CN115466196B - Preparation method of atorvastatin calcium intermediate - Google Patents
Preparation method of atorvastatin calcium intermediate Download PDFInfo
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- CN115466196B CN115466196B CN202211054112.6A CN202211054112A CN115466196B CN 115466196 B CN115466196 B CN 115466196B CN 202211054112 A CN202211054112 A CN 202211054112A CN 115466196 B CN115466196 B CN 115466196B
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- 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 13
- 229960001770 atorvastatin calcium Drugs 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 100
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 39
- 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 abstract description 25
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 claims abstract description 23
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 claims abstract description 22
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims abstract description 21
- 230000002140 halogenating effect Effects 0.000 claims abstract description 14
- 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 abstract description 12
- 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 abstract description 12
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229960003424 phenylacetic acid Drugs 0.000 claims abstract description 11
- 239000003279 phenylacetic acid Substances 0.000 claims abstract description 11
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 3
- 239000003054 catalyst Substances 0.000 claims abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 239000012044 organic layer Substances 0.000 claims description 82
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 78
- 238000003756 stirring Methods 0.000 claims description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- 238000001035 drying Methods 0.000 claims description 31
- 238000001914 filtration Methods 0.000 claims description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 30
- 238000005406 washing Methods 0.000 claims description 28
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 27
- 239000000047 product Substances 0.000 claims description 24
- 239000006227 byproduct Substances 0.000 claims description 11
- 229910021536 Zeolite Inorganic materials 0.000 claims description 10
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 10
- 239000002808 molecular sieve Substances 0.000 claims description 10
- 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 10
- 239000002904 solvent Substances 0.000 claims description 10
- 239000010457 zeolite Substances 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical group Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 9
- 239000012295 chemical reaction liquid Substances 0.000 claims description 9
- 238000010791 quenching Methods 0.000 claims description 9
- 230000000171 quenching effect Effects 0.000 claims description 9
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 9
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- 238000005658 halogenation reaction Methods 0.000 claims description 5
- 230000003113 alkalizing effect Effects 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000003795 chemical substances by application 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-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
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000007809 chemical reaction catalyst 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
- 125000001246 bromo group Chemical group Br* 0.000 abstract description 8
- 238000007086 side reaction Methods 0.000 abstract description 6
- 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 abstract description 3
- 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 abstract description 3
- 229960005370 atorvastatin Drugs 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 2
- 238000003912 environmental pollution Methods 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 111
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 69
- 239000000243 solution Substances 0.000 description 45
- 238000001953 recrystallisation Methods 0.000 description 28
- 238000004809 thin layer chromatography Methods 0.000 description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000010410 layer Substances 0.000 description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- 239000000843 powder Substances 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- 238000005194 fractionation Methods 0.000 description 14
- 238000000034 method Methods 0.000 description 13
- 230000006837 decompression Effects 0.000 description 12
- 238000004090 dissolution Methods 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 238000004821 distillation Methods 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 125000001309 chloro group Chemical class Cl* 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
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical class [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- 108010023302 HDL Cholesterol Proteins 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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical class BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 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
- 230000026030 halogenation Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000002351 wastewater Substances 0.000 description 2
- -1 2-methyl-1-oxo-propyl Chemical group 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
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- SYKNUAWMBRIEKB-UHFFFAOYSA-N [Cl].[Br] Chemical compound [Cl].[Br] SYKNUAWMBRIEKB-UHFFFAOYSA-N 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
- 239000004305 biphenyl Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- BWFCZHDTTAYGNN-CNZCJKERSA-N calcium;(3r,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound [Ca].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 BWFCZHDTTAYGNN-CNZCJKERSA-N 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000001258 dyslipidemic effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000001257 hydrogen Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- 238000001308 synthesis method Methods 0.000 description 1
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
- C07C45/61—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
- C07C45/63—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 halogen; by substitution of halogen atoms by other halogen atoms
-
- 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
-
- 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
- C07C45/67—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 isomerisation; by change of size of the carbon skeleton
- C07C45/68—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 isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
Abstract
The invention discloses a preparation method of an atorvastatin calcium intermediate, which comprises the following steps: phenylacetic acid reacts with thionyl chloride to obtain phenylacetyl chloride, then the phenylacetyl chloride reacts with fluorobenzene under the action of a catalyst to obtain 4-fluorophenyl acetophenone, a Davis reagent is added to oxidize the 4-fluorophenyl acetophenone solution after alkalization, hydroxyl is introduced on carbonyl alpha-carbon, the obtained 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone reacts with a halogenating reagent in a halogenating way to obtain 2-chloro-1- (4-fluorophenyl) -acetophenone, and the 2-chloro-1- (4-fluorophenyl) -acetophenone reacts with N-phenylisobutyrylacetamide to prepare the atorvastatin calcium intermediate M4. The invention has the beneficial effects that: the atorvastatin mother nucleus M4 is prepared by halogenating 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone to prepare 2-chloro (or bromo) -1- (4-fluorophenyl) -acetophenone, thereby reducing the generation of side reaction, improving the reaction yield, reducing the treatment difficulty of residual halogenating reagent and products by TMCS halogenating reagent and reducing the environmental pollution.
