CN115466196A - Preparation method of atorvastatin calcium intermediate - Google Patents
Preparation method of atorvastatin calcium intermediate Download PDFInfo
- Publication number
- CN115466196A CN115466196A CN202211054112.6A CN202211054112A CN115466196A CN 115466196 A CN115466196 A CN 115466196A CN 202211054112 A CN202211054112 A CN 202211054112A CN 115466196 A CN115466196 A CN 115466196A
- Authority
- CN
- China
- Prior art keywords
- reaction
- fluorophenyl
- acetophenone
- atorvastatin calcium
- reagent
- 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.)
- Granted
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 22
- 229960001770 atorvastatin calcium Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 112
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 39
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 38
- 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
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 claims abstract description 14
- 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 11
- 229960003424 phenylacetic acid Drugs 0.000 claims abstract description 11
- 239000003279 phenylacetic acid Substances 0.000 claims abstract description 11
- 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 5
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 claims abstract description 3
- 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
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 239000012044 organic layer Substances 0.000 claims description 85
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 72
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 34
- 238000001914 filtration Methods 0.000 claims description 32
- 238000005406 washing Methods 0.000 claims description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 29
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 27
- 238000001035 drying Methods 0.000 claims description 27
- 239000002904 solvent Substances 0.000 claims description 27
- 239000000047 product Substances 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 22
- -1 hexamethyl-azoxane Chemical compound 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- 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
- 239000010457 zeolite Substances 0.000 claims description 10
- 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 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 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 group 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
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 230000026030 halogenation Effects 0.000 claims description 4
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 4
- NEJOAEIRBZFRSF-UHFFFAOYSA-N fluorobenzene;1-phenylethanone Chemical compound FC1=CC=CC=C1.CC(=O)C1=CC=CC=C1 NEJOAEIRBZFRSF-UHFFFAOYSA-N 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
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 230000003113 alkalizing effect Effects 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 abstract description 8
- 238000007086 side reaction Methods 0.000 abstract description 6
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 abstract description 3
- 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 47
- 238000003756 stirring Methods 0.000 description 44
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 238000001953 recrystallisation Methods 0.000 description 23
- 239000010410 layer Substances 0.000 description 22
- 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
- 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
- 238000002156 mixing Methods 0.000 description 13
- 238000004821 distillation Methods 0.000 description 8
- 238000005194 fractionation Methods 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 239000012295 chemical reaction liquid Substances 0.000 description 7
- 238000000643 oven drying Methods 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-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
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- OGTSHGYHILFRHD-UHFFFAOYSA-N (4-fluorophenyl)-phenylmethanone Chemical compound C1=CC(F)=CC=C1C(=O)C1=CC=CC=C1 OGTSHGYHILFRHD-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- NPOAOTPXWNWTSH-UHFFFAOYSA-N 3-hydroxy-3-methylglutaric acid Chemical compound OC(=O)CC(O)(C)CC(O)=O NPOAOTPXWNWTSH-UHFFFAOYSA-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
- 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
- 125000001309 chloro group Chemical group Cl* 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
- 238000010586 diagram Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 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
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 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
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH 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)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 description 1
- 208000032928 Dyslipidaemia 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 compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
- 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
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 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
- 239000001257 hydrogen Substances 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
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
- 238000004065 wastewater treatment Methods 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
- C07C45/61—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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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, the phenylacetyl chloride and fluorobenzene are subjected to friedel-crafts acylation reaction under the action of a catalyst to obtain 4-fluorobenzeneacetophenone, a Davis reagent is added after the 4-fluorobenzeneacetophenone solution is alkalized to oxidize and introduce hydroxyl on carbonyl alpha-carbon, the obtained 1- (4-fluorophenyl) -2-hydroxyl-2-phenylacetone and a halogenating reagent are subjected to halogenating reaction to obtain 2-chloro-1- (4-fluorophenyl) -acetophenone, and the 2-chloro-1- (4-fluorophenyl) -acetophenone reacts with N-phenyl isobutyrylacetamide to prepare an atorvastatin calcium intermediate M4. The invention has the beneficial effects that: 2-chloro (or bromo) -1- (4-fluorophenyl) -acetophenone is prepared by halogenating 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone to prepare atorvastatin parent nucleus M4, so that the generation of side reactions is reduced, the reaction yield is improved, the TMCS halogenating reagent reduces the treatment difficulty of residual halogenating reagent and products, and the environmental pollution is reduced.
