CN115260051A - Preparation process of atorvastatin calcium intermediate - Google Patents
Preparation process of atorvastatin calcium intermediate Download PDFInfo
- Publication number
- CN115260051A CN115260051A CN202211033594.7A CN202211033594A CN115260051A CN 115260051 A CN115260051 A CN 115260051A CN 202211033594 A CN202211033594 A CN 202211033594A CN 115260051 A CN115260051 A CN 115260051A
- Authority
- CN
- China
- Prior art keywords
- reaction
- atorvastatin calcium
- fluorophenyl
- acetophenone
- fluorobenzene
- 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
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 title claims abstract description 21
- 229960001770 atorvastatin calcium Drugs 0.000 title claims abstract description 21
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 99
- 238000000034 method Methods 0.000 claims abstract description 33
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 28
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 26
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 claims abstract description 24
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 21
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229960003424 phenylacetic acid Drugs 0.000 claims abstract description 11
- 239000003279 phenylacetic acid Substances 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 8
- NEJOAEIRBZFRSF-UHFFFAOYSA-N fluorobenzene;1-phenylethanone Chemical compound FC1=CC=CC=C1.CC(=O)C1=CC=CC=C1 NEJOAEIRBZFRSF-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims abstract description 5
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 147
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 81
- 239000012044 organic layer Substances 0.000 claims description 59
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- 238000001914 filtration Methods 0.000 claims description 29
- 238000001035 drying Methods 0.000 claims description 25
- 238000005406 washing Methods 0.000 claims description 23
- 238000001953 recrystallisation Methods 0.000 claims description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 20
- ADHRFDCBLJVNFO-UHFFFAOYSA-N 4-methyl-3-oxo-n-phenylpentanamide Chemical compound CC(C)C(=O)CC(=O)NC1=CC=CC=C1 ADHRFDCBLJVNFO-UHFFFAOYSA-N 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- WHOZHGXCLWPXRD-UHFFFAOYSA-N 1-(4-fluorophenyl)-2-hydroxy-2-phenylethanone Chemical compound C=1C=CC=CC=1C(O)C(=O)C1=CC=C(F)C=C1 WHOZHGXCLWPXRD-UHFFFAOYSA-N 0.000 claims description 11
- 229910021536 Zeolite Inorganic materials 0.000 claims description 11
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 11
- 239000002808 molecular sieve Substances 0.000 claims description 11
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 11
- 239000010457 zeolite Substances 0.000 claims description 11
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 9
- CWYRBOMWOQXYFZ-UHFFFAOYSA-N 2-(4-fluorophenyl)-1-phenylethanone Chemical compound C1=CC(F)=CC=C1CC(=O)C1=CC=CC=C1 CWYRBOMWOQXYFZ-UHFFFAOYSA-N 0.000 claims description 8
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical group C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 230000006837 decompression Effects 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 3
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 230000003113 alkalizing effect Effects 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 26
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 7
- 229910052794 bromium Inorganic materials 0.000 abstract description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000460 chlorine Substances 0.000 abstract description 6
- 229910052801 chlorine Inorganic materials 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 4
- 238000005658 halogenation reaction Methods 0.000 abstract description 4
- 230000001476 alcoholic effect Effects 0.000 abstract description 3
- 230000026030 halogenation Effects 0.000 abstract description 3
- 239000002351 wastewater Substances 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000004065 wastewater treatment Methods 0.000 abstract description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract 1
- BKWBOLGMPNIRIG-UHFFFAOYSA-N n-acetyl-4-phenylbutanamide Chemical compound CC(=O)NC(=O)CCCC1=CC=CC=C1 BKWBOLGMPNIRIG-UHFFFAOYSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 48
- 238000003756 stirring Methods 0.000 description 33
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000000047 product Substances 0.000 description 21
- 238000004809 thin layer chromatography Methods 0.000 description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- 239000010410 layer Substances 0.000 description 15
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 14
- 239000007789 gas Substances 0.000 description 14
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical group Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 10
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 238000005194 fractionation Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000007795 chemical reaction product Substances 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 7
- 238000010791 quenching Methods 0.000 description 7
- 230000000171 quenching effect Effects 0.000 description 7
- 239000000376 reactant Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 238000005292 vacuum distillation Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 5
- 229960005370 atorvastatin Drugs 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- -1 phenylcarbamoyl Chemical group 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 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 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- 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 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 101710095342 Apolipoprotein B Proteins 0.000 description 2
- 102100040202 Apolipoprotein B-100 Human genes 0.000 description 2
- 108010023302 HDL Cholesterol Proteins 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 208000035150 Hypercholesterolemia Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- OGTSHGYHILFRHD-UHFFFAOYSA-N (4-fluorophenyl)-phenylmethanone Chemical compound C1=CC(F)=CC=C1C(=O)C1=CC=CC=C1 OGTSHGYHILFRHD-UHFFFAOYSA-N 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
- SNPBHOICIJUUFB-UHFFFAOYSA-N 2-[2-(4-fluorophenyl)-2-oxo-1-phenylethyl]-4-methyl-3-oxo-n-phenylpentanamide Chemical compound C=1C=CC=CC=1NC(=O)C(C(=O)C(C)C)C(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 SNPBHOICIJUUFB-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000032928 Dyslipidaemia Diseases 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 208000017170 Lipid metabolism disease Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 238000006086 Paal-Knorr synthesis reaction Methods 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000003741 agents affecting lipid metabolism Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 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
- 239000001639 calcium acetate Substances 0.000 description 1
- 235000011092 calcium acetate Nutrition 0.000 description 1
- 229960005147 calcium acetate Drugs 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000006352 cycloaddition reaction Methods 0.000 description 1
- 238000004807 desolvation Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000004989 dicarbonyl group Chemical group 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation process of an atorvastatin calcium intermediate, which comprises the steps of reacting phenylacetic acid with thionyl chloride to obtain phenylacetyl chloride, carrying out friedel-crafts acylation reaction on the obtained phenylacetyl chloride and fluorobenzene under the action of a catalyst and fluorobenzene to obtain 4-fluorobenzene acetophenone, alkalifying a 4-fluorobenzene acetophenone solution, adding a Davis reagent to oxidize and introduce hydroxyl on carbonyl alpha-carbon to obtain 1- (4-fluorophenyl) -2-hydroxy-2-acetophenone, and reacting the 1- (4-fluorophenyl) -2-hydroxy-2-acetophenone with N-phenylbutyryl acetamide under the action of a catalyst to prepare the atorvastatin calcium intermediate M4. The beneficial effects of the invention are: the method has the advantages that the alcoholic hydroxyl group is directly substituted, the byproduct is only one molecule of water, the generation of the byproduct is reduced, the atom economy is realized, the alcohol replaces the original halogenation process, the reaction selectivity is good, no simple substance chlorine or bromine is used, a large amount of chlorine-containing and bromine-containing wastewater cannot be generated, the wastewater treatment is convenient, and the method is environment-friendly.