Description
Technical Field
The invention relates to the technical field related to pharmaceutical chemistry, in particular to a preparation method of an atorvastatin calcium intermediate.
Background
Atorvastatin calcium (Atorvastain calium), known as (3R, 5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- (phenylcarbamoyl) pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid calcium, is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. In 1997, it was proposed by the american-type scion company as a third-generation statin lipid-regulating drug, and is widely used for preventing and treating hypercholesterolemia in clinical practice. This effect is exerted by lowering the Total Cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) levels in dyslipidemic patients. In addition, atorvastatin calcium has an anti-inflammatory effect in atherosclerotic plaques. Because of the characteristics of high efficiency, safety and the like. Is always one of the most popular drugs for treating hypercholesterolemia.
In the prior art, chinese patent publication No. CN106397296B discloses a process for preparing atorvastatin calcium, which uses phenylacetyl chloride to react with fluorobenzene to prepare 4-fluorophenyl acetophenone, and then performs chlorination (bromination) to prepare 2-chloro-1- (4-fluorophenyl) -2-phenylacetone (or 2-bromo-1- (4-fluorophenyl) -2-phenylacetone), and then reacts with N-phenylisobutyrylacetamide to prepare atorvastatin calcium intermediate 4-fluoro-alpha- (2-methyl-1-oxo-propyl) -gamma-oxo-N, beta-diphenyl phenylbutyramide (hereinafter referred to as M4), but when the intermediate M4 is prepared by simple substance substitution of chlorine or bromine, hydrogen on benzene ring of 4-fluorophenyl acetophenone is easily substituted, a large amount of benzene ring chloro (bromo) compounds of 4-fluorophenyl acetophenone are generated in the reaction process, the side reaction is more, the yield is too low, and the byproduct is easy to treat, so serious pollution is easily caused.
The invention provides a synthesis method of an atorvastatin intermediate, which aims at improving the halogenation process in the prior production process, reducing the occurrence of side reaction, improving the reaction yield and reducing the reaction pollution.
Disclosure of Invention
Aiming at the problems that a large amount of chloro (bromo) compounds are generated in the halogenation reaction process of the prior preparation method, the yield is too low and the pollution is serious due to more side reactions, the invention replaces the halogenation process of the prior process and adopts the following technical scheme: a process for the preparation of an atorvastatin calcium intermediate comprising the steps of:
firstly, reacting phenylacetic acid with thionyl chloride to obtain phenylacetyl chloride;
performing a Friedel-crafts acylation reaction on the obtained phenylacetyl chloride and fluorobenzene under the action of a catalyst to obtain 4-fluorophenyl acetophenone;
thirdly, adding Davis reagent to oxidize after alkalizing the 4-fluorophenyl acetophenone solution, and introducing hydroxyl on carbonyl alpha-carbon to prepare 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone;
a fourth step of carrying out halogenation reaction on a halogenating reagent and 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone to prepare 2-chloro (or bromo) -1- (4-fluorophenyl) -acetophenone;
fifth, 2-chloro (or bromo) -1- (4-fluorophenyl) -acetophenone reacts with N-phenylisobutyrylacetamide to prepare atorvastatin calcium intermediate M4.
Further, the second-step reaction catalyst is an aluminum trichloride supported zeolite molecular sieve.
Further, the reaction solvent in the third step is one or more of tetrahydrofuran, diethyl ether, 1, 4-dioxane, toluene and xylene, preferably tetrahydrofuran.
Further, the third step reaction alkalizing agent is KHMDS or NaHMDS, and the pH value of the solution reaction is 9-11, preferably 10.
Further, the reaction temperature of the third step is-75 to-80 ℃.
Further, the Davis reagent is recovered by oxidizing m-chloroperoxybenzoic acid.
Further, in the fourth reaction step, a solvent is added into the 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone, and the solvent is stirred and dissolved, and then a halogenating reagent is added into the obtained 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone solution.
Furthermore, the reaction solvent selected in the fourth step is DMSO, the halogenating agent selected in the fourth step is trimethylchlorosilane, the reaction temperature is 38-40 ℃, and the reaction time is 2-3 h.
Further, after the fourth step of reaction is completed, dilute hydrochloric acid is added into the reaction liquid for quenching, toluene reagent is added for extraction for 2-3 times, the organic layers are combined, the organic layers are washed by saturated saline water, the crude product is obtained after desolventizing, and the crude product is recrystallized, filtered and dried to obtain the product 2-chloro-1- (4-fluorophenyl) -acetophenone.
Further, in the fourth step, the solvent is recovered by rectification, and simultaneously, the byproduct hexamethyl-nitrogen-oxygen alkane in the solvent is recovered.
The beneficial effects of the invention are as follows: 1. the atorvastatin mother nucleus M4 is prepared by halogenating 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone to prepare 2-chloro (or bromo) -1- (4-fluorophenyl) -acetophenone, the reaction selectivity is higher, benzene ring chloro (bromo) compounds of the 4-fluorophenyl acetophenone are not generated, the generation of side reactions is reduced, the reaction yield is improved, simple substance chloro or bromo is not used, a large amount of chlorine-and bromine-containing wastewater is not caused, and the wastewater is convenient to treat and environment-friendly.
The reaction condition of the TMCS halogenating reagent and alcohol is mild, the selectivity is good, the generation of side reaction is reduced, the treatment difficulty of residual halogenating reagent and byproducts is reduced, the environmental pollution is reduced, and the product after the TMCS reaction is easy to recycle.
Drawings
FIG. 1 is a schematic illustration of the reaction scheme of the present invention;
FIG. 2 is a schematic diagram of a Davis reagent recovery reaction scheme.
Detailed Description
The technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Firstly, 6.8g of phenylacetic acid is dissolved in 40ml of chloroform, 7.8g of thionyl chloride is added into a reaction bottle, reflux reaction is carried out for 2-3 hours at 50-55 ℃, residual thionyl chloride is firstly distilled off after the reaction is finished, and then the phenylacetyl chloride is obtained by reduced pressure distillation, the purity is 98.5%, and the yield is 85%;
adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of aluminum trichloride loaded zeolite molecular sieve 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 liquid at 0 ℃ in the dropwise adding process, continuing to react for 2 hours after dropwise adding, adding sodium hydroxide solution for quenching after TLC tracking shows that the reaction is finished, layering, extracting a water layer with dichloromethane, merging an organic layer, washing the organic layer with saturated saline, decompressing and desolventizing the organic layer to dryness, adding 15ml of toluene for recrystallization, filtering, and drying to obtain 18.19g of 1- (4-fluorophenyl) acetophenone with the purity of 98.6% and the yield of 85%;
thirdly, 10.7g of 1- (4-fluorophenyl) acetophenone is dissolved in 100ml of THF, KHMDS is added to adjust the pH value of the solution to 9, 110ml of 5mol/L of Davis THF solution reagent is added to perform constant temperature stirring reaction for 24 hours at minus 78 ℃, TLC is tracked to show that the reaction is finished, THF, davis reagent and the like are recovered by vacuum fractionation, 50ml of dichloromethane is added after the fractionation is finished, the pH value is adjusted to about 7.0 by dilute acid water, stirring is performed to complete dissolution, layering is performed, the aqueous layer is extracted by dichloromethane, the organic layers are combined, the saturated saline is used for washing, the organic layers are decompressed and desolventized to dryness, 20ml of toluene is added to perform recrystallization, filtration and drying are performed, and the product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone 11.0g with the purity of 98.5 percent and the yield of 95.6 percent is obtained; the recovered Davis reagent can be reused after treatment;
step four, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone into 30ml of DMSO, stirring uniformly, adding 5.5g of trimethylchlorosilane, stirring and mixing for 3 hours at 38 ℃, slowly pouring the reaction solution into 150ml of 0.05M dilute hydrochloric acid after the reaction is finished, extracting for 2 times by 50ml of toluene, merging organic layers, washing the organic layers with saturated saline, decompressing and desolventizing the organic layers to dryness, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain a product, namely 12.2g of 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.2%, the yield is 98.3%, and recovering the byproduct hexamethyl-nitrogen-oxygen alkane through rectification;
fifthly, adding 12.5g of 2-chloro-1- (4-fluorophenyl) -acetophenone, 60ml of acetone, 10.3g of isobutyrylacetanilide and 7.6g of potassium carbonate powder into a 100ml flask, heating to a reflux state at 50 ℃ for reaction for 3 hours, and tracking by TLC (thin layer chromatography) to show the end of the reaction; vacuum desolventizing to dryness, adding 100ml of ethyl acetate and 100ml of water, stirring to complete dissolution, layering, extracting an aqueous layer with ethyl acetate, merging organic layers, washing with saturated saline solution, vacuum desolventizing to dryness, adding 30ml of methanol for recrystallization, filtering and drying to obtain 16.73g of white powder of a product M4, wherein the purity is 99.1%, and the yield is 80%.
Example 2
Firstly, 6.8g of phenylacetic acid is dissolved in 40ml of chloroform, 7.8g of thionyl chloride is added into a reaction bottle, reflux reaction is carried out for 2-3 hours at 50-55 ℃, residual thionyl chloride is firstly distilled off after the reaction is finished, then the residual thionyl chloride is distilled under reduced pressure to obtain 6.52g of phenylacetyl chloride, the purity is 98.6%, and the yield is 85%;
adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of aluminum trichloride loaded zeolite molecular sieve 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 liquid at 0 ℃ in the dropwise adding process, continuing to react for 2 hours after dropwise adding, adding sodium hydroxide solution for quenching after TLC tracking shows that the reaction is finished, layering, extracting a water layer with dichloromethane, merging an organic layer, washing the organic layer with saturated saline, decompressing and desolventizing the organic layer to dryness, adding 15ml of toluene for recrystallization, filtering, and drying to obtain 18.18g of 1- (4-fluorophenyl) acetophenone with the purity of 98.7% and the yield of 85%;
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 5mol/L of Davis THF solution reagent, stirring at a constant temperature of minus 78 ℃ for 24 hours, performing TLC tracking to show that the reaction is finished, recovering THF, davis reagent and the like by vacuum fractionation, adding 50ml of dichloromethane after the fractionation is finished, adjusting the pH value to about 7.0 by dilute acid water, stirring until the mixture is fully dissolved, layering, extracting the water layer by dichloromethane, merging the organic layers, washing the organic layers by saturated saline, performing vacuum desolventizing on of the organic layers to dryness, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.3g of a product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone, wherein the purity is 98.8%, and the yield is 98.3%, and the recovered Davis reagent can be repeatedly used by treatment;
step four, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone into 30ml of DMSO, stirring uniformly, adding 5.5g of trimethylchlorosilane, stirring and mixing for 3 hours at 40 ℃, slowly pouring the reaction solution into 150ml of 0.05M dilute hydrochloric acid after the reaction is finished, extracting for 2 times by 50ml of toluene, merging organic layers, washing the organic layers by saturated saline, decompressing and desolventizing the organic layers to dryness, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain a product, namely 12.3g of 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.1%, the yield is 99.1%, and a recovered solvent can be used for recovering byproduct hexamethyl-nitrogen-oxygen alkane by rectification;
and fifthly, adding 12.5g of 2-chloro-1- (4-fluorophenyl) -acetophenone, 60ml of acetone, 10.3g of isobutyrylacetanilide, 7.6g of potassium carbonate powder, heating to a reflux state of 50 ℃ for reaction for 3 hours, performing TLC tracking to show the end of the reaction, performing decompression desolventizing to dryness, adding 100ml of ethyl acetate and 100ml of water, stirring to complete dissolution, layering, extracting a water layer by using ethyl acetate, merging an organic layer, washing the organic layer by using saturated saline, performing decompression desolventizing to dryness, adding 30ml of methanol for recrystallization, filtering and drying to obtain 16.70g of white powder of a product M4, wherein the purity is 99.1%, and the yield is 80%.
Example 3
Firstly, 6.8g of phenylacetic acid is dissolved in 40ml of chloroform, 7.8g of thionyl chloride is added into a reaction bottle, reflux reaction is carried out for 2-3 hours at 50-55 ℃, residual thionyl chloride is firstly distilled off after the reaction is finished, and then the phenylacetyl chloride is obtained by reduced pressure distillation, the purity is 98.5%, and the yield is 85%;
adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of aluminum trichloride loaded zeolite molecular sieve 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 liquid at 0 ℃ in the dropwise adding process, continuing to react for 2 hours after dropwise adding, adding sodium hydroxide solution for quenching after TLC tracking shows that the reaction is finished, layering, extracting a water layer with dichloromethane, merging an organic layer, washing the organic layer with saturated saline, decompressing and desolventizing the organic layer to dryness, adding 15ml of toluene for recrystallization, filtering, and drying to obtain 18.15g of 1- (4-fluorophenyl) acetophenone with the purity of 99.0% and the yield of 85%;
thirdly, 10.7g of 1- (4-fluorophenyl) acetophenone is dissolved in 100ml of THF, KHMDS is added to adjust the pH value of the solution to 11, 110ml of 5mol/L of Davis THF solution reagent is added to perform constant temperature stirring reaction for 24 hours at minus 78 ℃, TLC is tracked to show that the reaction is finished, THF, davis reagent and the like are recovered by vacuum fractionation, 50ml of dichloromethane is added after the fractionation is finished, the pH value is adjusted to about 7.0 by dilute acid water, stirring is performed to complete dissolution, layering is performed, the aqueous layer is extracted by dichloromethane, the organic layers are combined, the organic layers are washed by saturated saline, the organic layers are decompressed and desolventized to dryness, 20ml of toluene is added to perform recrystallization, filtration and drying are performed, and the product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone 11.2g with the purity of 98.9 percent and the yield of 97.3 percent is obtained, and the recovered Davis reagent can be repeatedly used through treatment;
