(3R)-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one -Drug Synthesis Database

【结构式】

【分子编号】15929

【品名】(3R)-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one

【CA登记号】

【分子式】C₁₀H₁₂N₂O

【分子量】176.21816

【元素组成】C 68.16% H 6.86% N 15.9% O 9.08%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(IV)

A synthesis of L-692429 has been reported: The cyclization of isobutene (I) with chlorosulfonyl isocyanate (II) gives 1-(chlorosulfonyl)-4,4-dimethylazetidin-2-one (III), which is condensed with 3(R)-amino-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (IV) by means of triethylamine in methanol to yield 3-methyl-3-(methylsulfonamido)-N-[2-oxo-2,3,4,5-tetrahydro-1H-1-benzaze pin-3(R)-yl]butyramide (V). The reaction of (V) with 2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethyl bromide (VI) by means of NaH in THF/DMF affords protected L-692429, which is finally deprotected by a treatment with 5N HCl.

参考文献中间体

合成目标

【1】 Bergan, J.J.; Reider, P.J.; McNamara, J.M.; Volante, R.P.; Bhupathy, M.; A convergent synthesis of a novel non-peptidyl growth hormone secretagogue, L-692,429. Tetrahedron Lett 1995, 36, 52, 9445.
【2】 Schoen, W.R.; et al.; A novel 3-substituted benzazepinone growth hormone secretagogue (L-692,429). J Med Chem 1994, 37, 7, 897.

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)	15926	2-methyl-1-propene; isobutylene	115-11-7	C₄H₈	详情	详情
(II)	14101	Chlorosulfonyl isocyanate	1189-71-5	CClNO₃S	详情	详情
(III)	15928	2,2-dimethyl-4-oxo-1-azetanesulfonyl chloride		C₅H₈ClNO₃S	详情	详情
(IV)	15929	(3R)-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₂N₂O	详情	详情
(V)	15930	3-methyl-3-[(methylsulfonyl)amino]-N-[(3R)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]butanamide		C₁₆H₂₃N₃O₄S	详情	详情
(VI)	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
(VII)	15932	3-methyl-3-[(methylsulfonyl)amino]-N-((3R)-2-oxo-1-[[2'-(1-trityl-1H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)butanamide		C₄₉H₄₇N₇O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

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.

参考文献中间体

合成目标

【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3

该中间体在本合成路线中的序号：(IX)

4-Bromobenzyl alcohol (I) was protected as the silyl ether (II) by treatment with tert-butylchlorodiphenylsilane (TBDPSCl) and Et3N in DMF. Treatment of (II) with BuLi in THF at -78 C, followed by reaction with triisopropyl borate and acid hydrolysis afforded boronic acid (III). Palladium catalyzed coupling of (III) with N-Boc-2-bromobenzylamine (V) (obtained by reaction of 2-bromobenzylamine (IV) with di-tert-butyl dicarbonate), provided biphenyl (VI). This was desilylated by treatment with tetrabutyl ammonium fluoride in THF, and the resulting benzyl alcohol (VII) was converted to mesylate (VIII) with methanesulfonyl chloride and Et3N in CH2Cl2 at 0 C. Coupling of (R)-3-aminobenzazepinone (IX) with N-benzyloxycarbonyl-2-methylalanine (X) using benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP) gave amide (XI). Then, regioselective alkylation of (XI) with mesylate (VIII) in the presence of NaH in DMF at low temperature afforded (XII). Subsequent removal of the tert-butoxycarbonyl protecting group with HCl at r.t. yielded amine hydrochloride (XIII), which was condensed with methyl isocyanate to afford urea (XIV). Finally, the N-benzyloxycarbonyl group was removed by hydrogenolysis in the presence of Pd(OH)2 to furnish the title compound.

参考文献中间体

合成目标

【1】 A potent, orally bioavailable benzazepinone growth hormone secretagogue. J Med Chem 1998, 41, 10, 1716.

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)	19121	(4-bromophenyl)methanol	873-75-6	C₇H₇BrO	详情	详情
(II)	19122	[(4-bromobenzyl)oxy](tert-butyl)diphenylsilane; 4-bromobenzyl tert-butyl(diphenyl)silyl ether		C₂₃H₂₅BrOSi	详情	详情
(III)	19123	4-([[tert-butyl(diphenyl)silyl]oxy]methyl)phenylboronic acid		C₂₃H₂₇BO₃Si	详情	详情
(IV)	19124	(2-bromophenyl)methanamine; 2-bromobenzylamine	3959-05-5	C₇H₈BrN	详情	详情
(V)	19125	tert-butyl 2-bromobenzylcarbamate		C₁₂H₁₆BrNO₂	详情	详情
(VI)	19126	tert-butyl [4'-([[tert-butyl(diphenyl)silyl]oxy]methyl)[1,1'-biphenyl]-2-yl]methylcarbamate; 2-[[(tert-butoxycarbonyl)amino]methyl]-4'-([[tert-butyl(diphenyl)silyl]oxy]methyl)-1,1'-biphenyl		C₃₅H₄₁NO₃Si	详情	详情
(VII)	19127	2-[[(tert-butoxycarbonyl)amino]methyl]-4'-(hydroxymethyl)-1,1'-biphenyl; tert-butyl [4'-(hydroxymethyl)[1,1'-biphenyl]-2-yl]methylcarbamate		C₁₉H₂₃NO₃	详情	详情
(VIII)	19128	(2'-[[(tert-butoxycarbonyl)amino]methyl][1,1'-biphenyl]-4-yl)methyl methanesulfonate		C₂₀H₂₅NO₅S	详情	详情
(IX)	15929	(3R)-3-amino-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one		C₁₀H₁₂N₂O	详情	详情
(X)	19130	N-[(benzyloxy)carbonyl]-2-methylalanine	15030-72-5	C₁₂H₁₅NO₄	详情	详情
(XI)	19131	benzyl 1,1-dimethyl-2-oxo-2-[[(3R)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino]ethylcarbamate		C₂₂H₂₅N₃O₄	详情	详情
(XII)	19132	benzyl 2-([(3R)-1-[(2'-[[(tert-butoxycarbonyl)amino]methyl][1,1'-biphenyl]-4-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino)-1,1-dimethyl-2-oxoethylcarbamate		C₄₁H₄₆N₄O₆	详情	详情
(XIII)	19133	benzyl 2-[((3R)-1-[[2'-(aminomethyl)[1,1'-biphenyl]-4-yl]methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)amino]-1,1-dimethyl-2-oxoethylcarbamate hydrochloride		C₃₆H₃₉ClN₄O₄	详情	详情
(XIV)	19134	benzyl 1,1-dimethyl-2-[((3R)-1-[[2'-([[(methylamino)carbonyl]amino]methyl)[1,1'-biphenyl]-4-yl]methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)amino]-2-oxoethylcarbamate		C₃₈H₄₁N₅O₅	详情	详情

Extended Information