CN101119975A - Preparation of rosuvastatin - Google Patents
Preparation of rosuvastatin Download PDFInfo
- Publication number
- CN101119975A CN101119975A CNA200680005200XA CN200680005200A CN101119975A CN 101119975 A CN101119975 A CN 101119975A CN A200680005200X A CNA200680005200X A CN A200680005200XA CN 200680005200 A CN200680005200 A CN 200680005200A CN 101119975 A CN101119975 A CN 101119975A
- Authority
- CN
- China
- Prior art keywords
- compound
- reaction mixture
- solvent
- protective group
- alkyl
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 title abstract 2
- 229960000672 rosuvastatin Drugs 0.000 title abstract 2
- 238000000034 method Methods 0.000 claims abstract description 141
- 239000011541 reaction mixture Substances 0.000 claims description 126
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 93
- 150000001875 compounds Chemical class 0.000 claims description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 69
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 57
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 52
- 229940126657 Compound 17 Drugs 0.000 claims description 52
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 50
- 229940126086 compound 21 Drugs 0.000 claims description 50
- 239000003960 organic solvent Substances 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 47
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 40
- 239000003513 alkali Substances 0.000 claims description 35
- 238000005406 washing Methods 0.000 claims description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 32
- 125000006239 protecting group Chemical group 0.000 claims description 32
- 150000002148 esters Chemical class 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 31
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 27
- 229940125810 compound 20 Drugs 0.000 claims description 24
- 229920006395 saturated elastomer Polymers 0.000 claims description 24
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 20
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims description 20
- 229940126543 compound 14 Drugs 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- -1 alkyl Quilonum Retard Chemical compound 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 17
- 239000012074 organic phase Substances 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 239000012071 phase Substances 0.000 claims description 16
- 239000002798 polar solvent Substances 0.000 claims description 15
- 239000012043 crude product Substances 0.000 claims description 14
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 13
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 11
- 239000004215 Carbon black (E152) Substances 0.000 claims description 11
- 125000001931 aliphatic group Chemical group 0.000 claims description 11
- 229940126208 compound 22 Drugs 0.000 claims description 11
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 239000003849 aromatic solvent Substances 0.000 claims description 10
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 8
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 8
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 8
- 239000011707 mineral Substances 0.000 claims description 8
- 238000011084 recovery Methods 0.000 claims description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 230000002051 biphasic effect Effects 0.000 claims description 5
- 159000000007 calcium salts Chemical group 0.000 claims description 5
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 claims description 5
- 239000007789 gas Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 238000000638 solvent extraction Methods 0.000 claims description 5
- 125000003944 tolyl group Chemical group 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical group CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 230000001476 alcoholic effect Effects 0.000 claims description 4
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 4
- 150000004996 alkyl benzenes Chemical class 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 229910052728 basic metal Inorganic materials 0.000 claims description 4
- 150000003818 basic metals Chemical class 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 claims description 4
- 230000008020 evaporation Effects 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 2
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 2
- 150000003927 aminopyridines Chemical class 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 229910052744 lithium Inorganic materials 0.000 claims description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- KVNYFPKFSJIPBJ-UHFFFAOYSA-N ortho-diethylbenzene Natural products CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims 7
- 239000003205 fragrance Substances 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 18
- 239000012535 impurity Substances 0.000 abstract description 7
- 150000005215 alkyl ethers Chemical class 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 26
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- ITOFPJRDSCGOSA-KZLRUDJFSA-N (2s)-2-[[(4r)-4-[(3r,5r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]pentanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H](CC[C@]13C)[C@@H]2[C@@H]3CC[C@@H]1[C@H](C)CCC(=O)N[C@H](C(O)=O)CC1=CNC2=CC=CC=C12 ITOFPJRDSCGOSA-KZLRUDJFSA-N 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 11
- 238000005755 formation reaction Methods 0.000 description 11
- 239000011575 calcium Substances 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 10
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 9
- 229910052791 calcium Inorganic materials 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 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
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 238000005516 engineering process Methods 0.000 description 7
- 108010007622 LDL Lipoproteins Proteins 0.000 description 6
- 102000007330 LDL Lipoproteins Human genes 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 230000017531 blood circulation Effects 0.000 description 5
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000010977 jade Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 235000012000 cholesterol Nutrition 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000000935 solvent evaporation Methods 0.000 description 4
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- 238000007239 Wittig reaction Methods 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000012856 packing Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 2
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 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 2
- TUZYXOIXSAXUGO-UHFFFAOYSA-N Pravastatin Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(O)C=C21 TUZYXOIXSAXUGO-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 150000001348 alkyl chlorides Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910000085 borane Inorganic materials 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229960003765 fluvastatin Drugs 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 210000004185 liver Anatomy 0.000 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 2
- 229960004844 lovastatin Drugs 0.000 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 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229960002965 pravastatin Drugs 0.000 description 2
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin 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](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229960002855 simvastatin Drugs 0.000 description 2
- 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 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Substances C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 description 1
- KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical compound OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 1
- FLYIRERUSAMCDQ-UHFFFAOYSA-N 2-azaniumyl-2-(2-methylphenyl)acetate Chemical compound CC1=CC=CC=C1C(N)C(O)=O FLYIRERUSAMCDQ-UHFFFAOYSA-N 0.000 description 1
- VAHAPVOBLJZCBO-UHFFFAOYSA-N 2-tert-butyl-2-ethylpentanedioic acid Chemical compound CCC(C(C)(C)C)(C(O)=O)CCC(O)=O VAHAPVOBLJZCBO-UHFFFAOYSA-N 0.000 description 1
- 102100029077 3-hydroxy-3-methylglutaryl-coenzyme A reductase Human genes 0.000 description 1
- 101710158485 3-hydroxy-3-methylglutaryl-coenzyme A reductase Proteins 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 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
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 108010028554 LDL Cholesterol Proteins 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
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 1
- 241001274216 Naso Species 0.000 description 1
- NTKVWOTYTNWGRK-UHFFFAOYSA-N P.Br.Br.Br Chemical compound P.Br.Br.Br NTKVWOTYTNWGRK-UHFFFAOYSA-N 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical class [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000003570 biosynthesizing effect Effects 0.000 description 1
- UUEDINPOVKWVAZ-UHFFFAOYSA-N bis(2-ethylhexyl) 3,4,5,6-tetrabromobenzene-1,2-dicarboxylate Chemical compound CCCCC(CC)COC(=O)C1=C(Br)C(Br)=C(Br)C(Br)=C1C(=O)OCC(CC)CCCC UUEDINPOVKWVAZ-UHFFFAOYSA-N 0.000 description 1
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 229940073589 magnesium chloride anhydrous Drugs 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229950009116 mevastatin Drugs 0.000 description 1
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical group CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 238000000207 volumetry Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
-
- 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
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- 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
- C07F7/1896—Compounds having one or more Si-O-acyl linkages
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides rosuvastatin and intermediates thereof having a low level of alkylether impurity and processes for the preparation thereof.
Description
Related application
The application requires to benefit from the interim series of patents application of submitting on February 22nd, 2,005 60/655,580 of the U.S.; The interim series of patents application of submitting on April 28th, 2,005 60/676,388 of the U.S.; The interim series of patents application of submitting on October 3rd, 2,005 60/723,491 of the U.S.; The interim series of patents application of submitting on October 4th, 2,005 60/723,875 of the U.S.; The interim series of patents application of submitting on November 2nd, 2,005 60/732,979 of the U.S.; The interim series of patents application of submitting on December 15th, 2,005 60/751,079 of the U.S.; The interim series of patents application of submitting on January 19th, 2,006 60/760,506 of the U.S.; In the interim series of patents application of the U.S. that on January 25th, 2006 submitted to, application number is in wait (attorney docket 1662/71804) also.
Technical field
The present invention relates to prepare method and their purposes in preparation rochovastatin and rochovastatin salt of rochovastatin intermediate.
Background technology
In the U.S., cardiovascular complication accounts for half of all diseases as myocardial infarction, apoplexy and peripheral vascular disease.High-level low-density lipoprotein (LDL) connects [referring to Goodman and Gilman with the coronary artery pathological changes that forms block blood flow and promotion thrombus in blood flow, ThePharmacological Basis of Therapeutics, the 9th edition, the 879th page (1996)].Shown that reducing plasma LDL levels can reduce the patient who suffers from cardiovascular disorder and not suffer from cardiovascular disorder but clinical risk takes place for the patient that suffers from hypercholesterolemia.[ScandinavianSimvastatin Survival Study Group, 1994; Lipid Research ClinicsProgram, 1984a, 1984b.]
His spit of fland medicine is the most effective medicine of result of treatment for the level that the patient who suffers from cardiovascular disorder is used for reducing blood flow LDL at present.The medicine of this class is particularly including mevastatin, lovastatin, Simvastatin, Pravastatin and fluvastatin.
