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药物详细合成路线

Name Suprofen;TYN-762P(as Poultice);R-25061;Profenal;Suprol;Suprocil;Maldocil
Chemical Name p-(2-Thenoyl)-hydratropic acid;alpha-Methyl-4-(2-thienylcarbonyl)benzene acetic acid
CAS 40828-46-4
Related CAS
Formula C14H12O3S
Structure
Formula Weight 260.31394
Stage 撤市-1999
Company Cilag (Originator), Janssen (Originator), Taiyo (Originator), Alcon (Licensee)
Activity/Mechanism Antiinflammatory Ophthalmic Agents, Ocular Antiinflammatory and Antiinfective Agents, OCULAR MEDICATIONS, Ophthalmic Drugs, Non-Steroidal Antiinflammatory Drugs
Syn. Route 3
Route 1
the reaction of 2-thiophenecarbonyl chloride (i) with fluorobenzene (a) by means of alcl3 gives (4-fluorophenyl)(2-thienyl)ketone (ii), which is then condensed with diethyl methylmalonate (b) by means of nah in benzene-hmpa to yield diethyl 2-methyl-2-[4-(2-thienylcarbonyl)phenyl]malonate (iii); this product is finally hydrolyzed and partially decarboxylated with refluxing aqueous naoh.
List of intermediates No.
3-methoxy-1-butene (i)
ethynyl 4-methylphenyl sulfone; ethynyl(4-methylphenyl)dioxo-lambda(6)-sulfane (a)
(5s,7s,8z,10s,11s,12s,13z,16s,17r,18s,19s)-21,21-diethyl-17-[(4-methoxybenzyl)oxy]-7,11-bis(methoxymethoxy)-5-[(1r)-1-[(2r,4r,5s)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-2,2,3,3,10,12,14,16,18-nonamethyl-19-[(1s,2z)-1-methyl-2,4-pentadie; tert-butyl(dimethyl)silyl (1s,3s,4z,6s,7s,8s,9z,12s,13r,14s,15s,16s,17z)-13-[(4-methoxybenzyl)oxy]-3,7-bis(methoxymethoxy)-1-[(1r)-1-[(2r,4r,5s)-2-(4-methoxyphenyl)-5-methyl-1,3-dioxan-4-yl]ethyl]-6,8,10,12,14,16-hexamethyl-15-[(triethylsilyl)oxy]-4 (b)
2-amino-3-cyano-5-phenylpyrazin-1-ium-1-olate (ii)
3-amino-6-phenyl-2-pyrazinecarbonitrile (iii)
Reference 1:
    van daele, p.g.h.; et al.; synthesis of alpha-methyl-4-(2-thienylcarbonyl)benzene acetic acid, suprofen and derivatives. arzneim-forsch drug res 1975, 25, 10, 1495-1501.
Reference 2:
    castaner, j.; chatterjee, s.s.; suprofen. drugs fut 1976, 1, 3, 148.

Route 2
the reaction of 1-(4-bromophenyl)ethanol (iv) with 3,4-dihydro-2h-pyran (c) by means of hcl yields 2-[1-(4-bromophenyl)ethoxy]tetrahydro-2h-pyran (v); this product by condensation with 2-thiophenecarbonitrile (d) through its grignard complex in thf gives [4-(1-hydroxyethyl)phenyl](2-thienyl)ketone (vi), which without purification is treated with socl2 in benzene to give [4-(1-chloroethyl)phenyl](2-thienyl)ketone (vii); then the halogen is substituted by cn with nacn in dmso to afford alpha-methyl-4-(2-thienylcarbonyl)benzeneacetonitrile (viii), which, without purification, is hydrolyzed with h2so4 and acetic acid.
List of intermediates No.
methyl (2s,3s,4s,5r,6r)-6-[5-(4-[[2,4-dimethyl-7-oxo-6,7-dihydropyrido[2,3-d]pyrimidin-8(5h)-yl]methyl][1,1-biphenyl]-2-yl)-2h-1,2,3,4-tetraazol-2-yl]-3,4,5-trihydroxytetrahydro-2h-pyran-2-carboxylate (c)
3-amino-6-phenyl-2-pyrazinecarbonitrile (iv)
1-[(e)-2-phenylethenyl]pyrrolidine (v)
2-([[(4-methylphenyl)sulfonyl]oxy]imino)malononitrile (vi)
2-[[(e)-1-phenyl-2-(1-pyrrolidinyl)ethenyl]imino]malononitrile (vii)
6-phenyl-3-(phenylsulfanyl)-2-pyrazinecarbonitrile (viii)
6-phenyl-3-(phenylsulfonyl)-2-pyrazinecarbonitrile (d)
Reference 1:
    van daele, p.g.h.; et al.; synthesis of alpha-methyl-4-(2-thienylcarbonyl)benzene acetic acid, suprofen and derivatives. arzneim-forsch drug res 1975, 25, 10, 1495-1501.
Reference 2:
    castaner, j.; chatterjee, s.s.; suprofen. drugs fut 1976, 1, 3, 148.

Route 3
the condensation of thiophene (e) and 4-ethylbenzoyl chloride (ix) by means of sncl4 in ch2cl2 gives (4-ethylphenyl)(2-thienyl)ketone (x), which is brominated with n-bromosuccidine and benzoyl peroxide in ccl4 to [4-(1-bromoethyl)phenyl](2-thienyl)ketone (xi); then this product is treated with nacn in dmso to obtain the acetonitrile (viii), which, without purification, is hydrolyzed with h2so4 and acetic acid.
List of intermediates No.
1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid diacetoxyboron complex (e)
6-phenyl-3-(phenylsulfanyl)-2-pyrazinecarbonitrile (viii)
methyl 7-isocyanato-2-phenylthieno[2,3-b]pyrazine-6-carboxylate (ix)
methyl 7-[[([4-[(3ar,9br)-9-methoxy-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-2(3h)-yl]butyl]amino)carbonyl]amino]-2-phenylthieno[2,3-b]pyrazine-6-carboxylate (x)
methyl (e)-3-(4-formylphenyl)-2-propenoate (xi)
Reference 1:
    van daele, p.g.h.; et al.; synthesis of alpha-methyl-4-(2-thienylcarbonyl)benzene acetic acid, suprofen and derivatives. arzneim-forsch drug res 1975, 25, 10, 1495-1501.
Reference 2:
    castaner, j.; chatterjee, s.s.; suprofen. drugs fut 1976, 1, 3, 148.

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舒洛芬;英文名Suprofen;TYN-762P(as Poultice);R-25061;Profenal;Suprol;Suprocil;Maldocil;CAS[40828-46-4]

 
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