Description
Technical Field
The invention relates to the related technical field of pharmaceutical chemicals, in particular to a preparation process of an atorvastatin calcium intermediate.
Background
Atorvastatin calcium (Atorvastain calcium), chemically (3r, 5r) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) pyrrol-1-yl ] -3,5 dihydroxy calcium heptate, is a 3-hydroxy-3-methylglutaryl coenzyme a (HMG-CoA) reductase inhibitor. It was introduced by the U.S. pfeiri company in 1997 and is a third generation statin lipid regulating drug widely used in clinical practice for the prevention and treatment of hypercholesterolemia. This effect is exerted by lowering Total Cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) levels in dyslipidemia patients. Additionally, atorvastatin calcium has an anti-inflammatory effect in atherosclerotic plaques. Because of its high efficiency and safety. Is always one of the best-selling medicines for treating hypercholesterolemia.
At present, the preparation method of atorvastatin mainly comprises a racemate resolution method, a diastereoselective condensation method, a Paal-Knorr synthesis method, a cycloaddition method, a dicarbonyl asymmetric reduction method and the like, and the yield and the product purity of atorvastatin synthesized by the methods are low, so that the method for obtaining the atorvastatin compound with high purity, high yield and high content becomes a hotspot of current research.
Atorvastatin is prepared from the condensate (4R-Cis) -1, 1-dimethylethyl-6- [2- [2 (4-fluorophenyl) -5- (1-methylethyl) -3-phenyl-4- [ (phenylamino) -carboxy ] -1H-pyrrol-1-yl ] ethyl ] -2, 2-dimethyl-1, 3 dioxane-4-acetate by hydrolysis to form the sodium salt, followed by the addition of calcium acetate, wherein the core of the preparation of the condensate is the synthesis of two intermediates: 4-fluoro-alpha- (2-methyl-1-oxopropyl) -gamma-oxo-N, beta-diphenyl benzene butanamide (abbreviated as M4), (4R-Cis) -6-aminoethyl-2, 2-dimethyl-1, 3-dioxane-tert-butyl acetate (abbreviated as ATS-9), and then M4 and ATS-9 react to generate the product atorvastatin. The existing method for synthesizing M4 uses benzoic acid as an initial raw material, reacts with thionyl chloride to generate phenylacetyl chloride, then performs a friedel-crafts acylation reaction with fluorobenzene to generate 4-fluorobenzene acetophenone, and the 4-fluorobenzene acetophenone is further brominated and then reacts with isobutyrylacetanilide to generate M4, wherein a catalyst commonly used for the friedel-crafts acylation reaction of the phenylacetyl chloride and the fluorobenzene is ferric chloride, the ferric chloride is easy to complex with a generated product, the treatment is complex after the reaction is finished, and the yield of the product is reduced.
The chinese published invention document CN 10639296B discloses a process for preparing atorvastatin calcium, in which ferric chloride, an original catalyst, is replaced by a zeolite molecular sieve, so as to avoid a post-treatment process caused by complexation between the catalyst and a product, improve a reaction yield, reduce side reactions and facilitate purification, but still fail to solve the problems that 4-fluoro phenylacetophenone is substituted by a simple substance of chlorine or bromine during preparation of an intermediate M4 in a reaction process, hydrogen on a phenyl ring of 4-fluoro phenylacetophenone is easily substituted, a large amount of phenyl chloro (bromo) substituted compounds of 4-fluoro phenylacetophenone are generated in the reaction process, a large number of side reactions result in too low yield, and the byproducts are inconvenient to treat and cause serious pollution easily.
The invention provides a preparation process of an atorvastatin calcium intermediate, which is characterized in that hydroxyl is introduced to 4-fluorobenzeneacetophenone carbonyl alpha-carbon to obtain 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone, and the 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone and N-phenylisobutyrylacetamide directly react under the action of a ferric trichloride catalyst to prepare the intermediate M4, so that the original halogenation process is replaced, the halogenation reaction is avoided, halogen wastewater is not generated, and the product after the reaction is convenient to treat.
Disclosure of Invention
Aiming at the problems that when the 4-fluorophenylacetophenone is replaced by a simple substance of chlorine or bromine during the preparation of the intermediate M4, hydrogen on a phenyl ring of the 4-fluorophenylacetophenone is easy to replace, a large amount of phenyl ring chlorine (bromine) substituted compounds of the 4-fluorophenylacetophenone can be generated in the reaction process, the yield is low due to more side reactions, the by-products are inconvenient to treat, and serious pollution is easily caused, the invention adopts the following technical scheme:
a preparation process of an atorvastatin calcium intermediate comprises the following steps:
step one, phenylacetic acid reacts with thionyl chloride to obtain phenylacetyl chloride;
secondly, the obtained phenylacetyl chloride and fluorobenzene are subjected to friedel-crafts acylation reaction with fluorobenzene under the action of a catalyst to obtain 4-fluorobenzene acetophenone;
thirdly, adding a Davis reagent into the 4-fluorophenyl acetophenone solution after alkalization to oxidize and introduce hydroxyl on carbonyl alpha-carbon to prepare 1- (4-fluorophenyl) -2-hydroxyl-2-phenyl acetophenone;
fourthly, the 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone reacts with N-phenyl isobutyryl acetamide under the action of a catalyst to prepare an atorvastatin calcium intermediate M4.