step four, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone into 30ml of DMSO, stirring uniformly, adding 5.5g of trimethylchlorosilane, stirring and mixing for 2 hours at 40 ℃, slowly pouring the reaction solution into 150ml of 0.05M dilute hydrochloric acid after the reaction is finished, extracting for 2 times by 50ml of toluene, merging organic layers, washing the organic layers with saturated saline, decompressing and desolventizing the organic layers to dryness, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain a product, namely 12.2g of 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.1%, the yield is 98.3%, and recovering the byproduct hexamethyl-nitrogen-oxygen alkane through rectification;
and fifthly, adding 12.5g of 2-chloro-1- (4-fluorophenyl) -acetophenone, 60ml of acetone, 10.3g of isobutyrylacetanilide, 7.6g of potassium carbonate powder, heating to a reflux state of 50 ℃ for reaction for 3 hours, performing TLC tracking to show the end of the reaction, performing decompression desolventizing to dryness, adding 100ml of ethyl acetate and 100ml of water, stirring to complete dissolution, layering, extracting a water layer by using ethyl acetate, merging an organic layer, washing the organic layer by using saturated saline, performing decompression desolventizing to dryness, adding 30ml of methanol for recrystallization, filtering and drying to obtain 16.67g of white powder of a product M4, wherein the purity is 99.1%, and the yield is 80%.
Example 4
Firstly, 6.8g of phenylacetic acid is dissolved in 40ml of chloroform, 7.8g of thionyl chloride is added into a reaction bottle, reflux reaction is carried out for 2-3 hours at 50-55 ℃, residual thionyl chloride is firstly distilled off after the reaction is finished, and then the phenylacetyl chloride is obtained by reduced pressure distillation, the purity is 98.5%, and the yield is 85%;
adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of aluminum trichloride loaded zeolite molecular sieve 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 liquid at 0 ℃ in the dropwise adding process, continuing to react for 2 hours after dropwise adding, adding sodium hydroxide solution for quenching after TLC tracking shows that the reaction is finished, layering, extracting a water layer with dichloromethane, merging an organic layer, washing the organic layer with saturated saline, decompressing and desolventizing the organic layer to dryness, adding 15ml of toluene for recrystallization, filtering, and drying to obtain 18.16g of 1- (4-fluorophenyl) acetophenone with the purity of 99.0% and the yield of 85%;
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 5mol/L of Davis THF solution reagent, stirring at a constant temperature of minus 78 ℃ for 24 hours, performing TLC tracking to show that the reaction is finished, recovering THF, davis reagent and the like by vacuum fractionation, adding 50ml of dichloromethane after the fractionation is finished, adjusting the pH value to about 7.0 by dilute acid water, stirring until the mixture is fully dissolved, layering, extracting the water layer by dichloromethane, merging the organic layers, washing the organic layers by saturated saline, performing vacuum desolventizing on of the organic layers to dryness, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.2g of a product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone, wherein the purity is 98.7%, and the yield is 97.3%, and the recovered Davis reagent can be repeatedly used by treatment;
step four, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone into 30ml of DMSO, stirring uniformly, adding 5.5g of trimethylchlorosilane, stirring and mixing for 2 hours at 38 ℃, slowly pouring the reaction solution into 150ml of 0.05M dilute hydrochloric acid after the reaction is finished, extracting for 2 times by 50ml of toluene, merging organic layers, washing the organic layers with saturated saline, decompressing and desolventizing the organic layers to dryness, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain a product, namely 12.1g of 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.1%, the yield is 97.5%, and a recovered solvent can be used for recovering byproduct hexamethyl-nitrogen-oxygen alkane through rectification;
and fifthly, adding 12.5g of 2-chloro-1- (4-fluorophenyl) -acetophenone, 60ml of acetone, 10.3g of isobutyrylacetanilide, 7.6g of potassium carbonate powder, heating to a reflux state of 50 ℃ for reaction for 3 hours, performing TLC tracking to show the end of the reaction, performing decompression desolventizing to dryness, adding 100ml of ethyl acetate and 100ml of water, stirring to complete dissolution, layering, extracting a water layer by using ethyl acetate, merging an organic layer, washing the organic layer by using saturated saline, performing decompression desolventizing to dryness, adding 30ml of methanol for recrystallization, filtering and drying to obtain 16.72g of white powder of a product M4, wherein the purity is 99.1%, and the yield is 80%.
Example 5
Firstly, 6.8g of phenylacetic acid is dissolved in 40ml of chloroform, 7.8g of thionyl chloride is added into a reaction bottle, reflux reaction is carried out for 2-3 hours at 50-55 ℃, residual thionyl chloride is firstly distilled off after the reaction is finished, then the residual thionyl chloride is distilled under reduced pressure to obtain 6.51g of phenylacetyl chloride, the purity is 98.6%, and the yield is 85%;
adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of aluminum trichloride loaded zeolite molecular sieve 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 liquid at 0 ℃ in the dropwise adding process, continuing to react for 2 hours after dropwise adding, adding sodium hydroxide solution for quenching after TLC tracking shows that the reaction is finished, layering, extracting a water layer with dichloromethane, merging an organic layer, washing the organic layer with saturated saline, decompressing and desolventizing the organic layer to dryness, adding 15ml of toluene for recrystallization, filtering, and drying to obtain 18.16g of 1- (4-fluorophenyl) acetophenone with the purity of 99.0% and the yield of 85%;
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 5mol/L of Davis THF solution reagent, stirring at a constant temperature of minus 75 ℃ for 24 hours, performing TLC tracking to show that the reaction is finished, recovering THF, davis reagent and the like by vacuum fractionation, adding 50ml of dichloromethane after the fractionation is finished, adjusting the pH value to about 7.0 by dilute acid water, stirring until the mixture is fully dissolved, layering, extracting the water layer by dichloromethane, merging the organic layers, washing the organic layers by saturated saline, performing vacuum desolventizing on of the organic layers to dryness, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.0g of a product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone, wherein the purity is 98.9%, and the yield is 95.6%, and the recovered Davis reagent can be repeatedly used by treatment;
step four, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone into 30ml of DMSO, stirring uniformly, adding 5.5g of trimethylchlorosilane, stirring and mixing for 2 hours at 40 ℃, slowly pouring the reaction solution into 150ml of 0.05M dilute hydrochloric acid after the reaction is finished, extracting for 2 times by 50ml of toluene, merging organic layers, washing the organic layers with saturated saline, decompressing and desolventizing the organic layers to dryness, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain a product, namely 12.1g of 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.1%, the yield is 97.5%, and a recovered solvent can be used for recovering byproduct hexamethyl-nitrogen-oxygen alkane through rectification;
and fifthly, adding 12.5g of 2-chloro-1- (4-fluorophenyl) -acetophenone, 60ml of acetone, 10.3g of isobutyrylacetanilide, 7.6g of potassium carbonate powder, heating to a reflux state of 50 ℃ for reaction for 3 hours, performing TLC tracking to show the end of the reaction, performing decompression desolventizing to dryness, adding 100ml of ethyl acetate and 100ml of water, stirring to complete dissolution, layering, extracting a water layer by using ethyl acetate, merging an organic layer, washing the organic layer by using saturated saline, performing decompression desolventizing to dryness, adding 30ml of methanol for recrystallization, filtering and drying to obtain 16.70g of white powder of a product M4, wherein the purity is 99.1%, and the yield is 80%.
Example 6
Firstly, 6.8g of phenylacetic acid is dissolved in 40ml of chloroform, 7.8g of thionyl chloride is added into a reaction bottle, reflux reaction is carried out for 2-3 hours at 50-55 ℃, residual thionyl chloride is firstly distilled off after the reaction is finished, and then the phenylacetyl chloride is obtained by reduced pressure distillation, the purity is 98.6%, and the yield is 85%;
adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of aluminum trichloride loaded zeolite molecular sieve 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 liquid at 0 ℃ in the dropwise adding process, continuing to react for 2 hours after dropwise adding, adding sodium hydroxide solution for quenching after TLC tracking shows that the reaction is finished, layering, extracting a water layer with dichloromethane, merging an organic layer, washing the organic layer with saturated saline, decompressing and desolventizing the organic layer to dryness, adding 15ml of toluene for recrystallization, filtering, and drying to obtain 18.16g of 1- (4-fluorophenyl) acetophenone with the purity of 99.0% and the yield of 85%;
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 5mol/L of Davis THF solution reagent, stirring at a constant temperature of minus 80 ℃ for reaction for 24 hours, performing TLC tracking to show that the reaction is finished, recovering THF, davis reagent and the like by vacuum fractionation, adding 50ml of dichloromethane after the fractionation is finished, adjusting the pH value to about 7.0 by dilute acid water, stirring to be fully dissolved, layering, extracting the water layer by dichloromethane, merging the organic layers, washing the organic layers by saturated saline, performing vacuum desolventizing to dryness on the organic layers, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.0g of a product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone, wherein the purity is 98.6%, and the yield is 95.6%, and the recovered Davis reagent can be repeatedly used by treatment;
step four, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone into 30ml of DMSO, stirring uniformly, adding 5.5g of trimethylchlorosilane, stirring and mixing for 2 hours at 40 ℃, slowly pouring the reaction solution into 150ml of 0.05M dilute hydrochloric acid after the reaction is finished, extracting for 2 times by 50ml of toluene, merging organic layers, washing the organic layers with saturated saline, decompressing and desolventizing the organic layers to dryness, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain a product, namely 12.1g of 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.2%, the yield is 97.5%, and recovering the byproduct hexamethyl-nitrogen-oxygen alkane by rectification;
and fifthly, adding 12.5g of 2-chloro-1- (4-fluorophenyl) -acetophenone, 60ml of acetone, 10.3g of isobutyrylacetanilide, 7.6g of potassium carbonate powder, heating to a reflux state of 50 ℃ for reaction for 3 hours, performing TLC tracking to show the end of the reaction, performing decompression desolventizing to dryness, adding 100ml of ethyl acetate and 100ml of water, stirring to complete dissolution, layering, extracting a water layer by using ethyl acetate, merging an organic layer, washing the organic layer by using saturated saline, performing decompression desolventizing to dryness, adding 30ml of methanol for recrystallization, filtering and drying to obtain 16.77g of white powder of a product M4, wherein the purity is 99.1%, and the yield is 80%.