Some details of the mechanism of action of his spit of fland medicine is by sets forth in detail.His spit of fland medicine has destroyed the synthetic of in liver cholesterol and other sterol by suppressing 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (" HMG-CoA reductase enzyme ") competitively.HMG-CoA reductase enzyme catalysis HMG-CoA is transformed into mevalonic acid, and it is the step of decision speed in the cholesterol biosynthesizing.Its result, the HMG-CoA reductase inhibitor causes the decline of cholesterol formation speed in liver.The minimizing of the cholesterol of preparation causes the increase of ldl receptors a large amount of in blood flow and the decline of corresponding LDL particle concentration.The decline of LDL level has reduced the risk of coronary artery disease in blood flow.[J.A.M.A.1984，251，351-74]。
At present the available Statins comprises: lovastatin, Simvastatin, Pravastatin, fluvastatin, look cut down Ta Ting and Zarator, and they are all with the form of lactone, as sodium salt or calcium salt administration.
Rochovastatin (7-[4-(the fluorine-based phenyl of 4-)-6-sec.-propyl-2-(N-methyl-N-sulfonyloxy methyl amido) pyrimidine-5-yl] (3R, 5R)-dihydroxyl-(E)-the 6-heptenoic acid) calcium, the HMG-CoA reductase inhibitor can more effectively lower LDL-cholesterol and triglyceride levels than his spit of fland medicine of the first-generation.Rochovastatin has following chemical structural formula:
Rochovastatin calcium
The many relevant method of preparation rochovastatin and salt thereof is disclosed.Rochovastatin calcium, intermediate and their preparation method disclose in 440 (being called for short ' 440 here) at United States Patent (USP) 5,260.WO03/097614 discloses by nearest intermediate (3R)-3-(t-butyldimethylsilyloxy base)-5-oxo-6-triphenyl-phosphine subunit capronate and has synthesized rochovastatin, is disclosed in described intermediate exists ' 440.WO03/08112 discloses from different intermediates, (3R)-and 3-(t-butyldimethylsilyloxy base)-6-dimethoxy phosphino--5-oxo-caproate synthesizes rochovastatin.WO/0049014 discloses with the intermediate with other side chains and has reacted to synthesize rochovastatin by Wittig.EP850,902 have described removing of in mixture triphenylphosphine derivative.
Yet still needing in the art is the method for preparing rochovastatin that cost effectively has less purification step again, thereby makes them be more suitable for plant-scale production.
The invention summary
The invention provides the method for the intermediate of preparation rochovastatin and rochovastatin.
One aspect of the present invention provides the method that is prepared as follows structure midbody compound 17,
Compound 17
Described method is by diester, and the partial hydrolysis of the Compound I of following structure is carried out:
Compound (I)
Wherein Y is C
1-C
4Ester, W are carboxy protective groups, and X is a hydroxy-protective group.Described method comprises: the solution that Compound I and polar solvent are provided; Described solution is mixed with alkali and obtain about 10 to about 13 pH; And recovery compound 17.
Another aspect of the present invention provides the method that reclaims compound 17 from reaction mixture.Described method comprises: provide compound 17 crude products; Evaporate a part of solvent; Add entry; Use C
5-C
7The alkane washing; With being selected from following organic solvent extraction: saturated or aromatic C
5-C
12Hydrocarbon, list, two, three (C
1-C
4) benzene that replaces of alkyl; With mineral acid described mixture being acidified to pH is about 7 to about 5; And from organic phase, reclaim compound 17.
Randomly, can use technology well known by persons skilled in the art to come from reaction mixture, to reclaim compound 17.
In another aspect of the present invention, compound 17 by the inventive method preparation can be by conventional means, as describing in United States Patent (USP) 5260440 those are by being used to prepare the method preparation of any downstream intermediate, rochovastatin and its pharmaceutically-acceptable salts.For example, following reaction scheme has been described a kind of method that compound 17 is transformed into rochovastatin calcium, and wherein compound 17 to 22 is used numeral:
By the intermediate preparation rochovastatin
Wherein W represents carboxy protective group, and Z is C
1-C
6Or C
8Alkyl group, and X is a hydroxy-protective group.
On the other hand, the invention provides the method for the midbody compound 18 that is prepared as follows shown in the structure:
Compound 18
Wherein W represents carboxy protective group, and X is a hydroxy-protective group, and Z is C
1-C
8Alkyl group.Described method comprises: first kind of solution that will comprise compound 17, first kind of organic solvent and alkali joins and comprises list, two, three (C
1-C
4) alkyl the benzene chloro-formic ester, the saturated or aromatic C that replace
5-C
12Chloro-formic ester or C
1-8Be maintained at about-50 ℃ to about-10 ℃ temperature in second kind of solution of alkyl chloride manthanoate and second kind of organic solvent simultaneously and obtain reaction mixture; And keep the sufficiently long time of reaction mixture to obtain compound 18.
Randomly, can use technology known in the art from reaction mixture, to reclaim compound 18.
In another aspect of the present invention, the compound 18 by the inventive method preparation can be used to prepare any downstream intermediate, rochovastatin and its pharmaceutically-acceptable salts.
By methods known in the art, compound 18 can be transformed into the compound 19 of following structure
Compound 19
Wherein X is any hydroxy-protective group, and W is any carboxy protective group, as comprising that by the solution of compound 18 in toluene is joined gradually maintaining the temperature at approximately-60 ℃ in methyltriphenylphospbromide bromide , THF and the butyllithium refrigerative solution simultaneously obtains reaction mixtures down; And keep reaction mixture to obtain compound 19[referring to United States Patent (USP) 5,260,440] about-20 ℃ sufficiently long period of next section of top temperature.
Another aspect of the present invention has proposed the method that a kind of Wittig condensation by compound 19 and compound 14 prepares compound 20, and is as follows:
Wherein W is a carboxy protective group, and X is a hydroxy-protective group.Described method comprises: in inert atmosphere such as argon gas and nitrogen, compound 19, compound 14 and the appropriate organic solvent except that acetonitrile are provided and obtain reaction mixture; And obtain compound 20 in about this reaction mixture for some time of 70 ℃ of following reflux.
Randomly, can use technology known in the art from reaction mixture, to reclaim compound 20.
Another aspect of the present invention, the compound 20 for preparing by the inventive method can be used to prepare any downstream intermediate, rochovastatin and its pharmaceutically-acceptable salts.
Another aspect of the present invention provides the method that reclaims compound 21.Described method comprises: the biphasic system of the mixture of the mixture that comprises nonpolar fatty family solvent and nonpolar aromatic solvent and the pure and mild water of lower aliphatic is provided, and with respect to compound 21 and compound 21 crude products, the content of each is about 4 to about 6 times of volumes; Mixture washing nonpolar phase with the pure and mild water of lower aliphatic; And from organic phase, reclaim compound 21.
Subsequently midbody compound 21 reduction are carried out under condition well known by persons skilled in the art to form compound 22.In addition, the rochovastatin for preparing by the inventive method can be transformed into pharmacy acceptable salt, as calcium salt.
Another aspect the invention provides by compound 17 being transformed into the method that rochovastatin prepares rochovastatin and its pharmacy acceptable salt, and described method comprises:
A., the solution of Compound I and polar solvent is provided;
B. alkali is mixed with this solution and obtain about 10 to about 13 pH comprises compound 17 with formation first kind of solution;
C. add and comprise list, two, three (C
1-C
4) alkyl the benzene chloro-formic ester, the saturated or aromatic C that replace
5-C
12Chloro-formic ester or C
1-8Second kind of solution of the chloro-formic ester of alkyl and organic solvent obtains reaction mixture, keeps-50 ℃ to about-10 ℃ temperature approximately simultaneously;
D. keep the sufficiently long time of reaction mixture to obtain compound 18;
E. compound 18 is transformed into compound 19;
F. compound 19, compound 14 and the appropriate organic solvent except that acetonitrile are mixed, in inert atmosphere such as argon gas or nitrogen, obtain reaction mixture;
G. obtain compound 20 in about 70 ℃ of following reflux described reaction mixture for some time;
H. compound 20 is transformed into compound 21;
I. randomly reclaim compound 21: the two-phase system that provides the mixture by the mixture of the mixture of nonpolar fatty family solvent and nonpolar aromatic solvent and lower aliphatic alcohols and water to constitute by following manner, with respect to compound 21 and compound 21 crude products, the content of each is about 4 to about 6 times of volumes; Mixture washing nonpolar phase with the pure and mild water of lower aliphatic; And from organic phase, reclaim compound 21;
J. change compound 21 into compound 22;
K. and with compound 22 be transformed into rochovastatin.
Randomly, receive compound 17 from step b refunds, this is by a part of solvent of evaporation from first kind of solution; Add entry; Use C
5-7The alkane washing; With being selected from saturated or aromatic C
5-C
12Hydrocarbon, list, two, three (C
1-C
4) organic solvent extraction of the benzene that replaces of alkyl; With mineral acid described mixture being acidified to pH is about 7 to about 5; And from organic phase, reclaim compound 17 and realize.The compound 17 that reclaims mixes the described first kind of solution that comprises compound 17 with formation then with first kind of organic solvent and alkali.
The rochovastatin that is obtained by the method for the invention can be transformed into pharmaceutically acceptable rochovastatin salt, preferred calcium salt.
Detailed Description Of The Invention
KF used herein is meant Karl Fisher volumetry, a kind of method of widely used quantitative analysis water content.
RT used herein is meant room temperature, and comprises about 25 ± 5 ℃ temperature.
