benzyl N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]carbamate -Drug Synthesis Database

【结构式】

【分子编号】14522

【品名】benzyl N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]carbamate

【CA登记号】

【分子式】C₁₈H₁₉NO₃

【分子量】297.3538

【元素组成】C 72.71% H 6.44% N 4.71% O 16.14%

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：(Xa)

Various new routes for the large-scale synthesis of Ro-31-8959 have been described: 1) The condensation of N-protected-L-phenylalanine (I) with the Mg salt of malonic acid monoethyl ester (II) gives the keto ester (III), which is enantioselectively reduced with NaBH4 to yield the hydroxy ester (IV). The reaction of (IV) with 2,2-dimethoxypropane (V) by means of p-toluenesulfonic acid affords the oxazolidine (VI), which is hydrolyzed with NaOH in ethanol/water to the corresponding acid (VII). The treatment of (VII) with oxalyl chloride, mercaptopyridine-N-oxide (MPO) and bromotrichloromethane affords the bromomethyloxazolidine (VIII), which, without isolation, is treated with acetic acid to give the N-protected 3(S)-amino-2-bromo-4-phenyl-2(S)-butanol (IX). The reaction of (IX) with KOH in methanol yields the epoxide (X), which is condensed with (3S,4aS,8aS)-N-tert-butyldecahydroisoquinoline-3-carboxamide (XI), yielding the protected condensation product (XII). The deprotection of the amino group of (XII) by hydrogenation with H2 over Pd/C affords the amino derivative (XIII), which is condensed with N-benzyloxycarbonyl-asparagine (XIV) in the usual way, giving the protected peptide (XV). The deprotection of (XV) as before yields compound (XVI), with a free amino group that is finally condensed with quinoline-2-carboxylic acid (XVII) by means of dicyclohexylcarbodiimide and hydroxybenzotriazole.

参考文献中间体

合成目标

【1】 Parkes, K.E.B.; Bushnell, D.J.; Crackett, P.H.; et al.; Studies toward the large-scale synthesis of the HIV proteinase inhibitor Ro 31-8959. J Org Chem 1994, 59, 13, 3656.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(Va)	10722	1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane	77-76-9	C₅H₁₂O₂	详情	详情
(Ib)	12874	(2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine	13734-34-4	C₁₄H₁₉NO₄	详情	详情
(IIIb)	12876	ethyl (4S)-4-[(tert-butoxycarbonyl)amino]-3-oxo-5-phenylpentanoate		C₁₈H₂₅NO₅	详情	详情
(Ia)	14505	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropionic acid; N-Carbobenzyloxy-L-phenylalanine; N-Cbz-L-Phenylalanine	1161-13-3	C₁₇H₁₇NO₄	详情	详情
(IIIa)	14508	ethyl (4S)-4-[[(benzyloxy)carbonyl]amino]-3-oxo-5-phenylpentanoate		C₂₁H₂₃NO₅	详情	详情
(IVa)	14510	ethyl (3R,4S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-phenylpentanoate		C₂₁H₂₅NO₅	详情	详情
(VIa)	14514	benzyl (4S,5R)-4-benzyl-5-(2-ethoxy-2-oxoethyl)-2,2-dimethyl-1,3-oxazolane-3-carboxylate		C₂₄H₂₉NO₅	详情	详情
(VIb)	14515	ethyl 2-[(4S,5R)-4-benzyl-3-[(2,2-dimethylpropanoyl)oxy]-2,2-dimethyl-1,3-oxazolan-5-yl]acetate		C₂₁H₃₁NO₅	详情	详情
(VIIa)	14516	2-[(4S,5R)-4-benzyl-3-[(benzyloxy)carbonyl]-2,2-dimethyl-1,3-oxazolan-5-yl]acetic acid		C₂₂H₂₅NO₅	详情	详情
(VIIb)	14517	2-[(4S,5R)-4-benzyl-3-[(2,2-dimethylpropanoyl)oxy]-2,2-dimethyl-1,3-oxazolan-5-yl]acetic acid		C₁₉H₂₇NO₅	详情	详情
(VIIIa)	14518	benzyl (4S,5S)-4-benzyl-5-(bromomethyl)-2,2-dimethyl-1,3-oxazolane-3-carboxylate		C₂₁H₂₄BrNO₃	详情	详情
(VIIIb)	14519	(4S,5S)-4-benzyl-5-(bromomethyl)-3-[(2,2-dimethylpropanoyl)oxy]-2,2-dimethyl-1,3-oxazolane		C₁₈H₂₆BrNO₃	详情	详情
(IXa)	14520	benzyl N-[(1S,2S)-1-benzyl-3-bromo-2-hydroxypropyl]carbamate		C₁₈H₂₀BrNO₃	详情	详情
(IXb)	14521	(2S,3S)-1-bromo-3-[[(2,2-dimethylpropanoyl)oxy]amino]-4-phenyl-2-butanol		C₁₅H₂₂BrNO₃	详情	详情
(Xa)	14522	benzyl N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]carbamate		C₁₈H₁₉NO₃	详情	详情
(XIIa)	14526	benzyl (1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropylcarbamate		C₃₂H₄₅N₃O₄	详情	详情
(XIIb)	14527	(3S,4aS,8aS)-N-(tert-butyl)-2-((2R,3S)-3-[[(2,2-dimethylpropanoyl)oxy]amino]-2-hydroxy-4-phenylbutyl)decahydro-3-isoquinolinecarboxamide		C₂₉H₄₇N₃O₄	详情	详情
(IXb)	19730	tert-butyl (1S)-1-[(2S)oxiranyl]-2-phenylethylcarbamate	98737-29-2	C₁₅H₂₁NO₃	详情	详情
(IVb)	25725	2-[(4S,5R)-4-benzyl-3-(tert-butoxycarbonyl)-1,3-oxazolidin-5-yl]acetic acid		C₁₇H₂₃NO₅	详情	详情
(II)	14507	Malonic acid monoethyl ester magnesium salt		C₅H₆MgO₄	详情	详情
(XI)	13955	(3S,4aS,8aS)-N-(tert-Butyl)decahydro-3-isoquinolinecarboxamide		C₁₄H₂₆N₂O	详情	详情
(XIII)	14528	(3S,4aS,8aS)-2-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(tert-butyl)decahydro-3-isoquinolinecarboxamide		C₂₄H₃₉N₃O₂	详情	详情
(XIV)	14529	(2S)-4-amino-2-[[(benzyloxy)carbonyl]amino]-4-oxobutyric acid	2304-96-3	C₁₂H₁₄N₂O₅	详情	详情
(XV)	14530	benzyl (1S)-1-[([(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]amino)carbonyl]-3-amino-3-oxopropylcarbamate		C₃₆H₅₁N₅O₆	详情	详情
(XVI)	14531	(2S)-N(1)-[(1S,2R)-3-[(3S,4aS,8aS)-3-[(tert-butylamino)carbonyl]octahydro-2(1H)-isoquinolinyl]-1-benzyl-2-hydroxypropyl]-2-aminobutanediamide		C₂₈H₄₅N₅O₄	详情	详情
(XVII)	14532	2-Quinolinecarboxylic acid; Quinaldic Acid	93-10-7	C₁₀H₇NO₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

