Clopidogrel bisulfate, Clopidogrel hydrogensulfate, DV-7314, SR-25990C, Iscover, Plavix, -Drug Synthesis Database

【结构式】

【药物名称】Clopidogrel bisulfate, Clopidogrel hydrogensulfate, DV-7314, SR-25990C, Iscover, Plavix

【化学名称】(+)-(S)-2-(2-Chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetic acid methyl ester hydrogensulfate

【CA登记号】120202-66-6, 113665-84-2 (free base), 94188-84-8 (racemic;free base)

【分子式】C₁₆H₁₈ClNO₆S₂

【分子量】419.90596

【开发单位】Sanofi-synthélabo (Originator), Bristol-Myers Squibb (Licensee), Daiichi Pharmaceutical (Licensee)

【药理作用】Antiplatelet Therapy, Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Cerebrovascular Diseases, Treatment of, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, NEUROLOGIC DRUGS, Stroke, Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, P2Y12 (P2T) Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

The title product can be obtained in several steps: 1) (+)-2-(2-Chlorophenyl)glycine methyl ester [(+)-IV] is prepared as follows: a) Racemic 2-(2-chlorophenyl)glycine (I) is methylated with methanol - HCl to the methyl ester (II), which is resolved with (+)-tartaric acid to the active ester [(+)-IV]. b) Racemic (I) is resolved with (+)-10-camphorsulfonic acid to (+)-2-(2-chlorophenyl)glycine [(+)-III], which is then esterified as before to [(+)-IV]. 2) (+)-2-(2-Chlorophenyl)-N-[2-(2-thienyl)ethyl]glycine methyl ester [(+)-VII] is prepared as follows: a) Alkylation of [(+)-IV] with 2-[2-(phenylsulfonyloxy)ethyl]thiophene (V) or with 2-(2-bromoethyl)thiophene (VI). b) Optical resolution of racemic alkylated glycine ester (VIII) with (+)-10-camphorsulfonic acid. 3) Finally, (+)-clopidogrel is prepared as follows: a) Cyclization of active [(+)-VII] with formaldehyde - formic acid and aqueous HCl. b) Cyclization of racemic (VIII) as before, yielding racemic clopidogrel (PCR-4099), followed by optical resolution with (+)-10-camphorsulfonic acid.

参考文献中间体

【1】 Descamps, M.; Radisson, J. (Sanofi); Process for the preparation of an N-phenylacetic deriv. of tetrahydrothieno(3,2-c)pyridine and its intermediate of synthesis. EP 0446569 .
【2】 Badorc, A.; Frehel, D. (Sanofi-Synthélabo ); Dextrorotatory enantiomer of methyl alpha-(4,5,6,7-tetrahydrothieno[3,2-c]pyrid-5-yl)(2-chlorophenyl)acetate process for its preparation and pharmaceutical compsns. containing it. AU 8811292; EP 0281459; FR 2612929; FR 2623810; JP 1988203684; US 4847265 .
【3】 Aubert, D.; Ferrand, C.; Maffrand, J.-P. (Sanofi-Synthelabo ); Novel thieno(3,2-c)pyridine derivs., process for their preparation and their application in therapy. EP 0099802; US 4529596 .
【4】 Savi, P.; Maffrand, J.P.; Defreyn, G.; Frehel, D.; Badorc, A.; Herbert, J.M.; Kieffer, G.; Bernat, A.; Delebassee, D.; Clopidogrel Hydrogensulfate. Drugs Fut 1993, 18, 2, 107.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
((+)-IV)	12772	methyl (2S)-2-amino-2-(2-chlorophenyl)ethanoate	141109-14-0	C₉H₁₀ClNO₂	详情	详情
((+)-VII)	12775	methyl (2S)-2-(2-chlorophenyl)-2-[[2-(2-thienyl)ethyl]amino]ethanoate	141109-20-8	C₁₅H₁₆ClNO₂S	详情	详情
PCR 4099 (+/-)	63476	methyl 2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetate		C₁₆H₁₆ClNO₂S	详情	详情
(I)	12769	2-Amino-2-(2-chlorophenyl)acetic acid	88744-36-9	C₈H₈ClNO₂	详情	详情
(II)	12770	methyl 2-amino-2-(2-chlorophenyl)acetate		C₉H₁₀ClNO₂	详情	详情
(III)	12771	(2S)-2-Amino-2-(2-chlorophenyl)ethanoic acid	141315-50-6	C₈H₈ClNO₂	详情	详情
(V)	12773	2-(2-thienyl)ethyl benzenesulfonate		C₁₂H₁₂O₃S₂	详情	详情
(VI)	12774	2-(2-Bromoethyl)thiophene	26478-16-0	C₆H₇BrS	详情	详情
(VIII)	12776	methyl 2-(2-chlorophenyl)-2-[[2-(2-thienyl)ethyl]amino]acetate		C₁₅H₁₆ClNO₂S	详情	详情

合成路线2

The reaction of [benzene-U-13C]benzoic acid (I) with SOCl2 gives the corresponding acyl chloride (II), which is cyclized with the ethanolamine (III) to yield the oxazoline (IV).The chlorination of (IV) with sec-BuLi and hexachloroethane in toluene affords the 2-chlorophenyl derivative (V), which is methylated with MeI to provide the oxazolinium salt (VI). The reduction of (VI) with NaBH4 in ethanol yields the oxazolidine (VII), which is hydrolyzed with HCl to afford the labeled 2-chlorobenzaldehyde (VIII). The condensation of aldehyde (VIII) with the tetrahydrothienopyridine (IX) by means of acetone cyanohydrine in hot toluene affords the substituted acetonitrile (X), which is hydrolyzed to the substituted acetamide (XI) with HCl in methanol. Finally, this compound is treated with H2SO4 in refluxing methanol to afford the target labeled methyl ester as a racemic mixture.

参考文献中间体

【1】 Kashimura, S.; Kuwata, F.; Ishige, O.; Uyama, H.; Shono, T.; Yamaguchi, Y.; Formation of a novel acyl anion equivalent by the electroreduction of oxazolinium salts. Chem Lett 1987, 1511.
【2】 Burgos, A.; Simpson, I.; Herbert, J.M.; Ortho-metalation/chlorination of benzoic acid derivatives: Preparation of [benzene-U-C-13]-rac-clopidogrel ([benzene-U-C-13]-rac-SR25990C). J Label Compd Radiopharm 2000, 43, 9, 891.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	63476	methyl 2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetate		C₁₆H₁₆ClNO₂S	详情	详情
	63477	methyl 2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetate		C₁₆H₁₆ClNO₂S	详情	详情
(I)	10202	Benzoic acid	65-85-0	C₇H₆O₂	详情	详情
(I)	44623			C₇H₆O₂	详情	详情
(II)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(II)	45137			C₇H₅ClO	详情	详情
(III)	21513	2-amino-2-methyl-1-propanol；Karl Fischer;2-Amino-2-methyl-propan-1-ol；2-amino-2-methyl-1-propanol	124-68-5	C₄H₁₁NO	详情	详情
(IV)	44072	4,4-dimethyl-2-phenyl-4,5-dihydro-1,3-oxazole	19312-06-2	C₁₁H₁₃NO	详情	详情
(IV)	45138			C₁₁H₁₃NO	详情	详情
(V)	44073	2-(2-chlorophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole		C₁₁H₁₂ClNO	详情	详情
(V)	45139			C₁₁H₁₂ClNO	详情	详情
(VI)	44074	2-(2-chlorophenyl)-3,4,4-trimethyl-4,5-dihydro-1,3-oxazol-3-ium iodide		C₁₂H₁₅ClINO	详情	详情
(VI)	45140			C₁₂H₁₅ClINO	详情	详情
(VII)	44075	2-(2-chlorophenyl)-3,4,4-trimethyl-1,3-oxazolidine		C₁₂H₁₆ClNO	详情	详情
(VII)	45141			C₁₂H₁₆ClNO	详情	详情
(VIII)	24114	2-chlorobenzaldehyde	89-98-5	C₇H₅ClO	详情	详情
(VIII)	45142			C₇H₅ClO	详情	详情
(IX)	34011	4,5,6,7-tetrahydrothieno[3,2-c]pyridine	54903-50-3	C₇H₉NS	详情	详情
(X)	44076	2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetonitrile		C₁₅H₁₃ClN₂S	详情	详情
(X)	45143			C₁₅H₁₃ClN₂S	详情	详情
(XI)	44077	2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetamide		C₁₅H₁₅ClN₂OS	详情	详情
(XI)	45144			C₁₅H₁₅ClN₂OS	详情	详情

合成路线3

The condensation of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (I) with 2-chlorobenzaldehyde (II) by means of either KCN/HCl, KCN/AcOH, NaHSO3/KCN, NaHSO3 /NaCN, NaHSO3/Tms-CN, NaCN/HCl or AcOH/cyclo[(S)-His-(S)-Phe] and HCN purge gives 2-(2-chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetonitrile (III), which is hydrolyzed to the corresponding acetamide (IV) by means of either KOH, NaOH, NaOH followed by H2O2, refluxing HCl/TFA, formic acid/HCl, refluxing HBr, refluxing H2SO4 or refluxing HClO4. Finally, compound (III) is converted into the corresponding methyl ester with MeOH and either dimethylformamide dimethylacetal, H2SO4, Ms-OH, PPA, TiCl4, POCl3 or HCl.

参考文献中间体

【1】 Lohray, V.B.; Lohray, B.B.; Pandey, B. (Zydus-Cadila Group); Process for preparing clopidogrel. WO 02059128 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	63476	methyl 2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetate		C₁₆H₁₆ClNO₂S	详情	详情
(I)	34011	4,5,6,7-tetrahydrothieno[3,2-c]pyridine	54903-50-3	C₇H₉NS	详情	详情
(II)	24114	2-chlorobenzaldehyde	89-98-5	C₇H₅ClO	详情	详情
(III)	44076	2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetonitrile		C₁₅H₁₃ClN₂S	详情	详情
(IV)	44077	2-(2-chlorophenyl)-2-[6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl]acetamide		C₁₅H₁₅ClN₂OS	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)