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药物详细合成路线

Name Quinagolide hydrochloride;SDZ-205502;CV-205502;Norprolac
Chemical Name (±)-N,N-Diethyl-N-[(3alpha,4aalpha,10abeta)-6-hydroxy-1-propyl-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinolin-3-yl]sulfamide hydrochloride
CAS 94424-50-7
Related CAS 87056-78-8 (free base)
Formula C20H34ClN3O3S
Structure
Formula Weight 432.02928
Stage 上市-1994
Company Novartis (Originator)
Activity/Mechanism Contraceptives, Disorders of Sexual Function and Reproduction, Treatment of, ENDOCRINE DRUGS, Male Contraceptives, Pituitary Disorder Therapy, Treatment of Acromegaly, Treatment of Growth Hormone Secretion Disorders, Treatment of Hyperprolactinemia, Dopamine D2 Agonists, Prolactin Secretion Inhibitors
Syn. Route 2
Route 1
the reaction of 5-methoxy-2-tetralone (i) with benzenethiosulfonic acid s-phenyl ester and sodium acetate in methanol gives 1,1-bis(phenylsulfanyl)-2-tetralone (ii), which is condensed with 2-(bromomethyl)acrylic acid tert-butyl ester (iii) by means of n-buli and diisopropylamine (dia) in thf to yield the acrylic acid derivative (iv). desulfurization of (iv) with al/hg in thf/water affords compound (v), which is treated with o-methylhydroxylamine and na2hpo4 in methanol, providing the methoxyimino compound (vi). the reduction of (vi) with zn/hoac provides the methoxyamino compound (vii). the cyclization of (vii) by means of potassium hydrogen phosphate gives 1,6-dimethoxy-1,2,3,4,4a,5,10,10a-octahydrobenzo[g]quinoline-3-carboxylic acid tert-butyl ester as a diastereomeric mixture that is separated by chromatography to furnish the desired diastereomer (viii). hydrolysis of the tert-butoxy ester group of (viii) by means of tfa yields the carboxylic acid (ix), which is treated with diazomethane to afford the methyl ester (x). selective demethoxylation of (x) with zn/hoac provides the octahydrobenzoquinoline (xi).
List of intermediates No.
ethyl 3-[3-(2-[[(4-chlorophenyl)sulfonyl]amino]ethyl)-5-(4-fluorobenzyl)phenyl]propanoate (i)
4-acryloyl-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione (ii)
4-[(1r)-3-cyclohexen-1-ylcarbonyl]-10,10-dimethyl-3lambda~6~-thia-4-azatricyclo[5.2.1.0~1,5~]decane-3,3-dione (iii)
4-{[((1s,2e)-1-{(1s)-1-[2-((2r,3r,4e,7s,9s,10r,11s,13r)-3-allyl-2,10-bis{[tert-butyl(dimethyl)silyl]oxy}-9,11,14,14-tetramethoxy-5,7,13-trimethyl-4-tetradecenyl)-1,3-dithian-2-yl]ethyl}-3-{(1r,3r,4r)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2-methyl-2-propenyl)oxy]methyl}phenyl methyl ether (iv)
(1e,3s,4s,7r,8r,9e,12s,14s,15r,16s,18r)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-3-[(4-methoxybenzyl)oxy]-1-{(1r,3r,4r)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-1,9-nonadecadien-5-one (v)
(1e,3s,4s,7r,8r,9e,12s,14s,15r,16s,18r)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-14,16,19,19-tetramethoxy-1-{(1r,3r,4r)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-1,9-nonadecadien-5-one (vi)
(1e,3s,4r,5s,7r,8r,9e,12s,14s,15r,16s,18r)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-1-{(1r,3r,4r)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-1,9-nonadecadiene-3,5-diol (vii)
(1e,3s,4s,5s,7r,8r,9e,12s,14s,15r,16s,18r)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-1-{(1r,3r,4r)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-5-[(triisopropylsilyl)oxy]-1,9-nonadecadien-3-ol (viii)
(1s,2r,3s,5s,7e,9r,10r,12s,13s,14s,15e)-9-allyl-2,10-bis{[tert-butyl(dimethyl)silyl]oxy}-1-[(2r)-3,3-dimethoxy-2-methylpropyl]-3-methoxy-16-{(1r,3r,4r)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-5,7,13,15-tetramethyl-14-[(triethylsilyl)oxy]-12-[(triisopropylsilyl)oxy]-7,15-hexadecadienyl methyl ether (ix)
(2r,4s,5r,6s,8s,10e,12r,13r,15s,16s,17s,18e)-12-allyl-5,13-bis{[tert-butyl(dimethyl)silyl]oxy}-4,6-dimethoxy-19-{(1r,3r,4r)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,8,10,16,18-pentamethyl-17-[(triethylsilyl)oxy]-15-[(triisopropylsilyl)oxy]-10,18-nonadecadienal (x)
(2s)-1-{2-[(4-methoxybenzyl)oxy]acetyl}-2-piperidinecarboxylic acid (xi)
Reference 1:
    nordmann, r.; petcher, t.j.; octahydrobenzo[g]quinolines: potent dopamine agonists which show the relationship between ergolines and apomorphine. j med chem 1985, 28, 3, 367.
Reference 2:
    petcher, t.j.; nordmann, r. (novartis ag); novel pharmaceutically active 1,2,3,4,4a,5,10,10a-octahydrobenzo(g)quinoline derivs.. ep 0077754; es 8606281; es 8706120 .

Route 2
free nh group of (xi) is alkylated by reductocondensation with propionaldehyde (xii) and h2 over pd/c, giving the n-propyl derivative (xiii). the reaction of the ester group of (xiii) with hydrazine yields the corresponding hydrazide (xiv), which is submitted to degradation with nitrosyl chloride in thf to afford the amine (xv). the condensation of (xv) with n,n-diethylsulfamoyl chloride (xvi) by means of tea in chloroform gives the sulfamide (xvii), which is finally demethylated by a treatment with bbr3 in dichloromethane.
List of intermediates No.
(2r)-5-[[amino(imino)methyl]amino]-2-[(tert-butoxycarbonyl)amino]pentanoic acid (xii)
(2s)-1-{2-[(4-methoxybenzyl)oxy]acetyl}-2-piperidinecarboxylic acid (xi)
(2s)-1-{(4r,6s,7r,8s,10s,12e,14r,15r,17s,18s,19s,20e)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1r,3r,4r)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-19-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid (xiii)
(2s)-1-{(4r,6s,7r,8s,10s,12e,14r,15r,17s,18s,19s,20e)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1r,3r,4r)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-3-oxo-19-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid (xiv)
(2s)-1-{(4r,6s,7r,8s,10s,12e,14r,15r,17s,18s,19s,20e)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-19-hydroxy-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1r,3r,4r)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-3-oxo-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid (xv)
(3s,4s,5s,7r,8r,12s,14s,15r,16s,18r,26as)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16-dimethoxy-20-[(4-methoxybenzyl)oxy]-3-((e)-2-{(1r,3r,4r)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,24,25,26,26a-hexadecahydro-3h-pyrido[2,1-c][1,4]oxazacyclotricosine-1,19,21(4h,20h,23h)-trione (xvi)
ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate (xvii)
Reference 1:
    nordmann, r.; petcher, t.j.; octahydrobenzo[g]quinolines: potent dopamine agonists which show the relationship between ergolines and apomorphine. j med chem 1985, 28, 3, 367.
Reference 2:
    petcher, t.j.; nordmann, r. (novartis ag); novel pharmaceutically active 1,2,3,4,4a,5,10,10a-octahydrobenzo(g)quinoline derivs.. ep 0077754; es 8606281; es 8706120 .

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盐酸喹高莱;英文名Quinagolide hydrochloride;SDZ-205502;CV-205502;Norprolac;CAS[94424-50-7]

 
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