CN111454216A - Process for the preparation of HMG-CoA reductase inhibitors and intermediates thereof - Google Patents
Process for the preparation of HMG-CoA reductase inhibitors and intermediates thereof Download PDFInfo
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- CN111454216A CN111454216A CN202010399868.9A CN202010399868A CN111454216A CN 111454216 A CN111454216 A CN 111454216A CN 202010399868 A CN202010399868 A CN 202010399868A CN 111454216 A CN111454216 A CN 111454216A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 37
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 title claims abstract description 11
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 title claims abstract description 10
- 238000000034 method Methods 0.000 title claims description 15
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 title claims description 4
- 239000000543 intermediate Substances 0.000 title abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 104
- 238000006243 chemical reaction Methods 0.000 claims abstract description 48
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 58
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 41
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 36
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 26
- 239000002904 solvent Substances 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 16
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- -1 tetraTetrahydrofuran Chemical compound 0.000 claims description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 239000008213 purified water Substances 0.000 claims description 12
- 238000000926 separation method Methods 0.000 claims description 11
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 238000010791 quenching Methods 0.000 claims description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].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.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 LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 claims description 8
- 229960004796 rosuvastatin calcium Drugs 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 7
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 7
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 7
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- 229910017604 nitric acid Inorganic materials 0.000 claims description 7
- 230000000171 quenching effect Effects 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 claims description 5
- 239000001639 calcium acetate Substances 0.000 claims description 5
- 235000011092 calcium acetate Nutrition 0.000 claims description 5
- 229960005147 calcium acetate Drugs 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 3
- 150000003863 ammonium salts Chemical class 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000001967 indiganyl group Chemical group [H][In]([H])[*] 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- JIWDQJYCCQFDAF-UHFFFAOYSA-N potassium;2-methylpropan-2-olate;oxolane Chemical compound [K+].CC(C)(C)[O-].C1CCOC1 JIWDQJYCCQFDAF-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000007787 solid Substances 0.000 abstract description 9
- 238000000746 purification Methods 0.000 abstract description 5
- 150000001336 alkenes Chemical class 0.000 abstract description 3
- 239000000463 material Substances 0.000 abstract description 3
- 230000008030 elimination Effects 0.000 abstract description 2
- 238000003379 elimination reaction Methods 0.000 abstract description 2
- 239000012535 impurity Substances 0.000 abstract description 2
- 238000006317 isomerization reaction Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 20
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 8
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000002585 base Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229960000672 rosuvastatin Drugs 0.000 description 3
- 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 description 3
- 239000000126 substance Substances 0.000 description 3
- 102100029077 3-hydroxy-3-methylglutaryl-coenzyme A reductase Human genes 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- MMTXSCWTVRMIIY-PHDIDXHHSA-N (3r,5s)-3,5-dihydroxyhept-6-enoic acid Chemical compound OC(=O)C[C@H](O)C[C@H](O)C=C MMTXSCWTVRMIIY-PHDIDXHHSA-N 0.000 description 1
- LVUQCTGSDJLWCE-UHFFFAOYSA-N 1-benzylpyrrolidin-2-one Chemical compound O=C1CCCN1CC1=CC=CC=C1 LVUQCTGSDJLWCE-UHFFFAOYSA-N 0.000 description 1
- 101710158485 3-hydroxy-3-methylglutaryl-coenzyme A reductase Proteins 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 102000006410 Apoproteins Human genes 0.000 description 1
- 108010083590 Apoproteins Proteins 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 239000012028 Fenton's reagent Substances 0.000 description 1
- 208000030673 Homozygous familial hypercholesterolemia Diseases 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- 206010049287 Lipodystrophy acquired Diseases 0.000 description 1
- 206010045261 Type IIa hyperlipidaemia Diseases 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- QGAVSDVURUSLQK-UHFFFAOYSA-N ammonium heptamolybdate Chemical compound N.N.N.N.N.N.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.O.[Mo].[Mo].[Mo].[Mo].[Mo].[Mo].[Mo] QGAVSDVURUSLQK-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000003028 elevating effect Effects 0.000 description 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 208000006132 lipodystrophy Diseases 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- PFUVRDFDKPNGAV-UHFFFAOYSA-N sodium peroxide Chemical compound [Na+].[Na+].[O-][O-] PFUVRDFDKPNGAV-UHFFFAOYSA-N 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of HMG-CoA reductase inhibitor and intermediate thereof, wherein a new compound with Evans prosthetic group structure is introduced as a key intermediate in the synthetic route, JU L IA is adopted to form alkene, so that the selectivity of E/Z is improved, the condition is mild when the prosthetic group is removed, the isomerization and impurity elimination can be avoided, the synthetic route is simple, the key intermediates (the compound of formula 5 and the compound of formula 6) are solid, and the product purification and material scientific putting reaction are facilitated, so that a high-purity product is obtained.
