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【结 构 式】

【分子编号】49727

【品名】benzyl 8-oxa-3-azabicyclo[5.1.0]octane-3-carboxylate

【CA登记号】

【 分 子 式 】C14H17NO3

【 分 子 量 】247.29392

【元素组成】C 68% H 6.93% N 5.66% O 19.41%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(V)

N-Alkylation of benzyl N-allylcarbamate (I) with 5-bromo-1-pentene (II) by means of NaH in DMF provides olefin metathesis substrate (III), which is then converted into azepine (IV) by means of catalytic bis(tricyclohexylphosphine)benzylideneruthenium (IV) dichloride (Grubbs catalyst) in refluxing CH2Cl2. Epoxidation of (IV) with m-CPBA in CH2Cl2 affords oxirane (V), which is then treated with NaN3 and NH4Cl in H2O/MeOH to provide a mixture of regioisomers from which (VI) is chromatographically isolated. Reduction of azide (VI) with 1,3-propanedithiol and Et3N in MeOH furnishes amino alcohol derivative (VII), which is then acylated with Boc-Leu-OH by means of EDC and HOBt to provide protected derivative (IX). Removal of the Z protecting group by hydrogenolysis over Pd/C in MeOH gives amine (X), which is then condensed with 2-pyridylsulfonyl chloride (XI) by means of Et3N in CH2Cl2 to yield compound (XII). Boc removal from (XII) by treatment with HCl in MeOH/AcOEt affords amine (XIII), which is then acylated with benzofuran-2-carboxylic acid (XIV) by means of EDC and HOBt to give derivative (XV). Finally, the desired product is obtained by oxidation of (XV) with pyridine sulfur trioxide complex and Et3N in DMSO followed by diastereomer separation by HPLC.

1 Marquis, R.W.; et al.; Azepanone-based inhibitors of human and rat cathepsin K. J Med Chem 2001, 44, 9, 1380.
2 Cummings, M.D.; Veber, D.F.; Yamashita, D.; Ru, Y.; Marquis, R.W. Jr.; Thompson, S.K. (SmithKline Beecham Corp.); Protease inhibitors. EP 1158986; WO 0038687 .
3 Veber, D.F.; Marquis, R.W. Jr.; Thompson, S.K.; Ru, Y.; Cummings, M.D.; Yamashita, D. (GlaxoSmithKline Inc.); Protease inhibitors. WO 0195911 .
4 Veber, D.F.; Marquis, R.W. Jr.; Thompson, S.K.; Yamashita, D.S.; Ru, Y.; Cummings, M.D. (GlaxoSmithKline Inc.); Methods of treatment. WO 0178734 .
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) 49723 benzyl allylcarbamate C11H13NO2 详情 详情
(II) 49724 1-Bromo-4-Pentene; 5-Bromo-1-pentene; 4-Penten-1-yl Bromide 1119-51-3 C5H9Br 详情 详情
(III) 49725 benzyl allyl(4-pentenyl)carbamate C16H21NO2 详情 详情
(IV) 49726 benzyl 2,3,4,7-tetrahydro-1H-azepine-1-carboxylate C14H17NO2 详情 详情
(V) 49727 benzyl 8-oxa-3-azabicyclo[5.1.0]octane-3-carboxylate C14H17NO3 详情 详情
(VI) 49728 benzyl 4-azido-3-hydroxy-1-azepanecarboxylate C14H18N4O3 详情 详情
(VII) 49729 benzyl 4-amino-3-hydroxy-1-azepanecarboxylate C14H20N2O3 详情 详情
(VIII) 23663 (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid;N-Boc-L-leucine C11H21NO4 详情 详情
(IX) 49730 benzyl 4-([(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl]amino)-3-hydroxy-1-azepanecarboxylate C25H39N3O6 详情 详情
(X) 49731 tert-butyl (1S)-1-[[(3-hydroxy-4-azepanyl)amino]carbonyl]-3-methylbutylcarbamate C17H33N3O4 详情 详情
(XI) 49732 2-pyridinesulfonyl chloride C5H4ClNO2S 详情 详情
(XII) 49733 tert-butyl (1S)-1-([[3-hydroxy-1-(2-pyridinylsulfonyl)-4-azepanyl]amino]carbonyl)-3-methylbutylcarbamate C22H36N4O6S 详情 详情
(XIII) 49734 (2S)-2-amino-N-[3-hydroxy-1-(2-pyridinylsulfonyl)-4-azepanyl]-4-methylpentanamide C17H28N4O4S 详情 详情
(XIV) 35339 (2S,6S,9S)-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4,4,7,13,14,14-hexamethyl-3,5-dioxatetracyclo[8.3.1.0(1,9).0(2,6)]tetradeca-7,12-dien-9-ol C25H42O4Si 详情 详情
(XV) 49735 N-[(1S)-1-([[3-hydroxy-1-(2-pyridinylsulfonyl)-4-azepanyl]amino]carbonyl)-3-methylbutyl]-1-benzofuran-2-carboxamide C26H32N4O6S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(V)