Description
Technical Field
The invention relates to the technical field of pharmaceutical and chemical industry, in particular to a preparation method of an atorvastatin calcium intermediate.
Background
Atorvastatin calcium (Atorvastain calcium), with the chemical name of (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-methylglutaric acid monoacyl coenzyme A (HMG-CoA) reductase inhibitor. It was introduced by the united states of america pfeiri 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.
In the prior art, chinese patent publication No. CN106397296B discloses a process for preparing atorvastatin calcium, which comprises reacting phenylacetyl chloride with fluorobenzene to prepare 4-fluorobenzophenone, preparing 2-chloro-1- (4-fluorophenyl) -2-phenylacetophenone (or 2-bromo-1- (4-fluorophenyl) -2-phenylacetophenone) through chloro (bromo), and reacting with N-phenylbutylacetamide acetamide to prepare atorvastatin calcium intermediate 4-fluoro- α - (2-methyl-1-oxopropyl) - γ -oxo-N, β -diphenylphenylbutylamide (hereinafter referred to as M4), but when preparing intermediate M4 by using chlorine or bromine as a simple substance, hydrogen on the 4-fluorophenylacetophenone phenyl ring is easily substituted, a large amount of benzene ring chloro (bromo) substituted compounds of 4-fluorobenzophenone are generated during the reaction, and the side reaction results in a large amount of inconvenient yield, and the side products are easily treated to cause serious pollution.
The invention provides a synthetic method of an atorvastatin intermediate, which aims at improving the original halogenation process in the existing production process, reducing the occurrence of side reactions, improving the reaction yield and reducing the pollution of the reaction.
Disclosure of Invention
Aiming at the problems that a large amount of chloro (bromo) compounds are generated in the halogenation reaction process of the existing preparation method, side reactions are more, the yield is too low, and the pollution is serious, the invention replaces the halogenation process of the original process by the following technical scheme: a preparation method 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 carry out friedel-crafts acylation reaction with fluorobenzene under the action of a catalyst to obtain 4-fluorobenzene acetophenone;
thirdly, adding 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 halogenating reagent and the 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone have halogenating reaction to prepare the 2-chloro (or bromo) -1- (4-fluorophenyl) -acetophenone;
fifthly, 2-chloro (or bromo) -1- (4-fluorophenyl) -acetophenone is reacted with N-phenyl isobutyryl acetamide to prepare an atorvastatin calcium intermediate M4.
Further, the catalyst for the second step reaction is aluminum trichloride supported zeolite molecular sieve.
Further, in the third step of reaction, the reaction solvent is one or more of tetrahydrofuran, diethyl ether, 1,4-dioxane, toluene and xylene, and tetrahydrofuran is preferred.
Further, the third step reaction alkalizing agent is KHMDS or NaHMDS, and the solution reaction pH value is 9-11, preferably 10.
Furthermore, the reaction temperature of the third step is-75 to-80 ℃.
Further, the third step reaction Davis reagent is recovered by oxidation of m-chloroperoxybenzoic acid.
In the fourth reaction step, a solvent is added into the 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone, the mixture is stirred and dissolved, and a halogenating reagent is added into the obtained 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone solution.
Further, the reaction solvent selected in the fourth step is DMSO, the halogenation reagent selected is trimethylchlorosilane, the reaction temperature is 38-40 ℃, and the reaction time is 2-3 h.
Further, after the fourth step of reaction is finished, adding dilute hydrochloric acid into the reaction solution for quenching, adding a methane reagent for extraction for 2-3 times, combining organic layers, washing with saturated saline solution, desolventizing the organic layers to obtain a crude product, and recrystallizing, filtering and drying the crude product to obtain the product 2-chloro-1- (4-fluorophenyl) -acetophenone.
Further, in the fourth reaction step, the solvent is recovered by rectification, and hexamethyl-azoxane as a byproduct in the solvent is recovered.
