tert-butyl (1R)-1-(aminocarbonyl)-3-(methylsulfanyl)propylcarbamate -Drug Synthesis Database

【结构式】

【分子编号】26696

【品名】tert-butyl (1R)-1-(aminocarbonyl)-3-(methylsulfanyl)propylcarbamate

【CA登记号】

【分子式】C₁₀H₂₀N₂O₃S

【分子量】248.34648

【元素组成】C 48.36% H 8.12% N 11.28% O 19.33% S 12.91%

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：(III)

The reaction of D-methionine (I) with tert-butoxycarbonyl anhydride and NaOH in water gives the N-protected compound (II), which is treated with more tert-butoxycarbonyl anhydride and ammonium bicarbonate in pyridine/DMF yielding The N-protected methioninamide (III). The protection of the amide group of (III) with benzyloxycarbonyl chloride and BuLi in THF affords the fully protected methioninamidde (IV), which by reaction with methyl iodide in acetone or acetonitrile gives the dimethylsulfonium iodide (V). The cyclization of (V) by means of DOWEX 2X8-400 (hydroxide form) yields the protected 3-aminopyrrolidinone (VI), which by selective deprotection with HCl followed by acylation with methyl trifluoroacetate and NaHCO3 affords N-[1-(benzyloxycarbonyl)-2-oxopyrrolidin-3(R)-yl]trifluoroacetamide (VII). The reduction of the carbonyl group of (VII) with LiBH4 in THF provides the pyrrolidinol (VIII), which is treated with ethanol and conc. H2SO4 giving the ethyl ether (IX). The condensation of (IX) with the triisopropylsilyl derivative of ethyl 3-methylbutyrate (X) by means of BF3 ethearate in dichloromethane yields the 2-pyrrolidinylbutyrate (XI) as predominant isomer, which is destrifluoroacetylated with K2CO3 in refluxing ethanol/water affording aminopyrrolidine (XII). The cyclization of (XII) by means of tert-butylmagnesium chloride in THF gives a mixture of bicyclic pyrrolidones, from which the chiral isomer (XIII) was separated by crystallization. The mesylation of (XIII) with methanesulfonyl chloride and lithium hexamethyldisylazane in THF affords the sulfonamide (XIV), which is deprotected by hydrogenation with H2 over Pd(OH)2 in ethyl acetate/dioxane giving the bicyclic pyrrolidone (XV), which is finally acylated with 4-(1-piperidinyl)-2(E)-butenoic acid (XVI) by means of HOBT and triethylamine in acetonitrile or oxlayl chloride in dichloromethane.

参考文献中间体

合成目标

【1】 Macdonald, S.J.F.; et al.; A flexible, practical, and stereoselective synthesis of enantiomerically pure trans-5-oxohexahydropyrrolo[3,2-b]pyrroles (pyrrolidine-trans-lactams), a new class of serine protease inhibitors, using acyliminium methodology. J Org Chem 1999, 64, 14, 5166.

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)	26695	D-methionine	348-67-4	C₅H₁₁NO₂S	详情	详情
(II)	26710	(2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid	5241-66-7	C₁₀H₁₉NO₄S	详情	详情
(III)	26696	tert-butyl (1R)-1-(aminocarbonyl)-3-(methylsulfanyl)propylcarbamate		C₁₀H₂₀N₂O₃S	详情	详情
(IV)	26697	benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoylcarbamate		C₁₈H₂₆N₂O₅S	详情	详情
(V)	26698	[(3R)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl](dimethyl)sulfonium iodide		C₁₉H₂₉IN₂O₅S	详情	详情
(VI)	26699	benzyl (3R)-3-[(tert-butoxycarbonyl)amino]-2-oxo-1-pyrrolidinecarboxylate		C₁₇H₂₂N₂O₅	详情	详情
(VII)	26700	benzyl (3R)-2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₁₄H₁₃F₃N₂O₄	详情	详情
(VIII)	26701	benzyl (3R)-2-hydroxy-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₁₄H₁₅F₃N₂O₄	详情	详情
(IX)	26702	benzyl (3R)-2-ethoxy-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₁₆H₁₉F₃N₂O₄	详情	详情
(X)	26703	1-Ethoxy-3-methyl-1-(triisopropylsilyloxy)-1-butene		C₇H₁₃O₂Pr₃Si	详情	详情
(XI)	26704	benzyl (2S,3R)-2-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₂₁H₂₇F₃N₂O₅	详情	详情
(XII)	26705	benzyl (2S,3R)-3-amino-2-[(1S)-1-(ethoxycarbonyl)-2-methylpropyl]-1-pyrrolidinecarboxylate		C₁₉H₂₈N₂O₄	详情	详情
(XIII)	26706	benzyl (3aR,6S)-6-isopropyl-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate		C₁₇H₂₂N₂O₃	详情	详情
(XIV)	26707	benzyl (3aR,6S,6aS)-6-isopropyl-4-(methylsulfonyl)-5-oxohexahydropyrrolo[3,2-b]pyrrole-1(2H)-carboxylate		C₁₈H₂₄N₂O₅S	详情	详情
(XV)	26708	(3S,3aS,6aR)-3-isopropyl-1-(methylsulfonyl)hexahydropyrrolo[3,2-b]pyrrol-2(1H)-one		C₁₀H₁₈N₂O₃S	详情	详情
(XVI)	26709	(E)-4-(1-piperidinyl)-2-butenoic acid；(E)-4-(piperidin-1-yl)but-2-enoic acid		C₉H₁₅NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXIII)

