benzyl (4R)-5-amino-4-[[(2S)-2-aminopropanoyl]amino]-5-oxopentanoate -Drug Synthesis Database

【结构式】

【分子编号】27130

【品名】benzyl (4R)-5-amino-4-[[(2S)-2-aminopropanoyl]amino]-5-oxopentanoate

【CA登记号】

【分子式】C₁₅H₂₁N₃O₄

【分子量】307.34956

【元素组成】C 58.62% H 6.89% N 13.67% O 20.82%

与该中间体有关的原料药合成路线共 5 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5

合成路线1

该中间体在本合成路线中的序号：(XIV)

Alkylation of the sodium alkoxide of (X) with (S)-2-chloropropionic acid (XI), followed by esterification with diazomethane provided the methyl ester adduct (XII). Alkaline hydrolysis of ester (XII) with KOH yielded carboxylic acid (XIII), which was coupled with the dipeptide amide (XIV) to give the protected disaccharide dipeptide (XV). Subsequent acidic hydrolysis of the ketal functions of (XV) proceeded with concomitant cyclization to the pyranose form (XVI). The O-benzyl protecting groups of (XVI) were finally removed by catalytic hydrogenolysis in the presence of palladium black.

参考文献中间体

合成目标

【1】 Kusumoto, S.; et al.; Synthesis of N-acetyl-beta-D-glucosaminyl-(1-4)-N-acetylmuramyl-L-alanyl-D-isoglutamine. Tetrahedron Lett 1978, 45, 4407.
【2】 Kusumoto, S.; et al.; Chemical synthesis and biological activities of two disaccharide dipeptides corresponding to the repeating units of bacterial peptidoglycan. Bull Chem Soc Jpn 1986, 59, 5, 1411.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(X)	56331	N-{(1R,2R,3S)-3-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-1-(diethoxymethyl)-3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxypropyl}acetamide		C₄₄H₆₀N₂O₁₂	详情	详情
(XI)	56332	(S)-(-)-2-Chloropropionic acid; (S)-2-Chloropropionic acid	29617-66-1	C₃H₅ClO₂	详情	详情
(XII)	56333	methyl (2R)-2-[((1R,2R)-2-(acetylamino)-1-{(S)-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3,3-diethoxypropyl)oxy]propanoate		C₄₈H₆₆N₂O₁₄	详情	详情
(XIII)	56334	(2R)-2-[((1R,2R)-2-(acetylamino)-1-{(S)-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-3,3-diethoxypropyl)oxy]propanoic acid		C₄₇H₆₄N₂O₁₄	详情	详情
(XIV)	27130	benzyl (4R)-5-amino-4-[[(2S)-2-aminopropanoyl]amino]-5-oxopentanoate		C₁₅H₂₁N₃O₄	详情	详情
(XV)	56335	benzyl (5R,6R,8R,11S,14R)-5-(acetylamino)-6-{(S)-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-14-(aminocarbonyl)-4-ethoxy-8,11-dimethyl-9,12-dioxo-3,7-dioxa-10,13-diazaheptadecan-17-oate		C₆₂H₈₃N₅O₁₇	详情	详情
(XVI)	56336	benzyl (4R)-4-({(2S)-2-[((2R)-2-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-5-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-2-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy}propanoyl)amino]propanoyl}amino)-5-amino-5-oxopentanoate		C₅₅H₆₉N₅O₁₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XIV)

Coupling of acid (XXXIII) with the dipeptide amide (XIV) was conducted with DCC and NHS as the activating agents to give the lactoyl-dipeptide derivative (XXXIV). Hydrolytic removal of the isopropylidene ketal provided diol (XXXV). The benzyl groups of (XXXV) were finally removed by hydrogenolysis in the presence of Pd/C to afford the title compound.

参考文献中间体

合成目标

【1】 Kiso, M.; et al.; Synthesis and immunoadjuvant activities of the repeating, disaccharide-dipeptide unit of the bacterial, cell-wall peptidoglycan and of some carbohydrate analogs. Carbohydr Res 1982, 104, 2, 253.
【2】 Kiso, M.; et al.; A general, convenient synthesis of the repeating, disaccharide-dipeptide unit of the bacterial, cell-wall peptidoglycan by the oxazoline method. Carbohydr Res 1980, 83, 1, C8.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	27130	benzyl (4R)-5-amino-4-[[(2S)-2-aminopropanoyl]amino]-5-oxopentanoate	C₁₅H₂₁N₃O₄	详情	详情
(XXXIII)	56350	(2R)-2-({(2R,3S,4R,5R,6S)-3-{[(4aR,6R,7R,8R,8aS)-7-(acetylamino)-8-(benzyloxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy}-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)propanoic acid	C₄₃H₅₄N₂O₁₃	详情	详情
(XXXIV)	56351	benzyl (4R)-4-[((2S)-2-{[(2R)-2-({(2R,3S,4R,5R,6S)-3-{[(4aR,6R,7R,8R,8aS)-7-(acetylamino)-8-(benzyloxy)-2,2-dimethylhexahydropyrano[3,2-d][1,3]dioxin-6-yl]oxy}-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)propanoyl]amino}propanoyl)amino]-5-amino-5-oxopentanoate	C₅₈H₇₃N₅O₁₆	详情	详情
(XXXV)	56352	benzyl (4R)-4-[((2S)-2-{[(2R)-2-({(2S,3R,4R,5S,6R)-3-(acetylamino)-5-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-4-(benzyloxy)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-2-(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)propanoyl]amino}propanoyl)amino]-5-amino-5-oxopentanoate	C₅₅H₆₉N₅O₁₆	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XIV)

Alkylation of (XLVI) with (S)-2-chloropropionic acid (XI) provided the lactic acid derivative (XLVII). This was subsequently coupled with the dipeptide amide (XIV), via activation as the mixed anhydride with isobutyl chloroformate, to give the protected disaccharide dipeptide (XLVIII). Finally, hydrogenolysis of the O-benzyl protecting groups of (XLVIII) in the presence of palladium black led to the title compound.

参考文献中间体

合成目标

【1】 Durette, P.L.; et al.; Synthesis of O-(2-acetamido-2-deoxy-beta-D-glucosyl)-(1--4)-N-acetylmuramoyl-L-alanyl-D-isoglutamine, the repeating disaccharide-dipeptide unit of the bacterial cell-wall peptidoglycan. Carbohydr Res 1979, 77, C1.
【2】 Durette, P.L.; Shen, T.-Y. (Merck & Co., Inc.); Immunologically active peptidyl disaccharides, methods of preparation and vaccine. EP 0018901 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	56332	(S)-(-)-2-Chloropropionic acid; (S)-2-Chloropropionic acid	29617-66-1	C₃H₅ClO₂	详情	详情
(XIV)	27130	benzyl (4R)-5-amino-4-[[(2S)-2-aminopropanoyl]amino]-5-oxopentanoate		C₁₅H₂₁N₃O₄	详情	详情
(XLVI)	56363	N-{(2S,3R,4R,5S,6R)-2-({(2R,3S,4R,5R,6S)-5-(acetylamino)-6-(benzyloxy)-2-[(benzyloxy)methyl]-4-hydroxytetrahydro-2H-pyran-3-yl}oxy)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-3-yl}acetamide		C₅₁H₅₈N₂O₁₁	详情	详情
(XLVII)	56364	(2R)-2-({(2S,3R,4R,5S,6R)-3-(acetylamino)-5-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-2-(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)propanoic acid		C₅₄H₆₂N₂O₁₃	详情	详情
(XLVIII)	56365	benzyl (4R)-4-[((2S)-2-{[(2R)-2-({(2S,3R,4R,5S,6R)-3-(acetylamino)-5-({(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-bis(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-2-yl}oxy)-2-(benzyloxy)-6-[(benzyloxy)methyl]tetrahydro-2H-pyran-4-yl}oxy)propanoyl]amino}propanoyl)amino]-5-amino-5-oxopentanoate		C₆₉H₈₁N₅O₁₆	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XIV)

The disaccharide derivative (XXXVI) was isolated from the enzymatic hydrolysis of the cell walls obtained from cultures of Micrococcus lysodeikticus. Condensation of (XXXVI) with L-alanyl-D-isoglutamine benzyl ester (XIV), by means of N-ethyl-5-phenylisoxazolium-3'-sulfonate (NEPIS, Woodward's reagent K) as the coupling reagent, furnished amide (XLIX). The benzyl ester group of (XLIX) was finally cleaved by hydrogenolysis over Pd/C.

参考文献中间体

合成目标

【1】 Vosika, G.J.; Cornelius, D.A.; Bennek, J.A.; Swenson, K.E.; Gilbert, C.W. (DOR BioPharma, Inc.); Compsn. for macrophage activation. US 5416070; WO 9116347 .
【2】 Vosika, G.J.; Ma, F. (DOR BioPharma, Inc.); Preparation of glucosaminyl muramic acid derivs.. WO 9712894 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIV)	27130	benzyl (4R)-5-amino-4-[[(2S)-2-aminopropanoyl]amino]-5-oxopentanoate	C₁₅H₂₁N₃O₄	详情	详情
(XXXVI)	56354	2,3,4,5,6-pentafluorophenyl (2R)-2-{[(3R,4R,5S,6R)-3-(acetylamino)-5-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-2-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy}propanoate	C₂₅H₃₁F₅N₂O₁₃	详情	详情
(XLIX)	56366	benzyl (4R)-4-({(2S)-2-[((2R)-2-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-5-{[(2S,3R,4R,5S,6R)-3-(acetylamino)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl]oxy}-2-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]oxy}propanoyl)amino]propanoyl}amino)-5-amino-5-oxopentanoate	C₃₄H₅₁N₅O₁₆	详情	详情

合成路线5

该中间体在本合成路线中的序号：(V)

The reaction of phthalimidocarboxylic acid ethyl ester (I) with 2-(2-aminoethoxy)ethanol (II) in THF gives N-[2-(2-hydroxyethoxy)ethyl]phthalimide (III), which is oxidized with CrO3/sulfuric acid in acetone yielding 2-(phthalimidoethoxy)acetic acid (IV). The condensation of (IV) with L-alanyl-D-isoglutamine benzyl ester (V) by means of phenylphosphoryl azide (DPPA) and triethylamine in DMF gives N-[2-(2-phthalimidoethoxy)acetyl]-L-alanyl-D-isoglutamine benzyl ester (VI), which is finally debenzylated by hydrogenation over Pd/C in acetic acid.

参考文献中间体

合成目标

【1】 Urleb, U.; et al.; Synthesis of phthalimido-desmuramylpeptide analogues as potential immunomodulating agents. Arch Pharm 1995, 328, 2, 113.
【2】 Pecar, S.; Sollner, M.; Urleb, U.; Kikelj, D.; Marc, G.; Krbavcic, A.; Kotnik, V.; Wraber-Herzog, B.; Simcic, S.; Ihan, A.; Klamfer, L.; Provsic, L.; Kopitar, Z.; Stalc, A. (LEK Pharmaceutical and Chemical Co.; University of Ljubljana); Novel N-acyldipeptides, processes for the preparation thereof and pharmaceutical compsns. containing the same. EP 0477912; JP 1994220087 .

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)	10283	ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide	22509-74-6	C₁₁H₉NO₄	详情	详情
(II)	19029	2-(2-aminoethoxy)-1-ethanol	929-06-6	C₄H₁₁NO₂	详情	详情
(III)	27128	2-[2-(2-hydroxyethoxy)ethyl]-1H-isoindole-1,3(2H)-dione		C₁₂H₁₃NO₄	详情	详情
(IV)	27129	2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]acetic acid		C₁₂H₁₁NO₅	详情	详情
(V)	27130	benzyl (4R)-5-amino-4-[[(2S)-2-aminopropanoyl]amino]-5-oxopentanoate		C₁₅H₂₁N₃O₄	详情	详情
(VI)	27131	benzyl (4R)-5-amino-4-[[(2S)-2-([2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethoxy]acetyl]oxy)propanoyl]amino]-5-oxopentanoate		C₂₇H₂₉N₃O₉	详情	详情

Extended Information