The invention has the beneficial effects that: 1. the atorvastatin mother nucleus M4 is prepared from 2-chloro (or bromo) -1- (4-fluorophenyl) -acetophenone by halogenating 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone, the reaction selectivity is high, a benzene ring chloro (bromo) compound of the 4-fluoro phenyl acetophenone cannot be generated, the generation of side reactions is reduced, the reaction yield is improved, and meanwhile, elemental chlorine or bromine is not used, so that a large amount of chlorine-containing and bromine-containing wastewater cannot be generated, the wastewater treatment is convenient, and the method is environment-friendly.
The reaction condition of TMCS halogenating agent and alcohol is mild, the selectivity is good, the generation of side reaction is reduced, the treatment difficulty of residual halogenating agent and by-product is reduced, the environmental pollution is reduced, and the product after TMCS reaction is easy to recover.
Drawings
FIG. 1 is a schematic diagram 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 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 derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present 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 h at the temperature of 50-55 ℃, residual thionyl chloride is firstly evaporated after the reaction is finished, and then reduced pressure distillation is carried out to obtain 6.54g of phenylacetyl chloride, the purity is 98.5%, and the yield is 85%.
And secondly, 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 solution at 0 ℃ 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 18.19g of 1- (4-fluorophenyl) acetophenone with the purity of 98.6 percent and the yield of 85 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.
And fourthly, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone into 30ml of DMSO, uniformly stirring, adding 5.5g of trimethylchlorosilane, stirring and mixing at 38 ℃ for 3h, after the reaction is finished, slowly pouring the reaction liquid into 150ml of 0.05M diluted hydrochloric acid, extracting 2 times by 50ml of 2 toluene, combining organic layers, washing by using saturated saline solution, decompressing and desolventizing the organic layers till the organic layers are dry, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain 12.2g of the product 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.2 percent, and the yield is 98.3 percent. The recovered solvent is rectified to recover byproduct hexamethyl-azoxane.
Step five, 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 50 ℃ and reacting for 3h under a reflux state, and tracking by TLC to show that the reaction is finished. Removing solvent under reduced pressure to dry, adding 100ml ethyl acetate and 100ml water, stirring to dissolve completely, layering, extracting water layer with ethyl acetate, mixing organic layers, washing with saturated saline solution, removing solvent under reduced pressure to dry, adding 30ml methanol for recrystallization, filtering, and oven drying to obtain white powder 16.73g of product M4 with purity of 99.1% and yield of 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 h at the temperature of 50-55 ℃, residual thionyl chloride is firstly evaporated after the reaction is finished, and then reduced pressure distillation is carried out to obtain 6.52g of phenylacetyl chloride with the purity of 98.6 percent and the yield of 85 percent.
And secondly, 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 solution at 0 ℃ 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 18.18g of 1- (4-fluorophenyl) acetophenone with the purity of 98.7 percent and the yield of 85 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 5mol/L of Davis THF solution reagent 110ml, stirring the mixture for reaction at constant temperature of-78 ℃ for 24h, tracking the TLC to show that the reaction is finished, decompressing and fractionating 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 until the mixture is completely dissolved, layering, extracting a water layer by using dichloromethane, combining organic layers, washing the organic layers by using saturated saline, decompressing and desolventizing the organic layers until the organic layers are dried, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.3g of the product 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone, wherein the purity is 98.8 percent and the yield is 98.3 percent. The recovered Davis reagent can be reused after being treated.
And fourthly, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone into 30ml of DMSO, uniformly stirring, adding 5.5g of trimethylchlorosilane, stirring and mixing at 40 ℃ for 3h, after the reaction is finished, slowly pouring the reaction liquid into 150ml of 0.05M diluted hydrochloric acid, extracting 2 times by 50ml of 2 toluene, combining organic layers, washing by using saturated saline solution, decompressing and desolventizing the organic layers till the organic layers are dry, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain 12.3g of the product 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.1 percent, and the yield is 99.1 percent. The recovered solvent is rectified to recover the byproduct hexamethyl-azaoxane.
Step five, 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 50 ℃ and reacting for 3h under a reflux state, and tracking by TLC to show that the reaction is finished. Removing solvent under reduced pressure to dry, adding 100ml ethyl acetate and 100ml water, stirring to dissolve completely, layering, extracting water layer with ethyl acetate, mixing organic layers, washing with saturated saline solution, removing solvent under reduced pressure to dry, adding 30ml methanol to recrystallize, filtering, oven drying to obtain white powder 16.70g of product M4, purity 99.1%, yield 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 h at the temperature of 50-55 ℃, residual thionyl chloride is firstly evaporated after the reaction is finished, and then reduced pressure distillation is carried out to obtain 6.51g of phenylacetyl chloride, the purity is 98.5%, and the yield is 85%.