Alternative synthesis of intermediate (XVII) of Scheme 25142902b: In a further procedure, (R)-methionine (XXI), was protected as the Boc derivative (XXII). Subsequent treatment of (XXII) with Boc2O and then with ammonium bicarbonate yielded amide (XXIII), which was condensed with benzyl chloroformate to produce imide (XXIV). The S-alkylation with CH3I yielded sulfonium salt (XXV), which was then cyclized to pyrrolidinone (XXVI) in the presence of Dowex 2x8-400 resin. Acid deprotection of the Boc group of (XXVI), followed by condensation with methyl trifluoroacetate furnished intermediate (XVII) already described in Scheme 25142902b.

参考文献中间体

合成目标

【1】 Dowle, M.D.; Harrison, L.A.; Macdonald, S.J.F.; Inglis, G.G.A.; Johnson, M.R.; Shah, P.; Clarke, G.D.E.; The discovery and synthesis of some bicyclic trans-lactams having potent neutrophil elastase inhibitory properties. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.215.
【2】 Dowle, M.D.; Finch, H.; Harrison, L.A.; Inglis, G.G.A.; Johnson, M.R.; Macdonald, S.J.F.; Shah, P.; Smith, R.A. (Glaxo Wellcome plc); Pyrrolopyrrolone derivs. as inhibitors of neutrophil elastase. EP 0891362; JP 2000507950; US 5994344; WO 9736903 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVII)	26700	benzyl (3R)-2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₁₄H₁₃F₃N₂O₄	详情	详情
(XXI)	26695	D-methionine	348-67-4	C₅H₁₁NO₂S	详情	详情
(XXII)	26710	(2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid	5241-66-7	C₁₀H₁₉NO₄S	详情	详情
(XXIII)	26696	tert-butyl (1R)-1-(aminocarbonyl)-3-(methylsulfanyl)propylcarbamate		C₁₀H₂₀N₂O₃S	详情	详情
(XXIV)	26697	benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoylcarbamate		C₁₈H₂₆N₂O₅S	详情	详情
(XXV)	26698	[(3R)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl](dimethyl)sulfonium iodide		C₁₉H₂₉IN₂O₅S	详情	详情
(XXVI)	26699	benzyl (3R)-3-[(tert-butoxycarbonyl)amino]-2-oxo-1-pyrrolidinecarboxylate		C₁₇H₂₂N₂O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XVI)

The reaction of D-methionine (XIV) with Boc2O in dioxane gives the N-protected methionine (XV), which is treated with Boc2O, pyridine and ammonium bicarbonate to yield the methioninamide (XVI). The reaction of (XVI) with benzyl chloroformate (XVII) by means of BuLi in DMF/pyridine affords the carbamate (XVIII), which is treated with methyl iodide in acetone to provide the sulfonium salt (XIX). The cyclization of (XIX) by means of Dowex 2XB-400 (OH form) in acetonitrile gives the N-protected pyrrolidinone (XX), which is deprotected with HCl in dioxane to yield the amino compound (XXI). Finally, this compound is acylated with methyl trifluoroacetate (XXII) and NMM in dichloromethane to afford the target pyrrolidinone intermediate (XXIII).

参考文献中间体

合成目标

【1】 Dowle, M.D.; Finch, H.; Harrison, L.A.; Inglis, G.G.A.; Johnson, M.R.; Macdonald, S.J.F.; Shah, P.; Smith, R.A. (Glaxo Wellcome plc); Pyrrolopyrrolone derivs. as inhibitors of neutrophil elastase. EP 0891362; JP 2000507950; US 5994344; WO 9736903 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	26695	D-methionine	348-67-4	C₅H₁₁NO₂S	详情	详情
(XV)	26710	(2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butyric acid	5241-66-7	C₁₀H₁₉NO₄S	详情	详情
(XVI)	26696	tert-butyl (1R)-1-(aminocarbonyl)-3-(methylsulfanyl)propylcarbamate		C₁₀H₂₀N₂O₃S	详情	详情
(XVII)	10101	Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene	501-53-1	C₈H₇ClO₂	详情	详情
(XVIII)	26697	benzyl (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoylcarbamate		C₁₈H₂₆N₂O₅S	详情	详情
(XIX)	26698	[(3R)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butoxycarbonyl)amino]-4-oxobutyl](dimethyl)sulfonium iodide		C₁₉H₂₉IN₂O₅S	详情	详情
(XX)	26699	benzyl (3R)-3-[(tert-butoxycarbonyl)amino]-2-oxo-1-pyrrolidinecarboxylate		C₁₇H₂₂N₂O₅	详情	详情
(XXI)	47798	benzyl (3R)-3-amino-2-oxo-1-pyrrolidinecarboxylate		C₁₂H₁₄N₂O₃	详情	详情
(XXII)	47799	Methyl trifluoroacetate; Trifluoroacetic acid methyl ester; methyl 2,2,2-trifluoroacetate	431-47-0	C₃H₃F₃O₂	详情	详情
(XXIII)	26700	benzyl (3R)-2-oxo-3-[(2,2,2-trifluoroacetyl)amino]-1-pyrrolidinecarboxylate		C₁₄H₁₃F₃N₂O₄	详情	详情

Extended Information