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藥物詳細合成路線

Name Spirapril;TI-211-950(hydrochloride);Sch-33844(HCl);Setrilan;Sandopril;Renormax
Chemical Name (8S)-7-[(S)-N-[(S)-1-Carboxy-3-phenylpropyl]alanyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid 1-ethyl ester
CAS 83647-97-6
Related CAS 94841-17-5 (HCl)
Formula C22H30N2O5S2
Structure
Formula Weight 466.6228
Stage 上市-1995
Company Essex (Originator), Novartis (Originator), Schering-Plough (Originator), Pfizer (Licensee)
Activity/Mechanism CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Angiotensin-I Converting Enzyme (ACE) Inhibitors
Syn. Route 4
Route 1
a new synthesis of spirapril has been described:the cyclization of n-benzyloxycarbonyl-4-oxo-(s)-proline (i) with ethanedithiol by means of boron trifluoride ethearate in glacial acetic acid gives 7-(benzyloxycarbonyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(s)-carboxylic acid (ii), which is deprotected with hbr in acetic acid to yield 1,4-dithia-7-azaspiro[4.4]nonane-8(s)-carboxylic acid (iii). this compound is then condensed with n-[1(s)-(ethoxycarbonyl)-3-phenylpropyl]-(s)-alanine (iv) by means of n-hydroxysuccinimide (nos) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (dmcc) in dmf, or by means of n,n-disuccinimidyl carbonate and pyridine.
List of intermediates No.
tert-butyl 2-[[(1r)-2-[(2s)-2-([[(1s)-5-[[(benzyloxy)carbonyl]amino]-1-(1,3-thiazol-2-ylcarbonyl)pentyl]amino]carbonyl)pyrrolidinyl]-1-(cyclohexylmethyl)-2-oxoethyl](tert-butoxycarbonyl)amino]acetate (i)
1-methoxy-4-[(4-methoxyphenyl)disulfanyl]benzene; bis(4-methoxyphenyl) disulfide (ii)
4-methoxybenzenesulfinyl chloride (iii)
(1s,2r)-2-phenylcyclohexanol (iv)
Reference 1:
    swiss, g.f.; neustadt, b.r.; mcnamara, p.; baum, t.; smith, e.m.; gold, e.h.; sybertz, e.j.; angiotensin converting enzyme inhibitors: spirapril and related. j med chem 1989, 32, 7, 1600-6.

Route 2
a new synthesis of spirapril has been reported:the cyclization of n-benzyloxycarbonyl-4-oxo-(s)-proline (i) with ethandithiol by means of boron trifluoride ethearate in dichloromethane gives 7-(benzyloxycarbonyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(s)-carboxylic acid (ii), which is treated with concentrated hcl to yield 1,4-dithia-7-azaspiro[4.4]nonane-8(s)-carboxylic acid (iii). the protection of (iii) with tert-butoxycarbonyl chloride and with trimethylsilylethanol in the usual manner affords n-(tert-butoxycarbonyl)-1,4-dithia-7-azaspiro[4.4]nonane-8(s)-carboxyli c acid 2-(trimethylsilyl)ethyl ester (iv), which is condensed with n-[1(s)-(ethoxycarbonyl)-3-phenylpropyl]-(s)-alanine (v) by a first treatment with p-toluenesulfonic acid and a condensation step with dicyclohexylcarbodiimide (dcc) and hydroxybenzotriazole (hbt), giving spirapril 2-(trimethylsilyl)ethyl ester (vi). finally, this ester is hydrolyzed with tetrabutylammonium fluoride trihydrate in dmf.
List of intermediates No.
tert-butyl 2-[[(1r)-2-[(2s)-2-([[(1s)-5-[[(benzyloxy)carbonyl]amino]-1-(1,3-thiazol-2-ylcarbonyl)pentyl]amino]carbonyl)pyrrolidinyl]-1-(cyclohexylmethyl)-2-oxoethyl](tert-butoxycarbonyl)amino]acetate (i)
1-methoxy-4-[(4-methoxyphenyl)disulfanyl]benzene; bis(4-methoxyphenyl) disulfide (ii)
4-methoxybenzenesulfinyl chloride (iii)
(1s,2r)-2-phenylcyclohexanol (v)
4-[(4-methoxyphenyl)sulfinyl]benzaldehyde (iv)
6-nitro-2,3-dihydro-4h-chromen-4-one (vi)
Reference 1:
    powell, j.r.; cushman, d.w.; krapcho, j.; turk, c.; deforrest, j.m.; spitzmiller, e.r.; karanewsky, d.s.; duggan, m.; rovnyak, g.; schwartz, j.; et al.; angiotensin-converting enzyme inhibitors. mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines. j med chem 1988, 31, 6, 1148.

Route 3
the cyclization of 1-benzyloxycarbonyl-4-oxoproline methyl ester (i) with ethanedithiol (ii) by means of p-toluenesulfonic acid in refluxing acetic acid gives methyl 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate (iii), which is deprotected with 20% hbr to give methyl 1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate (iv). the condensation of (iv) with n-benzyloxycarbonyl alanine n-hydroxysuccinimide ester (v) affords the corresponding dipeptide methyl ester (vi), which is hydrolyzed with naoh to the free acid (vii), and deprotected with 20% hbr as before to 7-alanyl-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid (viii). finally, this compound is condensed with ethyl 2-oxo-4-phenylbutyrate (ix) by means of sodium cyanoborohydride in methanol.
List of intermediates No.
2-(4-[[(e)-benzylidene]amino]phenyl)butanenitrile (ix)
ethyl 3-bromo-4-hydroxy-5-iodobenzoate (i)
ethyl 3-bromo-4-(2-hydroxyethoxy)-5-iodobenzoate (ii)
3-chlorophenylboronic acid (a)
(iii)
(iv)
2,3,3a,4,5,6-hexahydro-1h-phenalen-1-one oxime (v)
(vi)
8-(7,8,9,9a-tetrahydro-1h-phenalen-3-yl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (vii)
(3r)-3-(palmitoyloxy)tetradecanoic acid (viii)
Reference 1:
    smith, e.m.; neustadt, b.r.; gold, e.h. (schering corp.); 7-carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids. jp 1989163197; us 4470972 .
Reference 2:
    prous, j.; castaner, j.; spirapril. drugs fut 1987, 12, 9, 860.

Route 4
the condensation of (ix) with alanine benzyl ester (x) with sodium cyanoboohydride as before gives n-[1-(ethoxycarbonyl)-3-phenylpropyl]alanine benzyl ester (xi), which is submitted to fractional crystallization with maleic acid yielding n-[1(s)-(ethoxycarbonyl)-3-phenylpropyl]-(s)-alanine benzyl ester (xii), which is debenzylated by hydrogenation with h2 over pd/c in ethanol yielding the free acid (xiii). finally, this compound is condensed with spirane (iv) through the n-hydroxysuccinimide ester, in the usual way.
List of intermediates No.
1-(2-fluoro[1,1-biphenyl]-4-yl)-1-propanone (x)
(1s,2r)-2-phenylcyclohexanol (xiii)
2-[4-(4-chlorophenyl)-1-(4-fluorophenyl)-1h-pyrazol-3-yl]acetonitrile (xii)
2-(4-[[(e)-benzylidene]amino]phenyl)butanenitrile (ix)
methyl 1-methyl-5-nitro-1h-imidazol-2-yl sulfide; 1-methyl-2-(methylsulfanyl)-5-nitro-1h-imidazole (a)
(iv)
(1r)-1-(2-[[(4ar,6r,7r,8r,8as)-6-(benzyloxy)-8-hydroxy-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]amino]-2-oxoethyl)dodecyl palmitate (xi)
Reference 1:
    smith, e.m.; neustadt, b.r.; gold, e.h. (schering corp.); 7-carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids. jp 1989163197; us 4470972 .
Reference 2:
    prous, j.; castaner, j.; spirapril. drugs fut 1987, 12, 9, 860.

來源:藥化網

作者:藥化小編

摘要:本文合成路線介紹的是藥物中文名螺普利;英文名Spirapril;TI-211-950(hydrochloride);Sch-33844(HCl);Setrilan;Sandopril;Renormax;CAS[83647-97-6]

 
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