And secondly, 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 solution at 0 ℃ 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 18.15g of 1- (4-fluorophenyl) acetophenone with the purity of 99.0 percent and the yield of 85 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 11, adding 5mol/L of Davis THF solution reagent 110ml, stirring the mixture for reaction at constant temperature of-78 ℃ for 24h, tracking the TLC to show that the reaction is finished, decompressing and fractionating 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 until the mixture is completely dissolved, layering, extracting a water layer by using dichloromethane, combining organic layers, washing the organic layers by using saturated saline, decompressing and desolventizing the organic layers until the organic layers are dried, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.2g of the product 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone, wherein the purity is 98.9 percent and the yield is 97.3 percent. The recovered Davis reagent can be reused after being treated.
And fourthly, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone into 30ml of DMSO, uniformly stirring, adding 5.5g of trimethylchlorosilane, stirring and mixing at 40 ℃ for 2h, after the reaction is finished, slowly pouring the reaction liquid into 150ml of 0.05M diluted hydrochloric acid, extracting 2 times by 50ml of 2 toluene, combining organic layers, washing by using saturated saline solution, decompressing and desolventizing the organic layers till the organic layers are dry, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain 12.2g of the product 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.1 percent, and the yield is 98.3 percent. The recovered solvent is rectified to recover byproduct hexamethyl-azoxane.
Step five, 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 50 ℃ and reacting for 3h under a reflux state, and tracking by TLC to show that the reaction is finished. Removing solvent under reduced pressure to dry, adding 100ml ethyl acetate and 100ml water, stirring to dissolve completely, layering, extracting water layer with ethyl acetate, combining organic layers, washing with saturated saline solution, removing solvent under reduced pressure to dry, adding 30ml methanol to recrystallize, filtering, drying to obtain white powder 16.67g of product M4, purity 99.1%, yield 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 h at the temperature of 50-55 ℃, residual thionyl chloride is firstly evaporated after the reaction is finished, and then reduced pressure distillation is carried out to obtain 6.50g of phenylacetyl chloride, the purity is 98.5%, and the yield is 85%.
And secondly, 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 solution at 0 ℃ 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 18.16g of 1- (4-fluorophenyl) acetophenone with the purity of 99.0 percent and the yield of 85 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 11.2g of the product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone, wherein the purity is 98.7 percent and the yield is 97.3 percent. The recovered Davis reagent can be reused after being treated.
And fourthly, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone into 30ml of DMSO, uniformly stirring, adding 5.5g of trimethylchlorosilane, stirring and mixing at 38 ℃ for 2h, after the reaction is finished, slowly pouring the reaction liquid into 150ml of 0.05M diluted hydrochloric acid, extracting 2 times by 50ml of 2 toluene, combining organic layers, washing by using saturated saline solution, decompressing and desolventizing the organic layers till the organic layers are dry, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain 12.1g of the product 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.1 percent, and the yield is 97.5 percent. The recovered solvent is rectified to recover the byproduct hexamethyl-azaoxane.
Step five, 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 50 ℃ and reacting for 3h under a reflux state, and tracking by TLC to show that the reaction is finished. Removing solvent under reduced pressure to dry, adding 100ml ethyl acetate and 100ml water, stirring to dissolve completely, layering, extracting water layer with ethyl acetate, mixing organic layers, washing with saturated saline solution, removing solvent under reduced pressure to dry, adding 30ml methanol to recrystallize, filtering, oven drying to obtain white powder 16.72g of product M4, purity 99.1%, yield 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 h at 50-55 ℃, residual thionyl chloride is firstly evaporated after the reaction is finished, and then reduced pressure distillation is carried out to obtain 6.51g of phenylacetyl chloride, the purity is 98.6%, and the yield is 85%.