Description
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a preparation method of an HMG-CoA reductase inhibitor and an intermediate thereof.
Background
Rosuvastatin (Rosuvastatin) is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme a reductase (HMG-CoA reductase), and can be used for the treatment of hypercholesterolemia and mixed dyslipidemia, and can reduce elevated concentrations of low density cholesterol, total cholesterol, triglycerides and apoprotein B, while elevating the concentration of high density cholesterol; can be used for the comprehensive treatment of primary hypercholesterolemia, mixed lipodystrophy and homozygous familial hypercholesterolemia, and is called super statin.
Rosuvastatin is administered as its calcium salt in therapy and is a single enantiomer, marketed in several countries and regions of the united states, japan, europe, china, etc., with the chemical name bis- [ E-7- [4- (4-fluorophenyl) -6-isopropyl-2- [ methyl (methylsulfonyl) amino ] -pyrimidin-5-yl ] (3R,5S) -3, 5-dihydroxyhept-6-enoic acid ] calcium salt (2: 1) and the chemical structure is as follows:
at present, a plurality of synthetic routes of rosuvastatin calcium are reported, but most of the synthetic routes are developed for avoiding the technical protection of original manufacturers.
For example: the synthesis methods are reported in EP0521471A1 and WO0049014A1, but the multi-step synthesis intermediates of the synthesis routes disclosed by the methods are oily substances, and most synthesis processes adopt WITIG reaction, so that the Z/E selectivity is poorly controlled.
The side chain synthesized by the synthesis method disclosed by CN201910190264 is oxidized from olefin to aldehyde, the yield is not high, and the product purity is not high easily due to the use of an oxidation system.
In general, the technical problems of the current synthetic routes are: the synthetic route is complex, the quality control and purification of oily intermediates are difficult, the E/Z selectivity needs to be improved, and higher product purity is difficult to obtain.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of an HMG-CoA reductase inhibitor and an intermediate thereof. A new compound with an Evans prosthetic group structure is introduced into the synthetic route as a key intermediate, so that the intermediate involved in the whole synthetic route is solid and convenient to purify, the provided E/Z selectivity is improved, and the product purity is high.
In order to solve the technical problems, the invention provides the following technical scheme:
in one aspect, the present invention provides a method for preparing an HMG-CoA reductase inhibitor, which comprises converting a compound of formula 6 into a compound of formula 8:
< formula 8>
< formula 6>
Wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
Further, the compound of formula 6 is oxidized under the action of alkali, and after the reaction is finished, the compound is regulated by acid, separated and reacted with a calcium reagent to prepare the compound of formula 8. Further, the reaction is carried out in a solvent selected from the group consisting of THF, dichloromethane, water, C1-C10 alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), dichloromethane, acetonitrile, and mixtures thereof; preferred are THF/water mixtures in a volume ratio of 1:1,1:2,1:3, 2:1,3:1, etc.
Still further, the base includes sodium hydroxide, lithium hydroxide, potassium carbonate, potassium phosphate, potassium hydrogen phosphate, ammonia water, and the like.
