CN116655652A - New synthesis method of clopidogrel - Google Patents
New synthesis method of clopidogrel Download PDFInfo
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- CN116655652A CN116655652A CN202310634122.5A CN202310634122A CN116655652A CN 116655652 A CN116655652 A CN 116655652A CN 202310634122 A CN202310634122 A CN 202310634122A CN 116655652 A CN116655652 A CN 116655652A
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- clopidogrel
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- 239000005552 B01AC04 - Clopidogrel Substances 0.000 title claims abstract description 55
- 229960003009 clopidogrel Drugs 0.000 title claims abstract description 55
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 title claims abstract description 47
- 238000001308 synthesis method Methods 0.000 title claims abstract description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 22
- ZMPGBVQQIQSQED-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)-2-hydroxyacetate Chemical compound COC(=O)C(O)C1=CC=CC=C1Cl ZMPGBVQQIQSQED-UHFFFAOYSA-N 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 17
- -1 tetrahydrothiophene pyridine hydrochloric acid Chemical compound 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- AJZBDZTYAJVGNV-UHFFFAOYSA-N (2-chlorophenyl)methyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1Cl AJZBDZTYAJVGNV-UHFFFAOYSA-N 0.000 claims abstract description 6
- RWOLDZZTBNYTMS-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-hydroxyacetic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1Cl RWOLDZZTBNYTMS-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 60
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- HMBUCZUZRQQJQD-UHFFFAOYSA-N methyl 2-bromo-2-(2-chlorophenyl)acetate Chemical compound COC(=O)C(Br)C1=CC=CC=C1Cl HMBUCZUZRQQJQD-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 16
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 230000002194 synthesizing effect Effects 0.000 claims description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- VLCDUOXHFNUCKK-UHFFFAOYSA-N N,N'-Dimethylthiourea Chemical compound CNC(=S)NC VLCDUOXHFNUCKK-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 4
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 239000003377 acid catalyst Substances 0.000 claims 2
- 239000000047 product Substances 0.000 abstract description 25
- 239000006227 byproduct Substances 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 239000012074 organic phase Substances 0.000 description 24
- 238000003756 stirring Methods 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 15
- 238000005406 washing Methods 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 238000001035 drying Methods 0.000 description 12
- 238000000605 extraction Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 238000010791 quenching Methods 0.000 description 11
- 230000000171 quenching effect Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000012467 final product Substances 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000005886 esterification reaction Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 6
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 3
- XTWYTFMLZFPYCI-UHFFFAOYSA-N Adenosine diphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O XTWYTFMLZFPYCI-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- RWOLDZZTBNYTMS-ZETCQYMHSA-N (2s)-2-(2-chlorophenyl)-2-hydroxyacetic acid Chemical compound OC(=O)[C@@H](O)C1=CC=CC=C1Cl RWOLDZZTBNYTMS-ZETCQYMHSA-N 0.000 description 2
- ZECLJEYAWRQVIB-UHFFFAOYSA-N 2-(2-chlorophenyl)-2-hydroxyacetonitrile Chemical compound N#CC(O)C1=CC=CC=C1Cl ZECLJEYAWRQVIB-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- MIOPJNTWMNEORI-XVKPBYJWSA-N (R)-camphorsulfonic acid Chemical compound C1C[C@]2(CS(O)(=O)=O)C(=O)C[C@H]1C2(C)C MIOPJNTWMNEORI-XVKPBYJWSA-N 0.000 description 1
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 description 1
- OGUWOLDNYOTRBO-UHFFFAOYSA-N 4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1NCCC2=C1C=CS2 OGUWOLDNYOTRBO-UHFFFAOYSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- ITATYELQCJRCCK-UHFFFAOYSA-N Mandelic Acid, Methyl Ester Chemical compound COC(=O)C(O)C1=CC=CC=C1 ITATYELQCJRCCK-UHFFFAOYSA-N 0.000 description 1
- 108010033272 Nitrilase Proteins 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001186 cumulative effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- ZFSLODLOARCGLH-UHFFFAOYSA-N isocyanuric acid Chemical compound OC1=NC(O)=NC(O)=N1 ZFSLODLOARCGLH-UHFFFAOYSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012450 pharmaceutical intermediate 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
- 238000004321 preservation Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- QDCOOMOMJAXUJR-UHFFFAOYSA-N pyridine thiophene hydrochloride Chemical compound Cl.N1=CC=CC=C1.S1C=CC=C1 QDCOOMOMJAXUJR-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a new synthesis method of clopidogrel, which belongs to the technical field of drug synthesis and provides a new synthesis method of clopidogrel, wherein the method comprises the steps of reacting R (-) -o-chloromandelic acid with methanol under the action of a catalyst to generate R (-) -o-chloromandelic acid methyl ester, reacting R (-) -o-chloromandelic acid methyl ester with catalyst in an organic solvent to generate 2-bromo-2 (2-chlorophenyl) methyl acetate, and reacting 2-bromo-2 (2-chlorophenyl) methyl acetate with tetrahydrothiophene pyridine hydrochloric acid in the organic solvent to generate clopidogrel; the invention has the advantages of less byproduct generation and high product yield.
Description
Technical Field
The invention relates to a novel synthesis method of clopidogrel, belonging to the field of preparation of pharmaceutical intermediates.
Background
Clopidogrel (Clopidogrel), an orally active platelet inhibitor targeting the P2Y12 receptor, also selectively inhibits Adenosine Diphosphate (ADP) binding to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPlllb/llla complex, thus inhibiting platelet aggregation, and can be used to inhibit blood clotting in coronary artery disease, peripheral vascular disease, and cerebrovascular disease.
Patent document CN100406568C discloses a clopidogrel new production process, in which 2-chlorobenzaldehyde is used as a starting material, racemic (±) 2- (2-chlorophenyl) -2-hydroxyacetonitrile is obtained by reaction with cyanuric acid, racemic (±) 2- (2-chlorophenyl) -2-hydroxyacetonitrile is hydrolyzed by nitrilase to obtain corresponding (R) -2 '-chlorophenyl-2-hydroxyacetic acid, namely (R) -mandelic acid organic acid, and is converted into corresponding methyl mandelate by esterification reaction, and corresponding sulfonic acid halide or sulfonic anhydride is reacted to prepare methyl- (R) -2-benzenesulfonyl-2- (2' -chlorophenyl) acetate, and finally, 4,5,6, 7-tetrahydro-thieno [3,2-C ] pyridine is reacted with sulfonic acid ester intermediate to obtain (S) -enantiomer clopidogrel; in the scheme, a plurality of steps are required to be carried out at extremely low temperature, the reaction conditions are strict, and concentrated sulfuric acid is adopted as an esterification catalyst in the scheme, so that byproducts are easy to generate, and the product yield is low. The specific synthetic route is as follows:
patent document CN101845050a discloses a preparation method of clopidogrel, wherein R, S-o-chloromandelic acid is used as a starting material, and is subjected to esterification reaction with methanol under the action of an acidic catalyst (such as concentrated sulfuric acid) to generate methyl R, S-o-chloromandelate (iii). The method comprises the steps of reacting R, S-o-chloromandelic acid methyl ester with benzenesulfonyl chloride compound under the action of an alkaline catalyst to generate 2-benzenesulfonyl-2 (2-chlorophenyl) methyl acetate of a formula (IV), carrying out substitution reaction on the 2-benzenesulfonyl-2 (2-chlorophenyl) methyl acetate and 4,5,6, 7-tetrahydrothiophene pyridine hydrochloride under the alkaline condition to generate a compound R, S-clopidogrel of a formula (V), taking a resolution solution as a medium, resolving the compound R, S-clopidogrel with a resolving agent, and then, dissociating to obtain S-clopidogrel (I), wherein concentrated sulfuric acid is used as an esterification catalyst in the scheme, so that byproducts are easy to generate and production equipment is corroded, and the final product yield is influenced. The specific synthetic route is as follows:
as can be seen from the above-disclosed patent documents and literature, the common clopidogrel synthesis method uses concentrated sulfuric acid as a catalyst for the esterification step, which results in lower product yield, easy generation of byproducts during the reaction, easy corrosion of production equipment, lower reaction selectivity, easy occurrence of side reactions and low reaction yield.
Therefore, there is a need to find a preparation method with less byproducts and higher product yield.
Disclosure of Invention
Aiming at the defects in the prior art, the invention provides a novel synthesis method of clopidogrel, and solves the problems of reducing the generation of byproducts and improving the yield of products.
The invention aims at realizing the following technical scheme, namely a novel synthesis method of clopidogrel, which comprises the following steps:
s1: reacting R (-) -o-chloromandelic acid with methanol under the action of a catalyst to generate R (-) -o-chloromandelic acid methyl ester;
s2: in an organic solvent, R (-) -methyl o-chloromandelate is reacted with a catalyst to generate 2-bromo-2 (2-chlorophenyl) methyl acetate;
s3: in an organic solvent, 2-bromo-2 (2-chlorophenyl) acetic acid methyl ester and tetrahydrothiophene pyridine hydrochloride react to generate clopidogrel.
According to the invention, R (-) -methyl o-chloromandelate is obtained after the esterification reaction of R (-) -o-chloromandelate, p-toluenesulfonic acid and trifluoromethanesulfonic acid are adopted to replace concentrated sulfuric acid in the traditional esterification process, so that byproducts and corrosion to equipment caused by the use of sulfuric acid are reduced, then the R (-) -methyl o-chloromandelate is subjected to halogenation reaction to generate 2-bromo-2 (2-rate grade) methyl acetate, and then the 2-bromo-2 (2-rate grade) methyl acetate is reacted with tetrahydrothiophene pyridine hydrochloric acid to generate final product clopidogrel through palladium catalysis.
In the above synthesis method of clopidogrel, preferably, the catalyst in step S1 is an acidic catalyst.
In the above method for synthesizing clopidogrel, preferably, the acidic catalyst in step S1 may be one of p-toluenesulfonic acid, trifluoromethanesulfonic acid, and the like. Most preferably, p-toluenesulfonic acid is selected as a catalyst, so that the reaction byproducts are fewer, and the reaction yield is better.
In the above method for synthesizing clopidogrel, preferably, the organic solvent in step S2 may be one of dichloromethane, tetrahydrofuran, dioxane, and the like. Most preferably, dichloromethane is used as a reaction solvent, so that the substrate dissolution rate is high, and the reaction is mild.
In the above method for synthesizing clopidogrel, preferably, the catalyst in the step S2 is N, N' -dimethylthiourea or N-bromosuccinimide. Most preferably, the reaction conditions are mild when N, N' -dimethylthiourea and N-bromosuccinimide are used as the catalyst.
In the above-mentioned clopidogrel synthesis method, the reaction temperature in step S2 is preferably 15 to 40 ℃. Most preferably, the reaction temperature is 25℃with less side reactions.
In the above synthesis method of clopidogrel, preferably, the catalyst in the step S3 is Pd (OAc) 2 and sodium tert-butoxide. Most preferably, palladium acetate and sodium tert-butoxide are used as catalysts to improve the selectivity of the reaction.
In the above synthesis method of clopidogrel, preferably, the reaction ligand in step S3 is DPPF. Most preferably, DPPF is used as the ligand in a higher reaction yield.
In the above synthesis method of clopidogrel, preferably, the organic solvent in step S3 may be one of acetone, dichloromethane or diethyl ether. Most preferably, acetone is selected as the reaction solvent to have good solubility.
In the above-mentioned clopidogrel synthesis method, the reaction temperature in the step S3 is preferably 20 to 70 ℃. Most preferably, the reaction selectivity is high at room temperature, and the activity of chlorine is high after the temperature is too high, so that the reaction yield is low by increasing the byproducts.
In summary, compared with the prior art, the invention has the following advantages:
1. compared with the traditional technology that R (-) -o-chloromandelic acid methyl ester is subjected to halogenation reaction to generate an intermediate product and then palladium catalytic reaction to generate a final product, compared with the traditional technology that benzene sulfonyl chloride compound is substituted for hydroxyl and then is subjected to reaction condensation with tetrahydrothiophene pyridine hydrochloric acid, the method has the advantages that the reaction steps are shorter, the reaction is mild, the byproducts are fewer, and the product yield and the product purity are higher;
2. according to the invention, when the methyl 2-bromo-2 (2-chlorophenyl) acetate reacts with tetrahydrothiophene pyridine hydrochloride, the activity of chlorine on a benzene ring can be reduced by controlling the temperature, the participation of chlorine in the reaction is reduced, the generation of byproducts is reduced, and the product yield is improved.
Drawings
FIG. 1 shows the synthetic route of the present invention.
Detailed Description
The technical scheme of the present invention will be further specifically described by means of specific examples, but the present invention is not limited to these examples.
Example 1
Preparation of R (-) -methyl o-chloromandelate:
18.66g (0.1 mol) of R (-) -o-chloromandelic acid is placed in a beaker, 200mL of methanol is added for stirring and dissolution, 8.61g (0.05 mol) of p-toluenesulfonic acid is added for stirring for 30min, the temperature is raised to 60 ℃, the reaction is kept for 3h, water generated in the reaction is collected, the reaction is cooled to room temperature after the completion of the reaction, and sodium bicarbonate solution is added for quenching the reaction. Desolventizing under reduced pressure, adding 100mL of diethyl ether for extraction for 3 times, combining organic phases, washing the organic phases with 200mL of saturated saline water, distilling the solvent under reduced pressure, recrystallizing, filtering and drying to obtain 18.52g of R (-) -o-chloromandelic acid methyl ester, wherein the product yield is 92.6%, and the product purity is 99%.
Example 2
Preparation of methyl 2-bromo-2 (2-chlorophenyl) acetate:
150mL of methylene chloride is placed in a beaker, 20g of R (-) -methyl o-chloromandelate is added, stirring is carried out for dissolution, 27g (0.15 mol) of N-bromosuccinimide is added, 4.69g (0.045 mol) of N, N' -dimethylthiourea is added, reaction is carried out for 3h at 25 ℃, and ice water quenching reaction is added after the substrate is completely consumed. Desolventizing under reduced pressure, adding 100mL of ethyl acetate for extraction 3 times, combining the organic phases, washing the organic phases with 200mL of saturated saline, distilling the solvent under reduced pressure, recrystallizing, filtering and drying to obtain 22.53g of 2-bromo-2 (2-chlorophenyl) acetic acid methyl ester, wherein the product yield is 86%, and the product purity is 99.2%.
Example 3
Preparation of clopidogrel:
200mL of acetone is placed in a beaker, 26.19g of methyl 2-bromo-2 (2-chlorophenyl) acetate is added, 1.12g of palladium acetate and 1.06g of palladium dichloride are added, stirring is carried out for 20min, 9.61g of sodium tert-butoxide is added, heating is carried out to 30 ℃, 17.57g of tetrahydrothiophene pyridine hydrochloride is slowly added, stirring is carried out for 5h, and HCl solution is added for quenching reaction after the reaction is completed. Desolventizing under reduced pressure, adding 100mL of ethyl acetate for extraction for 3 times, combining the organic phases, washing the organic phases with 200mL of saturated saline, distilling the solvent under reduced pressure, recrystallizing, filtering and drying to obtain the final product clopidogrel with 28.1g, the product yield of 87.5% and the product purity of 99.4%.
Example 4
Preparation of R (-) -methyl o-chloromandelate:
18.66g (0.1 mol) of R (-) -o-chloromandelic acid is placed in a beaker, 200mL of methanol is added for stirring and dissolution, 16.91g (0.05 mol) of trifluoromethanesulfonic acid is added for stirring for 30min, the temperature is raised to 60 ℃, the reaction is kept for 3h, water generated in the reaction is collected, the reaction is cooled to room temperature after the completion of the reaction, and sodium bicarbonate solution is added for quenching the reaction. Desolventizing under reduced pressure, adding 100mL of diethyl ether for extraction for 3 times, combining organic phases, washing the organic phases with 200mL of saturated saline water, distilling the solvent under reduced pressure, recrystallizing, filtering and drying to obtain 17.04g of R (-) -o-chloromandelic acid methyl ester, wherein the product yield is 85.2%, and the product purity is 99%.
Example 5
Preparation of methyl 2-bromo-2 (2-chlorophenyl) acetate:
150mL of tetrahydrofuran was placed in a beaker, 20g of R (-) -methyl o-chloromandelate was added, the mixture was stirred and dissolved, 27g (0.15 mol) of N-bromosuccinimide was added, 4.69g (0.045 mol) of N, N' -dimethylthiourea was added, the mixture was reacted at 25℃for 3 hours, and after the substrate was completely consumed, the mixture was quenched with ice water. Desolventizing under reduced pressure, adding 100mL of ethyl acetate for extraction 3 times, combining the organic phases, washing the organic phases with 200mL of saturated saline, distilling the solvent under reduced pressure, recrystallizing, filtering and drying to obtain 22.45g of 2-bromo-2 (2-chlorophenyl) acetic acid methyl ester, wherein the product yield is 85.7%, and the product purity is 99.2%.
Example 6
Preparation of methyl 2-bromo-2 (2-chlorophenyl) acetate:
150mL dioxane was placed in a beaker, 20g of R (-) -methyl o-chloromandelate was added, the mixture was stirred and dissolved, 27g (0.15 mol) of N-bromosuccinimide was added, 4.69g (0.045 mol) of N, N' -dimethylthiourea was added, the mixture was reacted at 25℃for 3 hours, and after the substrate was completely consumed, ice water was added to quench the reaction. Desolventizing under reduced pressure, adding 100mL of ethyl acetate for extraction 3 times, combining the organic phases, washing the organic phases with 200mL of saturated saline, distilling the solvent under reduced pressure, recrystallizing, filtering and drying to obtain 22.31g of 2-bromo-2 (2-chlorophenyl) acetic acid methyl ester, wherein the product yield is 85.2%, and the product purity is 99.2%.
Example 7
Preparation of methyl 2-bromo-2 (2-chlorophenyl) acetate:
150mL of methylene chloride is placed in a beaker, 20g of R (-) -methyl o-chloromandelate is added, stirring is carried out for dissolution, 27g (0.15 mol) of N-bromosuccinimide is added, 4.69g (0.045 mol) of N, N' -dimethylthiourea is added, reaction is carried out for 5h at 15 ℃, and ice water quenching reaction is added after the substrate is completely consumed. Desolventizing under reduced pressure, adding 100mL of ethyl acetate for extraction for 3 times, combining the organic phases, washing the organic phases with 200mL of saturated saline, distilling the solvent under reduced pressure, recrystallizing, filtering and drying to obtain 22.16g of 2-bromo-2 (2-chlorophenyl) acetic acid methyl ester, wherein the product yield is 84.6%, and the product purity is 99%.
Example 8
Preparation of methyl 2-bromo-2 (2-chlorophenyl) acetate:
150mL of methylene chloride is placed in a beaker, 20g of R (-) -methyl o-chloromandelate is added, stirring is carried out for dissolution, 27g (0.15 mol) of N-bromosuccinimide is added, 4.69g (0.045 mol) of N, N' -dimethylthiourea is added, reaction is carried out for 2h at 40 ℃, and ice water quenching reaction is added after the substrate is completely consumed. Desolventizing under reduced pressure, adding 100mL of ethyl acetate for extraction for 3 times, combining the organic phases, washing the organic phases with 200mL of saturated saline, distilling the solvent under reduced pressure, recrystallizing, filtering and drying to obtain 22.24g of 2-bromo-2 (2-chlorophenyl) acetic acid methyl ester, wherein the product yield is 84.9%, and the product purity is 99.3%.
Example 9
Preparation of clopidogrel:
200mL of methylene chloride is placed in a beaker, 26.19g of methyl 2-bromo-2 (2-chlorophenyl) acetate is added, 1.12g of palladium acetate and 1.06g of palladium dichloride are added, stirring is carried out for 20min, 9.61g of sodium tert-butoxide is added, heating is carried out to 30 ℃, 17.57g of tetrahydrothiophene pyridine hydrochloride is slowly added, stirring is carried out for 5h, and HCl solution is added for quenching reaction after the reaction is completed. Desolventizing under reduced pressure, adding 100mL of ethyl acetate for extraction for 3 times, combining the organic phases, washing the organic phases with 200mL of saturated saline, distilling the solvent under reduced pressure, recrystallizing, filtering and drying to obtain the final product clopidogrel with the yield of 85.8% and the purity of 99%.
Example 10
Preparation of clopidogrel:
200mL of diethyl ether was placed in a beaker, 26.19g of methyl 2-bromo-2 (2-chlorophenyl) acetate was added, 1.12g of palladium acetate and 1.06g of palladium dichloride were added, stirring was performed for 20min, 9.61g of sodium tert-butoxide was added, heating was performed to 30℃and 17.57g of tetrahydrothiophene pyridine hydrochloride was slowly added, stirring was performed for 5h, and after completion of the reaction, HCl solution was added to quench the reaction. Desolventizing under reduced pressure, adding 100mL of ethyl acetate for extraction for 3 times, combining the organic phases, washing the organic phases with 200mL of saturated saline, distilling the solvent under reduced pressure, recrystallizing, filtering and drying to obtain the final product clopidogrel with the yield of 84.9% and the purity of 99%.
Example 11
Preparation of clopidogrel:
200mL of acetone is placed in a beaker, 26.19g of methyl 2-bromo-2 (2-chlorophenyl) acetate is added, 1.12g of palladium acetate and 1.06g of palladium dichloride are added, stirring is carried out for 20min, 9.61g of sodium tert-butoxide is added, the temperature is controlled at 20 ℃, 17.57g of tetrahydrothiophene pyridine hydrochloride is slowly added, stirring is carried out for 5h, and HCl solution is added for quenching reaction after the reaction is completed. Desolventizing under reduced pressure, adding 100mL of ethyl acetate for extraction for 3 times, combining the organic phases, washing the organic phases with 200mL of saturated saline, distilling the solvent under reduced pressure, recrystallizing, filtering and drying to obtain the final product clopidogrel with the yield of 86.8% and the purity of 99.1%.
Example 12
Preparation of clopidogrel:
200mL of acetone is placed in a beaker, 26.19g of methyl 2-bromo-2 (2-chlorophenyl) acetate is added, 1.12g of palladium acetate and 1.06g of palladium dichloride are added, stirring is carried out for 20min, 9.61g of sodium tert-butoxide is added, the temperature is raised to 70 ℃, 17.57g of tetrahydrothiophene pyridine hydrochloride is slowly added, stirring is carried out for 5h, and HCl solution is added for quenching reaction after the reaction is completed. Desolventizing under reduced pressure, adding 100mL of ethyl acetate for extraction for 3 times, combining the organic phases, washing the organic phases with 200mL of saturated saline, distilling the solvent under reduced pressure, recrystallizing, filtering and drying to obtain the final product clopidogrel with the yield of 78.3% and the purity of 99.6%.
Comparative example
This embodiment is that of published patent CN101845050 a:
a) Synthesis of methyl R, S-O-chloromandelate (Chuan)
20.5g of R, S-O-chloromandelic acid (0.11 mol), 130ml of methanol and 4g of concentrated sulfuric acid are put into a reaction flask, the temperature is raised to 60-65 ℃, and the reaction is carried out for 3 hours under the heat preservation. After the reaction, methanol was recovered to dryness, 100ml of methylene chloride and 40ml of an aqueous potassium carbonate solution (15%) were added to the oily residue, and the mixture was washed with water and left to stand, and an organic layer was separated for use in the next reaction.
b) Synthesis of Compound methyl 2-benzenesulfonate-2 (2-chlorophenyl) acetate (V)
To the methylene chloride solution of R, S-o-chloromandelate prepared in the step a), 30g of tri-n-propylamine (0.21 mol) was added, stirred, cooled to 0-5 ℃ with chilled brine, 25g of benzenesulfonyl chloride (014 mol) was slowly added dropwise thereto, and the reaction was continued for about 3 hours until completion. After that, 10m130% hydrochloric acid is added into the reaction system, stirred, stewed, layered and the oil layer is washed with water until the pH is 6-7. After that, methylene chloride was recovered to dryness to give 34g of oil (IV) (0.10 mol), and the cumulative molar yield of the two-step reactions of operations a) and b) was 90.9%.
Synthesis of cR, S-clopidogrel (V)
To 34g of the oily substance (V) obtained in the step b) (0.10 mol) were added 100m of n-propyl acetate, 94g of an aqueous potassium carbonate solution (30%), 30g of thiophene pyridine hydrochloride (0.17 mol), stirred at 20 to 30℃for 1 hour, then heated to 80 to 85℃and reacted at a constant temperature for 4 hours. After that, cooling, standing, layering, fully washing an oil layer, removing a water layer, distilling the oil layer under reduced pressure, and recovering n-propyl acetate until the n-propyl acetate is dried to obtain 30.1g of R, S-clopidogrel free alkali (0.093 mol) with a molar yield of 93.6%.
d) Synthesis of S-clopidogrel (I)
120ml of acetone was added to 30.1g of R, S-clopidogrel free base (0.093 mol) in the step c), and the mixture was stirred and dissolved, followed by addition of 23g of L-camphorsulfonic acid (0.099 mol) and crystallization at 30 to 35℃for 10 hours. After that, the filter cake was rinsed with 10ml of endo-ketone and dried at 70℃under normal pressure. The dried clopidogrel levocamphorsulfonate was dissociated under alkaline condition to obtain 10.1g of S-clopidogrel (0.031 mol), the molar yield was 33.55%, and the optical purity of the product was 99.6%.
Compared with the synthesis method in the invention, the reaction condition of the comparative example is high, the reaction yield is low, the reaction process is complex, and the method is not suitable for industrial production.
The embodiments of the present invention are not limited to the examples described above, and those skilled in the art can make various changes and modifications in form and detail without departing from the spirit and scope of the present invention, which are considered to fall within the scope of the present invention.
Claims (10)
1. The novel synthesis method of clopidogrel is characterized by comprising the following steps of:
s1: reacting R (-) -o-chloromandelic acid with methanol under the action of a catalyst to generate R (-) -o-chloromandelic acid methyl ester;
s2: in an organic solvent, R (-) -methyl o-chloromandelate is reacted with a catalyst to generate 2-bromo-2 (2-chlorophenyl) methyl acetate;
s3: in an organic solvent, 2-bromo-2 (2-chlorophenyl) acetic acid methyl ester and tetrahydrothiophene pyridine hydrochloride react to generate clopidogrel.
2. The method for synthesizing clopidogrel according to claim 1, which is characterized in that: the catalyst in the step S1 is an acid catalyst.
3. The method for synthesizing clopidogrel according to claim 2, which is characterized in that: in the step S1, the acid catalyst can be selected from one of p-toluenesulfonic acid or trifluoromethanesulfonic acid.
4. A method for synthesizing clopidogrel according to claim 3, characterized in that: in the step S2, the organic solvent may be selected from one of dichloromethane, tetrahydrofuran, dioxane, etc.
5. The method for synthesizing clopidogrel according to claim 4, which is characterized in that: the catalyst in the step S2 is N, N' -dimethyl thiourea and N-bromosuccinimide.
6. The method for synthesizing clopidogrel according to claim 5, which is characterized in that: the reaction temperature in the step S2 is 15-40 ℃.
7. The method for synthesizing clopidogrel according to claim 6, which is characterized in that: the catalyst in the step S3 is Pd (OAc) 2 And sodium tert-butoxide.
8. The method for synthesizing clopidogrel according to claim 7, wherein: the reaction ligand in step S3 is DPPF.
9. The method for synthesizing clopidogrel according to claim 8, which is characterized in that: the organic solvent in the step S3 can be one of acetone, dichloromethane or diethyl ether.
10. The method for synthesizing clopidogrel according to claim 9, which is characterized in that: the reaction temperature in the step S3 is 20-70 ℃.
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