And secondly, 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 solution at 0 ℃ 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 18.16g of 1- (4-fluorophenyl) acetophenone with the purity of 99.0 percent and the yield of 85 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 5mol/L of Davis THF solution reagent 110ml, stirring the mixture for reaction at constant temperature of-75 ℃, tracking and displaying the reaction by TLC, 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 the mixture until the mixture is completely dissolved, layering, extracting a water layer by using dichloromethane, combining organic layers, washing the organic layers by using saturated saline, decompressing and desolventizing the organic layers until the organic layers are dried, adding 20ml of toluene for recrystallization, filtering and drying to obtain 11.0g of the product 1- (4-fluorophenyl) -2-hydroxy-2-phenylethanone, wherein the purity is 98.9 percent and the yield is 95.6 percent. The recovered Davis reagent can be reused after being treated.
And fourthly, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone into 30ml of DMSO, uniformly stirring, adding 5.5g of trimethylchlorosilane, stirring and mixing at 40 ℃ for 2h, after the reaction is finished, slowly pouring the reaction liquid into 150ml of 0.05M diluted hydrochloric acid, extracting 2 times by 50ml of 2 toluene, combining organic layers, washing by using saturated saline solution, decompressing and desolventizing the organic layers till the organic layers are dry, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain 12.1g of the product 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.1 percent, and the yield is 97.5 percent. The recovered solvent is rectified to recover byproduct hexamethyl-azoxane.
Step five, 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 50 ℃ under reflux for reaction for 3h, and tracking by TLC to show that the reaction is finished. Removing solvent to dryness under reduced pressure, adding 100ml ethyl acetate and 100ml water, stirring to dissolve completely, layering, extracting water layer with ethyl acetate, mixing organic layers, washing with saturated saline solution, removing solvent to dryness under reduced pressure, adding 30ml methanol for recrystallization, filtering, and oven drying to obtain white powder 16.70g of product M4 with purity of 99.1% and yield of 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 h at 50-55 ℃, residual thionyl chloride is firstly evaporated after the reaction is finished, and then reduced pressure distillation is carried out to obtain 6.54g of phenylacetyl chloride, the purity is 98.6%, and the yield is 85%.
And secondly, 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 solution at 0 ℃ 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 18.16g of 1- (4-fluorophenyl) acetophenone with the purity of 99.0 percent and the yield of 85 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 11.0g of the product 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone, wherein the purity is 98.6 percent and the yield is 95.6 percent. The recovered Davis reagent can be reused after being treated.
And fourthly, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone into 30ml of DMSO, uniformly stirring, adding 5.5g of trimethylchlorosilane, stirring and mixing at 40 ℃ for 2h, after the reaction is finished, slowly pouring the reaction liquid into 150ml of 0.05M diluted hydrochloric acid, extracting 2 times by 50ml of 2 toluene, combining organic layers, washing by using saturated saline solution, decompressing and desolventizing the organic layers till the organic layers are dry, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain 12.1g of the product 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.2 percent, and the yield is 97.5 percent. The recovered solvent is rectified to recover byproduct hexamethyl-azoxane.
Step five, 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 50 ℃ and reacting for 3h under a reflux state, and tracking by TLC to show that the reaction is finished. Removing solvent under reduced pressure to dry, adding 100ml ethyl acetate and 100ml water, stirring to dissolve completely, layering, extracting water layer with ethyl acetate, mixing organic layers, washing with saturated saline solution, removing solvent under reduced pressure to dry, adding 30ml methanol to recrystallize, filtering, oven drying to obtain white powder 16.77g of product M4, purity 99.1%, yield 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 h at the temperature of 50-55 ℃, residual thionyl chloride is firstly evaporated after the reaction is finished, and then reduced pressure distillation is carried out to obtain 6.54g of phenylacetyl chloride with the purity of 98.8 percent and the yield of 85 percent.
And secondly, 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 solution at 0 ℃ 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 18.19g of 1- (4-fluorophenyl) acetophenone with the purity of 98.5 percent and the yield of 85 percent.
And thirdly, dissolving 10.7g of 1- (4-fluorophenyl) acetophenone in 100ml of mixed solution of THF and toluene with the volume ratio of 1:1, adding KHMDS to adjust the pH value to 10, adding 110ml of Davis THF solution reagent with the concentration of 5mol/L, stirring at constant temperature at 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 until the solution is completely dissolved, carrying out layering, extracting a water layer by using dichloromethane, combining organic layers, washing by using saturated salt, carrying out reduced pressure desolventization on the organic layer until the organic layer is dried, adding 20ml of toluene for recrystallization, filtering and drying to obtain the product of 1- (4-fluorophenyl) -2-hydroxy-2-acetophenone, wherein the purity is 11.0g, the purity is 98.7 percent, and the yield is 95.6 percent. The recovered Davis reagent can be reused after being treated.
