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【结 构 式】 
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【分子编号】20891 【品名】3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one 【CA登记号】 |
【 分 子 式 】C10H10N4O 【 分 子 量 】202.21576 【元素组成】C 59.4% H 4.98% N 27.71% O 7.91% |
合成路线1
该中间体在本合成路线中的序号：(VIII)A new synthesis of CGS-14824A is given: The reaction of 3-bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile (II), which is hydrolyzed to the corresponding butyric acid (III). The cyclization of (III) with polyphosphoric acid affords 1-tetralone (IV), which is brominated to 2-bromo-1-tetralone (V) and treated with hydroxylamine to give the oxime (VI). The Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with sodium azide to afford the azide derivative (VIII). The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means of KOH and tetrabutylammonium bromide in THF gives the N-alkylated azide (X), which is reduced by catalytic hydrogenation to the corresponding amine (XI). The hydrolysis of the ester group of (XI) with NaOH yields the free acetic acid derivative (XII), which is finally reductocondensed with ethyl 2-oxo-4-phenylbutyrate (XIII) by means of sodium cyanoborohydride.
| 【1】 Chaudhuri, N.K.; Patera, R.; Markus, B.; Sung, M.-S.; Synthesis of 14C-labeled 3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid hydrochloride ([14C]CGS 14824A). J Label Compd Radiopharm 1987, 24, 10, 1177-84. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (II) | 20885 | 4-phenylbutanenitrile | 2046-18-6 | C10H11N | 详情 | 详情 |
| (III) | 20886 | Benzenebutyric acid; 4-Phenylbutyric acid | 1821-12-1 | C10H12O2 | 详情 | 详情 |
| (IV) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (V) | 20721 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone | C10H9BrO | 详情 | 详情 | |
| (VI) | 20722 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime | C10H10BrNO | 详情 | 详情 | |
| (VII) | 20723 | 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10BrNO | 详情 | 详情 | |
| (VIII) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
| (IX) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (X) | 20893 | ethyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C14H16N4O3 | 详情 | 详情 | |
| (XI) | 20894 | ethyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | 109010-60-8 | C14H18N2O3 | 详情 | 详情 |
| (XII) | 20895 | 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid | C12H14N2O3 | 详情 | 详情 | |
| (XIII) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)The reaction of 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (I) with PCl5 in hot xylene gives 3,3-dichloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (II), which is treated with sodium acetate and reduced with H2 over Pd/C in acetic acid yielding 3-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (III). The reaction of (III) with sodium azide in DMSO affords 3-azido-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (IV), which is condensed with benzyl bromoacetate (V) by means of NaH in DMF giving 3-azido-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VI). The treatment of (VI) with Raney-Ni in ethanol-water yields 3-amino-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol affording 3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VIII). Finally, this compound is condensed with ethyl 3-benzylpyruvate (IX) by means of sodium cyanoborohydride in methanol acetic acid.
| 【1】 Watthey, J.W.H. (Novartis AG); Benzazepin-2-ones, process for their preparation, pharmaceutical preparations containing these compounds and the compounds for therapeutical use. EP 0072352; GB 2103614; JP 8338260 . |
| 【2】 Castaner, J.; Serradell, M.N.; CGS-14824 A. Drugs Fut 1984, 9, 5, 317. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 30511 | 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H11NO | 详情 | 详情 | |
| (II) | 30512 | 3,3-dichloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H9Cl2NO | 详情 | 详情 | |
| (III) | 30513 | 3-chloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10ClNO | 详情 | 详情 | |
| (IV) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
| (V) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VI) | 30514 | benzyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C19H18N4O3 | 详情 | 详情 | |
| (VII) | 30515 | benzyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C19H20N2O3 | 详情 | 详情 | |
| (VIII) | 30516 | 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetic acid | C12H14N2O3 | 详情 | 详情 | |
| (IX) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XII)The selective monoesterification of 2,2-dimethylsuccinic acid (VIII) with methanol and sulfuric acid gives 2,2-dimethylsuccinic acid 4-methyl ester (IX), which is submitted to degradation with diphenylphosphoryl azide, TEA and benzyl alcohol in refluxing benzene, yielding 3-(benzyloxycarbonylamino)-3-methylbutyric acid methyl ester (X). The hydrolysis of (X) with NaOH in methanol affords the corresponding butyric acid (XI). The hydrogenation of 3-azido-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (XII) with H2 over Pt/C in methanol gives the racemic 3-amino derivative (XIII), which is submitted to optical resolution by crystallization of the L-tartrate salt, yielding the 3(R)-amino derivative (XIV). The condensation of amine (XIV) with acid (XI) by means of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BTPF) and DIEA in dichloromethane affords the corresponding amide (XV), which is condensed with the tetrazole derivative (VII) by means of NaH in DMF to provide the protected adduct (XVI). Finally, this compound is deprotected by hydrogenation with H2 over Pd/C in methanol and a treatment with TFA.
| 【1】 Watthey, J.W.; et al.; Synthesis and biological properties of (carboxyalkyl)amino-substituted bicyclic lactam inhibitors of angiotensin converting enzyme. J Med Chem 1985, 28, 10, 1511. |
| 【2】 Fisher, M.H.; Wyvratt, M.J.; Schoen, W.R.; DeVita, R.J. (Merck & Co., Inc.); Benzo-fused lactams promote release of growth hormone. EP 0513974; JP 1994172316; US 5206235; WO 9216524 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 15538 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole | 124750-51-2 | C33H25BrN4 | 详情 | 详情 |
| (VIII) | 46622 | 2,2-dimethylsuccinic acid | C6H10O4 | 详情 | 详情 | |
| (IX) | 46623 | 4-methoxy-2,2-dimethyl-4-oxobutyric acid | C7H12O4 | 详情 | 详情 | |
| (X) | 46624 | methyl 3-[[(benzyloxy)carbonyl]amino]-3-methylbutanoate | C14H19NO4 | 详情 | 详情 | |
| (XI) | 46625 | 3-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid | C13H17NO4 | 详情 | 详情 | |
| (XII) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
| (XIII) | 46628 | 3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H12N2O | 详情 | 详情 | |
| (XIV) | 15929 | (3R)-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H12N2O | 详情 | 详情 | |
| (XV) | 46626 | benzyl 1,1-dimethyl-3-oxo-3-[[(3R)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino]propylcarbamate | C23H27N3O4 | 详情 | 详情 | |
| (XVI) | 46627 | benzyl 1,1-dimethyl-3-oxo-3-[((3R)-2-oxo-1-[[2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)amino]propylcarbamate | C56H51N7O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)Sodium azide (I) is treated with sulfuric acid to give hydrazoic acid (II), which is condensed with 1-tetralone (III) in hot aqueous sulfuric acid yielding 2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (IV). The bromination of (IV) with Br2 in chloroform affords the 3-bromo derivative (V), which is treated with sodium azide in DMSO to give the corresponding azido derivative (VI). The condensation of (VI) with ethyl 2-bromoacetate (VII) by means of KOH and tetrabutylammonium bromide in THF yields the adduct (VIII). The azido group of (VIII) is reduced with H2 over Pd/C in ethanol the amine (IX) as a racemic mixture, which is submitted to optical resolution with L-tartaric acid affording the desired (S)-enantiomer (X). The condensation of intermediate (X) with 2(R)-benzyl-3-benzyloxyamino)propionic acid (XI) by means of HOBT and EDAC in dichloromethane provides the amide (XII), which is formylated with formic acid and acetic anhydride yielding the formamide (XIII). The debenzylation of (XIII) with H2 over Pd/C in methanol affords the intermediate (XIV), which is finally hydrolyzed with NaOH in methanol.
| 【1】 Asaad, M.M.; Robl, J.A.; Simpkins, L.M.; N-Formyl hydroxylamine containing dipeptides: Generation of a new class of vasopeptidase inhibitors. Bioorg Med Chem Lett 2000, 10, 3, 257. |
| 【2】 Robl, J.A. (Bristol-Myers Squibb Co.); N-Formyl hydroxylamine containing cpds. useful as ACE inhibitors and/or NEP inhibitors. WO 9738705 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 37288 | 1H-triazirine | HN3 | 详情 | 详情 | |
| (III) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (IV) | 30511 | 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H11NO | 详情 | 详情 | |
| (V) | 20723 | 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10BrNO | 详情 | 详情 | |
| (VI) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
| (VII) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (VIII) | 20893 | ethyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C14H16N4O3 | 详情 | 详情 | |
| (IX) | 37292 | ethyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C14H18N2O3 | 详情 | 详情 | |
| (X) | 20894 | ethyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | 109010-60-8 | C14H18N2O3 | 详情 | 详情 |
| (XI) | 37283 | (2R)-2-benzyl-3-[(benzyloxy)amino]propionic acid | C17H19NO3 | 详情 | 详情 | |
| (XII) | 37289 | ethyl 2-[(3S)-3-([(2R)-2-benzyl-3-[(benzyloxy)amino]propanoyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C31H35N3O5 | 详情 | 详情 | |
| (XIII) | 37290 | ethyl 2-[(3S)-3-([(2R)-2-benzyl-3-[(benzyloxy)(formyl)amino]propanoyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C32H35N3O6 | 详情 | 详情 | |
| (XIV) | 37291 | ethyl 2-[(3S)-3-([(2R)-2-benzyl-3-[formyl(hydroxy)amino]propanoyl]amino)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | C25H29N3O6 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)Treatment of 3-aminobenzyl alcohol (I) with isopropyl isocyanate produced urea (II). Mesylation of alcohol (III), followed by reaction with LiBr gave benzyl bromide (III). Then, alkylation of 3-azidobenzazepine (IV) with (III) under phase-transfer conditions afforded (V). The azido group of (V) was reduced to amine (VI) by catalytic hydrogenation over Pd/C. Subsequent treatment of (VI) with carbonyl diimidazole produced isocyanate (VII). This was finally converted to the target compound by condensation with 6-aminobenzothiazole (VIII).
| 【1】 Hara, H.; Murakami, Y.; Okada, T.; et al.; 1,3-Disubstituted benzazepines as novel, potent, selective neuropeptide Y Y1 receptor antagonists. J Med Chem 1999, 42, 14, 2621. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 26153 | (3-aminophenyl)methanol | 1877-77-6 | C7H9NO | 详情 | 详情 |
| (II) | 26154 | N-[3-(hydroxymethyl)phenyl]-N'-isopropylurea | C11H16N2O2 | 详情 | 详情 | |
| (III) | 26155 | N-[3-(bromomethyl)phenyl]-N'-isopropylurea | C11H15BrN2O | 详情 | 详情 | |
| (IV) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
| (V) | 26156 | N-[3-[(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)methyl]phenyl]-N'-isopropylurea | C21H24N6O2 | 详情 | 详情 | |
| (VI) | 26157 | N-[3-[(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)methyl]phenyl]-N'-isopropylurea | C21H26N4O2 | 详情 | 详情 | |
| (VII) | 26158 | N-[3-[(3-isocyanato-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)methyl]phenyl]-N'-isopropylurea | C22H24N4O3 | 详情 | 详情 | |
| (VIII) | 17908 | 1,3-benzothiazol-6-ylamine; 1,3-benzothiazol-6-amine; 6-Aminobenzothiazole | 533-30-2 | C7H6N2S | 详情 | 详情 |