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Name Clopidogrel bisulfate;Clopidogrel hydrogensulfate;DV-7314;SR-25990C;Iscover;Plavix
Chemical Name (+)-(S)-2-(2-Chlorophenyl)-2-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)acetic acid methyl ester hydrogensulfate
CAS 120202-66-6
Related CAS 113665-84-2 (free base), 94188-84-8 (racemic;free base)
Formula C16H18ClNO6S2
Structure
Formula Weight 419.90596
Stage 上市-1998
Company Sanofi-synthélabo (Originator), Bristol-Myers Squibb (Licensee), Daiichi Pharmaceutical (Licensee)
Activity/Mechanism 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
Syn. Route 3
Route 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.
List of intermediates No.
n-alpha-(2,2-diphenylacetyl)-n-omega-nitro-d-arginine (i)
n-[4-(aminomethyl)benzyl]urea (ii)
n-alpha-(2,2-diphenylacetyl)-n-omega-nitro-n1-[4-(ureidomethyl)benzyl]-d-arginine (iii)
3-(chloromethyl)benzoyl chloride (+-iv)
methyl (2s)-2-[(butoxycarbonyl)amino]-3-[[3-(chloromethyl)benzoyl]amino]propanoate (v)
4-hydroxybenzonitrile (vi)
methyl (2s)-2-[(butoxycarbonyl)amino]-3-([3-[(4-cyanophenoxy)methyl]benzoyl]amino)propanoate (+-vii)
1-(7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (viii)
Reference 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 .
Reference 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 .
Reference 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 .
Reference 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.

Route 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.
List of intermediates No.
4-methoxybenzyl (7r)-7-([2-([[(1s)-2-(benzhydryloxy)-1-methyl-2-oxoethyl]oxy]imino)-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino)-8-oxo-3-[([1,3]thiazolo[4,5-c]pyridin-2-ylsulfanyl)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (i)
(3-amino-1-benzofuran-2-yl)(4-methoxyphenyl)methanone (ii)
4-[(3r,4r)-7-methoxy-2-oxo-3-phenyl-3,4-dihydro-2h-chromen-4-yl]phenyl acetate (iii)
n-(4-nitrophenyl)acetamide (viii)
4-[(3ar,9br)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3h)-yl]-1-butanamine; 4-[(3ar,9br)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3h)-yl]butylamine (ix)
3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1h-pyrazolo[3,4-d]pyrimidin-4-amine; 3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1h-pyrazolo[3,4-d]pyrimidin-4-ylamine (iv)
4-phenoxyphenylboronic acid (v)
2-bromo-4-methylaniline; 2-bromo-p-toluidine; 3-bromo-4-aminotoluene; 4-amino-3-bromotoluene (vi)
8-bromo-6-methylquinoline (vii)
8-bromo-6-(bromomethyl)quinoline (x)
8-bromo-6-[(methylsulfonyl)methyl]quinoline; (8-bromo-6-quinolinyl)methyl methyl sulfone (xi)
2,2-difluoro-1,3-benzodioxol-5-ylboronic acid (i)
ethyl (1s,2r,3s,4r,5r)-2-(benzylsulfanyl)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxycyclopentanecarboxylate (ii)
ethyl (1s,2r,3s,4r,5r)-2-(benzylsulfanyl)-3,4,5-trihydroxycyclopentanecarboxylate (iv)
ethyl (3ar,4s,5r,6s,6as)-5-(benzylsulfanyl)-6-hydroxy-2,2-dimethyltetrahydro-3ah-cyclopenta[d][1,3]dioxole-4-carboxylate (v)
ethyl (3ar,6r,6as)-6-hydroxy-2,2-dimethyl-6,6a-dihydro-3ah-cyclopenta[d][1,3]dioxole-4-carboxylate (vi)
ethyl (3ar,6ar)-2,2-dimethyl-6-oxo-6,6a-dihydro-3ah-cyclopenta[d][1,3]dioxole-4-carboxylate (vii)
(3as,4s,6ar)-6-(hydroxymethyl)-2,2-dimethyl-4,6a-dihydro-3ah-cyclopenta[d][1,3]dioxol-4-ol (viii)
(3as,4s,6ar)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-4,6a-dihydro-3ah-cyclopenta[d][1,3]dioxol-4-ol (x)
9-[(3as,4r,6ar)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-4,6a-dihydro-3ah-cyclopenta[d][1,3]dioxol-4-yl]-9h-purin-6-ylamine; 9-[(3as,4r,6ar)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-4,6a-dihydro-3ah-cyclopenta[d][1,3]dioxol-4-yl]-9h-purin-6-amine (xi)
Reference 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.
Reference 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.

Route 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.
List of intermediates No.
n-(4-nitrophenyl)acetamide (ii)
4-[(3ar,9br)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3h)-yl]-1-butanamine; 4-[(3ar,9br)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3h)-yl]butylamine (i)
8-bromo-6-(bromomethyl)quinoline (iii)
8-bromo-6-[(methylsulfonyl)methyl]quinoline; (8-bromo-6-quinolinyl)methyl methyl sulfone (iv)
Reference 1:
    lohray, v.b.; lohray, b.b.; pandey, b. (zydus-cadila group); process for preparing clopidogrel. wo 02059128 .

来源:药化网

作者:药化小编

摘要:本文合成路线介绍的是药物中文名硫酸氯吡格雷;英文名Clopidogrel bisulfate;Clopidogrel hydrogensulfate;DV-7314;SR-25990C;Iscover;Plavix;CAS[120202-66-6]

 
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