Carboxy protective group in the structure in the application's scope can be any suitable carboxy protective group, as ester, aminocompound, benzene or hydrazides.More preferably, carboxy protective group is an ester, most preferably is the tertiary butyl ester in structure of the present invention.Some examples of hydroxy-protective group comprise methoxymethyl ester, THP trtrahydropyranyl ester, trimethyl silyl, t-butyldiphenylsilyl, tin derivative and acetic ester.Preferred three (C
1-C
6Alkyl) silyl is three (C
1To C
4Alkyl) silyl, more preferably trimethyl silyl or t-butyldimethylsilyl (TBDMS), TBDMS is particularly preferred.More carboxyl or hydroxy-protective group are described in " the Protective Groups inOrganic Synthesis " of T.W.Greene, John Wiley and Sons company (1981).
Lower aliphatic alcohols used herein comprises C
1-C
4Alcohol.
The wherein R that suffix used herein " TB " has been described described in summary is the midbody compound of the tertiary butyl.For example, term " 17TB " is meant that wherein R is the midbody compound 17 of the tertiary butyl.Suffix " M " represents that wherein R is the midbody compound of methyl.For example, term " 17M " is meant that wherein R is the midbody compound 17 of methyl.Suffix " TBPH " has been described wherein, and R is that the tertiary butyl and PH are the compounds of the present invention of phenyl.Suffix " TBRE " has been described wherein, and R is that the tertiary butyl and RE are the compounds of the present invention of rochovastatin ester.Suffix " TBDMS " has been described wherein, and R is that the tertiary butyl and DMS are the compounds of the present invention of t-butyldimethylsilyl.
The invention provides the improved method of using cost-effective reagent high productivity to prepare rochovastatin and its intermediate.Method of the present invention provides the quantitative transformation of reagent and the minimizing that byproduct forms, and the result makes does not need more purification step in preparing the method for rochovastatin.Example under specific circumstances distributes in the text.
In one aspect of the invention, provide the method for the midbody compound 17 that is prepared as follows structure,
Compound 17
Described method is by with diester, and the Compound I partial hydrolysis of following structure prepares,
Compound (I)
Wherein Y is C
1-C
4Ester, W are carboxy protective groups, and X is a hydroxy-protective group.Described method comprises: the solution of Compound I and polar solvent is provided, described solution is mixed with alkali and obtains about 10 to about 13 pH; And recovery compound 17.In the method, the synthetic of compound 17 makes that preparing single acid derivative with two acid derivatives that contain small amount of impurities becomes possibility.
Described polar solvent is selected from C
1-4Alcohol, nitrile, acetone, two alkane and THF, most preferably methyl alcohol or ethanol.With respect to Compound I, the amount of described polar solvent about 2 is to about 15 times of volumes, and preferred about 5 to about 10 times of volumes, and most preferably the amount of described polar solvent is about 5 times of volumes.
Employed alkali is any suitable alkali, and it can be selected from list, two, three (C
1-4Alkyl) aminopyridine, list, two, three (C
1-4Alkyl) amine, basic metal, alkaline earth metal hydroxides, alkaline-earth metal alkyl oxide and C
1-4The alkyl Quilonum Retard.Preferably, described alkali is at least a in sodium hydroxide, potassium hydroxide or the lithium hydroxide.Most preferably, described alkali is sodium hydroxide.Preferably, with respect to Compound I, the concentration of described alkali is about 0.9 to about 1.8 times of volumes.Most preferably, concentration is about 1.2 times of volumes.
In particularly preferred embodiments, in the mode that drips described alkali is joined in the solution of compound (I).Can add alkali in batches and keep pH in this level.The amount of implementing the needed alkali of reaction will depend on the scale of reaction, and those skilled in the art maybe need not test with test seldom and adopt technique means such as TLC just can determine it at an easy rate.
Preferably, described reaction mixture is heated to about 70 ℃ of temperature at about 30 ℃.Most preferably, described reaction mixture is heated to about 55 ℃ of temperature at about 45 ℃.The heating and continuous time will be depended on scale and blended operation, can be decided by measuring not existing of restricted reagent by using the technology as HPLC or TLC by those skilled in the art.For example, when using the Compound I of 288 mmoles, be about 1 hour to about 10 hours heat-up time, is preferably about 7 hours.
Another aspect of the present invention provides the method that reclaims compound 17 from reaction mixture.Described method comprises: provide compound 17 crude products; Evaporate a part of solvent; Add entry; Use C
5-C
7The alkane washing; With being selected from saturated or aromatic C
5-C
12Hydrocarbon, list, two, three (C
1-C
4) organic solvent extraction of alkyl substituted benzene; With mineral acid described mixture being acidified to pH is about 7 to about 5; And from organic phase, reclaim compound 17.
Preferably, with respect to compound 17 crude products, the content of employed water is about 2 to about 10 times of volumes.Most preferably be 4 times of volumes.Preferably, C
5-C
7Alkane is hexane.Can be with many batches, preferred about 2 batches of washings.Described organic solvent is preferably toluene.Any mineral acid may be used to acidifying, preferred HCl.Preferably, acidifying is will reach pH to be about 6.From organic phase, reclaim can by as at MgSO
4Middle exsiccant method.
Another aspect of the present invention, the compound 17 by the inventive method preparation can be by conventional modes, described at United States Patent (USP) 5260440, be used to prepare any downstream intermediate, rochovastatin or its pharmaceutically-acceptable salts.For example, following reaction scheme has been described a kind of method that compound 17 is transformed into rochovastatin calcium, and wherein compound 17 to 22 is used numeral.
By the intermediate preparation rochovastatin
Wherein W represents carboxy protective group, and Y is C
1-C
6Or C
8Alkyl group, and X is a hydroxy-protective group.
In another aspect of this invention, provide a kind of method that is prepared as follows the midbody compound 18 shown in the structure:
Compound 18
Wherein W is a carboxy protective group, and X is a hydroxy-protective group, and Z is the C1-8 alkyl.Described method comprises: first kind of solution that will comprise compound 17, first kind of organic solvent and alkali joins and comprises list, two, three (C
1-C
4) alkyl the benzene chloro-formic ester, the saturated or aromatic C that replace
5-C
12Chloro-formic ester or C
1-8In second kind of solution of alkyl chloride manthanoate and second kind of organic solvent and obtain reaction mixture, maintain the temperature at approximately-50 ℃ simultaneously to approximately under-10 ℃; And keep the reaction mixture time enough to obtain compound 18.
Described alkali can be any suitable organic bases, and including, but not limited to wherein said alkyl group can be two identical or different (C
1-C
4Alkyl) pyridine, wherein said alkyl group can be identical or different single, two or three (C
1-C
4Alkyl) amine, alkaline-earth metal, alkaline earth metal hydroxides, alkaline-earth metal alkyl oxide and C
1-C
4Lithium alkylide.Preferably, described alkali is C
1-C
4Trialkylamine is more preferably triethylamine.
Described first kind of organic solvent and second kind of solvent of being fit to use in the method for the invention include, but not limited to saturated or aromatic C
5-12Hydrocarbon, list, two, three (C
1-C
4) the alkyl benzene and the benzene that replace.For example, can use THF, toluene, methylene dichloride, diethyl ether, benzene and chloroform.Toluene or THF are preferred organic.Described first kind of organic solvent and second kind of organic solvent preferably use with a kind of organic solvent.
Preferably, single, two, three (C
1-C
4) alkyl the benzene chloro-formic ester, the saturated or aromatic C that replace
5-12Chloro-formic ester or C
1-8The chloro-formic ester of alkyl is C
1-4The chloro-formic ester of alkyl, more preferably Vinyl chloroformate or methyl-chloroformate, Vinyl chloroformate is particularly preferred.The mol ratio of chloro-formic ester and compound 17 is about 1 mole in reaction mixture: about 3 moles, be preferably about 1 mole: about 1.5 moles.
Described first kind of solution is being mixed to about-10 ℃ of temperature at about-50 ℃ with second kind of solution, more preferably mixing under-30 ℃ of temperature extremely approximately, most preferably under about-45 ℃ to about-40 ℃, mixing at-50 ℃.Mixed about 30 minutes time of preferred solution.
By being heated to approximately-10 ℃ gradually, more preferably be heated to about 0 ℃ temperature gradually and keep described reaction mixture to about 30 ℃ temperature.Obtain compound 18 needed time enough and for example will depend on scale and blended operation.This can by those skilled in the art by use as the technology of HPLC or TLC by measure restricted reagent lack to come definite.Preferably, then with described reaction mixture cancellation, preferred water cancellation.
Randomly, compound 18 can reclaim from reaction mixture by technology well known by persons skilled in the art.Preferably, the organic layer that will form during quenching is separated from reaction mixture; With the alkali (pH7-11) of gentleness as NaHCO
3The washing organic layer reclaims compound 18.Can come the washing reaction mixture by adding NaCl.With the organic layer drying, for example use metal-salt then, preferably use Na
2SO
4Or MgSO
4Dry.Then solvent evaporation is obtained compound 18.Replacedly, reaction mixture is filtered the salt that during reaction forms to remove.
Prepared according to the methods of the invention compound 18 has reduced the formation of symmetric anhydride impurity, and allows the quantitative formation of mixed acid anhydride product.In addition, method of the present invention can be used for industrial-scale production at an easy rate, because do not use extreme temperature, it is different from United States Patent (USP) 5260440, wherein uses-70 ℃ to about-85 ℃ temperature ideally.
