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药物详细合成路线

Name Carboxyamidotriazole;CAI;NSC-609974;L-651582
Chemical Name 5-Amino-1-[3,5-dichloro-4-(4-chlorobenzoyl)benzyl]-1,2,3-triazole-4-carboxamide
CAS 99519-84-3
Related CAS
Formula C17H12Cl3N5O2
Structure
Formula Weight 424.67649
Stage III 期临床
Company Merck & Co. (Originator), National Cancer Institute (Licensee)
Activity/Mechanism ANTIINFECTIVE THERAPY, Lung Cancer Therapy, Oncolytic Drugs, Ovarian Cancer Therapy, Renal Cancer Therapy, Small Cell Lung Cancer Therapy, Treatment of Protozoal Diseases, Angiogenesis Inhibitors, Inhibitors of Signal Transduction Pathways
Syn. Route 2
Route 1
reduction of 3,5-dichlorobenzoyl chloride (i) with nabh4 in thf in the presence of n-methyl pyrrolidone (nmp) provides benzyl alcohol derivative (ii), which is then treated with tert-butyl dimethylsilyl chloride (tbdmscl) in dmf in the presence of imidazole and dmap to furnish protected compound (iii). lithiation of (iii) with buli (occasionally in the presence of tetramethylethylenediamine) in thf followed by reaction with p-chlorobenzoyl chloride (iv) in thf affords benzophenone derivative (v), which is then deprotected by means of concentrated hcl to yield benzyl alcohol derivative (vi). conversion of alcohol (vi) into chloride (vii) is then performed by reaction with socl2. next, reaction of (vii) with nan3 and nai in refluxing ethanol gives benzylazide derivative (viii), which is finally converted into the desired product by reaction with cyanoacetamide (ix) and k2co3 in dmso.
List of intermediates No.
[(1s)-2-bromo-2-(bromomethyl)cyclopropyl]methyl acetate (iv)
1-(2-chlorophenyl)-2-(2-phenyl-1-pyrrolidinyl)-1-ethanol (ix)
benzyl 8-[[(tert-butoxycarbonyl)(2-pyridinyl)amino]methyl]-3-[([(2s)-3-(tert-butoxy)-2-[(mesitylsulfonyl)amino]-3-oxopropyl]amino)carbonyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-7-carboxylate (ii)
8-(bromomethyl)quinoline (i)
1-fluoro-4-isopropenylbenzene (iii)
[1-ethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydro-3-pyridinyl]methanol
[(3s)-1-ethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydro-3-pyridinyl]methanol (v)
[(3r)-1-ethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydro-3-pyridinyl]methanol (vi)
[(3s,4r)-1-ethyl-4-(4-fluorophenyl)piperidinyl]methanol (vii)
[(3r,4r)-1-ethyl-4-(4-fluorophenyl)piperidinyl]methanol (viii)
Reference 1:
    bochis, r.j.; chabala, j.c.; fisher, m.h. (merck & co., inc.); 5-(amino or substd.amino)-1,2,3-triazoles. ep 0151529; jp 1985188376; us 4590201 .
Reference 2:
    hube, d. (merck & co., inc.); 5-amino or substd. amino-1,2,3-triazoles useful as anti-metastasis agents. jp 1991056417; us 5045543 .
Reference 3:
    hupe, d.; azzolina, b.a.; argenbright, l.; behrens, n. (merck & co., inc.); 5-amino or substd. amino 1,2,3-triazoles useful as antiproliferative agents. ep 0304221; jp 1989068321; us 4847257 .

Route 2
alternatively, the target compound can be obtained as follows: condensation between 2,6-dichloro-4-methylbenzonitrile (x) and 4-chloroiodobenzene (xi) by means of mg in refluxing ether gives methyleneimine derivative (xii), which is then converted into 4-(4-chlorobenzoyl)-3,5-dichlorotoluene (xiii) by refluxing in dioxane-aqueous phosphate buffer. (alternatively, compound (xiii) can also be obtained either by condensation of 3,5-dichlorotoluene (xiv) with p-chlorobenzoyl chloride (iv) by means of buli in thf or by treatment of 2,6-dichloro-4-methylbenzoic acid (xv) with thionyl chloride (socl2) in refluxing dmf to give (xvi), which then reacts with chlorobenzene (xvii) by means of alcl3 in refluxing ccl4). bromination of (xiii) is then performed by reaction with n-bromosuccinimide and dibenzoyl peroxide in refluxing benzene to give 4-(4-chlorobenzoyl)-3,5-dichlorobenzyl bromide (xviii). (alternatively, (xviii) can also be synthesized by treatment of the already reported benzophenone derivative (v) with hoac in thf/h2o followed by reaction with phosphorus tribromide in diethyl ether.) finally, (xviii) is converted into the desired compound either by treatment with 5-amino-1,2,3-triazole-4-carboxamide (xix) by means of nah in refluxing etoh or by first reaction of (xviii) with kn3 in refluxing etoh to furnish benzyl azide (viii), followed by reaction with cyanoacetamide (ix) and naome in refluxing etoh.
List of intermediates No.
7-methoxy-1,2,3,4-tetrahydroisoquinoline; methyl 1,2,3,4-tetrahydro-7-isoquinolinyl ether (xvii)
[(1s)-2-bromo-2-(bromomethyl)cyclopropyl]methyl acetate (iv)
1-(2-chlorophenyl)-2-(2-phenyl-1-pyrrolidinyl)-1-ethanol (ix)
(2-amino-4,5-dimethoxyphenyl)(3,4-dimethoxyphenyl)methanone (xi)
[(3s)-1-ethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydro-3-pyridinyl]methanol (v)
[(3r,4r)-1-ethyl-4-(4-fluorophenyl)piperidinyl]methanol (viii)
(3s,4r)-3-[(1,3-benzodioxol-5-yloxy)methyl]-1-ethyl-4-(4-fluorophenyl)piperidine; 1,3-benzodioxol-5-yl [(3s,4r)-1-ethyl-4-(4-fluorophenyl)piperidinyl]methyl ether (x)
1-(4h-1,3-benzodioxin-6-yl)-2-bromo-1-ethanone (xii)
(1r)-1-(4h-1,3-benzodioxin-6-yl)-2-bromo-1-ethanol (xiii)
6-[(2r)oxiranyl]-4h-1,3-benzodioxine (xiv)
6-(4-phenylbutoxy)-1-hexanamine; 6-(4-phenylbutoxy)hexylamine (xv)
(1r)-1-(4h-1,3-benzodioxin-6-yl)-2-{[6-(4-phenylbutoxy)hexyl]amino}-1-ethanol (xvi)
1-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-bromo-1-ethanone (xviii)
(1r)-1-[4-(benzyloxy)-3-(hydroxymethyl)phenyl]-2-bromo-1-ethanol (xix)
Reference 1:
    bochis, r.j.; chabala, j.c.; fisher, m.h. (merck & co., inc.); 5-(amino or substd.amino)-1,2,3-triazoles. ep 0151529; jp 1985188376; us 4590201 .

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5-氨基-1-(3,5-二氯-4-(4-氯苯甲酰基)苄基)-1H-1,2,3-三氮唑-4-甲酰胺;英文名Carboxyamidotriazole;CAI;NSC-609974;L-651582;CAS[99519-84-3]

 
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