benzyl (1S)-1-benzyl-3-chloro-2-oxopropylcarbamate -Drug Synthesis Database

【结构式】

【分子编号】37926

【品名】benzyl (1S)-1-benzyl-3-chloro-2-oxopropylcarbamate

【CA登记号】26049-94-5

【分子式】C₁₈H₁₈ClNO₃

【分子量】331.79856

【元素组成】C 65.16% H 5.47% Cl 10.69% N 4.22% O 14.47%

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：(I)

Reduction of N-Cbz-L-phenylalaninyl chloromethyl ketone (I) with NaBH4 provided a 1:3 mixture of diastereoisomeric chlorohydrins (II) and (III), from which the required isomer (III) was isolated by recrystallization from ethyl acetate-hexane. Treatment of (III) with KOH afforded epoxide (IV), which was opened with isobutyl amine (V) in refluxing isopropanol to give amino alcohol (VI). Subsequent coupling of the amino group of (VI) with tert-butyl carbamate (VII) produced urea (VIII). Removal of the carbamate protecting group of (VIII) by hydrogenation over Pd/C and coupling of the free amine (IX) with N-Cbz-L-asparagine (X) yielded amide (XI). Further removal of the Cbz group of (XI) gave rise to amine (XII), which was finally coupled with 2-quinolinecarboxylic acid N-hydroxysuccinimidyl ester (XIII) to furnish the title quinolinecarboxamide.

参考文献中间体

合成目标

【1】 Talley, J.J.; Getman, D.P.; DeCrescenzo, G.A.; Lin, K.-O.; Vazquez, M.L.; Mueller, R.A.; Reed, K.L.; Heintz, R.M.; Clare, M.; Freskos, J.N.; Sun, E.T. (Pharmacia Corp.); Urea-containing hydroxyethylamine cpds. as retroviral protease inhibitors. JP 1995508041; WO 9323368 .
【2】 Clare, M.; DeCrescenzo, G.A.; Freskos, J.N.; Getman, D.P.; Heintz, R.M.; Lin, K.-C.; Mueller, R.A.; Reed, K.L.; Talley, J.J.; Vazquez, M.L.; Sun, E.T.O. (Pharmacia Corp.); Retroviral protease inhibitors. EP 0558630; WO 9208701 .
【3】 Getman, D.P.; et al.; Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere. J Med Chem 1993, 36, 2, 288.

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)	37926	benzyl (1S)-1-benzyl-3-chloro-2-oxopropylcarbamate	26049-94-5	C₁₈H₁₈ClNO₃	详情	详情
(II)	37927	benzyl (1S,2R)-1-benzyl-3-chloro-2-hydroxypropylcarbamate		C₁₈H₂₀ClNO₃	详情	详情
(III)	37928	benzyl (1S,2S)-1-benzyl-3-chloro-2-hydroxypropylcarbamate		C₁₈H₂₀ClNO₃	详情	详情
(IV)	14522	benzyl N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]carbamate		C₁₈H₁₉NO₃	详情	详情
(V)	13306	2-Methyl-1-propanamine; Isobutylamine	78-81-9	C₄H₁₁N	详情	详情
(VI)	37929	benzyl (1S,2R)-1-benzyl-2-hydroxy-3-(isobutylamino)propylcarbamate		C₂₂H₃₀N₂O₃	详情	详情
(VII)	16976	tert-butylisocyanate; tert-butyl isocyanate; 2-isocyanato-2-methylpropane	1609-86-5	C₅H₉NO	详情	详情
(VIII)	37930	benzyl (1S,2R)-1-benzyl-3-[[(tert-butylamino)carbonyl](isobutyl)amino]-2-hydroxypropylcarbamate		C₂₇H₃₉N₃O₄	详情	详情
(IX)	37931	N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N'-(tert-butyl)-N-isobutylurea		C₁₉H₃₃N₃O₂	详情	详情
(X)	14529	(2S)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid	2304-96-3	C₁₂H₁₄N₂O₅	详情	详情
(XI)	37932	benzyl (1S)-3-amino-1-[([(1S,2R)-1-benzyl-3-[[(tert-butylamino)carbonyl](isobutyl)amino]-2-hydroxypropyl]amino)carbonyl]-3-oxopropylcarbamate		C₃₁H₄₅N₅O₆	详情	详情
(XII)	37933	(2S)-2-amino-N(1)-[(1S,2R)-1-benzyl-3-[[(tert-butylamino)carbonyl](isobutyl)amino]-2-hydroxypropyl]butanediamide		C₂₃H₃₉N₅O₄	详情	详情
(XIII)	37934	1-[(2-quinolinylcarbonyl)oxy]-2,5-pyrrolidinedione		C₁₄H₁₀N₂O₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Coupling of piperazine (I) with chloro derivative (II) by means of K2CO3 and KI in acetone affords protected compound (III), which is then condensed with acid chloride (IV) by means of n-BuLi in THF to yield amide (V). Deprotection of (V) by hydrogenation over Pd/C in EtOH provides (VI), which is finally cyclized by treatment with POCl3 in DMF. Alternatively, the synthesis of the target product can be achieved by an analogous route: Acylation of amine (VII) with acid chloride (IV) by means of K2CO3 in CH2Cl2 provides amide (VIII), which is then cyclized by heating with POCl3 in DMF/benzene to give oxazole (IX). Finally, (IX) is condensed with piperazine (I) by means of K2CO3 and KI in acetone.

参考文献中间体

合成目标

【1】 Schechter, L.E.; Smith, D.L.; Nelson, F.C.; Greenblatt, L.P.; Kelly, M.G.; Novel trisubstituted oxazole derivatives as 5-HT1A receptor ligands. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 117.
【2】 Kelly, M.G.; Greenblatt, L.P.; Nelson, F.C. (American Home Products Corp.); Trisubstd. oxazole derivs. as serotonin ligands. US 6242448 .

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)	11882	1-(2-Methoxyphenyl)piperazine; Methyl 2-piperazinophenyl ether; 1-(2-Methoxyphenyl)-piperazine	35386-24-4	C₁₁H₁₆N₂O	详情	详情
(II)	37926	benzyl (1S)-1-benzyl-3-chloro-2-oxopropylcarbamate	26049-94-5	C₁₈H₁₈ClNO₃	详情	详情
(III)	46228	benzyl 1-benzyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxopropylcarbamate		C₂₉H₃₃N₃O₄	详情	详情
(IV)	17220	cyclohexanecarbonyl chloride; Cyclohexanecarboxylic acid chloride	2719-27-9	C₇H₁₁ClO	详情	详情
(V)	46229	benzyl 1-benzyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxopropyl(cyclohexylcarbonyl)carbamate		C₃₆H₄₃N₃O₅	详情	详情
(VI)	46230	N-[1-benzyl-3-[4-(2-methoxyphenyl)-1-piperazinyl]-2-oxopropyl]cyclohexanecarboxamide		C₂₈H₃₇N₃O₃	详情	详情
(VII)	46231	3-amino-1-chloro-4-phenyl-2-butanone		C₁₀H₁₂ClNO	详情	详情
(VIII)	46232	N-(1-benzyl-3-chloro-2-oxopropyl)cyclohexanecarboxamide		C₁₇H₂₂ClNO₂	详情	详情
(IX)	46233	4-benzyl-5-(chloromethyl)-2-cyclohexyl-1,3-oxazole		C₁₇H₂₀ClNO	详情	详情

Extended Information