Further, the catalyst for the second-step reaction is zeolite molecular sieve loaded aluminum trioxide.
Further, in the third step of reaction, the reaction solvent is one or more of tetrahydrofuran, diethyl ether, 1, 4-dioxane, toluene and xylene.
Further, the third step reaction alkalization reagent is KHMDS or NaHMDS, and the solution reaction pH value is 9-11.
Furthermore, the reaction temperature of the third step is-78 to-80 ℃.
Further, the Davis reagent of the third reaction step is recovered by oxidizing m-chloroperoxybenzoic acid.
Further, the fourth step of reaction is to dissolve the 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone obtained in the third step by using a solvent, and FeCl is added 3 The catalyst is stirred and mixed evenly, and then N-phenyl isobutyryl acetamide is added, heated and stirred.
Furthermore, the solvent required by the fourth step of reaction is one or more of tetrahydrofuran, diethyl ether, dichloromethane and toluene, the reaction temperature is 30-35 ℃, and the reaction time is 5-6 h.
Further, the raw material and FeCl in the fourth reaction step 3 The molar ratio of the catalyst is 1:0.1.
and further, after the fourth step of reaction is finished, washing the reaction solution for 2-3 times by using saturated saline solution, combining organic layers, performing decompression and desolventizing to dryness, adding methanol for recrystallization, and filtering and drying to obtain a product.
The invention has the beneficial effects that: the innovation points of the invention are that hydroxyl is generated in one step, M4 is obtained by direct condensation under the catalysis of ferric trichloride in two steps, the reaction steps are not changed, halogen is avoided, the hydroxyl is directly substituted by alcoholic hydroxyl, the original halogenation process is replaced by the alcoholic substitution process, the reaction selectivity is better, the reaction product is convenient to treat, no simple substance chlorine or bromine is used in the reaction, a large amount of chlorine-containing and bromine-containing waste water is not generated, the waste water treatment is convenient, and the method is environment-friendly.
Drawings
FIG. 1 is an overall reaction scheme of the present invention;
FIG. 2 is a flow diagram of the Davis reagent recovery process of the present invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
Example 1
Firstly, 13.6g of phenylacetic acid is dissolved in 100ml of chloroform, 15.6g of thionyl chloride is added into a reaction bottle, reaction is carried out at room temperature to release sulfur dioxide and hydrogen chloride gas, when a large amount of gas is not released any more from reactants, the reaction mixture is heated to 30-40 ℃, heat preservation is carried out for 25h, 30ml of benzene is added, volatile matters are removed by low-temperature distillation, pressure is gradually reduced to 0.133kPa, after all volatile matters are removed, 55-57 ℃ (0.133 kPa) fractions are evaporated, 12.90g of phenylacetyl chloride is obtained, the purity is 98.5%, and the yield is 83.7%.
And secondly, adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of zeolite molecular sieve loaded aluminum trichloride under ice bath, then dropwise adding 40ml of dichloromethane containing 15.4g of phenylacetyl chloride into the solution under ice bath condition, keeping the temperature of the reaction solution not more than 10 ℃ in the dropwise adding process, continuing to react for 2h after the dropwise adding is finished, and tracking by TLC to show that the reaction is finished. After the reaction is finished, adding a sodium hydroxide solution for quenching, layering, extracting an aqueous layer by using dichloromethane, combining organic layers, washing the organic layer by using saturated saline solution, decompressing and desolventizing the organic layer until the organic layer is dried, adding 15ml of methylbenzene for recrystallization, filtering and drying to obtain 17.12g of 1- (4-fluorophenyl) acetophenone, wherein the purity is 98.3 percent, and the yield is 80 percent.
And thirdly, dissolving 10.7g of 1- (4-fluorophenyl) acetophenone in 100ml of THF, adding KHMDS to adjust the pH value of the solution to 9, adding 110ml of Davis THF solution reagent of 5mol/L, stirring for reaction at constant temperature of-78 ℃, tracking by TLC to show that the reaction is finished, decompressing and fractionating to recover THF and Davis reagent and the like, adding 50ml of dichloromethane after the fractionation is finished, adjusting the pH value to be about 7.0 by using dilute acid water, stirring until the solution is completely dissolved, layering, extracting a water layer by using dichloromethane, combining organic layers, washing by using saturated saline, decompressing and desolventizing the organic layer until the organic layer is dried, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.0g of the product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone, wherein the purity is 98.5 percent and the yield is 95.6 percent. The recovered Davis reagent can be reused after being treated.
Fourthly, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone into a 100ml flask, adding 100ml of dichloromethane, stirring and mixing, adding 1.62g of ferric chloride catalyst, adding 10.3g of N-phenyl isobutyryl acetamide, heating and stirring at 35 ℃, refluxing for 5 hours to complete the reaction, filtering after the reaction is completed, adding 50ml of dichloromethane for extraction for 2-3 times, combining organic layers, adding 100ml of saturated saline solution for washing for 2-3 times, decompressing and desolventizing to be dry, adding 30ml of toluene for recrystallization, filtering and drying to obtain a reaction product M4, and obtaining 19.8g of the product, the yield is 95%, and the purity is 99.0%.
Example 2
Firstly, 13.6g of phenylacetic acid is dissolved in 100ml of chloroform, 15.6g of thionyl chloride is added into a reaction bottle to react at room temperature to release sulfur dioxide and hydrogen chloride gas, when a large amount of gas is not released any more from reactants, the reaction mixture is heated to 30-40 ℃, the temperature is kept for 25h, 30ml of benzene is added, volatile matters are removed by low-temperature distillation, the pressure is gradually reduced to 0.133kPa, after all volatile matters are removed, 55-57 ℃ (0.133 kPa) fractions are evaporated to obtain 12.91g of phenylacetyl chloride, the purity is 98.6 percent, and the yield is 83.8 percent.
