patent/TR200403001T3/xx unknown
- 2001-02-27 JP JP2001565354A patent/JP2003525935A/ja active Pending
- 2001-02-27 SK SK1378-2002A patent/SK13782002A3/sk not_active Application Discontinuation
-
2002
- 2002-08-29 IS IS6533A patent/IS6533A/is unknown
- 2002-09-02 ZA ZA200207023A patent/ZA200207023B/en unknown
- 2002-09-05 HR HRP20020730 patent/HRP20020730A2/hr not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| IS6533A (is) | 2002-08-29 |
| ZA200207023B (en) | 2003-09-02 |
| US20020002288A1 (en) | 2002-01-03 |
| CZ20023201A3 (cs) | 2003-09-17 |
| HRP20020730A2 (en) | 2004-12-31 |
| DE01913139T1 (de) | 2005-03-31 |
| CA2402061A1 (en) | 2001-09-13 |
| WO2001066538A1 (en) | 2001-09-13 |
| KR20030069790A (ko) | 2003-08-27 |
| IL151583A0 (en) | 2003-04-10 |
| TR200403001T3 (tr) | 2005-02-21 |
| SK13782002A3 (sk) | 2004-02-03 |
| EP1265884A4 (en) | 2003-05-21 |
| HUP0301214A2 (hu) | 2003-08-28 |
| PL357533A1 (en) | 2004-07-26 |
| AU4183301A (en) | 2001-09-17 |
| JP2003525935A (ja) | 2003-09-02 |
| EP1265884A1 (en) | 2002-12-18 |
| US6521762B2 (en) | 2003-02-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6583295B1 (en) | Salts of HMG-CoA reductase inhibitors | |
| US4342767A (en) | Hypocholesteremic fermentation products | |
| BG100204A (bg) | Метод за изолиране на ловастатин | |
| CN1443182A (zh) | 一种可降低二聚体杂质水平的提纯洛伐他汀和辛伐他汀的方法 | |
| IE53740B1 (en) | Mb-530b derivatives, their preparation and pharmaceutical compositions containing them | |
| JPH07505768A (ja) | シムバスタチンの生化学的精製 | |
| IE58365B1 (en) | Preparation of clavulanic acid and its salts and esters | |
| CN1193022C (zh) | 在制备他汀类的过程中的内酯化方法 | |
| CN1315946A (zh) | 选择性内酯化方法 | |
| EP0070649A2 (en) | ML-236B Derivatives, a process for their preparation and pharmaceutical compositions containing them | |
| US7566792B2 (en) | Method for the manufacture of Lovastatin | |
| CN1197854C (zh) | 他汀类化合物制备中的内酯化处理方法 | |
| RU2261901C2 (ru) | Штамм гриба aspergillus terreus № 44-62 - продуцент ловастатина, промышленный способ выделения ловастатина и способ лактонизации статинов | |
| AU2001241833A2 (en) | A process for purifying lovastatin and simvastatin with reduced levels of dimeric impurities | |
| US7189558B2 (en) | Process for producing pravastatin sodium salt using streptomyces flavidovirens dsm 14455 | |
| JP2003012607A (ja) | 新規なメバスタチン誘導体 | |
| US20060223150A1 (en) | Process for the isolation and purification of mevinolin | |
| JPH0366297B2 (zh) | ||
| RU2001121943A (ru) | Микробный процесс получения правастатина | |
| JPH06225777A (ja) | 光学活性第二アルコールの製造法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |