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药物详细合成路线

Name Conivaptan hydrochloride;CI-1025;YM-087
Chemical Name N-[4-(2-Methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-ylcarbonyl)phenyl]biphenyl-2-carboxamide hydrochloride
CAS 168626-94-6
Related CAS 210101-16-9 (free base)
Formula C32H27ClN4O2
Structure
Formula Weight 535.05059
Stage 上市-2006
Company Yamanouchi (Originator), Pfizer (Licensee)
Activity/Mechanism CARDIOVASCULAR DRUGS, Diuretics, Heart Failure Therapy, RENAL-UROLOGIC DRUGS, Oxytocin Antagonists, Vasopressin V1a Antagonists, Vasopressin V2 Antagonists
Syn. Route 3
Route 1
acylation of 2,3,4,5-tetrahydro-1h-1-benzazepin-5-one (i) with 4-nitrobenzoyl chloride (ii) by means of tea in ch2cl2 gives 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1h-1-benzazepin-5-one (iii), which is hydrogenated with h2 over raney-ni in meoh, yielding the corresponding amine derivative (iv). acylation of (iv) with biphenyl-2-carboxylic acid (v) by means of oxalyl chloride in ch2cl2 affords the expected amide (vi) which is brominated with either br2 or cubr2, providing the alpha-bromo ketone (vii). this ketone (vii) is cyclized with acetamidine hydrochloride (viii) by means of k2co3 in mecn, furnishing a mixture of conivaptan and oxazolo[4,5-d][1]benzodiazepine compound. finally, conivaptan is separated by column chromatography over silica gel and is treated with 4n hcl to provide the desired hydrochloride.
List of intermediates No.
ethyl 3-(3-hydroxy-2-pyridinyl)propanoate (viii)
tert-butyl (2s)-2-[(tert-butoxycarbonyl)amino]-5-isothiocyanatopentanoate (v)
1-[(e)-3-chloro-1-propenyl]-3-methoxy-2-nitrobenzene; 3-[(e)-3-chloro-1-propenyl]-2-nitrophenyl methyl ether (ii)
n-(3-chloro-4-fluorophenyl)-6-(methylsulfinyl)pyrimido[5,4-d]pyrimidin-4-amine; n-(3-chloro-4-fluorophenyl)-n-[6-(methylsulfinyl)pyrimido[5,4-d]pyrimidin-4-yl]amine (i)
n-(3-chloro-4-fluorophenyl)-6-(methylsulfonyl)pyrimido[5,4-d]pyrimidin-4-amine; n-(3-chloro-4-fluorophenyl)-n-[6-(methylsulfonyl)pyrimido[5,4-d]pyrimidin-4-yl]amine (iii)
1-methyl-4-piperidinamine; 1-methyl-4-piperidinylamine (iv)
1-fluoro-4-iodobenzene; 4-fluoroiodobenzene; 4-iodofluorobenzene; p-fluoroiodobenzene (vi)
4-fluorobenzoic acid (vii)
Reference 1:
    casta?er, r.m.; norman, p.; rabasseda, x.; leeson, p.a.; casta?er, j.; conivaptan hydrochloride. drugs fut 2000, 25, 11, 1121.
Reference 2:
    tanaka, a.; koshio, h.; taniguchi, n.; matsuhisa, a.; sakamoto, k.; yamazaki, a.; yatsu, t. (yamanouchi pharmaceutical co., ltd.); fused benzazepine deriv. and pharmaceutical compsn. containing the same. ep 0709386; jp 1995505056; us 5723606; wo 9503305 .
Reference 3:
    koshio, h.; taniguchi, n.; tanaka, a.; yatsu, t.; matsuhisa, a.; nonpeptide arginine vasopressin antagonists for both v1a and v2 receptors: synthesis and pharmacological properties of 4-(1,4,5,6-tetrahydroimidazo[4,5-d][1]benzoazepine-6-carbonyl)benzanilide derivatives and 4-(5,6-dihydro-4h-thiazolo[5,4-d][1]benzoaze. chem pharm bull 2000, 48, 1, 21.