Furthermore, the oxidizing agent used in the oxidation reaction comprises hydrogen peroxide, sodium peroxide, Fenton reagent and the like.
Still further, the acid is hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid, and mixtures thereof; preferably an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid. Furthermore, the mass percentage concentration of the acid is 1-5%, and preferably 3%.
Further, the separation process is as follows: and adding an ether solvent into the mixture after acid adjustment for extraction and separation, and directly reacting the solvent layer with a calcium reagent after concentration. Ether type solvents include MTBE, THF, CPME and the like.
Further, the separation process is as follows: MTBE (methyl tert-butyl ether) is added into the mixture after the pH value is adjusted to 9-10 by acid for extraction and separation, and an MTBE layer is directly used for reaction with calcium acetate after being concentrated.
In another aspect, the invention provides a compound of formula 6:
< formula 6>
Wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
In yet another aspect, the present invention provides a method for preparing a compound of formula 6, comprising converting a compound of formula 5 into a compound of formula 6:
< formula 5>
Wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
Further, the compound of formula 5 is hydrolyzed by acid to prepare the compound of formula 6. Still further, the acid is hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid, and mixtures thereof; preferably an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid; further, the acid has a concentration of, by mass percent1 to 10%, preferably 1 to 5%, preferably 5%. Further, the reaction is carried out in a solvent selected from the group consisting of THF, dichloromethane, water, C1-10Alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), dichloromethane, acetonitrile, and mixtures thereof.
In another aspect, the invention provides a compound of formula 5:
< formula 5>
Wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
In yet another aspect, the present invention provides a method for preparing a compound of formula 5, comprising reacting a compound of formula 4 with a compound of formula Z9 to prepare a compound of formula 5:
wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
Further, the compound of the formula 4 and the compound of the formula Z9 react under the action of alkali, and the compound of the formula 5 is prepared after quenching by ammonium salt.
Further, the base is a potassium alkoxide/alcohol reagent, a sodium alkoxide/alcohol reagent, or the like; the alcohol is C1-4Alcohols of (a), for example: methanol and ethanolN-propanol, isopropanol, n-butanol, tert-butanol, and the like. The ammonium salt is ammonium chloride and the like. The reaction is carried out in a reagent of THF, dichloromethane, water, C1-C10 alcohols (such as methanol, ethanol, isopropanol, butanol, etc.), dichloromethane, acetonitrile and mixtures thereof. The base is mixed with a solvent and then added dropwise before being added to the reaction system.
In another aspect, the present invention provides a compound of formula 4:
< formula 4>
Wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
In yet another aspect, the present invention provides a method for preparing a compound of formula 4, comprising reacting a compound of formula 3, DCC, R-pyrrolidone, and DMAP to produce a compound of formula 4:
wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group.
Further, the reaction is carried out in a solvent, which is water, a C1-C10 alcohol (such as methanol, ethanol, isopropanol, butanol, etc.), dichloromethane, tetrahydrofuran, acetonitrile, and mixtures thereof. The reaction is carried out at room temperature. The molar ratio of the compound of the formula 3 to the DCC to the R-pyrrolidone is 1:1: 2. The DMAP was used in an amount of 10% wt of the total reactants.