In another aspect of the present invention, the compound 18 by the inventive method preparation can be used to prepare the intermediate in any downstream of rochovastatin or its pharmaceutically-acceptable salts.
Compound 18 can be transformed into the compound 19 of following structure:
Compound 19
Wherein X is any hydroxy-protective group, W is any carboxy protective group, described method is passed through methods known in the art, as by the solution of compound 18 in toluene is joined in the refrigerative solution that comprises methyltriphenylphospbromide bromide phosphorus, THF and butyllithium gradually, maintain the temperature at pact simultaneously and get off to obtain reaction mixture for-60 ℃; Keep reaction mixture to obtain compound 19[referring to United States Patent (USP) 5,260,440] Gao Yue-20 ℃ enough time of next section of temperature.
In another aspect of the present invention, the compound 19 by the inventive method preparation can be used to prepare intermediate, rochovastatin and its pharmacy acceptable salt in any downstream.
In another aspect of the present invention, the method that a kind of Wittig condensation by compound 19 and compound 14 prepares compound 20 has been proposed, as follows:
Wherein W is a carboxy protective group, and X is a hydroxy-protective group.Described method comprises: in inert atmosphere such as argon gas and nitrogen, provide compound 19, compound 14 and the appropriate organic solvent except that acetonitrile to obtain reaction mixture; Obtain compound 20 about 70 ℃ these reaction mixture for some time of refluxing down.
Organic solvent can be any appropriate organic solvent, includes, but not limited to saturated or aromatic C
5-C
12Hydrocarbon, list, two, three (C
1To C
4Benzene and benzene that alkyl replaces).Preferably, organic solvent is a toluene.
With respect to compound 14, the amount of compound 19 is 1.5 equivalents.And the described organic solvent except that acetonitrile is about 10 times of volumes with respect to the amount of compound 14.Described reaction mixture is heated under about 70 ℃ to about 110 ℃.Most preferably be heated to about 100 ℃.Necessary time span depends on the scale and the temperature of method, can anyone easily determines by this area.
When obtaining compound 20, can analyze content by compound 20 crude products of the inventive method preparation.Typically, as measuring with HPLC by relatively the time, obtaining the compound of about 50% weight unit with standard.This assay determination the formation of byproduct of the pollution of salt in the compound or non-ultraviolet impurity or degraded, especially in the situation of Wittig reaction.Do not consider these impurity, the compound 20 that forms by described method can directly be used and need be further purified in next step to form compound 21.
By and large, this method has caused the quantitative transformation of raw material.Preferably, when measuring with HPLC, the amount of compound 14 is less than 5%, and more preferably when measuring with HPLC, the amount of compound 14 is less than 2%.
Triphenylphosphine oxide forms as the by product of this reaction, and it can be removed from described reaction mixture.Preferably, by adding metal-salt, preferred Magnesium Chloride Anhydrous makes triphenylphosphine oxide and metal-salt formation complex compound and triphenylphosphine oxide is removed in reaction mixture, as disclosed in EP patent 0850902A1; By being heated to about 100 ℃, be cooled to 0 ℃, filter, water or toluene wash, and evaporating solvent comes separating compound 20.
In another aspect of the present invention, the compound 20 by the inventive method preparation is used to prepare the intermediate in any downstream of rochovastatin and its pharmaceutically-acceptable salts.
Compound 21 can go by the hydroxyl of compound 20 to protect and prepare, and is as disclosed in WO2003/097614A2, as follows:
Wherein W is a carboxy protective group, and X is a hydroxy-protective group.In one embodiment, the solution of compound 20 in methyl alcohol, THF or acetonitrile is mixed with removing protective material such as fluoride ion source or the mineral acid except that HF, obtain reaction mixture; This reaction mixture is maintained under time enough and the temperature to obtain compound 21.
In another aspect of the present invention, provide the method that reclaims compound 21, described method comprises:
A., the biphasic system of being made up of the mixture of the mixture of the mixture of nonpolar fatty family solvent and nonpolar aromatic solvent and lower aliphatic alcohols and water is provided, and with respect to compound 21 and compound 21 crude products, the content of each about 4 is to about 6 times of volumes;
B. the mixture with the pure and mild water of lower aliphatic washs nonpolar phase;
C. from organic phase, reclaim compound 21.
Can obtain purity greater than about 80% with this recovery method, preferred about 90% (as measuring by HPLC) and productive rate are preferably greater than about 95% compound 21 greater than about 90%.
Preferably, the amount of each equals about 5 times of volumes with respect to compound 21 in the nonpolar fatty family solvent in step a, nonpolar aromatic solvent, the pure and mild water of lower aliphatic.Preferably, described nonpolar fatty family solvent is a hexane.Preferably, described nonpolar aromatic solvent is a toluene.Preferably, described lower aliphatic alcohols is an ethanol.Preferably, provide the two-phase system of step a to comprise the reagent of mixing step a at room temperature, till obtaining clarifying solvent and allowing mixture to be separated into different phases.
Preferably divide several times with the mixture of polar solvent and water washing nonpolar phase and to carry out, wherein 5 times should be enough.In preferred embodiment, use 4 parts second alcohol and water.Preferably, the ratio of ethanol and water is about 2: 1 volume ratios.Preferably, described alcoholic acid amount is about 4 to about 6 times of volumes.Preferably, wherein with respect to compound 21, described alcoholic acid amount is about 5 times of volumes.And with respect to compound 21, the amount of described water is about 8 to about 12 times of volumes.Preferred about 10 times of volumes.Preferably, collect merging and preferred under reduced pressure concentrated to obtain the oily residue of compound 21 from the cut 2-5 of 5 cuts.
The method of above-mentioned recovery compound 21 allows after to the three-dimensional selective reduction of compound compound 22 to be carried out crystallization.If necessary, the production of the compound 22 of the solid form that is obtained by purifying compounds 21 allows rochovastatin to be further purified.The crystallization of compound 21 can further reduce the impurity of existence.But such crystallization can not provide satisfied productive rate.
Carry out subsequently the reduction of middle compound 21 to form compound 22, following demonstration:
Wherein W is a carboxy protective group, and X is a hydroxy-protective group.Described method is carried out under condition well known by persons skilled in the art, preferably uses diethyl methoxyl group borine to carry out in THF and sodium borohydride.
With compound 22 saponification the time, obtain rochovastatin.
Another aspect the invention provides a kind of by compound 17 being transformed into the method that rochovastatin prepares rochovastatin and its pharmaceutically-acceptable salts.Described method comprises:
A., the solution of Compound I and polar solvent is provided,
B. alkali is mixed with this solution and obtains about 10 to about 13 pH and comprise first kind of solution of compound 17 with formation,
C. add and comprise list, two, three (C
1-C
4) alkyl the benzene chloro-formic ester, the saturated or aromatic C that replace
5-C
12Chloro-formic ester or C
1-8Second kind of solution of the chloro-formic ester of alkyl and a kind of organic solvent obtains reaction mixture, keeps-50 ℃ to about-10 ℃ temperature approximately simultaneously;
D. keep the sufficiently long time of reaction mixture to obtain compound 18;
E. compound 18 is transformed into compound 19;
F., compound 19, compound 14 and the appropriate organic solvent except that acetonitrile are provided, in inert atmosphere such as argon gas or nitrogen, obtain reaction mixture;
G. obtain compound 20 in about 70 ℃ of following reflux described reaction mixture for some time;
H. compound 20 is transformed into compound 21;
I. randomly by providing biphasic system to reclaim compound 21, described biphasic system comprises mixture and the mixture of lower aliphatic alcohols and the mixture of water of nonpolar fatty family solvent and nonpolar aromatic solvent, with respect to compound 21 and compound 21 crude products, the content of each is about 4 to about 6 times of volumes; Mixture washing nonpolar phase with the pure and mild water of lower aliphatic; And from organic phase, reclaim compound 21;
J. change compound 21 into compound 22; And
K. compound 22 is transformed into rochovastatin.
Randomly, compound 17 through the following steps b reclaim: by from first kind of solution the evaporation a part of solvent; Add entry; Use C
5-7The alkane washing; With being selected from saturated or aromatic C
5-C
12Hydrocarbon, list, two, three (C
1-C
4) organic solvent extraction of the benzene that replaces of alkyl; With mineral acid described mixture is acidified to pH about 7 to about 5; From organic phase, reclaim compound 17.The compound 17 that reclaims can be mixed the first kind of solution that comprises compound 17 with formation with first kind of organic solvent and alkali then.
The rochovastatin that obtains by method of the present invention can be transformed into rochovastatin pharmacy acceptable salt, preferred calcium salt.[referring to for example United States Patent (USP) 5,260440].The method that rochovastatin can be transformed into its pharmacy acceptable salt comprises rochovastatin contacted with calcium hydroxide, or contacts with stronger alkali such as sodium hydroxide.Preferably under suitable temperature, 25 ℃ according to appointment ± 5 ℃, with described alkali dropwise with the rochovastatin reaction mixture.Can be with suitable organic solvent washing reaction mixture that can not be miscible with water.Suitable can not include but not limited to hydrocarbon with the miscible organic solvent of water, can not be toluene with the miscible organic solvent of water preferably.Can not can remove by being separated with the miscible organic solvent of water.Residual can not can preferably under decompression (being lower than about 50mmHg), under about 40 ℃ temperature, the distillation and remove by the reaction mixture distillation is come with the miscible organic solvent of water.