Alkylation of benzyl N-allylcarbamate (I) with 5-bromo-1-pentene (II) in the presence of NaH provides the aza diene derivative (III). Cyclization of (III) under olefin metathesis conditions, employing a ruthenium catalyst, gives rise to the tetrahydroazepine (IV). Oxidation of (IV) with m-chloroperbenzoic acid yields epoxide (V), which is subsequently converted into the trans azido alcohol (VI) upon ring opening with NaN3 and NH4Cl. Azide (VI) is reduced to the corresponding amine (VII) by using 1,3-propanedithiol. Acylation of the racemic trans amino alcohol (VII) by N-Boc-L-leucine (VIII) produces a diastereomeric mixture of amides, which are separated by column chromatography. The desired isomer (IX) is then subjected to catalytic hydrogenolysis of the N-carbobenzoxy group to afford azepine (X). Then, acylation of (X) with 3-(2-pyridyl)phenylacetic acid (XI) furnishes amide (XII).

1 Cummings, M.D.; Veber, D.F.; Yamashita, D.; Ru, Y.; Marquis, R.W. Jr.; Thompson, S.K. (SmithKline Beecham Corp.); Protease inhibitors. EP 1158986; WO 0038687 .
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) 49723 benzyl allylcarbamate C11H13NO2 详情 详情
(II) 49724 1-Bromo-4-Pentene; 5-Bromo-1-pentene; 4-Penten-1-yl Bromide 1119-51-3 C5H9Br 详情 详情
(III) 49725 benzyl allyl(4-pentenyl)carbamate C16H21NO2 详情 详情
(IV) 49726 benzyl 2,3,4,7-tetrahydro-1H-azepine-1-carboxylate C14H17NO2 详情 详情
(V) 49727 benzyl 8-oxa-3-azabicyclo[5.1.0]octane-3-carboxylate C14H17NO3 详情 详情
(VI) 57657 benzyl (3S,4S)-4-azido-3-hydroxy-1-azepanecarboxylate C14H18N4O3 详情 详情
(VII) 57658 benzyl (3S,4S)-4-amino-3-hydroxy-1-azepanecarboxylate C14H20N2O3 详情 详情
(VIII) 31819 (2R)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid 16937-99-8 C11H21NO4 详情 详情
(IX) 57659 benzyl (3S,4S)-4-({(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl}amino)-3-hydroxy-1-azepanecarboxylate C25H39N3O6 详情 详情
(X) 57660 tert-butyl (1S)-1-({[(3S,4S)-3-hydroxyazepanyl]amino}carbonyl)-3-methylbutylcarbamate C17H33N3O4 详情 详情
(XI) 50904 2-[3-(2-pyridinyl)phenyl]acetic acid C13H11NO2 详情 详情
(XII) 57661 tert-butyl (1S)-1-{[((3S,4S)-3-hydroxy-1-{2-[3-(2-pyridinyl)phenyl]acetyl}azepanyl)amino]carbonyl}-3-methylbutylcarbamate C30H42N4O5 详情 详情
Extended Information