methyl (2R,3R)-3-[(tert-butoxycarbonyl)amino]-2-(3-cyanobenzyl)butanoate -Drug Synthesis Database

【结构式】

【分子编号】38458

【品名】methyl (2R,3R)-3-[(tert-butoxycarbonyl)amino]-2-(3-cyanobenzyl)butanoate

【CA登记号】

【分子式】C₁₈H₂₄N₂O₄

【分子量】332.39964

【元素组成】C 65.04% H 7.28% N 8.43% O 19.25%

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：(IX)

Protection of methyl (R)-3-aminobutyrate (VI) with di-tert-butyl dicarbonate provided the Boc derivative (VII), which was alkylated with 3-cyanobenzyl bromide (VIII) in the presence of lithium bis(trimethylsilyl)amide at -78 C to afford adduct (IX). Acid deprotection of the Boc group of (IX) yielded amino ester (X). Alternatively, (X) was obtained by protection of methyl 3-aminobutyrate (VI) with benzyl chloroformate, followed by alkylation with 3-cyanobenzyl bromide to give (XI). The carbobenzoxy group of (XI) was then deprotected by hydrogenation over Pd/C. Coupling of amino ester (X) with acid chloride (V) gave rise to amide (XII). Conversion of (XII) to the required amidine was then achieved by treatment with methanolic HCl, followed by reaction of the resulting imidate with ammonia in boiling MeOH. The title compound was isolated after conversion to the trifluoroacetate salt.

参考文献中间体

合成目标

【1】 Gong, Y.; Guertin, K.R.; McGarry, D.G.; Pauls, H.W.; Klein, S.I.; Spada, A.P. (Aventis Pharmaceuticals, Inc.); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. CA 2264556; EP 0931060; WO 9900356 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(V)	38455	3',4'-dimethoxy[1,1'-biphenyl]-4-carbonyl chloride		C₁₅H₁₃ClO₃	详情	详情
(VI)	38456	methyl (3R)-3-aminobutanoate		C₅H₁₁NO₂	详情	详情
(VII)	38457	methyl (3R)-3-[(tert-butoxycarbonyl)amino]butanoate		C₁₀H₁₉NO₄	详情	详情
(VIII)	13244	alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile	28188-41-2	C₈H₆BrN	详情	详情
(IX)	38458	methyl (2R,3R)-3-[(tert-butoxycarbonyl)amino]-2-(3-cyanobenzyl)butanoate		C₁₈H₂₄N₂O₄	详情	详情
(X)	38459	methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate		C₁₃H₁₆N₂O₂	详情	详情
(XI)	38460	methyl (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-(3-cyanobenzyl)butanoate		C₂₁H₂₂N₂O₄	详情	详情
(XII)	38461	methyl (2R,3R)-2-(3-cyanobenzyl)-3-[[(3',4'-dimethoxy[1,1'-biphenyl]-4-yl)carbonyl]amino]butanoate		C₂₈H₂₈N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Methyl (R)-3-aminobutyrate (I) is protected as the N-Boc derivative (II) using di-tert-butyl dicarbonate. Diastereoselective alkylation of the lithium enolate of (II) with 3-cyanobenzyl bromide (III) yields adduct (IV). Deprotection of (IV) is then effected by treatment with trifluoroacetic acid, to afford amino ester (V). Alternatively, aminobutyrate (I) is protected as the N-(benzyloxycarbonyl) derivative (VI), which is then alkylated with 3-cyanobenzyl bromide (III) to give (VII). Catalytic hydrogenolysis of (VII) in the presence of Pd/C yields the target intermediate (V).

参考文献中间体

合成目标

【1】 Guertin, K.R.; Klein, S.I.; Spada, A.P. (Aventis Pharma SA); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. EP 0906094; JP 2000502710; US 6080767; WO 9724118 .
【2】 Gong, Y.; Guertin, K.R.; McGarry, D.G.; Pauls, H.W.; Klein, S.I.; Spada, A.P. (Aventis Pharmaceuticals, Inc.); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. CA 2264556; EP 0931060; WO 9900356 .

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)	38456	methyl (3R)-3-aminobutanoate		C₅H₁₁NO₂	详情	详情
(II)	38457	methyl (3R)-3-[(tert-butoxycarbonyl)amino]butanoate		C₁₀H₁₉NO₄	详情	详情
(III)	13244	alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile	28188-41-2	C₈H₆BrN	详情	详情
(IV)	38458	methyl (2R,3R)-3-[(tert-butoxycarbonyl)amino]-2-(3-cyanobenzyl)butanoate		C₁₈H₂₄N₂O₄	详情	详情
(V)	38459	methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate		C₁₃H₁₆N₂O₂	详情	详情
(VI)	58216	methyl (3R)-3-{[(benzyloxy)carbonyl]amino}butanoate		C₁₃H₁₇NO₄	详情	详情
(VII)	38460	methyl (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-(3-cyanobenzyl)butanoate		C₂₁H₂₂N₂O₄	详情	详情

Extended Information