Route 2
the bromination of 1-(p-toluenesulfonyl)-2,3,4,5-tetrahydro-1h-1-benzazepin-5-one (ix) with br2 in chcl3 gives the alpha-bromo ketone (x), which is cyclized with acetamidine hydrochloride (viii) by means of k2co3, yielding the expected imidazo-benzazepine (xi). this compound is detosylated with hot h2so4 to provide 2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepine (xii). acylation of (xii) with 4-nitroben-zoic acid (xiii) by means of pyridine in either hot mecn or dmf affords the 6-(4-nitro-benzoyl) derivative (xiv), which is reduced with h2 and raney-ni in meoh to the corres-ponding 6-(4-aminobenzoyl) compound (xv). finally, this compound is condensed with biphenyl-2-carbonyl chloride (xvi) [ obtained by treatment of biphenyl-2-carboxylic acid (v) with oxalyl chloride in ch2cl2/dmf] by means of pyridine in acetonitrile and treated with 4n hcl.
List of intermediates No.
3-[[tert-butyl(dimethyl)silyl]oxy]-2-[1-(1-hydroxy-1-methyl-2-propynyl)cyclopropyl]-5-(trimethylsilyl)-4-pentyn-2-ol (ix)
ethyl 3-(3-hydroxy-2-pyridinyl)propanoate (viii)
11-[[11-(acetoxy)undecanoyl]peroxy]-11-oxoundecyl acetate (xiii)
tert-butyl (2s)-2-[(tert-butoxycarbonyl)amino]-5-isothiocyanatopentanoate (v)
tert-butyl (2s)-2-[(tert-butoxycarbonyl)amino]-5-[[(hydroxyamino)carbothioyl]amino]pentanoate (xvi)
4-fluorobenzonitrile (x)
4-fluorobenzoic acid (xi)
n-[(3r,4s)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2h-chromen-4-yl]-2,5-dibromo-4-fluorobenzamide (xii)
percyanoethylene; tetracyanoethylene (xiv)
2-amino-5-bromo-1h-pyrrole-3,4-dicarbonitrile (xv)
Reference 1:
    casta?er, r.m.; norman, p.; rabasseda, x.; leeson, p.a.; casta?er, j.; conivaptan hydrochloride. drugs fut 2000, 25, 11, 1121.
Reference 2:
    yamazaki, a.; tanaka, a.; tsunoda, t. (yamanouchi pharmaceutical co., ltd.); novel preparation method of condensed benzazepine derivs.. jp 1996198879 .

Route 3
alternatively, treatment of biphenyl-2-carboxylic acid (v) with socl2 and dmf in ch2cl2 provides the acyl chloride (xvi), which is condensed with 4-aminobenzoic acid (xvii) by means of n,n-dimethylaniline in acetone to give the corresponding 4-(2-phenylbenzamido)benzoic acid (xviii). treatment of (xviii) with socl2 and dmf in dry thf affords the acyl chloride (xix), which is finally condensed with the inmidazobenzazepine (xii) by means of pyridine in mecn and treated with 4n hcl.
List of intermediates No.
tert-butyl (2s)-2-[(tert-butoxycarbonyl)amino]-5-isothiocyanatopentanoate (v)
tert-butyl (2s)-2-[(tert-butoxycarbonyl)amino]-5-[[(hydroxyamino)carbothioyl]amino]pentanoate (xvi)
1h-1,2,3,4-tetraazole; tetrazole (xvii)
(5r,9s)-2,9-dimethyl-10-[(triisopropylsilyl)oxy]-3-decyne-2,5-diol (xix)
n-[(3r,4s)-6-acetyl-3-hydroxy-2,2-dimethyl-3,4-dihydro-2h-chromen-4-yl]-2,5-dibromo-4-fluorobenzamide (xii)
ethyl 5-bromo-3,4-dicyano-1h-pyrrol-2-yliminoformate (xviii)
Reference 1:
    casta?er, r.m.; norman, p.; rabasseda, x.; leeson, p.a.; casta?er, j.; conivaptan hydrochloride. drugs fut 2000, 25, 11, 1121.
Reference 2:
    yamazaki, a.; tanaka, a.; tsunoda, t. (yamanouchi pharmaceutical co., ltd.); novel preparation method of condensed benzazepine derivs.. jp 1996198879 .

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考尼伐坦;英文名Conivaptan hydrochloride;CI-1025;YM-087;CAS[168626-94-6]

 
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