Example 7
Firstly, 6.8g of phenylacetic acid is dissolved in 40ml of chloroform, 7.8g of thionyl chloride is added into a reaction bottle, reflux reaction is carried out for 2-3 hours at 50-55 ℃, residual thionyl chloride is firstly distilled off after the reaction is finished, and then the phenylacetyl chloride is obtained by reduced pressure distillation, the purity is 98.8%, and the yield is 85%;
adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of aluminum trichloride loaded zeolite molecular sieve 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 liquid at 0 ℃ in the dropwise adding process, continuing to react for 2 hours after dropwise adding, adding sodium hydroxide solution for quenching after TLC tracking shows that the reaction is finished, layering, extracting a water layer with dichloromethane, merging an organic layer, washing the organic layer with saturated saline, decompressing and desolventizing the organic layer to dryness, adding 15ml of toluene for recrystallization, filtering, and drying to obtain 18.19g of 1- (4-fluorophenyl) acetophenone with the purity of 98.5% and the yield of 85%;
thirdly, dissolving 10.7g of 1- (4-fluorophenyl) acetophenone into a mixed solution with the volume ratio of 100ml of THF to toluene being 1:1, adding KHMDS to adjust the pH value of the solution to 10, adding 110ml of 5mol/L of Davis THF solution reagent, stirring at constant temperature at minus 78 ℃ for reaction for 24 hours, carrying out TLC tracking to show that the reaction is finished, carrying out vacuum fractionation to recover THF, davis reagent and the like, adding 50ml of dichloromethane after the fractionation is finished, adjusting the pH value to about 7.0 by using dilute acid water, stirring until the mixture is fully dissolved, layering, extracting a water layer by using dichloromethane, merging an organic layer, washing the organic layer by using saturated saline, carrying out vacuum desolventizing on the organic layer to dryness, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.0g of a product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone, wherein the purity is 98.7%, and the yield is 95.6%, and the recovered Davis reagent can be repeatedly used after treatment;
step four, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone into 30ml of DMSO, stirring uniformly, adding 5.5g of trimethylchlorosilane, stirring and mixing for 2 hours at 40 ℃, slowly pouring the reaction solution into 150ml of 0.05M dilute hydrochloric acid after the reaction is finished, extracting for 2 times by 50ml of toluene, merging organic layers, washing the organic layers with saturated saline, decompressing and desolventizing the organic layers to dryness, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain a product, namely 12.2g of 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.1%, the yield is 98.3%, and recovering the byproduct hexamethyl-nitrogen-oxygen alkane through rectification;
and fifthly, adding 12.5g of 2-chloro-1- (4-fluorophenyl) -acetophenone, 60ml of acetone, 10.3g of isobutyrylacetanilide, 7.6g of potassium carbonate powder, heating to a reflux state of 50 ℃ for reaction for 3 hours, performing TLC tracking to show the end of the reaction, performing decompression desolventizing to dryness, adding 100ml of ethyl acetate and 100ml of water, stirring to complete dissolution, layering, extracting a water layer by using ethyl acetate, merging an organic layer, washing the organic layer by using saturated saline, performing decompression desolventizing to dryness, adding 30ml of methanol for recrystallization, filtering and drying to obtain 16.75g of white powder of a product M4, wherein the purity is 99.1%, and the yield is 80%.
Publication CN106397296B embodiment:
in the first step, 6.8g of phenylacetic acid is dissolved in 40ml of chloroform, 7.8g of thionyl chloride is added into a reaction bottle, the temperature is raised, the reflux reaction is carried out for 2-3 hours, the residual thionyl chloride is firstly distilled off after the reaction is finished, then 6.31g of phenylacetyl chloride is obtained through reduced pressure distillation, and the yield is 80%.