And fourthly, adding 11.5g of 1- (4-fluorophenyl) -2-hydroxy-2-phenyl acetophenone into 30ml of DMSO, uniformly stirring, adding 5.5g of trimethylchlorosilane, stirring and mixing at 40 ℃ for 2h, after the reaction is finished, slowly pouring the reaction liquid into 150ml of 0.05M diluted hydrochloric acid, extracting 2 times by 50ml of 2 toluene, combining organic layers, washing by using saturated saline solution, decompressing and desolventizing the organic layers till the organic layers are dry, adding 20ml of ethyl acetate for recrystallization, filtering and drying to obtain 12.2g of the product 2-chloro-1- (4-fluorophenyl) -acetophenone, wherein the purity is 99.1 percent, and the yield is 98.3 percent. The recovered solvent is rectified to recover byproduct hexamethyl-azoxane.
Step five, 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 50 ℃ and reacting for 3h under a reflux state, and tracking by TLC to show that the reaction is finished. Removing solvent under reduced pressure to dry, adding 100ml ethyl acetate and 100ml water, stirring to dissolve completely, layering, extracting water layer with ethyl acetate, mixing organic layers, washing with saturated saline solution, removing solvent under reduced pressure to dry, adding 30ml methanol to recrystallize, filtering, oven drying to obtain white powder 16.75g of product M4, purity 99.1%, yield 80%.
Published patent document CN106397296B 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 zeolite molecular sieve under ice bath, 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. 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 with yield of 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 evaporated off and extracted with 40ml ethyl acetate and 40ml water. The column layer analysis gave 1.63g of M-4,M-4 as a white powder with a yield of 78%.
Obviously, the yield of the intermediate M4 in the technical scheme provided by the invention is higher than that recorded in CN106397296B, and the purity of the intermediate M4 product is higher and the pollution is less.
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 specification describes embodiments, not every embodiment includes only a single embodiment, and such description is for clarity purposes only, and it is to be understood that all embodiments may be combined as appropriate by one of ordinary skill in the art to form other embodiments as will be apparent to those of skill in the art from the description herein.
Claims (10)
1. A preparation method of an atorvastatin calcium intermediate is characterized by comprising 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 halogenating reagent and the 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone are subjected to halogenating reaction to prepare the 2-chloro-1- (4-fluorophenyl) -acetophenone;
fifthly, 2-chloro-1- (4-fluorophenyl) -acetophenone is reacted with N-phenyl isobutyryl acetamide to prepare an atorvastatin calcium intermediate M4.
2. The process of claim 1 for the preparation of an atorvastatin calcium intermediate wherein: the catalyst for the second step reaction is aluminum trichloride loaded zeolite molecular sieve.
3. The process of claim 1, wherein the step of preparing the atorvastatin calcium intermediate comprises: the reaction solvent in the third step 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 alkalizing reagent is KHMDS or NaHMDS, and the pH value of the solution reaction is 9-11.
5. The process of claim 1 for the preparation of an atorvastatin calcium intermediate wherein: the reaction temperature of the third step is-75 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 the preparation of an atorvastatin calcium intermediate wherein: in the fourth step of reaction, a solvent is added into the 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone, the mixture is stirred and dissolved, and a halogenating reagent is added into the obtained 1- (4-fluorophenyl) -2-hydroxy-2-phenyl ethanone solution.
8. The process of claim 7 for the preparation of an atorvastatin calcium intermediate wherein: the fourth step of reaction uses DMSO as a reaction solvent, trimethylchlorosilane as a halogenation reagent, the reaction temperature is 38-40 ℃, and the reaction time is 2-3 h.
9. The process of claim 7 for the preparation of an atorvastatin calcium intermediate wherein: and after the fourth step of reaction is finished, adding dilute hydrochloric acid into the reaction solution for quenching, adding a methane reagent for extraction for 2-3 times, combining organic layers, washing with saturated saline solution, desolventizing the organic layers to obtain a crude product, and recrystallizing, filtering and drying the crude product to obtain the product 2-chloro-1- (4-fluorophenyl) -acetophenone.