On one hand, the invention provides a preparation method of rosuvastatin calcium, which comprises the following specific steps:
1) preparation of the Compound of formula 2
PMTA、Na2CO3And the compound of the formula 1 are heated to react to obtain a compound of a formula 2;
2) preparation of the Compound of formula 3
A compound of formula 2, amine heptamolybdate and H2O2Stirring and reacting to obtain a compound shown in a formula 3;
3) preparation of the Compound of formula 4
Reacting the compound of the formula 3, R-pyrrolidone, DCC and DMAP to obtain a compound of a formula 4; wherein R is H, alkyl, phenyl, benzyl, etc.; further, R is H, C1-12Alkyl, phenyl, benzyl, etc.; further, R is H, C1-6Alkyl, phenyl, benzyl, etc.; further, R is H, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, phenyl, benzyl, etc. R may be further substituted with any group;
4) preparation of Compounds of formula 5
Dripping t-BuOK THF/t-BuOH solution into the mixed solution of the compound of the formula 4 and the compound of the formula Z-9, continuing the reaction after the addition is finished, and dripping saturated ammonium chloride after the reaction is finished to quench to obtain a compound of the formula 5;
5) preparation of the Compound of formula 6
Dissolving the compound shown in the formula 5 in THF, dropwise adding acid, and stirring to complete hydrolysis to obtain a compound shown in the formula 6;
6) preparation of the Compound of formula 7
Compounds of formula 6 with L iOH and H2O2After the stirring reaction is completed, the mixture obtained by post-treatment is directly used for the next reaction;
7) preparation of the Compound of formula 8
Adding purified water into the mixture obtained in the last step for dissolving, dropwise adding a calcium acetate solution, stirring for reacting, centrifuging, leaching purified water, and spin-drying to obtain a rosuvastatin calcium wet refined product;
further, in step 1), the PMTA and Na2CO3And the compound of formula 1 in a molar ratio of 1:1 to 1.5: 1; preferably 1:1.2: 1; the temperature of the heating reaction is 90 ℃; the reaction is carried out in a solvent, wherein the solvent is water and C1-10Alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), DMF, tetrahydrofuran, acetonitrile, and mixtures thereof.
Further, in the step 2), the reaction is carried out in a solvent at room temperature, wherein the solvent is water and C1-10Alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), DMF, tetrahydrofuran, acetonitrile, and mixtures thereof. In the invention, the room temperature is 15-35 ℃, for example: 25 ℃,18 ℃ and the like.
Further, in the step 3), the molar ratio of the compound of the formula 3 to the R-pyrrolidone to the DCC is 1:1: 2; the reaction is carried out in a solvent at room temperature, wherein the solvent is water and C1-10Alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), DMF, dichloromethane, tetrahydrofuran, acetonitrile, and mixtures thereof.
Further, in the step 4), the reaction is carried out in a solvent at room temperature, wherein the solvent is water and C1-10Alcohols (e.g., methanol, ethanol, isopropanol, butanol, etc.), DMF, dichloromethane, tetrahydrofuran, acetonitrile, and mixtures thereof.
Further, in step 5), the reaction is carried out at room temperature, and further, the acid is hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid and a mixture thereof; preferably an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or nitric acid; furthermore, the mass percentage concentration of the acid is 1-10%, preferably 1-5%, preferably 5%.
Further, in step 6), the compound of formula 6 is dissolved in THF/H2In O, with L iOH and H2O2After the stirring reaction is completed, saturated sodium bisulfite quenches hydrogen peroxide, and thenRemoving THF by pressure distillation, adding purified water, adjusting pH to 9-10 by 3% HCl, adding MTBE into the reactor, stirring, separating liquid, washing the water phase once again by the MTBE, distilling at 40 +/-5 ℃ under reduced pressure until the MTBE is less than or equal to 5000ppm, and directly using the obtained mixture for the next reaction.
Advantageous effects
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a preparation method of an HMG-CoA reductase inhibitor and an intermediate thereof.A new compound with an Evans prosthetic group structure is introduced as a key intermediate in a synthetic route, JU L IA is adopted to form alkene, so that the selectivity of E/Z is improved, the conditions are mild when the prosthetic group is removed, the isomerization and impurity elimination can be avoided, the synthetic route is simple, the key intermediates (a compound shown in a formula 5 and a compound shown in a formula 6) are solid, the product purification and the material scientific putting reaction are facilitated, and the high-purity product is obtained.
At present, JU L IA alkene-forming reaction mostly needs ultralow temperature and expensive strong base, materials used in the synthesis route are all reagents with low price or easy obtaining in the conventional way, and the alkene-forming reaction is carried out at relatively high temperature, so that the operation is simple, the cost is low, and the pollution is small.
In the process of synthesizing rosuvastatin calcium, the harsh conditions of low-temperature reaction (the lowest temperature of the invention is only-40 ℃) are avoided, most of the intermediate synthesis process can be carried out at room temperature, the industrial production is more favorably realized, and the yield and the purity of the synthesized product are improved.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments, but it should not be construed that the scope of the subject matter of the present invention is limited to the examples.
The process equipment or devices not specifically noted in the following examples are conventional in the art; all reagents are commercially available.
Example 1
Preparation of Compound 2
PMTA (3.2g,18.0mmol) was dissolved in DMF (20m L) at room temperatureAdding Na for a while2CO3(2.2g,21.6mmol) and Compound 1(4g,18mmol), heated to 90 deg.C for 24h, and detected by L C-Ms.
After addition of 10m L water, pH 5-6 adjusted with 10% HCl, extraction with dichloromethane (40m L× 2), combination of organic phases, water (10m L× 2), drying and concentration in vacuo at 40 ℃ gave an oil which was used in the next step.
LC-Ms：[M+H]＝365.20。
Preparation of Compound 3
To the oil from the previous step, iPrOH (20m L) was added at room temperature followed by amine heptamolybdate (1.1g) and H2O2(20m L), after the addition, the reaction was stirred for 18h at 25 ℃ and was detected to be complete by L c-Ms.
After extraction and liquid separation by adding 60m L dichloromethane, saturated sodium bisulfite is used for quenching hydrogen peroxide, liquid separation is carried out, the organic phase is washed by 20m L water, drying and vacuum concentration at 40 ℃ is carried out to obtain 4g of product, and the total yield of the two steps is 56%.
LC-Ms：[M+H]＝397.05
Preparation of Compound 4
At room temperature, 30M L dichloromethane was added to compound 3(4g,10.1mmol), followed by benzyl pyrrolidone (1.78g,10.1mmol), DCC (4.16g,20.2mmol) and DMAP (0.4g, 10% wt) in that order, stirring was continued for 18h, vacuum concentration was performed, and purification by column chromatography (EA/PE ═ 1:2) gave 4.9g product, yield 87%, [ M + Na ] ═ 578.15 ] L C-Ms: (M + Na ]: 578.15)
Preparation of Compound 5
Compound 4(4.0g, 7.20mmol) and Z-9(2.53g, 7.20mmol) were dissolved in 40m L THF at room temperature, cooled to-40 ℃, t-BuOK (1.1eq) in THF/t-BuOH was added dropwise, the reaction was continued for 4h, quenched with 10m L saturated ammonium chloride, warmed to room temperature, separated by stirring, and concentrated in vacuo at 40 ℃ to give an oil which was purified by column chromatography (EA/PE ═ 1:4) to give 3.8g of a white solid (R ═ benzyl) in 78% yield.
HNMR(CDCl3，400M)：(ppm)：1.30(8H,m),1.41(3H,s),1.55(3H,s),2.68(1H,dd),3.05(1H,dd),3.20(1H,dd),3.30(1H,dd),3.41(1H,m),3.51(3H,s),3.60(3H,s),4.20(2H,m) ,4.51(2H,m),4.71(1H,m),5.52(1H,dd),6.55(1H,d),7.11(2H,m),7.25(5H,m),7.68(2H,m)
Preparation of Compound 6
Compound 5(3.5g, 5.15mmol) was dissolved in THF (35m L) at rt, 5% diluted hydrochloric acid was added dropwise to pH 2-4, stirred for 2h, hydrolysis was complete EA (50m L) was added and extracted once and washed with saturated brine (15m L), separated, and the organic phase was concentrated in vacuo to give 3.1g of a white solid (R ═ benzyl) in 95% yield.
LC-Ms：[M+H]＝641.15
HNMR(CDCl3，400M)：(ppm)：1.35(2H,m),1.45(3H,s),1.60(3H,s),2.70(1H,dd),3.10(1H,dd),3.25(1H,dd),3.35(1H,dd),3.42(1H,m),3.52(3H,s),3.62(3H,s),4.21(2H,m) ,4.52(2H,m),4.71(1H,m),5.52(1H,dd),6.60(1H,d),7.15(2H,m),7.28(5H,m),7.70(2H,m)
Preparation of Compound 7
Compound 6(1.1g,1.7mmol) was dissolved in THF/H at 0 deg.C2To O, L iOH (0.5g,20.8mmol) and H were added sequentially2O2(2m L), after the reaction is completely stirred, quenching hydrogen peroxide by saturated sodium bisulfite, removing THF by reduced pressure distillation, adding purified water (3m L/g), adjusting the pH to 9-10 by 3% HCl, adding MTBE (8m L/g) into the reactor, stirring for 30min, separating liquid, washing the water phase once again by MTBE (8m L/g), reducing the pressure distillation at 40 +/-5 ℃ until the MTBE is less than or equal to 5000ppm, and directly using the obtained water liquid for the next reaction
Preparation of API
Adding purified water (20m L) into the water solution obtained in the last step, controlling the temperature to 25 ℃, dropwise adding a calcium acetate (12.3g) solution, stirring for 30min after dropwise adding, carrying out suction filtration, washing with purified water to obtain a rosuvastatin calcium wet refined product, carrying out vacuum drying at 50 +/-5 ℃ until the water content is less than or equal to 3.0 percent to obtain 0.61g of white solid, wherein the yield in the two steps is 71 percent, and the purity is 99.9 percent.
Example 2
Preparation of Compound 2
PMTA (12.0g,67.5mmol) was dissolved in DMF (50m L) at room temperature and Na was added sequentially2CO3(7.1g,67.5mmol) and Compound 1(10g,45.0mmol) were heated to 90 ℃ and reacted for 24h to completion.
After addition of 25m L water, pH 5-6 adjusted with 10% HCl, extraction with dichloromethane (100m L× 2), combination of organic phases, water (25m L× 2), drying and concentration in vacuo at 40 ℃ gave an oil which was used in the next step.
Preparation of Compound 3
To the oil from the previous step, iPrOH (50m L) was added at room temperature followed by ammonium heptamolybdate (2.7g) and H2O2(50m L), and stirring the reaction at 25 ℃ for 18h to complete the reaction.
After 150m L dichloromethane extraction liquid separation, saturated sodium hydrogen sulfite is used for quenching hydrogen peroxide, liquid separation is carried out, 50m L water is used for washing an organic phase, drying is carried out, vacuum concentration is carried out at 40 ℃, 12.0g of a product is obtained, and the total yield of the two steps is 68%.
Preparation of Compound 4
80M L M dichloromethane was added to compound 3(12.0g,30.4mmol) at room temperature followed by pyrrolidone (2.6g,30.4mmol), DCC (12.5g,60.8mmol) and DMAP (1.2g, 10% wt) in that order, stirring was continued for 20h after addition, vacuum concentration was carried out, and column chromatography purification (EA/PE ═ 1:2) gave 11.5g product, 81% yield L c-Ms: [ M + Na ] ═ 488.12
Preparation of Compound 5
Compound 4(10.0g, 21.5mmol) and Z-9(7.0g, 20.0mmol) were dissolved in 50m L THF at room temperature, cooled to-40 ℃, t-BuOK (1.1eq) in THF/t-BuOH was added dropwise, the reaction was continued for 4H, quenched with 5m L saturated ammonium chloride dropwise, warmed to room temperature, separated by stirring, and concentrated in vacuo at 40 ℃ to give an oil which was purified by column chromatography (EA/PE ═ 1:4) to give 10.0g of a white solid (R ═ H) in 85% yield.
Lc-Ms:[M+H]＝591.22
HNMR(CDCl3，400M)：(ppm)：1.31(8H,m),1.42(3H,s),1.57(3H,s),2.70(1H,dd),3.10(1H,dd),3.41(1H,m),3.52(3H,s),3.60(3H,s),4.05(2H,t),4.21(2H,m),4.55(2H,t),5. 52(1H,dd),6.55(1H,d),7.11(2H,m),7.68(2H,m)
Preparation of Compound 6
Compound 5(8.0g, 13.5mmol) was dissolved in THF (100m L) at rt, 5% diluted hydrochloric acid was added dropwise to pH 2-4, stirred for 2H, hydrolysis was complete EA (100m L) was added and extracted once and washed with saturated brine (50m L), separated, and the organic phase was concentrated in vacuo to give 7.0g of a white solid (R ═ H) with 94% yield.
Lc-Ms:[M+H]＝551.20
HNMR(CDCl3，400M)：(ppm)：1.36(2H,m),1.45(3H,s),1.61(3H,s),2.70(1H,dd),3.10(1H,dd),3.41(1H,m),3.52(3H,s),3.60(3H,s),4.07(2H,t),4.22(2H,m),4.57(2H,t),5. 53(1H,dd),6.60(1H,d),7.16(2H,m),7.71(2H,m)
Preparation of Compound 7
Compound 6(7.0g, 12.7mmol) was dissolved in THF/H at 0 deg.C2To O, L iOH (3.0g, 12.7mmol) and H were added sequentially2O2(14m L), after the reaction is completely stirred, quenching hydrogen peroxide by saturated sodium bisulfite, removing THF by reduced pressure distillation, adding purified water (3m L/g), adjusting the pH to 9-10 by 3% HCl, adding MTBE (8m L/g) into the reactor, stirring for 30min, separating liquid, washing the water phase once again by MTBE (8m L/g), reducing the pressure and distilling at 40 +/-5 ℃ until the MTBE is less than or equal to 5000ppm, and directly using the obtained water liquid for the next reaction
Preparation of API
Adding purified water (140m L) into the water solution obtained in the last step, controlling the temperature to 25 ℃, dropwise adding a calcium acetate (70g) solution, stirring for 30min after dropwise adding, carrying out suction filtration, washing with purified water, obtaining a rosuvastatin calcium wet refined product, carrying out vacuum drying at 50 +/-5 ℃ until the water content is less than or equal to 3.0%, obtaining 4.7g of white solid, wherein the yield of the two steps is 75%, and the purity is 99.9%.
It will be understood that the above embodiments are merely exemplary embodiments taken to illustrate the principles of the present invention, which is not limited thereto. It will be apparent to those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention, and these changes and modifications are also considered to be included in the scope of the invention.
Claims (6)
1. A process for the preparation of an HMG-CoA reductase inhibitor, comprising:
a) converting the compound of formula 5 to a compound of formula 6:
< formula 5>
Wherein R is H, alkyl, phenyl, benzyl;
or, the compound of formula 5 is hydrolyzed by acid to produce the compound of formula 6;
b) converting the compound of formula 6 to a compound of formula 8:
< formula 8>
< formula 6>
Wherein R is H, alkyl, phenyl, benzyl;
the compound of the formula 6 is subjected to oxidation reaction under the action of alkali, and after the reaction is finished, the compound is subjected to acid regulation and separation and then reacts with a calcium reagent to prepare a compound of a formula 8;
or, the separation process is as follows: and adding an ether solvent into the mixture after acid adjustment for extraction and separation, and directly reacting the solvent layer with a calcium reagent after concentration.