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3

该中间体在本合成路线中的序号：(I)

Intermediate (III) was prepared by condensation of epoxide (I) with piperazine (II). After removal of the carbobenzoxy protecting group of (III) by catalytic hydrogenation, the resulting amine (IV) was coupled to the valine derivative (V) using EDC to afford amide (VI). Subsequent cleavage of the Boc protecting group of (VI) under acidic conditions gave (VII), which was finally alkylated with the benzodioxolylmethyl halide (VIII) to provide the target compound.

参考文献中间体

合成目标

【1】 Chen, X.; Kempf, D.J.; Sham, H.L.; Green, B.E.; Molla, A.; Korneyeva, M.; Vasavanonda, S.; Wideburg, N.E.; Saldivar, A.; Marsh, K.C.; McDonald, E.; Norbeck, D.W.; Potent piperazine hydroxyethylamine HIV protease inhibitors containing novel P3 ligands. Bioorg Med Chem Lett 1998, 8, 24, 3531.
【2】 Chen, X.; Mohammadi, F.; Norbeck, D.W.; Kempf, D.J. (Abbott Laboratories Inc.); Retroviral protease inhibiting cpds.. WO 9959994 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	14522	benzyl N-[(1S)-1-[(2S)oxiranyl]-2-phenylethyl]carbamate	C₁₈H₁₉NO₃	详情	详情
(II)	16422	methyl (1R,4S)-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate	C₈H₁₁NO₂	详情	详情
(III)	30251	tert-butyl (3S)-4-((2R,3S)-3-[[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl)-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate	C₃₂H₄₆N₄O₆	详情	详情
(IV)	30252	tert-butyl (3S)-4-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-3-[(tert-butylamino)carbonyl]-1-piperazinecarboxylate	C₂₄H₄₀N₄O₄	详情	详情
(V)	30255	(2S)-2-([[(2-isopropyl-1,3-thiazol-4-yl)methoxy]carbonyl]amino)-3-methylbutyric acid	C₁₃H₂₀N₂O₄S	详情	详情
(VI)	30253	tert-butyl (3S)-3-[(tert-butylamino)carbonyl]-4-((2R,3S)-2-hydroxy-3-[[(2S)-2-([[(2-isopropyl-1,3-thiazol-4-yl)methoxy]carbonyl]amino)-3-methylbutanoyl]amino]-4-phenylbutyl)-1-piperazinecarboxylate	C₃₇H₅₈N₆O₇S	详情	详情
(VII)	30254	(2-isopropyl-1,3-thiazol-4-yl)methyl (1S)-1-[[((1S,2R)-1-benzyl-3-[(2S)-2-[(tert-butylamino)carbonyl]piperazinyl]-2-hydroxypropyl)amino]carbonyl]-2-methylpropylcarbamate	C₃₂H₅₀N₆O₅S	详情	详情
(VIII)	28617	5-(chloromethyl)-1,3-benzodioxole	C₈H₇ClO₂	详情	详情

Extended Information