benzyl allyl(4-pentenyl)carbamate -Drug Synthesis Database

【结构式】

【分子编号】49725

【品名】benzyl allyl(4-pentenyl)carbamate

【CA登记号】

【分子式】C₁₆H₂₁NO₂

【分子量】259.34828

【元素组成】C 74.1% H 8.16% N 5.4% O 12.34%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(III)

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.

参考文献中间体

合成目标

【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：(III)

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).

参考文献中间体

合成目标

【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