And secondly, adding 10.6g of fluorobenzene into 100ml of dichloromethane, stirring, adding 13g of zeolite molecular sieve 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 higher than 10 ℃ during the dropwise adding process, continuing to react for 2 hours after the dropwise adding, and tracking by TLC (thin layer chromatography) to display the end of the reaction. Filtration and spin drying gave a pale yellow solid, which was recrystallized to give 17.12g of 4-fluorophenyl acetophenone in 80% yield.
Thirdly, 10.7g of 4-fluorophenyl acetophenone is dissolved in 100ml glacial acetic acid, 15ml of 40% hydrobromic acid is added, stirring is carried out, 9ml of 30% hydrogen peroxide by mass fraction is slowly added dropwise, the reaction is carried out for 16 hours at 40 ℃, and TLC tracking shows that the reaction is finished. A saturated aqueous sodium sulfite solution was added to the reaction solution to remove unreacted bromine. 200ml of ethyl acetate and an appropriate amount of aqueous sodium carbonate solution were added for extraction, and an organic layer was separated, and the organic layer was further washed with aqueous sodium carbonate solution for 2 times and dried over anhydrous magnesium sulfate. Filtration and spin drying gave 13.25g of 2-bromo-1- (4-fluorophenyl) -acetophenone as a yellow thick liquid in 90% yield.
Fourth, 1.47g of 2-bromo-1- (4-fluorophenyl) -acetophenone, 30ml of acetone, 1.03g of isobutyrylacetanilide and 0.76g of potassium carbonate powder were charged into a 100ml flask, and the reaction was heated and carried out under reflux for 2 hours, and TLC tracing showed the completion of the reaction. The acetone was distilled off, 40ml of ethyl acetate and 40ml of water were added for extraction. Column chromatography analysis gave M-4 as a white powder, 1.63g by mass and 78% yield.
Obviously, the yield of the intermediate M4 of the technical scheme provided by the invention is higher than that of the technical scheme recorded in the disclosure CN106397296B, and the intermediate M4 has higher purity and less pollution.
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 characteristics 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 disclosure describes embodiments, not every embodiment is provided with a separate embodiment, and that this description is provided for clarity only, and that the disclosure is not limited to the embodiments described in detail below, and that the embodiments described in the examples may be combined as appropriate to form other embodiments that will be apparent to those skilled in the art.
Claims (1)
1. The preparation method of the atorvastatin calcium intermediate is characterized by comprising the following steps of:
firstly, reacting phenylacetic acid with thionyl chloride to obtain phenylacetyl chloride;
performing a Friedel-crafts acylation reaction on the obtained phenylacetyl chloride and fluorobenzene under the action of a catalyst to obtain 4-fluorophenyl acetophenone;
thirdly, adding Davis reagent to oxidize after alkalizing the 4-fluorophenyl acetophenone solution, and introducing hydroxyl on carbonyl alpha-carbon to prepare 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone;
fourthly, carrying out halogenation reaction on a halogenating reagent and 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone to prepare 2-chloro-1- (4-fluorophenyl) -acetophenone;
fifthly, reacting 2-chloro-1- (4-fluorophenyl) -acetophenone with N-phenylisobutyrylacetamide to prepare an atorvastatin calcium intermediate M4;
the second-step reaction catalyst is an aluminum trichloride-loaded zeolite molecular sieve; the reaction solvent in the third step is one or more of tetrahydrofuran, diethyl ether, 1, 4-dioxane, toluene and xylene; the third step of reaction is carried out in the presence of KHMDS or NaHMDS as an alkalizing agent, and the pH value of the solution reaction is 9-11; the reaction temperature of the third step is-75 to-80 ℃; the Davis reagent in the third step is recovered by oxidizing m-chloroperoxybenzoic acid; in the fourth step of reaction, adding a solvent into 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone, stirring and dissolving, and then adding a halogenating reagent into the obtained 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone solution; the reaction solvent selected in the fourth step is DMSO, the halogenating reagent selected is trimethylchlorosilane, the reaction temperature is 38-40 ℃, and the reaction time is 2-3 h; after the fourth step of reaction is finished, adding dilute hydrochloric acid into the reaction liquid for quenching, adding toluene reagent for extraction for 2-3 times, merging organic layers, washing the organic layers by saturated saline water, desolventizing the organic layers to obtain a crude product, and recrystallizing, filtering and drying the crude product to obtain a product 2-chloro-1- (4-fluorophenyl) -acetophenone; in the fourth step of reaction, the solvent is recovered through rectification, and simultaneously, byproduct hexamethyl-nitrogen-oxygen alkane in the solvent is recovered.
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