2. The process for the preparation of HMG-CoA reductase inhibitors according to claim 1, comprising the steps of:
1) preparation of the Compound of formula 2
PMTA、Na2CO3And the compound of the formula 1 are heated to react to obtain a compound of a formula 2;
2) preparation of the Compound of formula 3
A compound of formula 2, amine heptamolybdate and H2O2Stirring and reacting to obtain a compound shown in a formula 3;
3) preparation of the Compound of formula 4
Reacting the compound of the formula 3, R-pyrrolidone, DCC and DMAP to obtain a compound of a formula 4; wherein R is H, alkyl, phenyl, benzyl;
4) preparation of Compounds of formula 5
Dripping t-BuOK THF/t-BuOH solution into the mixed solution of the compound of the formula 4 and the compound of the formula Z-9, continuing the reaction after the addition is finished, and dripping saturated ammonium chloride after the reaction is finished to quench to obtain a compound of the formula 5;
5) preparation of the Compound of formula 6
Dissolving the compound shown in the formula 5 in THF, dropwise adding acid, and stirring to complete hydrolysis to obtain a compound shown in the formula 6;
6) preparation of the Compound of formula 7
Compounds of formula 6 with L iOH and H2O2After the stirring reaction is completed, the mixture obtained by post-treatment is directly used for the next reaction;
7) preparation of rosuvastatin calcium
Adding purified water into the mixture obtained in the last step for dissolving, dropwise adding a calcium acetate solution, stirring for reacting, centrifuging, leaching purified water, and spin-drying to obtain a rosuvastatin calcium wet refined product;
3. the process for preparing HMG-CoA reductase inhibitors as claimed in claim 2, wherein in step 1), said PMTA, Na2CO3The mol ratio of the compound to the compound in the formula 1 is 1: 1-1.5: 1; the temperature of the heating reaction is 90 ℃; the reaction is carried out in a solvent, wherein the solvent is water and C1-10Alcohols, DMF, tetrahydrofuran, acetonitrile, and mixtures thereof;
in the step 2), the reaction is carried out in a solvent at room temperature, wherein the solvent is water and C1-10Alcohols, DMF, tetrahydrofuran, acetonitrile, and mixtures thereof;
in the step 3), the molar ratio of the compound of the formula 3, R-pyrrolidone and DCC is 1: 2; the reaction is carried out in a solvent at room temperature, wherein the solvent is water and C1-10Alcohol, DMF, dichloromethane, tetraTetrahydrofuran, acetonitrile and mixtures thereof;
in the step 4), the reaction is carried out in a solvent at room temperature, wherein the solvent is water and C1-10Alcohols, DMF, dichloromethane, tetrahydrofuran, acetonitrile, and mixtures thereof;
in the step 5), the reaction is carried out at room temperature, and the acid is hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, formic acid, sulfonic acid and a mixture thereof;
in step 6), the compound of formula 6 is dissolved in THF/H2In O, with L iOH and H2O2After the reaction is completely stirred, quenching hydrogen peroxide by saturated sodium bisulfite, distilling under reduced pressure to remove THF, adding purified water, adjusting the pH value to 9-10 by 3% HCl, adding MTBE into the reactor, stirring, separating liquid, washing the water phase once by MTBE again, distilling under reduced pressure at 40 +/-5 ℃ until the MTBE is less than or equal to 5000ppm, and directly using the obtained mixture in the next reaction.
4. A compound of formula 5 having the formula:
< formula 5>
Wherein R is H, alkyl, phenyl, benzyl.
5. A method of preparing a compound of formula 5, comprising reacting a compound of formula 4 with a compound of formula Z9 to produce a compound of formula 5:
wherein R is H, alkyl, phenyl, benzyl;
or, the compound of formula 4 and the compound of formula Z9 react under the action of alkali, and the compound of formula 5 is prepared after quenching by ammonium salt.
6. The method of claim 5, comprising reacting the compound of formula 3, DCC, R-pyrrolidone, and DMAP to produce a compound of formula 4:
wherein R is H, alkyl, phenyl, benzyl.
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| CN110642790B (en) | 2021-02-23 |
| CN110642790A (en) | 2020-01-03 |
| CN111454216B (en) | 2021-06-29 |
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