10. The process of claim 9 for the preparation of an atorvastatin calcium intermediate wherein: in the fourth step of reaction, the solvent is recovered by rectification, and a byproduct hexamethyl-azoxane in the solvent is recovered.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211054112.6A CN115466196B (en) | 2022-08-30 | 2022-08-30 | Preparation method of atorvastatin calcium intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211054112.6A CN115466196B (en) | 2022-08-30 | 2022-08-30 | Preparation method of atorvastatin calcium intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN115466196A true CN115466196A (en) | 2022-12-13 |
| CN115466196B CN115466196B (en) | 2024-03-26 |
Family
ID=84369493
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202211054112.6A Active CN115466196B (en) | 2022-08-30 | 2022-08-30 | Preparation method of atorvastatin calcium intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115466196B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007096751A1 (en) * | 2006-02-21 | 2007-08-30 | Cadila Healthcare Limited | Process for the preparation of atorvastatin calcium |
| 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 |
-
2022
- 2022-08-30 CN CN202211054112.6A patent/CN115466196B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007096751A1 (en) * | 2006-02-21 | 2007-08-30 | Cadila Healthcare Limited | Process for the preparation of atorvastatin calcium |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| YONGNIAN GAO ET AL: "Polymer-Supported N-Phenylsulfonyloxaziridine (Davis Reagent):AVersatile Oxidant", 《ADV. SYNTH. CATAL.》, vol. 350, pages 2937 - 2946 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN115466196B (en) | 2024-03-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Paulsen et al. | Stereoselective Mukaiyama–Michael/Michael/Aldol Domino Cyclization as the Key Step in the Synthesis of Pentasubstituted Arenes: An Efficient Access to Highly Active Inhibitors of Cholesteryl Ester Transfer Protein (CETP) | |
| FR2689887A1 (en) | Process for the preparation of a biphenyl derivative | |
| CN115466196A (en) | Preparation method of atorvastatin calcium intermediate | |
| Aikawa et al. | Copper-catalyzed allylic difluoromethylation of allyl carbonates with (difluoromethyl) zinc reagent | |
| CN106397296A (en) | Preparation technology of atorvastatin | |
| CN109836350A (en) | The environment-friendly preparation method of Atorvastatin key intermediate | |
| JPS606332B2 (en) | Method for producing a carboxylic acid or sulfinic acid derivative having a perfluoroalkyl group | |
| CN115260051A (en) | Preparation process of atorvastatin calcium intermediate | |
| CN114085150A (en) | Synthetic method of beta- (-) -L-menthyl-acrylate compound and application of beta- (-) -L-menthyl-acrylate compound in cigarettes | |
| JPH11130706A (en) | Production of 4,4'-bischloromethylbiphenyl | |
| CN1037509C (en) | Process for the preparation of ortho-hydroxy substituted aromatic nitriles via dehydration of the corresponding aldoximes | |
| EP1970369B1 (en) | Method for producing purified formylcyclopropane compound and intermediate of such formylcyclopropane compound | |
| JP4662026B2 (en) | Method for producing glycidyl methacrylate | |
| CN113801005B (en) | Preparation method of alpha-bromoacetophenone compound | |
| JP5482233B2 (en) | Method for producing diaryl disulfide compound | |
| US4577025A (en) | Method of preparing α-aromatic propionic acids and intermediates thereof | |
| JP4423494B2 (en) | Method for producing 2-hydroxycarboxylic acid | |
| JP5105825B2 (en) | Method for producing 4-hydroxy-2-adamantanone compound | |
| JP2011042602A (en) | Method for producing isopropyl 2-(3-nitrobenzylidene)acetoacetate | |
| JPS6160822B2 (en) | ||
| JP6434261B2 (en) | Iodobenzamide type alcohol oxidation catalyst | |
| Yim et al. | Effects of ultrasound on the formation of α-benzoylbenzyl cyanide from benzyl cyanide and alkylphenyl ketone from α-alkylbenzyl cyanide by potassium superoxide in the presence of crown ether | |
| Meshram et al. | Synthesis and characterizations of heterocyclic esters in solvent free condition | |
| SU252319A1 (en) | METHOD OF OBTAINING 2,6-DICHLOROPHENOL | |
| CN100404479C (en) | Method for producing aromatic unsaturated compound |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |