SB-331750, -Drug Synthesis Database

【结构式】

【药物名称】SB-331750

【化学名称】N-[3-Methyl-1(S)-[N-[3-oxo-1-[2-[3-(2-pyridyl)phenyl]acetyl]perhydroazepin-4(S)-yl]carbamoyl]butyl]-5-[2-(4-morpholinyl)ethoxy]benzofuran-2-carboxamide

【CA登记号】281217-40-1, 281214-55-9 (stereoisomer)

【分子式】C₄₀H₄₇N₅O₇

【分子量】709.84989

【开发单位】GlaxoSmithKline (Originator)

【药理作用】Bone Diseases, Treatment of, Bone Resorption Inhibitors, METABOLIC DRUGS, Treatment of Osteoporosis, Cathepsin K Inhibitors

合成路线1 合成路线2

合成路线1

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

【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

合成路线2

Acidic cleavage of the Boc protecting group of (XII) affords amine (XIII). This is coupled with 5-[2-(morpholin-4-yl)ethoxy]benzofuran-2-carboxylic acid (XIV) using EDC to furnish amide (XV). The azepine 3-hydroxyl group of (XV) is finally oxidized to the target ketone using DMSO in the presence of sulfur trioxide-pyridine complex.

参考文献中间体

【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	分子式	供应商	用于合成
(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
(XIII)	57662	(2S)-2-amino-N-((3S,4S)-3-hydroxy-1-{2-[3-(2-pyridinyl)phenyl]acetyl}azepanyl)-4-methylpentanamide	C₂₅H₃₄N₄O₃	详情	详情
(XIV)	50913	5-[2-(4-morpholinyl)ethoxy]-1-benzofuran-2-carboxylic acid	C₁₅H₁₇NO₅	详情	详情
(XV)	57663	N-((1S)-1-{[((3S,4S)-3-hydroxy-1-{2-[3-(2-pyridinyl)phenyl]acetyl}azepanyl)amino]carbonyl}-3-methylbutyl)-5-[2-(4-morpholinyl)ethoxy]-1-benzofuran-2-carboxamide	C₄₀H₄₉N₅O₇	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)