And secondly, adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of zeolite molecular sieve loaded aluminum trichloride under ice bath, then dropwise adding 40ml of dichloromethane containing 15.4g of phenylacetyl chloride into the solution under ice bath condition, keeping the temperature of the reaction solution not more than 10 ℃ in the dropwise adding process, continuing to react for 2h after the dropwise adding is finished, and tracking by TLC to show that the reaction is finished. After the reaction is finished, adding a sodium hydroxide solution for quenching, layering, extracting a water layer by using dichloromethane, combining organic layers, washing the organic layer by using saturated saline solution, decompressing and desolventizing the organic layer until the organic layer is dried, adding 15ml of toluene for recrystallization, filtering and drying to obtain 17.13g of 1- (4-fluorophenyl) acetophenone with the purity of 98.7 percent and the yield of 80 percent.
And thirdly, dissolving 10.7g of 1- (4-fluorophenyl) acetophenone in 100ml of THF, adding KHMDS to adjust the pH value of the solution to 10, adding 110ml of Davis THF solution reagent of 5mol/L, stirring for reaction at constant temperature of-78 ℃, tracking by TLC to show that the reaction is finished, decompressing and fractionating to recover THF and Davis reagent and the like, adding 50ml of dichloromethane after the fractionation is finished, adjusting the pH value to be about 7.0 by using dilute acid water, stirring until the solution is completely dissolved, layering, extracting a water layer by using dichloromethane, combining organic layers, washing by using saturated saline, decompressing and desolventizing the organic layer until the organic layer is dried, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.3g of the product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone, wherein the purity is 99.1% and the yield is 98.2%. The recovered Davis reagent can be reused after being treated.
Fourthly, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethyl ketone into a 100ml flask, adding 100ml of dichloromethane, stirring and mixing, adding 1.62g of ferric chloride catalyst, adding 10.3g of N-phenyl isobutyryl acetamide, heating and stirring at 30 ℃, refluxing for 5h to complete the reaction, filtering after the reaction is completed, adding 50ml of dichloromethane for extraction for 2-3 times, combining organic layers, adding 100ml of saturated salt water for washing for 2-3 times, decompressing and desolventizing to dryness, adding 30ml of toluene for recrystallization, filtering and drying to obtain a reaction product M4, and obtaining 19.2g of a product, the yield is 92 percent, and the purity is 99.2 percent.
Example 3
Firstly, 13.6g of phenylacetic acid is dissolved in 100ml of chloroform, 15.6g of thionyl chloride is added into a reaction bottle, reaction is carried out at room temperature to release sulfur dioxide and hydrogen chloride gas, when a large amount of gas is not released any more from reactants, the reaction mixture is heated to 30-40 ℃, heat preservation is carried out for 25h, 30ml of benzene is added, volatile matters are removed by low-temperature distillation, pressure is gradually reduced to 0.133kPa, after all volatile matters are removed, 55-57 ℃ (0.133 kPa) fractions are evaporated, 12.93g of phenylacetyl chloride is obtained, the purity is 98.5%, and the yield is 83.9%.
And secondly, adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of zeolite molecular sieve loaded aluminum trichloride under ice bath, then dropwise adding 40ml of dichloromethane containing 15.4g of phenylacetyl chloride into the solution under ice bath condition, keeping the temperature of the reaction solution not more than 10 ℃ in the dropwise adding process, continuing to react for 2h after the dropwise adding is finished, and tracking by TLC to show that the reaction is finished. After the reaction is finished, adding a sodium hydroxide solution for quenching, layering, extracting a water layer by using dichloromethane, combining organic layers, washing the organic layer by using saturated saline solution, decompressing and desolventizing the organic layer until the organic layer is dried, adding 15ml of toluene for recrystallization, filtering and drying to obtain 17.15g of 1- (4-fluorophenyl) acetophenone with the purity of 98.4 percent and the yield of 80 percent.
And thirdly, dissolving 10.7g of 1- (4-fluorophenyl) acetophenone in 100ml of THF, adding KHMDS to adjust the pH value of the solution to be 11, adding 110ml of Davis THF solution reagent of 5mol/L, stirring for reaction at constant temperature of-78 ℃, tracking by TLC to show that the reaction is finished, decompressing and fractionating to recover THF and the Davis reagent, and after the fractionation is finished, adding 50ml of dichloromethane, adjusting the pH value to be about 7.0 by using dilute acid water, stirring until the solution is completely dissolved, layering, extracting a water layer by using dichloromethane, combining organic layers, washing by using saturated saline, decompressing and desolventizing the organic layer until the organic layer is dried, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.1g of the product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone, wherein the purity is 99.0 percent, and the yield is 96.5 percent. The recovered Davis reagent can be reused after being treated.
Fourthly, 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone is added into a 100ml flask, 100ml of dichloromethane is added, stirring and mixing are carried out, 1.62g of ferric chloride catalyst is added, 10.3g of N-phenyl isobutyryl acetamide is added, heating and stirring are carried out at 35 ℃, refluxing is carried out for 6 hours, the reaction is completed, after the reaction is completed, filtering is carried out, 50ml of dichloromethane is added for extraction for 2-3 times, organic layers are combined, 100ml of saturated common salt water is added for washing for 2-3 times, decompression and desolventization are carried out until the mixture is dried, 30ml of toluene is added for recrystallization, filtering and drying are carried out, and the reaction product M4 is obtained, wherein 20.0g of the product is obtained, the yield is 95.7%, and the purity is 99.2%.
Example 4
Firstly, 13.6g of phenylacetic acid is dissolved in 100ml of chloroform, 15.6g of thionyl chloride is added into a reaction bottle to react at room temperature to release sulfur dioxide and hydrogen chloride gas, when a large amount of gas is not released any more from reactants, the reaction mixture is heated to 30-40 ℃, the temperature is kept for 25h, 30ml of benzene is added, volatile matters are removed by low-temperature distillation, the pressure is gradually reduced to 0.133kPa, after all volatile matters are removed, 55-57 ℃ (0.133 kPa) fractions are evaporated to obtain 12.90g of phenylacetyl chloride, the purity is 98.3 percent, and the yield is 83.7 percent.
And secondly, adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of zeolite molecular sieve loaded aluminum trichloride under ice bath, then dropwise adding 40ml of dichloromethane containing 15.4g of phenylacetyl chloride into the solution under ice bath condition, keeping the temperature of the reaction solution not more than 10 ℃ in the dropwise adding process, continuing to react for 2h after the dropwise adding is finished, and tracking by TLC to show that the reaction is finished. After the reaction is finished, adding a sodium hydroxide solution for quenching, layering, extracting a water layer by using dichloromethane, combining organic layers, washing the organic layer by using saturated saline solution, decompressing and desolventizing the organic layer until the organic layer is dried, adding 15ml of toluene for recrystallization, filtering and drying to obtain 17.16g of 1- (4-fluorophenyl) acetophenone with the purity of 98.5 percent and the yield of 80 percent.
And thirdly, dissolving 10.7g of 1- (4-fluorophenyl) acetophenone in 100ml of THF, adding NaHMDS to adjust the pH value of the solution to 10, adding 110ml of Davis THF solution reagent of 5mol/L, stirring for reaction at constant temperature of-78 ℃, tracking by TLC to show that the reaction is finished, decompressing and fractionating to recover THF and Davis reagent and the like, adding 50ml of dichloromethane after the fractionation is finished, adjusting the pH value to be about 7.0 by using dilute acid water, stirring until the solution is completely dissolved, layering, extracting a water layer by using dichloromethane, combining organic layers, washing by using saturated saline, decompressing and desolventizing the organic layer until the organic layer is dried, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.3g of the product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone, wherein the purity is 98.8 percent, and the yield is 98.3 percent. The recovered Davis reagent can be reused after being treated.
Fourthly, 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone is added into a 100ml flask, 100ml of dichloromethane is added, stirring and mixing are carried out, 1.62g of ferric chloride catalyst is added, 10.3g of N-phenyl isobutyryl acetamide is added, heating and stirring are carried out at 30 ℃, reflux is carried out for 6 hours, after the reaction is completed, filtration is carried out, 50ml of dichloromethane is added for extraction for 2-3 times, organic layers are combined, 100ml of saturated common salt water is added for washing for 2-3 times, decompression and desolventization is carried out until the mixture is dried, 30ml of toluene is added for recrystallization, filtration and drying are carried out to obtain a reaction product M4, 19.7g of the product is obtained, the yield is 94.2%, and the purity is 99.2%.
Example 5
Firstly, 13.6g of phenylacetic acid is dissolved in 100ml of chloroform, 15.6g of thionyl chloride is added into a reaction bottle, reaction is carried out at room temperature to release sulfur dioxide and hydrogen chloride gas, when a large amount of gas is not released any more from reactants, the reaction mixture is heated to 30-40 ℃, heat preservation is carried out for 25h, 30ml of benzene is added, volatile matters are removed by low-temperature distillation, pressure is gradually reduced to 0.133kPa, after all volatile matters are removed, 55-57 ℃ (0.133 kPa) fractions are evaporated, 12.88g of phenylacetyl chloride is obtained, the purity is 98.6%, and the yield is 83.7%.
And secondly, adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of zeolite molecular sieve loaded aluminum trichloride under an ice bath condition, then dropwise adding 40ml of dichloromethane containing 15.4g of phenylacetyl chloride into the solution under the ice bath condition, keeping the temperature of the reaction solution not more than 10 ℃ in the dropwise adding process, continuing to react for 2h after the dropwise adding is finished, and tracking by TLC (thin layer chromatography) to show that the reaction is finished. After the reaction is finished, adding a sodium hydroxide solution for quenching, layering, extracting an aqueous layer by using dichloromethane, combining organic layers, washing the organic layer by using saturated saline solution, decompressing and desolventizing the organic layer until the organic layer is dried, adding 15ml of methylbenzene for recrystallization, filtering and drying to obtain 17.15g of 1- (4-fluorophenyl) acetophenone, wherein the purity is 98.8 percent, and the yield is 80 percent.
And thirdly, dissolving 10.7g of 1- (4-fluorophenyl) acetophenone in 100ml of THF, adding KHMDS to adjust the pH value of the solution to 10, adding 110ml of Davis THF solution reagent of 5mol/L, stirring for reaction at constant temperature of-80 ℃, tracking by TLC to show that the reaction is finished, decompressing and fractionating to recover THF and Davis reagent and the like, adding 50ml of dichloromethane after the fractionation is finished, adjusting the pH value to be about 7.0 by using dilute acid water, stirring until the solution is completely dissolved, layering, extracting a water layer by using dichloromethane, combining organic layers, washing by using saturated saline, decompressing and desolventizing the organic layer until the organic layer is dried, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.1g of the product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone, wherein the purity is 98.5 percent and the yield is 96.5 percent. The recovered Davis reagent can be reused after being treated.
Fourthly, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethyl ketone into a 100ml flask, adding 100ml of THF, stirring and mixing, adding 1.62g of ferric chloride catalyst, adding 10.3g of N-phenyl isobutyryl acetamide, heating and stirring at 35 ℃, refluxing for 6h to complete the reaction, filtering after the reaction is completed, adding 50ml of dichloromethane for extraction for 2-3 times, combining organic layers, adding 100ml of saturated salt water for washing for 2-3 times, decompressing and desolventizing to dryness, adding 30ml of toluene for recrystallization, filtering and drying to obtain a reaction product M4, and obtaining 19.4g of a product, wherein the yield is 93 percent and the purity is 99.1 percent.
Example 6
Firstly, 13.6g of phenylacetic acid is dissolved in 100ml of chloroform, 15.6g of thionyl chloride is added into a reaction bottle to react at room temperature to release sulfur dioxide and hydrogen chloride gas, when a large amount of gas is not released any more from reactants, the reaction mixture is heated to 30-40 ℃, the temperature is kept for 25h, 30ml of benzene is added, volatile matters are removed by low-temperature distillation, the pressure is gradually reduced to 0.133kPa, after all volatile matters are removed, 55-57 ℃ (0.133 kPa) fractions are evaporated to obtain 12.90g of phenylacetyl chloride, the purity is 98.5 percent, and the yield is 83.7 percent.
And secondly, adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of zeolite molecular sieve loaded aluminum trichloride under ice bath, then dropwise adding 40ml of dichloromethane containing 15.4g of phenylacetyl chloride into the solution under ice bath condition, keeping the temperature of the reaction solution not more than 10 ℃ in the dropwise adding process, continuing to react for 2h after the dropwise adding is finished, and tracking by TLC to show that the reaction is finished. After the reaction is finished, adding a sodium hydroxide solution for quenching, layering, extracting a water layer by using dichloromethane, combining organic layers, washing the organic layers by using saturated saline solution, decompressing and desolventizing the organic layers till the organic layers are dried, adding 15ml of methylbenzene for recrystallization, filtering and drying to obtain 17.13g of 1- (4-fluorophenyl) acetophenone, wherein the purity is 98.6 percent, and the yield is 80 percent.
And thirdly, dissolving 10.7g of 1- (4-fluorophenyl) acetophenone in 100ml of toluene, adding KHMDS to adjust the pH value of the solution to 10, adding 110ml of Davis THF solution reagent of 5mol/L, stirring for reaction at constant temperature of-78 ℃, tracking by TLC to show that the reaction is finished, decompressing and fractionating to recover THF and the Davis reagent, and after the fractionation, adding 50ml of dichloromethane, adjusting the pH value to be about 7.0 by using dilute acid water, stirring to be completely dissolved, layering, extracting a water layer by using dichloromethane, combining organic layers, washing by using saturated saline, decompressing and desolventizing the organic layer to be dry, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.0g of the product 1- (4-fluorophenyl) -2-hydroxy-2-acetophenone, wherein the purity is 99.0 percent, and the yield is 95.6 percent. The recovered Davis reagent can be reused after being treated.
Fourthly, 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone is added into a 100ml flask, 100ml of toluene is added, the mixture is stirred and mixed, 1.62g of ferric chloride catalyst is added, 10.3g of N-phenyl isobutyryl acetamide is added, the mixture is heated and stirred at the temperature of 35 ℃, the reflux is carried out for 6 hours, the reaction is completed, after the reaction is completed, the mixture is filtered, 50ml of dichloromethane is added for extraction for 2 to 3 times, organic layers are combined, 100ml of saturated common salt water is added for washing for 2 to 3 times, decompression and desolventization is carried out until the mixture is dried, 30ml of toluene is added for recrystallization, the reaction product M4 is obtained by filtering and drying, 19.3g of the product is obtained, the yield is 92.3 percent, and the purity is 99.1 percent.
Example 7
Firstly, 13.6g of phenylacetic acid is dissolved in 100ml of chloroform, 15.6g of thionyl chloride is added into a reaction bottle, reaction is carried out at room temperature to release sulfur dioxide and hydrogen chloride gas, when a large amount of gas is not released any more from reactants, the reaction mixture is heated to 30-40 ℃, heat preservation is carried out for 25h, 30ml of benzene is added, volatile matters are removed by low-temperature distillation, pressure is gradually reduced to 0.133kPa, after all volatile matters are removed, 55-57 ℃ (0.133 kPa) fractions are evaporated, 12.91g of phenylacetyl chloride is obtained, the purity is 98.7%, and the yield is 83.8%.
And secondly, adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of zeolite molecular sieve loaded aluminum trichloride under an ice bath condition, then dropwise adding 40ml of dichloromethane containing 15.4g of phenylacetyl chloride into the solution under the ice bath condition, keeping the temperature of the reaction solution not more than 10 ℃ in the dropwise adding process, continuing to react for 2h after the dropwise adding is finished, and tracking by TLC (thin layer chromatography) to show that the reaction is finished. After the reaction is finished, adding a sodium hydroxide solution for quenching, layering, extracting a water layer by using dichloromethane, combining organic layers, washing the organic layer by using saturated saline solution, decompressing and desolventizing the organic layer until the organic layer is dried, adding 15ml of toluene for recrystallization, filtering and drying to obtain 17.15g of 1- (4-fluorophenyl) acetophenone, wherein the purity is 98.9 percent, and the yield is 80 percent.
And thirdly, dissolving 10.7g of 1- (4-fluorophenyl) acetophenone in 100ml of mixed solution of THF and toluene in a volume ratio of 1:1, adding KHMDS to adjust the pH value of the solution to 10, adding 110ml of Davis THF solution reagent of 5mol/L, stirring the mixture at constant temperature of-78 ℃ for reaction for 24h, tracking by TLC to show that the reaction is finished, carrying out reduced pressure fractionation to recover THF, davis reagent and the like, adding 50ml of dichloromethane after the fractionation is finished, adjusting the pH value to be about 7.0 by using dilute acid water, stirring the mixture to be completely dissolved, layering, extracting a water layer by using dichloromethane, combining organic layers, washing the organic layers by using saturated saline solution, carrying out reduced pressure desolvation on the organic layers until the organic layers are dried, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.1g of the product 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone, wherein the purity is 99.1% and the yield is 96.5%. The recovered Davis reagent can be reused after being treated.
Fourthly, 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethyl ketone is added into a 100ml flask, 100ml of mixed solution of THF and toluene with the volume ratio of 1.
Comparative publication CN 10639296B example:
firstly, 6.8g of phenylacetic acid is dissolved in 40ml of chloroform, 7.8g of thionyl chloride is added into a reaction bottle, the reaction is performed for 2 to 3 hours by heating and refluxing, the residual thionyl chloride is firstly evaporated after the reaction is finished, then the reduced pressure distillation is performed to obtain 6.31g of phenylacetyl chloride, and the yield is 80 percent.
And secondly, adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of aluminum trichloride supported zeolite molecular sieve under ice bath, then dropwise adding 40ml of dichloromethane containing 15.4g of phenylacetyl chloride into the solution under ice bath, keeping the temperature of the reaction solution not more than 10 ℃ in the dropwise adding process, continuing to react for 2h after the dropwise adding is finished, and tracking by TLC (thin layer chromatography) to show that the reaction is finished. Filtering, spin-drying to obtain light yellow solid, and recrystallizing to obtain 17.12g of 4-fluorobenzophenone with yield of 80%.
And step three, dissolving 10.7g of 4-fluorobenzene acetophenone in 100ml of glacial acetic acid, adding 15ml of 40% hydrobromic acid, stirring, slowly dropwise adding 9ml of 30% hydrogen peroxide by mass fraction, reacting for 169h at 40 ℃, and tracking by TLC to show that the reaction is finished. To the reaction solution was added a saturated aqueous sodium sulfite solution to remove unreacted bromine. Adding 200ml ethyl acetate and appropriate amount of sodium carbonate aqueous solution, extracting, separating organic layer, washing with sodium carbonate aqueous solution for 2 times, and drying with anhydrous magnesium sulfate. Filtering and spin-drying to obtain 13.25g of yellow thick liquid 2-bromo-1- (4-fluorophenyl) -acetophenone, and the yield is 90%.
Fourthly, 1.47g of 2-bromo-1- (4-fluorophenyl) -acetophenone, 30ml of acetone, 1.03g of isobutyrylacetanilide and 0.76g of potassium carbonate powder are added into a 100ml flask, the mixture is heated and reacted for 2h under the reflux state, and the TLC tracing shows that the reaction is finished. The acetone was distilled off, and 40ml of ethyl acetate and 40ml of water were added for extraction. Column layer analysis gave 1.63g of M-4 as a white powder, and the yield was 78%.
It is clear that the product intermediate M4 obtained according to the invention is obtained in higher yields than the reference.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (10)
1. The preparation process of the atorvastatin calcium intermediate is characterized by comprising the following steps of:
step one, phenylacetic acid reacts with thionyl chloride to obtain phenylacetyl chloride;
secondly, the obtained phenylacetyl chloride and fluorobenzene are subjected to friedel-crafts acylation reaction with fluorobenzene under the action of a catalyst to obtain 4-fluorobenzene acetophenone;
thirdly, adding a Davis reagent into the 4-fluorophenyl acetophenone solution after alkalization to oxidize and introduce hydroxyl on carbonyl alpha-carbon to prepare 1- (4-fluorophenyl) -2-hydroxyl-2-phenyl acetophenone;
fourthly, the 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone reacts with N-phenyl isobutyryl acetamide to prepare an atorvastatin calcium intermediate M4.
2. The process of claim 1 for preparing an intermediate of atorvastatin calcium, wherein: the catalyst for the second step reaction is zeolite molecular sieve loaded aluminum trichloride.
3. The process of claim 1, wherein the step of preparing the intermediate comprises: in the third step of reaction, the reaction solvent is one or more of tetrahydrofuran, diethyl ether, 1, 4-dioxane, toluene and xylene.
4. The process of claim 1 for the preparation of an atorvastatin calcium intermediate, wherein: the third step is that the reaction alkalizing agent is KHMDS or NaHMDS, and the pH value of the solution reaction is 9-11.
5. The process of claim 1 for preparing an intermediate of atorvastatin calcium, wherein: the reaction temperature of the third step is-78 to-80 ℃.
6. The process of claim 1 for the preparation of an atorvastatin calcium intermediate, wherein: the Davis reagent in the third step is recovered by oxidizing m-chloroperoxybenzoic acid.
7. The process of claim 1 for preparing an intermediate of atorvastatin calcium, wherein: the fourth step of reaction is that the 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone obtained in the third step is dissolved by a solvent, feCl is added 3 The catalyst is stirred and mixed evenly, and then N-phenyl isobutyryl acetamide is added, heated and stirred.
8. The process of claim 7 for the preparation of an atorvastatin calcium intermediate, wherein: the solvent required by the fourth step of reaction is one or more of tetrahydrofuran, diethyl ether, dichloromethane and toluene, the reaction temperature is 30-35 ℃, and the reaction time is 5-6 h.
9. The process of claim 7 for the preparation of an atorvastatin calcium intermediate, wherein: in the fourth step of reaction, raw material and FeCl are added 3 The molar ratio of the catalyst is 1:0.1.
10. the process of claim 7 for the preparation of an atorvastatin calcium intermediate, wherein: and after the fourth step of reaction is finished, washing the reaction solution for 2-3 times by using saturated saline solution, combining organic layers, performing decompression and desolventizing until the organic layers are dried, adding methanol for recrystallization, and filtering and drying to obtain a product.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211033594.7A CN115260051A (en) | 2022-08-26 | 2022-08-26 | Preparation process of atorvastatin calcium intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211033594.7A CN115260051A (en) | 2022-08-26 | 2022-08-26 | Preparation process of atorvastatin calcium intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115260051A true CN115260051A (en) | 2022-11-01 |
Family
ID=83755662
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211033594.7A Pending CN115260051A (en) | 2022-08-26 | 2022-08-26 | Preparation process of atorvastatin calcium intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115260051A (en) |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325844A (en) * | 2000-05-31 | 2001-12-12 | 中国医学科学院药物研究所 | Process for synthesizing (+/-)p-fluoro-2(2-methyl-propionyl)-4-oxy-N,3-diphenyl-phenylbutylamide |
| CN102702014A (en) * | 2012-05-28 | 2012-10-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Method for preparing atorvastatin calcium intermediate |
| US20130184493A1 (en) * | 2011-04-21 | 2013-07-18 | Vijayasri Organics Limited | PROCESS FOR PREPARATION OF 4-FLUORO-alpha-[2METHYL-L-OXOPROPYL]-gamma-OXO-N-beta-DIPHENYLBENZENE BUTANE AMIDE |
| CN106397296A (en) * | 2016-08-29 | 2017-02-15 | 江苏阿尔法药业有限公司 | Preparation technology of atorvastatin |
| CN113788766A (en) * | 2021-10-20 | 2021-12-14 | 宿迁盛基医药科技有限公司 | Preparation method of atorvastatin calcium intermediate |
| CN113816867A (en) * | 2021-10-20 | 2021-12-21 | 宿迁盛基医药科技有限公司 | Method for preparing atorvastatin calcium intermediate by using continuous flow tubular reactor |
| CN114773221A (en) * | 2022-04-22 | 2022-07-22 | 江苏阿尔法药业股份有限公司 | Preparation method of atorvastatin calcium drug intermediate |
-
2022
- 2022-08-26 CN CN202211033594.7A patent/CN115260051A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1325844A (en) * | 2000-05-31 | 2001-12-12 | 中国医学科学院药物研究所 | Process for synthesizing (+/-)p-fluoro-2(2-methyl-propionyl)-4-oxy-N,3-diphenyl-phenylbutylamide |
| US20130184493A1 (en) * | 2011-04-21 | 2013-07-18 | Vijayasri Organics Limited | PROCESS FOR PREPARATION OF 4-FLUORO-alpha-[2METHYL-L-OXOPROPYL]-gamma-OXO-N-beta-DIPHENYLBENZENE BUTANE AMIDE |
| CN102702014A (en) * | 2012-05-28 | 2012-10-03 | 扬子江药业集团江苏海慈生物药业有限公司 | Method for preparing atorvastatin calcium intermediate |
| CN106397296A (en) * | 2016-08-29 | 2017-02-15 | 江苏阿尔法药业有限公司 | Preparation technology of atorvastatin |
| CN113788766A (en) * | 2021-10-20 | 2021-12-14 | 宿迁盛基医药科技有限公司 | Preparation method of atorvastatin calcium intermediate |
| CN113816867A (en) * | 2021-10-20 | 2021-12-21 | 宿迁盛基医药科技有限公司 | Method for preparing atorvastatin calcium intermediate by using continuous flow tubular reactor |
| CN114773221A (en) * | 2022-04-22 | 2022-07-22 | 江苏阿尔法药业股份有限公司 | Preparation method of atorvastatin calcium drug intermediate |
Non-Patent Citations (1)
| Title |
|---|
| YONGNIAN GAO ET AL.: "Polymer-Supported N-Phenylsulfonyloxaziridine (Davis Reagent):A Versatile Oxidant", ADV. SYNTH. CATAL., vol. 350, pages 2937 - 2946 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1054846C (en) | Use of intermediates for production of aromatic aminoalcohol derivatives having anti-diabetic and anti-obesity properties | |
| KR100447370B1 (en) | Improved Process for the Synthesis of Protected Esters of (S)-3,4-Dihydroxybutyric Acid | |
| KR20060030110A (en) | Preparation of 1,3-diphenylprop-2-en-1-one derivatives | |
| CN106397296A (en) | Preparation technology of atorvastatin | |
| JP6565685B2 (en) | Method for producing cyclobutanetetracarboxylic acid derivative | |
| CN115466196B (en) | Preparation method of atorvastatin calcium intermediate | |
| Davies et al. | Influence of a β‐Alkoxy Substituent on the C H Activation Chemistry of Alkyl Ethers | |
| JP5309318B2 (en) | Process for producing esters, carboxylic acids and amides | |
| Gotoh et al. | Diphenylprolinol silyl ether as a catalyst in an asymmetric, catalytic and direct α-benzoyloxylation of aldehydes | |
| CN115260051A (en) | Preparation process of atorvastatin calcium intermediate | |
| KR102261108B1 (en) | Highly enantioselective bifunctional chiral organocatalytic compound, method for preparing the same, and method for preparing non-natural gamma-amino acid from nitrocompound using thereof | |
| EP1868978B1 (en) | Novel 1-bromo-4- (4'-bromophenoxy)-2-pentadecyl benzene and a process for the preparation thereof | |
| JP5193664B2 (en) | A method for producing an asymmetric catalyst Michael reaction product and a method for producing a pharmaceutical compound. | |
| JP4269902B2 (en) | Method for producing aromatic unsaturated compound | |
| CN111056890A (en) | Method for preparing aryl ketone by free radical-free radical coupling reaction of ketoacid decarboxylation and fatty aldehyde decarbonylation based on iron catalysis | |
| JPH05261295A (en) | Asymmetric induction catalyst | |
| EP1970369B1 (en) | Method for producing purified formylcyclopropane compound and intermediate of such formylcyclopropane compound | |
| Yin et al. | Direct Conversion of Aromatic Ketones to Arenecarboxylic Esters via Carbon–Carbon Bond-Cleavage Reactions | |
| KR20060136357A (en) | Method for producing aromatic unsaturated compound | |
| KR100884558B1 (en) | Method of manufacturing optically active amide with high yield and high purity | |
| JP2011042602A (en) | Method for producing isopropyl 2-(3-nitrobenzylidene)acetoacetate | |
| JP2009227594A (en) | Method for producing optically active amino acid ester derivative, and optically active amino acetal derivative | |
| JP4125916B2 (en) | Method for producing high purity ester | |
| CN116332882A (en) | Synthesis process of key intermediate of englitz | |
| US6818786B2 (en) | Process for the preparation of ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |