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药物详细合成路线

Name Aprepitant;MK-869;MK-0869;L-754030;Emend
Chemical Name 5-[2(R)-[1(R)-[3,5-Bis(trifluoromethyl)phenyl]ethoxy]-3(S)-(4-fluorophenyl)morpholin-4-ylmethyl]-3,4-dihydro-2H-1,2,4-triazol-3-one
CAS 170729-80-3
Related CAS 170902-81-5 ((1S)-isomer), 221350-96-5 (deleted CAS), 172822-28-5 (stereoisomer), 172822-29-6 (ster
Formula C23H21F7N4O3
Structure
Formula Weight 534.43762
Stage 上市-2003
Company Merck & Co. (Originator)
Activity/Mechanism Antidepressants, Mood Disorders, Treatment of, Nausea and Vomiting, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, Tachykinin NK1 Antagonists
Syn. Route 4
Route 1
reduction of morpholinone (i) with l-selectride in thf at -78 c produced the intermediate lactol (ii), which was condensed at low temperature with 3,5-bis(trifluoromethyl)benzoyl chloride (iii) to afford acyl acetal (iv). further reaction with dimethyl titanocene in thf-toluene at 80 c provided enol ether (v). catalytic hydrogenation of the double bond, with concomitant n-benzyl group hydrogenolysis, yielded a 8:1 mixture of diastereomers, from which the major isomer (vi) was isolated by column chromatography. alkylation of morpholine (vi) with n-methoxycarbonyl-2-chloroacetamidrazone (vii) (obtained by reaction of chloroacetonitrile (ix) with naome and methyl carbazate in meoh) in the presence of n-ethyl diisopropylamine (diea) in acetonitrile gave the intermediate (viii), which was finally cyclized to the desired triazolone in refluxing xylene.
List of intermediates No.
(1r,5s,6s)-6-(1(r)-hydroxyethyl)-2-[1,1-dimethyl-5(s)-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-ylcarbonyl]pyrrrolidinium-3(s)-ylsulfanyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester fluorosulfonate; (1r,5s,6s)-6-(1(r)-hydroxyethyl)-2-[1,1-dimethyl-5(s)-[4-(4-nitrobenzyloxycarbonyl)piperazin-1-ylcarbonyl]pyrrrolidinium-3(s)-ylsulfanyl]-1-methyl-1-carba-2-penem-3-carboxylic acid 4-nitrobenzyl ester fluorosulfonate (ix)
isopropyl isocyanate; 2-isocyanatopropane (i)
Reference 1:
    castaner, j.; silvestre, j.s.; bayes, m.; sorbera, l.a.; aprepitant and l-758298. drugs fut 2002, 27, 3, 211.
Reference 2:
    cowden, c.j.; et al.; a new synthesis of 1,2,4-triazolin-5-ones: application to the convergent synthesis of an nk1 antagonist. tetrahedron lett 2000, 41, 44, 8661.
Reference 4:
    dorn, c.p.; hale, j.j.; maccoss, m.; mills, s.g.; ladduwahetty, t.; shah, s.k. (merck & co., inc.); morpholine and thiomorpholine tachykinin receptor antagonists. ep 0577394; jp 1994172178; us 5719147; wo 9400440; wo 9516679 .
Reference 5:
    dorn, c.p.; hale, j.j.; maccoss, m.; mills, s.g. (merck & co., inc.); prodrugs of morpholine tachykinin receptor antagonists. ep 0748320; jp 1997509935; us 5691336; wo 9523798 .
Reference 6:
    maccoss, m.; hale, j.j.; mills, s.g.; et al.; phosphorylated morpholine acetal human neurokinin-1 receptor antagonists as water-soluble prodrugs. j med chem 2000, 43, 6, 1234.
Reference 7:
    dolling, u.h.; wilson, r.d.; hands, d.; cottrell, i.f. (merck sharp & dohme ltd.); chemical synthesis of morpholine derivs.. wo 9965900 .
Reference 8:
    cowden, c.j. (merck sharp & dohme ltd.); process for the preparation of 1,2,4-triazolin-5-one derivs.. wo 0196315 .
Reference 3:
    hale, j.j.; mills, s.g.; maccoss, m.; finke, p.e.; cascieri, m.a.; sadowski, s.; ber, e.; chicchi, g.g.; kurtz, m.; metzger, j.; eiermann, g.; tsou, n.n.; tattersall, f.d.; rupniak, n.m.; williams, a.r.; rycroft, w.; hargreaves, r.; macintyre, d.e.; structural optimization affording 2-(r)-(1-(r)-3,5-bis(trifluoromethyl)phenylethoxy)-3(s)-(4-fluoro)phenyl-4-(3-oxo-1,2,4-triazol-5-yl)methylmorpholine, a potent, orally active, long-acting morpholine acetal human nk-1 receptor antagonist. j med chem 1998, 41, 23, 4607.

Route 2
synthesis of morpholine intermediate (i): treatment of 4-fluorophenyl acetic acid (x) with trimethylacetyl chloride (xi) and et3n in et2o followed by reaction with 4-(s)-benzyl-2-oxazolidinone (xii) in thf and n-buli in hexane affords oxazolidinone derivative (xiii). conversion of (xiii) into azido derivative (xv) is achieved by first treatment of (xiii) in thf with a potassium bis(trimethylsilyl)amide solution in toluene followed by treatment with 2,4,6-triisopropylphenylsulfonyl azide (xiv) in thf. hydrolysis of azido-oxazolidinone derivative (xv) by means of lioh in thf/h2o yields azido acetic acid derivative (xvi), which is then hydrogenated over pd/c in h2o/hoac to afford (s)-(4-fluorophenyl)glycine (xvii). treatment of (s)-(4-fluorophenyl)glycine (xvii) with benzaldehyde (xviii), naoh and nabh4 in meoh yields n-benzyl (s)-(4-fluorophenyl)glycine (xix), which is then cyclized with 1,2-dibromoethane (xx) in the presence of diea in dmf to furnish morpholine intermediate (i).
List of intermediates No.
ethyl 2-[2-([[(4-chlorophenyl)sulfonyl]amino]methyl)-2,3-dihydro-1h-inden-5-yl]-2-(methylsulfanyl)acetate (xx)
methyl 3-[5-(2-chlorophenyl)-2-oxo-2,3-dihydro-1h-thieno[2,3-e][1,4]diazepin-7-yl]propanoate (xviii)
3-sulfanyl-1-propanol (xi)
(3as,4r,8r,8as)-4,8-dibenzyl-2,2-dimethylhexahydro-6h-[1,3]dioxolo[4,5-e][1,3]diazepin-6-one (xii)
isopropyl isocyanate; 2-isocyanatopropane (i)
1-azabicyclo[1.1.0]butane (x)
tert-butyl (2s,4r)-2-[(dimethylamino)carbonyl]-4-hydroxy-1-pyrrolidinecarboxylate (xvii)
2-(1-hydroxyethylidene)-5,5-dimethyl-1,3-cyclohexanedione (xiii)
(2s)-1-{2-[(2-{[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl]amino}ethyl)amino]acetyl}-2-pyrrolidinecarboxamide (xiv)
tert-butyl 2-[(2s)-2-(aminocarbonyl)pyrrolidinyl]-2-oxoethyl(2-{[1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl]amino}ethyl)carbamate (xv)
tert-butyl 2-[(2s)-2-(aminocarbonyl)pyrrolidinyl]-2-oxoethyl(2-aminoethyl)carbamate (xvi)
tert-butyl 2-[(2s)-2-(aminocarbonyl)pyrrolidinyl]-2-oxoethyl{2-[(5-cyano-2-pyridinyl)amino]ethyl}carbamate (xix)
Reference 1:
    castaner, j.; silvestre, j.s.; bayes, m.; sorbera, l.a.; aprepitant and l-758298. drugs fut 2002, 27, 3, 211.
Reference 2:
    dorn, c.p.; hale, j.j.; maccoss, m.; mills, s.g. (merck & co., inc.); prodrugs of morpholine tachykinin receptor antagonists. ep 0748320; jp 1997509935; us 5691336; wo 9523798 .
Reference 3:
    dorn, c.p.; hale, j.j.; maccoss, m.; mills, s.g.; ladduwahetty, t.; shah, s.k. (merck & co., inc.); morpholine and thiomorpholine tachykinin receptor antagonists. ep 0577394; jp 1994172178; us 5719147; wo 9400440; wo 9516679 .

Route 3
alternatively (xvii) can be obtained as follows: reaction of 4-fluorophenyl acetic (x) with thionyl chloride in toluene in the presence of dmf provides 4-fluorophenyl acetyl chloride (xxii), which is treated with bromine and light irradiation followed by reaction with methanol to furnish methyl bromoacetate derivative (xxiii). treatment of (xxiii) with benzyl triethylammonium chloride (xxiv) and nan3 in meoh followed by hydrogenation over pd/c in meoh gives methyl glycine derivative (xxv) in a racemic mixture, from which (xvii) is obtained by crystallization of the corresponding dibenzoyl tartaric (dbt) salts followed by salt hydrolysis by means of refluxing hcl.
List of intermediates No.
1-azabicyclo[1.1.0]butane (x)
3-tetrahydro-2h-thiopyran-2-ylpyridine (xxiv)
(6r,7r)-7-[[2-[2-([(2s)-2-[(tert-butoxycarbonyl)amino]propanoyl]amino)-1,3-thiazol-4-yl]-2-(methoxyimino)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (xxii)
tert-butyl (2s,4r)-2-[(dimethylamino)carbonyl]-4-hydroxy-1-pyrrolidinecarboxylate (xvii)
n-{2-[(5-cyano-2-pyridinyl)amino]ethyl}-n-{2-[(2s)-2-cyanopyrrolidinyl]-2-oxoethyl}-2,2,2-trifluoroacetamide (xxiii)
r(-)-1-phenyl-1,2-ethanediolr(-)-phenylethylene glycol (xxv)
Reference 1:
    castaner, j.; silvestre, j.s.; bayes, m.; sorbera, l.a.; aprepitant and l-758298. drugs fut 2002, 27, 3, 211.
Reference 2:
    dorn, c.p.; hale, j.j.; maccoss, m.; mills, s.g. (merck & co., inc.); prodrugs of morpholine tachykinin receptor antagonists. ep 0748320; jp 1997509935; us 5691336; wo 9523798 .
Reference 3:
    dorn, c.p.; hale, j.j.; maccoss, m.; mills, s.g.; ladduwahetty, t.; shah, s.k. (merck & co., inc.); morpholine and thiomorpholine tachykinin receptor antagonists. ep 0577394; jp 1994172178; us 5719147; wo 9400440; wo 9516679 .

Route 4
synthesis of 250157: alternatively, the final compound can be obtained by direct condensation of (vi) with chlorotriazolinone (xxvi) in dmf/h2o in the presence of k2co3 or diea.for the obtention of (xxvi), two routes can be followed: 1. reaction of semicarbazide (xxvii) with orthoester (xxviii) in meoh; and 2. condensation of semicarbazide (xxvii) with benzyloxyacetyl chloride (xxix) in thf/h2o in the presence of naoh to provide adduct (xxx), which is then cyclized by means of refluxing naoh to afford triazolinone (xxxi). debenzylation of (xxxi) by hydrogenation over pd/c in meoh/h2o yields alcohol (xxxii), which is finally treated with thionyl chloride.
List of intermediates No.
diethyl 2-(3-oxopropyl)malonate (xxix)
ethyl (e)-3-(2-furyl)-2-propenoate (vi)
(2s)-2-hydroxy-2-phenylethyl 4-methylbenzenesulfonate (xxvii)
(3r)-3-hydroxy-3-phenylpropanenitrile (xxx)
(1r)-3-amino-1-phenyl-1-propanol (xxxi)
(3r)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylamine; (3r)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]-1-propanamine (xxxii)
methyl (3r)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propylcarbamate (xxvi)
Reference 1:
    castaner, j.; silvestre, j.s.; bayes, m.; sorbera, l.a.; aprepitant and l-758298. drugs fut 2002, 27, 3, 211.
Reference 2:
    cowden, c.j.; et al.; a new synthesis of 1,2,4-triazolin-5-ones: application to the convergent synthesis of an nk1 antagonist. tetrahedron lett 2000, 41, 44, 8661.
Reference 3:
    cowden, c.j. (merck sharp & dohme ltd.); process for the preparation of 1,2,4-triazolin-5-one derivs.. wo 0196315 .
Reference 4:
    dolling, u.h.; wilson, r.d.; hands, d.; cottrell, i.f. (merck sharp & dohme ltd.); chemical synthesis of morpholine derivs.. wo 9965900 .

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阿瑞吡坦;英文名Aprepitant;MK-869;MK-0869;L-754030;Emend;CAS[170729-80-3]

 
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