With reaction mixture and basic metal, comprise that calcium source such as calcium chloride or lime acetate mix, then to form the salt [referring to United States Patent (USP) 6,777,552] of rochovastatin.For example, can be in suitable temperature, 35 ℃ to about 45 ℃ of temperature according to appointment, preferably under about 40 ℃, calcium chloride are dropwise joined in the reaction mixture of rochovastatin, through about 30 to about 90 minutes.Gac be introduced in the reaction mixture of rochovastatin to remove impurity from reaction mixture.If during the pharmacy acceptable salt that rochovastatin is transformed into it, use gac, rochovastatin can used gac with before basic metal contacts or contact back.
The pharmacy acceptable salt that rochovastatin is transformed into it also can comprise reaction mixture is filtered.Reaction mixture can be filtered, as filtering with Synter and Hyflo , with can not with the miscible organic solvent washing of water before or after carry out.
Illustrate the present invention of some embodiment by following non-restrictive example.
Here all purity of mentioning relates to the quantized productive rate of weight, is to record by HPLC and known standard comparison with product.
Embodiment
Embodiment 1: the preparation of compound 17TB
In being equipped with 1 liter flask of condenser, mechanical stirrer, pH meter and thermometer, add the tert-butyl ethylglutaric acid (100 grams, 288 micromoles) of TBDMA protection and straight alcohol (500 milliliters) and the formation reaction mixture.This reaction mixture is heated to 50 ℃, the NaOH (115.2 milliliters) of 1N is dropwise added, the pH of mensuration is 12.8.
After under this temperature 1 hour, measuring pH is 10.59.The NaOH (115.2 milliliters) that adds 1N again.Measuring pH is 12.25.After 1 hour, add the NaOH (115.2 milliliters) of 1N again.
This reaction mixture is remained on 50 ℃ continue 7 hours down, till can not detecting raw material by TLC.Reaction mixture is cooled to room temperature, and being evaporated to final volume is 300 milliliters.With H
2O (400 milliliters) and ethanol (95%, 50 milliliter) join in the reaction mixture.With hexane (each 300 milliliters) washing reaction mixture.
Toluene (300 milliliters) is joined aqueous phase, with HCl (32%) neutralization reaction mixture to pH be 6.Use toluene extracting twice (each 300 milliliters) again.Toluene layer is merged, use MgSO
4(about 12 grams) drying is evaporated, and obtains the xanchromatic oil of 78.3 grams (productive rate 85%).
Embodiment 2: the preparation of compound 18TB
In 2 liters flask, add the first kind solution of Vinyl chloroformate (16.44 milliliters) in 900 milliliters dry toluene (KF=is less than 0.01%), solution is cooled to-45 ℃.By dropping funnel in about 30 minutes time with compound 17TB (50 gram) and Et
3The second kind solution of N (26.06 milliliters) in 100 milliliters toluene dropwise joins in first kind of solution, makes that the temperature of reaction mixture remains on-45 ℃ to-40 ℃.
With 1.5 hours reaction mixture slowly is heated to 0 ℃, uses water quenching then.Reaction mixture is transferred to immediately in 2 liters the separating funnel, uses NaHCO
3(saturated, 250 milliliters) and NaCl (saturated, 250 milliliters) wash organic layer, use MgSO
4Dry.With solvent evaporation, residue is used for next procedure and need not carries out any purification step.
Embodiment 3: the preparation of compound 19TBPH
Methyltriphenylphospbromide bromide (224.3 gram) is suspended among the THF (600 milliliters), under-55 to-50 ℃ temperature approximately with 30 minutes adding butyllithiums (1.6M, 392.5 milliliters).With time of 1.5 hours reaction mixture is heated to about 0 ℃ then, is cooled to-60 ℃ approximately then.
The solution of anhydrous compound 18TB (122.6 grams, 314 mmoles) in toluene (360 milliliters) was dropwise joined reaction mixture about 2 hours, and the temperature that keeps reaction mixture simultaneously is at-55 to-65 ℃ approximately.With reaction mixture heating 1.5 hours to about 0 ℃, water (250 milliliters) quenched.Water phase separated uses toluene (100 milliliters) from the aqueous phase extraction product.Two portions organic layer is mixed and uses NaHCO
3(saturated, 2 * 100 milliliters) and NaCl (2 * 100 milliliters) washing.Organic phase is kept at NaSO under about-25 ℃
4In spend the night, before use with solvent evaporation.
Embodiment 4: prepare compound 20TB by the Wittig reaction from 19TBPH
N is being provided
2Pack in 100 ml flasks of the lucifuge of air-flow compound 14 (3.6 gram, 10.5 mmoles), compound 19TBPH (9.05 grams, 15.7 mmoles) and dried toluene (36 milliliters, 10 times of volumes for compound 14).Reaction mixture is heated to about 100 ℃ continues 19.5 hours.By the sample of HPLC analyze reaction mixture, it contains 1.7% compound 14.
With anhydrous MgCl
2(2 grams, with respect to compound 19TBPH, 2 equivalents) join in the reaction mixture, reaction mixture was stirred 2 hours down at 100 ℃.Reaction mixture is cooled to 0 ℃ continues 2 hours, filter, do not wash solid.Obtain filtrate and water (each 100 milliliters) washing,, obtain the brown solid of 7.56 grams solvent evaporation.
Embodiment 5: prepare compound 20M by the Wittig reaction from 19M
N is being provided
2Pack in 250 ml flasks of the lucifuge of air-flow compound 14 (4.38 gram, 12.5 mmoles), compound 19M (10 grams, 18.7 mmoles) and superfine dried toluene (100 milliliters).Reaction mixture is heated to about 100 ℃ continues 15 hours.After reaction is finished, with anhydrous MgCl
2(4.8 grams, 2.7 equivalents) join in the reaction mixture, and reaction mixture was heated 2 hours down at 100 ℃.With about 2 hours reaction mixture is cooled to 0 ℃, filters,, obtain the oil of 12.73 gram viscosity with 45 milliliters of toluene wash.
Embodiment 6 prepares compound 21TB in HCl/ methyl alcohol
The mixture of HCl (in water 32%, 1 milliliter), water (0.5 milliliter) and methyl alcohol (8 milliliters) is dropwise joined in the solution of compound 20TB (2 gram) in methyl alcohol (10 milliliters).Reaction mixture 30 ℃ of following stir abouts 1.5 hours, is shown that up to TLC (hexane/ethanol, 4: 1) raw material all runs out of.
Ethyl acetate (150 milliliters) is joined in the reaction mixture, with saturated NaHCO
3Solution (50 milliliters * 2) washing reaction mixture forms organic layer.At MgSO
4In dry organic layer, under reduced pressure solvent is removed, obtain compound 21TB (1.72 gram).
Embodiment 7: preparation compound 21TB in HCl/THF
The mixture of preparation HCl (32%, 0.57 gram in water), water (2 milliliters) and THF (17.5 milliliters).5.4 milliliters of these mixtures are dropwise joined in the solution of the compound 20TB (2.7 gram) in THF (8.1 milliliters).Reaction mixture stirring at room temperature under 30 ℃ is spent the night, show to react up to TLC and finish monitoring reaction.
Ethyl acetate (20 milliliters) is joined in the reaction mixture water (20 milliliters) washing reaction mixture.Form water layer, with ethyl acetate (20 milliliters) extraction.Organic layer is merged, with the Et of pH about 10.5
3The solution washing of N (2 * 5 milliliters).At MgSO
4In dry organic layer, under reduced pressure solvent is removed, obtain oily compound 21TB (2.03 gram).
Embodiment 8: prepare compound 21TB with tetrabutyl ammonium fluoride/THF.
Compound 20TB (5 gram) is dissolved among the THF (40 milliliters).To dropwise join in the solution at the tetrabutyl ammonium fluoride among the THF (8.46 milliliters, 1M solution), form reaction mixture.At room temperature with reaction mixture stir about 1 hour.Under reduced pressure solvent is removed.Toluene (300 milliliters) is joined in the solution.Use NaHCO
3Saturated solution (50 milliliters) washing soln three times under reduced pressure concentrates, and obtains compound 21TB.
Embodiment 9: by using CsF, K
2CO
3And NH
2OHHCl goes protection to prepare compound 21TB to TBDMS.
At room temperature compound 20TB (0.3 gram) is dissolved in the acetonitrile (10 milliliters).With CsF (70 milligrams), K
2CO
3(300 milligrams) and NH
2OHHCl (160 milligrams) joins in the solution, forms reaction mixture.At about 75 ℃ of following reacting by heating mixtures.Observe compound after about 4.5 hours in heating and partly go protection.
Embodiment 10: by going protection to prepare compound 21TB with CsF to TBDMS.
Compound 20TB (300 milligrams) is dissolved in the acetonitrile (10 milliliters).CsF (70 milligrams) is joined in the solution, form pulpous state, this soup compound was heated about 17 hours down at about 75 ℃, on this aspect, observe material and go protection fully.
Embodiment 11: prepare compound 21TB by the protection of sloughing TBDMS with the tetrabutyl ammonium fluoride of 20TB.
Compound 20TB (5 gram) is dissolved among the THF (40 milliliters), dropwise adds tetrabutyl ammonium fluoride as the 1M solution in THF (8.46 milliliters).At room temperature stirred the mixture 1 hour, and under reduced pressure solvent was removed.Toluene (300 milliliters) is joined in the resistates.Use NaHCO
3Saturated solution (50 milliliters * 3) washing soln under reduced pressure concentrates, and obtains the 21TB crude product.
Embodiment 12: preparation compound 21TB in methylsulfonic acid/methyl alcohol.
Methanesulfonic acid solution (15 milliliters, 0.2M is in methanol, the solution in 10: 1) is joined in the solution of compound 20TB (3 gram) in methyl alcohol (15 milliliters).About 3 hours of 30 ℃ of following stirred reaction mixtures, show that up to TLC (hexane/ethanol, 4: 1) raw material all runs out of.
Toluene (200 milliliters) is joined in the reaction mixture, use saturated NaHCO
3Solution (50 milliliters * 2) washing reaction mixture forms organic layer.At MgSO
4In dry organic layer, under reduced pressure solvent is removed, obtain compound 21TB (2.97 gram).
Embodiment 13: remove the protection of TBDMS and prepare compound 21TB by being used in first semi-annular jade pendant acid in the methyl alcohol.
The solution of first semi-annular jade pendant acid (1.66 gram) in methyl alcohol (200 milliliters) and water (19 milliliters) is joined in the solution (20.26 grams, 81.2% analyzes) of 20TB in methyl alcohol (185 milliliters).Stir the mixture that obtains down at about 30 ℃.After 10.5 hours, HPLC shows that the level of raw material is 6% (area), is cooled to room temperature with solution.
Add ethyl acetate (400 milliliters), with salt solution (400 milliliters) washing soln.Use saturated NaHCO then
3Solution (2 * 200 milliliters) washing organic layer is used salt solution (2 * 100 milliliters) washing at last.
At Na
2SO
4In dry organic layer, under reduced pressure solvent is removed, obtain 21TB (19.9 gram).
Embodiment 14: remove the protection of TBDMS and prepare compound 21M by being used in first semi-annular jade pendant acid in the methyl alcohol.
First semi-annular jade pendant acid solution (50 milliliters, 0.2M is in methanol, in 10: 1) is joined in the solution (10 gram) of the compound 20M in methyl alcohol (50 milliliters), form reaction mixture.Stirred this reaction mixture about 4 hours down at about 30 ℃.First semi-annular jade pendant acid (0.35 milliliter) is joined in the reaction mixture, stir this reaction mixture and finish up to reaction.
With toluene (2 * 100 milliliters) extracted products, use saturated NaHCO
3Solution (100 milliliters) washing forms organic layer.At MgSO
4In dry organic layer, under reduced pressure solvent is removed, obtain 9.15 the gram oil.
Embodiment 15: extract compounds 21TB
In being equipped with 1 liter flask of mechanical stirrer, pack into 21TB crude product (41.6 gram, analytical value=40.8%), toluene (200 milliliters), ethanol (200 milliliters), heptane (200 milliliters) and water (200 milliliters), formation suspension.At room temperature stir this suspension up to obtaining clear soln.Pouring this solution into separating funnel then is separated it.Ethanol/water is removed mutually.Use the mixture of ethanol/water (400 milliliters: 200 milliliters) to wash toluene/hexane 4 times mutually then, collect each cut, merge cut 2-5 and under reduced pressure it is concentrated the buttery residue of the 21TB (24.2 grams, the productive rate of analytical value=56.0%, 80%) that obtains purifying.
Embodiment 16: the preparation of compound 22TB (TBRE)
Under about 78 ℃, be added in the diethyl methoxyl group borine (1M) among the THF (2 milliliters) in the 21TB in exsiccant THF (26 milliliters) and dry methyl alcohol (7 milliliters) (1 gram) solution, form reaction mixture.This reaction mixture was stirred 0.5 hour, add NaBH
4, continuously stirring 3 hours joins acetate (1.2 milliliters) in the reaction mixture, and reaction mixture is warmed to room temperature.
Ethyl acetate (150 milliliters) is joined in the reaction mixture, by adding spissated NaHCO
3The aqueous solution is regulated pH to 8.This layer is separated, come extraction water by the ethyl acetate (50 milliliters) that adds other quantity.Merge organic layer and at MgSO
4Middle dry.The vapourisation under reduced pressure solvent stays residue then.Residue is handled with methyl alcohol, then methyl alcohol is evaporated.Carry out methyl alcohol and handle and evaporate more than twice, obtain compound 22TB crude product (0.87 gram, 86%).
Embodiment 17: be used in the method for extracting in the ethyl acetate compound 22TB is transformed into rochovastatin calcium
The ethanol of packing in being equipped with 1 liter reactor of mechanical stirrer (3 liters), water (1800 milliliters) and TBRE (600 gram) form reaction mixture.At room temperature, slowly NaOH (47%, 1.2 equivalent, 114 grams) is joined in the reaction mixture.Reaction mixture was stirred 2 hours under about room temperature.Under reduced pressure filter this mixture to remove the small-particle that exists with Synter and Hyflo.Under reduced pressure reaction mixture is being concentrated till the volume of reaction mixture also remains half under about 40 ℃.
Water (2000 milliliters) is joined in the reaction mixture, and stirred reaction mixture is 5 minutes under about room temperature.Form water and organic phase.Carry out the separation of phase,, at room temperature stir half an hour with ethyl acetate (3000 milliliters) washing water.Discard organic phase.
Under about 40 ℃, under reduced pressure water is concentrated till volume also remains half.Water (2800 milliliters) is joined aqueous phase, under about room temperature, stirred water 5 minutes.Under about room temperature in batches with CaCl
2(124 gram) joined aqueous phase about 10 minutes.Under about room temperature, stirred water about 1 hour then, filter, and, obtain powdered compounds (491 restrain 88%) with 1200 milliliters water washing.
Embodiment 18: be used in the method for extracting in the toluene compound 22TB is transformed into rochovastatin calcium
The ethanol of packing in being equipped with 500 milliliters reactor of mechanical stirrer (150 milliliters), water (90 milliliters) and 22TB (30 gram) form reaction mixture.At room temperature, slowly NaOH (47%, 1.2 equivalent, 5.7 grams) is joined in the reaction mixture.Reaction mixture was stirred 2 hours under about room temperature.Under reduced pressure filter this mixture to remove the small-particle that exists with Synter and Hyflo.With toluene (150 milliliters) washing reaction mixture and stir about half an hour at room temperature, form water and organic phase.Be separated two, discard organic phase.
Under the decompression water is concentrated till volume also remains half down at about 40 ℃.Water (104 milliliters) is joined aqueous phase, under about room temperature, stirred water 5 minutes.Under about room temperature with 1 minute with CaCl
2(6.2 gram) dropwise joins aqueous phase.Under about room temperature, stirred water about 1 hour then, filter, and, obtain powdered compounds (26 restrain 92%) with 1200 milliliters water washing.
Embodiment 19: be used in that method of extraction is transformed into rochovastatin calcium with compound 22TB (TBRE) in the toluene
The ethanol of packing in being equipped with 1 liter reactor of mechanical stirrer (300 milliliters), water (90 milliliters) and 22TB (60 gram) form reaction mixture.At room temperature, dropwise NaOH (47%, 1.2 equivalent, 11.4 grams) is joined in the reaction mixture.Reaction mixture was stirred 2 hours under about room temperature.Under reduced pressure filter this mixture to remove the small-particle that exists with Synter and Hyflo.Water (420 milliliters) is joined in the reaction mixture.
Use toluene (3000 milliliters) to extract this mixture then, and at room temperature stir half an hour.Form water and with its separation.Under the decompression water is concentrated till volume also remains half down at about 40 ℃.Remaining half water is transferred in 500 milliliters the reactor, adds entry, obtain solution, under about room temperature, stirred this solution 5 minutes.At room temperature use 1 minute dropwise with Ca (OAc)
2(8.8 gram) joins in this solution.At room temperature stirred this solution then about 1 hour, and filtered, and, obtain powdered compounds (26 restrain 94%) with 60 milliliters water washing.
Claims (67)
1. be prepared as follows the method for the compound 17 of structure,
Wherein, W is a carboxy protective group, and X is a hydroxy-protective group, and described method comprises: the Compound I of array structure and the solution of polar solvent are provided down,
Wherein Y is C
1-C
4Ester, W are carboxy protective groups, and X is a hydroxy-protective group; Described solution mixed with alkali and to obtain pH be about 10 to about 13 reaction mixture and reclaim compound 17.
2. the process of claim 1 wherein that described polar solvent is selected from C
1-4Alcohol, nitrile, acetone, two alkane and THF.
3. the method for claim 2, wherein said solvent is methyl alcohol or ethanol.
4. the process of claim 1 wherein that with respect to Compound I the amount of described polar solvent is about 2 to about 15 times of volumes.
5. the method for claim 4, wherein with respect to Compound I, the amount of described polar solvent is about 5 to about 10 times of volumes.
6. the method for claim 5, wherein with respect to Compound I, the amount of described polar solvent is about 5 times of volumes.
7. the process of claim 1 wherein that described alkali is selected from list, two, three (C
1-4Alkyl) aminopyridine, list, two, three (C
1-4Alkyl) amine, basic metal, alkaline earth metal hydroxides, alkaline-earth metal alkyl oxide and C
1-4The alkyl Quilonum Retard.
8. the method for claim 7, wherein said alkali are at least a in sodium hydroxide, potassium hydroxide or the lithium hydroxide.
9. the method for claim 8, wherein said alkali is sodium hydroxide.
10. the process of claim 1 wherein that with respect to Compound I the concentration that exists of described alkali is about 0.9 to about 1.8 times of volumes.
11. the method for claim 10, wherein with respect to Compound I, the concentration that exists of described alkali is about 1.2 times of volumes.
12. the process of claim 1 wherein and add described alkali in the mode that drips.
13. the process of claim 1 wherein and described solution is heated with resulting described reaction mixture after described alkali mixes to about 70 ℃ of temperature at about 30 ℃.
14. the method for claim 13 wherein heats described reaction mixture to about 55 ℃ of temperature at about 45 ℃.
15. the process of claim 1 wherein that the step of described recovery compound 17 comprises: the solution that compound 17 crude products are provided; Evaporate a part of solvent; Add entry; Use C
5-C
7The alkane washing; Extract with being selected from following organic solvent: C saturated or fragrance
5-C
12The benzene that hydrocarbon, list, two, three (C1-C4) alkyl replace; With mineral acid described mixture being acidified to pH is about 7 to about 5; And recovery compound 17.
16. prepare the method for rochovastatin and salt thereof, comprise that the method according to claim 1 prepares compound 17, and be converted into rochovastatin or its salt.
17. preparation has the method for the compound 18 of following structure:
Wherein W is a carboxy protective group, and X is a hydroxy-protective group, and Z is C
1-8Alkane, described method comprises: approximately-50 ℃ will comprise to-10 ℃ the temperature approximately compound 17 with following array structure,
First kind of solution of first kind of organic solvent and alkali joins benzene chloro-formic ester, the saturated or aromatic C that comprises that list, two, three (C1-C4) alkyl replaces
5-C
12Chloro-formic ester or C
1-8In second kind of solution of the chloro-formic ester of alkyl and second kind of organic solvent and obtain reaction mixture; And keep the sufficiently long time of reaction mixture and obtain compound 18.
18. the method for claim 17, wherein said alkali is organic bases.
19. the method for claim 18, wherein said alkali is selected from: two (C
1-C
4Alkyl) pyridine, list, two or three (C
1-C
4Alkyl) amine, alkaline-earth metal, alkaline earth metal hydroxides, alkaline-earth metal alkyl oxide and C
1-C
4Lithium alkylide.
20. the method for claim 19, wherein said alkali is triethylamine.
21. the method for claim 17, wherein said first kind of organic solvent and second kind of solvent are selected from: saturated or aromatic C
5-12Hydrocarbon, list, two, three (C
1-4) the alkyl benzene and the benzene that replace.
22. the method for claim 21, wherein said first kind of organic solvent and second kind of solvent are selected from: THF, toluene, methylene dichloride, diethyl ether, benzene and chloroform.
23. the method for claim 22, wherein said first kind of organic solvent and second kind of organic solvent are toluene or THF.
24. the method for claim 17, wherein said first kind of organic solvent is identical with second kind of organic solvent.
25. the method for claim 17, wherein said C
1-8The chloro-formic ester of alkyl is C
1-4The chloro-formic ester of alkyl.
26. the method for claim 25, wherein said C
1-4The chloro-formic ester of alkyl is Vinyl chloroformate or methyl-chloroformate.
27. the method for claim 26, wherein said C
1-4The chloro-formic ester of alkyl is a Vinyl chloroformate.
28. the method for claim 17, wherein the mol ratio at chloro-formic ester described in the described reaction mixture and compound 17 is about 1 mole: about 3 moles.
29. the method for claim 28, wherein the mol ratio at chloro-formic ester described in the described reaction mixture and compound 17 is about 1 mole: about 1.5 moles.
30. the method for claim 17 is wherein mixed with second kind of solution described first kind of solution under about-50 ℃ to about-30 ℃ temperature.
31. the method for claim 30, wherein said temperature are-45 ℃ to-40 ℃ approximately approximately.
32. the method for claim 17 is wherein kept described reaction mixture, is heated to-10 ℃ to about 30 ℃ approximately simultaneously gradually.
33. the method for claim 30 is wherein kept described reaction mixture, is heated to about 0 ℃ gradually simultaneously.
34. the method for claim 17, the wherein compound 18 of the following structure of recovery from described reaction mixture:
Wherein W is a carboxy protective group, and X is a hydroxy-protective group, and Z is C
1-8Alkyl.
35. prepare the method for rochovastatin and salt thereof, comprise that the method according to claim 17 prepares compound 18, and be converted into rochovastatin or its salt.
36. be prepared as follows the method for the compound 20 of structure,
Wherein W is a carboxy protective group, and X is a hydroxy-protective group, and described method is included in the compound 19 that following structure is provided in the inert atmosphere
Wherein W be carboxy protective group and X be hydroxy-protective group,
The compound 14 of following structure
With appropriate organic solvent except that acetonitrile and obtain reaction mixture;
And at about 70 ℃ of described reaction mixtures of heating and obtain compound 20 under about reflux temperature.
37. the method for claim 36, wherein said organic solvent are selected from saturated and aromatic C
5-C
12Hydrocarbon, list, two, three (C
1To C
4) the alkyl benzene and the benzene that replace.
38. the method for claim 36, wherein with respect to compound 14, the amount of compound 19 is 1.5 equivalents.
39. the method for claim 36, wherein said organic solvent is a toluene.
40. the method for claim 36, wherein with respect to compound 14, the amount of described organic solvent is about 10 times of volumes.
41. the method for claim 36 wherein heats described reaction mixture down at about 70 ℃ to about 110 ℃.
42. the method for claim 41 wherein heats described reaction mixture down at about 70 ℃ to about 110 ℃.
43. the method for claim 36 is wherein measured by HPLC, compound 14 is present in the compound 20 with the content less than 5%.
44. the method for claim 42 is wherein measured by HPLC, compound 14 is present in the compound 20 with the content less than 2%.
45. the method for claim 36 has wherein formed triphenylphosphine oxide, and it is removed from described reaction mixture.
46. the method for claim 36, wherein compound 20 further is converted into the compound 21 of following structure:
Wherein W is a carboxy protective group.
47. reclaim the method for the compound 21 of following structure:
Wherein W is a carboxy protective group, described method comprises: the two-phase system that provides the mixture by the mixture of the mixture of nonpolar fatty family solvent and nonpolar aromatic solvent and lower aliphatic alcohols and water to constitute, with respect to compound 21 and compound 21 crude products, the content of each is about 4 to about 6 times of volumes; Mixture washing nonpolar phase with the pure and mild water of lower aliphatic; And from organic phase, reclaim compound 21.
48. the method for claim 47 is wherein measured by HPLC, the purity of the compound 21 that is reclaimed is greater than about 80%.
49. the method for claim 48 is wherein measured by HPLC, the purity of the compound 21 that is reclaimed is greater than about 90%.
50. the method for claim 49, wherein productive rate is greater than about 90%.
51. the method for claim 50, wherein productive rate is greater than about 95%.
52. the method for claim 47, wherein with respect to compound 21, each in nonpolar aliphatic solvent, nonpolar aromatic solvent, the pure and mild water of lower aliphatic all exists with the equal volume of about 5 times of volumes.
53. the method for claim 47, wherein said nonpolar aliphatic solvent is a heptane.
54. the method for claim 47, wherein said nonpolar aromatic solvent is a toluene.
55. the method for claim 47, wherein said lower aliphatic alcohols is an ethanol.
56. the method for claim 47, wherein said two-phase system obtains by at room temperature mixing up to obtaining clarifying solvent, and this moment, mixture was allowed to be separated into different phases.
57. the method for claim 47, wherein the mixture with polar solvent and water divides many batches to wash nonpolar phase.
58. the method for claim 57 wherein divides about 4 batches to about 5 batches to wash.
59. the method for claim 47, wherein the ratio of ethanol and water is about 2: 1 volume ratio.
60. the method for claim 47, wherein with respect to compound 21, described alcoholic acid amount is about 4 to about 6 times of volumes.
61. the method for claim 60, wherein with respect to compound 21, described alcoholic acid amount is about 5 times of volumes.
62. the method for claim 47, wherein with respect to compound 21, the amount of described water is about 8 to about 12 times of volumes.
63. the method for claim 62, wherein with respect to compound 21, the amount of described water is about 10 times of volumes.
64. the method for preparation rochovastatin and its pharmaceutically-acceptable salts comprises:
A., the Compound I of following structure and the solution of polar solvent are provided,
Wherein Y is C
1-C
4Ester, W are carboxy protective groups, and X is a hydroxy-protective group;
B. this solution is mixed with alkali and obtains about 10 to about 13 pH, thereby form first kind of solution of the compound 17 that comprises following structure,
Wherein W is a carboxy protective group, and X is a hydroxy-protective group;
C. add and comprise list, two, three (C
1-C
4) alkyl the benzene chloro-formic ester, the saturated or aromatic C that replace
5-C
12Chloro-formic ester or C
1-8Second kind of solution of the chloro-formic ester of alkyl and organic solvent and obtain reaction mixture keeps approximately-50 ℃ simultaneously to-10 ℃ temperature approximately;
D. keep the compound 18 of reaction mixture time enough to obtain following structure:
Wherein W is a carboxy protective group, and X is a hydroxy-protective group, and Z is C
1-8Alkyl;
E. compound 18 is transformed into the compound 19 of following structure
Wherein W is that carboxy protective group and X are hydroxy-protective groups;
F. with the compound 14 of compound 19 with following structure
Mix with the appropriate organic solvent except that acetonitrile, in inert atmosphere such as argon gas or nitrogen, obtain reaction mixture;
G. obtain the compound 20 of following structure in about 70 ℃ of following reflux described reaction mixture for some time
Wherein W is that carboxy protective group and X are hydroxy-protective groups;
H. compound 20 is transformed into the compound 21 of following structure
Wherein W is a carboxy protective group;
I. randomly reclaim compound 21: the biphasic system that provides the mixture by the mixture of the mixture of nonpolar fatty family solvent and nonpolar aromatic solvent and lower aliphatic alcohols and water to constitute by following manner, with respect to compound 21 and compound 21 crude products, the content of each is about 4 to about 6 times of volumes; Mixture washing nonpolar phase with the pure and mild water of lower aliphatic; And from organic phase, reclaim compound 21;
J. compound 21 is changed into the compound 22 of following structure
Wherein W is a carboxy protective group;
K. compound 22 is transformed into rochovastatin.
65. the method for claim 64, wherein
A. by from step b., reclaiming the compound 17 of following structure
Wherein W is a carboxy protective group, and X is a hydroxy-protective group,
This be by: from first kind of solution the evaporation a part of solvent; Add entry; Use C
5-7The alkane washing; With being selected from saturated or aromatic C
5-C
12Hydrocarbon, list, two, three (C
1-C
4) organic solvent extraction of the benzene that replaces of alkyl; With mineral acid described mixture being acidified to pH is about 7 to about 5; And from organic phase, reclaim compound 17 and realize; And
B. compound 17 is mixed with first kind of organic solvent and alkali and form the first kind of solution that comprises compound 17.
66. the method for claim 64 wherein further is transformed into resulting rochovastatin pharmaceutically acceptable rochovastatin salt.
67. the method for claim 66, wherein said rochovastatin salt is calcium salt.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65558005P | 2005-02-22 | 2005-02-22 | |
| US60/655,580 | 2005-02-22 | ||
| US60/676,388 | 2005-04-28 | ||
| US60/723,491 | 2005-10-03 | ||
| US60/723,875 | 2005-10-04 | ||
| US60/732,979 | 2005-11-02 | ||
| US60/751,079 | 2005-12-15 | ||
| US60/760,506 | 2006-01-19 | ||
| US60/762,348 | 2006-01-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101119975A true CN101119975A (en) | 2008-02-06 |
Family
ID=39055581
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800056424A Pending CN101128437A (en) | 2005-02-22 | 2006-02-22 | Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof |
| CNA200680005200XA Pending CN101119975A (en) | 2005-02-22 | 2006-02-22 | Preparation of rosuvastatin |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800056424A Pending CN101128437A (en) | 2005-02-22 | 2006-02-22 | Rosuvastatin and salts thereof free of rosuvastatin alkylether and a process for the preparation thereof |
Country Status (2)
| Country | Link |
|---|---|
| KR (1) | KR101045895B1 (en) |
| CN (2) | CN101128437A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584717A (en) * | 2011-01-17 | 2012-07-18 | 浙江九洲药业股份有限公司 | Intermediate for preparing rosuvastatin and preparation method and application thereof |
| CN103421037A (en) * | 2013-09-03 | 2013-12-04 | 浙江新东港药业股份有限公司 | 1-ethoxycarbonyl-5-methyl-(3R)-tert-butydimethylsilyloxy glutarate synthesizing process |
| CN104130281A (en) * | 2014-08-05 | 2014-11-05 | 苏州维永生物医药技术有限公司 | Method for preparing rosuvastatin calcium intermediate |
| CN104262383A (en) * | 2014-03-31 | 2015-01-07 | 南京欧信医药技术有限公司 | Method for synthesizing compound |
| CN104292252A (en) * | 2014-09-19 | 2015-01-21 | 浙江科技学院 | Synthesis technology of 1-ethoxycarbonyl-5-methyl-(3R)-(tert-butyldimethylsilyloxy) glutaric ester |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2003228010A1 (en) * | 2002-05-21 | 2003-12-02 | Ranbaxy Laboratories Limited | Process for the preparation of rosuvastatin |
-
2006
- 2006-02-22 CN CNA2006800056424A patent/CN101128437A/en active Pending
- 2006-02-22 KR KR1020097020417A patent/KR101045895B1/en not_active IP Right Cessation
- 2006-02-22 CN CNA200680005200XA patent/CN101119975A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102584717A (en) * | 2011-01-17 | 2012-07-18 | 浙江九洲药业股份有限公司 | Intermediate for preparing rosuvastatin and preparation method and application thereof |
| CN102584717B (en) * | 2011-01-17 | 2014-12-10 | 浙江九洲药业股份有限公司 | Intermediate for preparing rosuvastatin and preparation method and application thereof |
| CN103421037A (en) * | 2013-09-03 | 2013-12-04 | 浙江新东港药业股份有限公司 | 1-ethoxycarbonyl-5-methyl-(3R)-tert-butydimethylsilyloxy glutarate synthesizing process |
| CN103421037B (en) * | 2013-09-03 | 2015-12-23 | 浙江新东港药业股份有限公司 | The synthesis technique of 1-ethoxycarbonyl-5-methyl-(3R)-tertiary butyl dimethylsilyloxy glutarate |
| CN104262383A (en) * | 2014-03-31 | 2015-01-07 | 南京欧信医药技术有限公司 | Method for synthesizing compound |
| CN104130281A (en) * | 2014-08-05 | 2014-11-05 | 苏州维永生物医药技术有限公司 | Method for preparing rosuvastatin calcium intermediate |
| CN104292252A (en) * | 2014-09-19 | 2015-01-21 | 浙江科技学院 | Synthesis technology of 1-ethoxycarbonyl-5-methyl-(3R)-(tert-butyldimethylsilyloxy) glutaric ester |
| CN104292252B (en) * | 2014-09-19 | 2017-01-18 | 浙江科技学院 | Synthesis technology of 1-ethoxycarbonyl-5-methyl-(3R)-(tert-butyldimethylsilyloxy) glutaric ester |
Also Published As
| Publication number | Publication date |
|---|---|
| KR20090110883A (en) | 2009-10-22 |
| CN101128437A (en) | 2008-02-20 |
| KR101045895B1 (en) | 2011-07-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100945763B1 (en) | Preparation of rosuvastatin | |
| US20070037979A1 (en) | Preparation of rosuvastatin | |
| KR910003428B1 (en) | Imidazole analogs of mevalon-alactone and derivatives thereof | |
| CN1821242B (en) | Novel method for preparing dihydroxy acid HMG CoA reductase inhibitor | |
| CN101675058A (en) | Process for production of prasugrel hydrochloride having high purity | |
| CN100378081C (en) | Process for the manufacture of organic compounds | |
| CN101119975A (en) | Preparation of rosuvastatin | |
| CN102143967A (en) | Purification method for adefovir dipivoxil | |
| WO2008053334A2 (en) | An improved process for preparing rosuvastatin calcium | |
| JPH01213277A (en) | Novel hmg-coa reductase inhibitor | |
| US4645854A (en) | Process for preparing HMG-CoA reductase inhibitors with a 3,5-dihydroxypentanoate subunit | |
| CN103483393A (en) | Preparation method of chiral intermediate for synthesizing statins | |
| US20090069563A1 (en) | Rosuvastatin intermediates and their preparation | |
| CN103804414B (en) | For the preparation of rosuvastain calcium midbody compound and prepared the method for rosuvastain calcium by it | |
| CN102212081B (en) | Preparation method of chiral intermediate product for synthesis of statins | |
| EP0164049B1 (en) | Process for preparing hmg-coa reductase inhibtors with a 3,5-dihydroxypentanoate subunit | |
| MX2007006647A (en) | Preparation of rosuvastatin. | |
| CN101316825A (en) | Preparation of rosuvastatin | |
| CN101591302B (en) | Preparation technique of heptenoic acid ester derivative | |
| CN101918416A (en) | 1 of preparation replacement, the method for 3-oxathiolane, especially lamivudine and intermediate | |
| CN103288871A (en) | Intermediate for preparing dihydroxy acid HMG-CoA reductase inhibitor, and preparation method and applications thereof | |
| CN1207740A (en) | Novel intermediates and their use to prepare N,N'-bridged bisindolylmaleimides | |
| EP0456214A1 (en) | Fluorinated derivatives of mevinic acids | |
| JPS61267571A (en) | 2-(4-chlorophenoxy)-2-methylpropionic acid ester and antilipemic agent containing said compound as active constituent | |
| CN102898367B (en) | Preparation method of pitavastatin calcium crude drug midbody |
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 |
Open date: 20080206 |