tert-butyl (2S)-2-aminopropanoate -Drug Synthesis Database

【结构式】

【分子编号】29385

【品名】tert-butyl (2S)-2-aminopropanoate

【CA登记号】

【分子式】C₇H₁₅NO₂

【分子量】145.20164

【元素组成】C 57.9% H 10.41% N 9.65% O 22.04%

与该中间体有关的原料药合成路线共 4 条

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

该中间体在本合成路线中的序号：(I)

The condensation of alanine tert-butyl ester (I) with ethyl 2-bromo-4-phenylbutanoate (II) by means of triethylamine in hot DMF gives ethyl 2-[[1-(tert-butoxycarbonyl)ethyl]amino]-4-phenylbutanoate (III), which is partially hydrolyzed with trifluoroacetic acid yielding ethyl 2-[[1-carboxyethyl]amino]-4-phenylbutanoate (IV). The condensation of (IV) with benzyl 1,2,3,4-tetrahydroisoquinoline-3-carboxylate (V) [prepared from the corresponding acid (VI) and benzyl alcohol (A) by means of polyphosphoric acid] by means of triethylamine and 1-hydroxybenzotriazole affords benzyl 2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (VII), which is finally debenzylated by hydrogenolysis with H2 over Pd/C in THF.

参考文献中间体

合成目标

【1】 Hoefle, M.L.; Klutchko, S. (Pfizer Inc.); Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids. DD 201787; EP 0049605; EP 0096157; US 4344949 .
【2】 Castaner, J.; Serradell, M.N.; Blancafort, P.; CI-906. Drugs Fut 1983, 8, 12, 1014.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	18710	Benzyl alcohol; Phenylmethanol	100-51-6	C₇H₈O	详情	详情
(I)	29385	tert-butyl (2S)-2-aminopropanoate		C₇H₁₅NO₂	详情	详情
(II)	20810	ethyl 2-bromo-4-phenylbutanoate		C₁₂H₁₅BrO₂	详情	详情
(III)	31121	ethyl 2-[[(1S)-2-(tert-butoxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate		C₁₉H₂₉NO₄	详情	详情
(IV)	31124	(2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid		C₁₅H₂₁NO₄	详情	详情
(V)	31122	benzyl 1,2,3,4-tetrahydro-3-isoquinolinecarboxylate		C₁₇H₁₇NO₂	详情	详情
(VI)	13953	(3S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid; (S)-(-)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid	74163-81-8	C₁₀H₁₁NO₂	详情	详情
(VII)	31123	benzyl 2-((2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate		C₃₂H₃₆N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The condensation of alanine tert-butyl ester (I) with ethyl 2-bromo-4-phenylbutanoate (II) by means of triethylamine in hot DMF gives ethyl 2-[[1-(tert-butoxycarbonyl)ethyl]amino]-4-phenylbutanoate (III), which is partially hydrolyzed with trifluoroacetic acid yielding ethyl 2-[[1-carboxyethyl]amino]-4-phenylbutanoate (IV). The condensation of (IV) with tert-butyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (VIII) [prepared from the corresponding acid (VI) and isobutylene (B) by means of H2SO4] as before gives tert-butyl-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (IX), which is finally hydrolyzed partially by treatment with trifluoroacetic acid.

参考文献中间体

合成目标

【1】 Hoefle, M.L.; Klutchko, S. (Pfizer Inc.); Substituted acyl derivatives of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acids. DD 201787; EP 0049605; EP 0096157; US 4344949 .
【2】 Castaner, J.; Serradell, M.N.; Blancafort, P.; CI-906. Drugs Fut 1983, 8, 12, 1014.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	15926	2-methyl-1-propene; isobutylene	115-11-7	C₄H₈	详情	详情
(I)	29385	tert-butyl (2S)-2-aminopropanoate		C₇H₁₅NO₂	详情	详情
(II)	20810	ethyl 2-bromo-4-phenylbutanoate		C₁₂H₁₅BrO₂	详情	详情
(III)	31121	ethyl 2-[[(1S)-2-(tert-butoxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate		C₁₉H₂₉NO₄	详情	详情
(IV)	31124	(2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid		C₁₅H₂₁NO₄	详情	详情
(VI)	13953	(3S)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid; (S)-(-)-1,2,3,4-Tetrahydro-3-isoquinolinecarboxylic acid	74163-81-8	C₁₀H₁₁NO₂	详情	详情
(VIII)	31125	tert-butyl 1,2,3,4-tetrahydro-3-isoquinolinecarboxylate		C₁₄H₁₉NO₂	详情	详情
(IX)	31126	tert-butyl 2-((2S)-2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]propanoyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate		C₂₉H₃₈N₂O₅	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XV)

The compound was also prepared by solution-phase synthesis. Treatment of O-tert-butyl-D-serine (XIII) with isobutyl chloroformate (XII) produced carbamate (XIV). Subsequent coupling of (XIV) with L-alanine tert-butyl ester (XV) by means of EDC and HOBt yielded the protected dipeptide (XVI). Deprotection of both tert-butyl groups of (XVI) with trifluoroacetic acid produced dipeptide (XVII), which was coupled to nitro-L-arginine ethyl aminal (XVIII) to furnish tripeptide (XIX). Hydrogenolysis of the nitro group of (XIX) over Pd/C gave (XX). The ethyl acetal of (XX) was finally hydrolyzed in 3M HCl to yield the title compound.

参考文献中间体

合成目标

【1】 Cohen, C.R.; Weinhouse, M.I.; Roberts, C.; et al.; Synthesis and biological activity of transition-state urokinase inhibitors. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 090.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	13423	1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate	543-27-1	C₅H₉ClO₂	详情	详情
(XIII)	29383	(2R)-2-amino-3-(tert-butoxy)propionic acid		C₇H₁₅NO₃	详情	详情
(XIV)	29384	(2R)-3-(tert-butoxy)-2-[(isobutoxycarbonyl)amino]propionic acid		C₁₂H₂₃NO₅	详情	详情
(XV)	29385	tert-butyl (2S)-2-aminopropanoate		C₇H₁₅NO₂	详情	详情
(XVI)	29386	tert-butyl (2S)-2-([(2R)-3-(tert-butoxy)-2-[(isobutoxycarbonyl)amino]propanoyl]amino)propanoate		C₁₉H₃₆N₂O₆	详情	详情
(XVII)	29387	(2S)-2-([(2R)-3-hydroxy-2-[(isobutoxycarbonyl)amino]propanoyl]amino)propionic acid		C₁₁H₂₀N₂O₆	详情	详情
(XVIII)	29388	3(S)-Amino-2-ethoxy-N2-nitropiperidine-1-carboxamidine		C₈H₁₇N₅O₃	详情	详情
(XIX)	29389	Isobutoxycarbinyl-D-seryl-L-alanine 1-[2-ethoxy-1-(N2-nitroamidino)piperidin-3(S)-ylamide		C₁₉H₃₅N₇O₈	详情	详情
(XX)	29390	isobutyl (1R)-2-[[(1S)-2-([(3S)-1-[amino(imino)methyl]-2-ethoxypiperidinyl]amino)-1-methyl-2-oxoethyl]amino]-1-(hydroxymethyl)-2-oxoethylcarbamate		C₁₉H₃₆N₆O₆	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XI)

Acylation of O-t-butyl-D-serine methyl ester (VII) with sulfonyl chloride (VIII) yields sulfonamide (IX). After saponification of the methyl ester group of (IX) employing LiOH, the resultant carboxylic acid (X) is coupled to L-alanine t-butyl ester (XI) to furnish the sulfonyl dipeptide (XII). Acidic cleavage of the t-butyl ester group of (XII) gives rise to the carboxylic acid (XIII). This is then coupled to the benzylic amine (VI) to afford amide (XIV). Finally, the N-Boc protecting groups of (XIV) are removed by treatment with trifluoroacetic acid in CH2Cl2. (1,2)

参考文献中间体

合成目标

【1】 Tamiz, A.P.; Weinhouse, M.I.; Ahn, J.S.; Alfaro-Lopez, J.; Gaudette, J.; Meneses, J.K.; Roberts, C.; Madison, E.L.; Semple, J.E.; Levy, O.E..; Synthesis and biological activity of non-transition state urokinase inhibitors. 28th Natl Med Chem Symp (June 8 2002, San Diego) 2002, Abst 59.
【2】 Semple, J.E.; Levy, O.E.; Tamiz, A.P.; Madison, E.L.; Weinhouse, M.I. (Corvas International, Inc.); Non-covalent inhibitors of urokinase and blood vessel formation. EP 1182207; WO 0214349 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	64374	tert-butyl {[4-(aminomethyl)phenyl]imino}[(tert-butoxycarbonyl)amino]methylcarbamate	C₁₈H₂₈N₄O₄	详情	详情
(VII)	64375	methyl (2R)-2-amino-3-(tert-butoxy)propanoate	C₈H₁₇NO₃	详情	详情
(VIII)	64376	(4-bromophenyl)methanesulfonyl chloride	C₇H₆BrClO₂S	详情	详情
(IX)	64377	methyl (2R)-2-{[(4-bromobenzyl)sulfonyl]amino}-3-(tert-butoxy)propanoate	C₁₅H₂₂BrNO₅S	详情	详情
(X)	64378	(2R)-2-{[(4-bromobenzyl)sulfonyl]amino}-3-(tert-butoxy)propanoic acid	C₁₄H₂₀BrNO₅S	详情	详情
(XI)	29385	tert-butyl (2S)-2-aminopropanoate	C₇H₁₅NO₂	详情	详情
(XII)	64379	tert-butyl (2S)-2-{[(2R)-2-{[(4-bromobenzyl)sulfonyl]amino}-3-(tert-butoxy)propanoyl]amino}propanoate	C₂₁H₃₃BrN₂O₆S	详情	详情
(XIII)	64380	(2S)-2-[((2R)-2-{[(4-bromobenzyl)sulfonyl]amino}-3-hydroxypropanoyl)amino]propanoic acid	C₁₃H₁₇BrN₂O₆S	详情	详情
(XIV)	64381	tert-butyl ({4-[(4S,7R)-10-(4-bromophenyl)-7-(hydroxymethyl)-4-methyl-3,6,9,9-tetraoxo-9lambda~6~-thia-2,5,8-triazadec-1-yl]phenyl}imino)[(tert-butoxycarbonyl)amino]methylcarbamate	C₃₁H₄₃BrN₆O₉S	详情	详情

Extended Information