tert-butyl (1R)-2-amino-1-methyl-2-oxoethylcarbamate -Drug Synthesis Database

【结构式】

【分子编号】46750

【品名】tert-butyl (1R)-2-amino-1-methyl-2-oxoethylcarbamate

【CA登记号】

【分子式】C₈H₁₆N₂O₃

【分子量】188.22672

【元素组成】C 51.05% H 8.57% N 14.88% O 25.5%

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：(XII)

N-Boc-D-Alanine (XI) is converted to the corresponding amide (XII) by reaction with ammonia in the presence of EDC and HOBt. Subsequent treatment of (XII) with Belleau's reagent (2,4-bis(4-phenoxyphenyl)-1,3,2,4-dithiaphosphetane-2,4-disulfide) furnishes thioamide (XIII). S-Alkylation of thioamide (XIII) with ethyl bromopyruvate (XIV) gives intermediate (XV), which is cyclized to thiazole (XVI) upon treatment with trifluoroacetic anhydride and 2,6-lutidine. After saponification of the ester group of (XVI) with LiOH, the resultant acid (XVII) is coupled with tripeptide (X) to provide precursor (XVIII).

参考文献中间体

合成目标

【1】 Ley, S.V.; et al.; Total synthesis of the cyclic heptapeptide argyrin B: A new potent inhibitor of T-cell independent antibody formation. Org Lett 2002, 4, 5, 711.

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)	58834	methyl 2-{[(2S)-2-{[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino}-3-(4-methoxy-1H-indol-3-yl)propanoyl]amino}acetate		C₂₆H₂₉N₅O₅	详情	详情
(XI)	15859	Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid	7764-95-6	C₈H₁₅NO₄	详情	详情
(XII)	46750	tert-butyl (1R)-2-amino-1-methyl-2-oxoethylcarbamate		C₈H₁₆N₂O₃	详情	详情
(XIII)	48364	tert-butyl (1R)-2-amino-1-methyl-2-thioxoethylcarbamate		C₈H₁₆N₂O₂S	详情	详情
(XIV)	25183	ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate	70-23-5	C₅H₇BrO₃	详情	详情
(XV)	58835	ethyl 3-({(2R)-2-[(tert-butoxycarbonyl)amino]propanimidoyl}sulfanyl)-2-oxopropanoate		C₁₃H₂₂N₂O₅S	详情	详情
(XVI)	48366	ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-1,3-thiazole-4-carboxylate		C₁₃H₂₀N₂O₄S	详情	详情
(XVII)	58836	2-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-1,3-thiazole-4-carboxylic acid		C₁₁H₁₆N₂O₄S	详情	详情
(XVIII)	58837	methyl 2-{[(2S)-2-{[(2S)-2-{[(2-{(1R)-1-[(tert-butoxycarbonyl)amino]ethyl}-1,3-thiazol-4-yl)carbonyl]amino}-3-(1H-indol-3-yl)propanoyl]amino}-3-(4-methoxy-1H-indol-3-yl)propanoyl]amino}acetate		C₃₇H₄₃N₇O₈S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

N-Boc-D-alanine (I) was coupled to the resin using diisopropyl carbodiimide and 1-hydroxybenzotriazole to afford resin (II). Subsequent cleavage of the Boc protecting group by means of trifluoroacetic acid provided the D-alanine-bound resin (III). Sequential coupling and deprotection cycles were carried out with the following protected amino acids: N-Boc-L-proline (IV), N-alpha-Boc-N6-isopropyl-N6-carbobenzoxy-L-lysine (VI) and N-Boc-L-leucine (VIII) to afford the respective peptide resins (V), (VII) and (IX). N-alpha-Boc-D-4-(Fmoc-amino)phenylalanine (X) was coupled to (IX), yielding resin (XI). Cleavage of the side-chain Fmoc protecting group with piperidine in DMF gave the aniline derivative (XII). After conversion to the corresponding urea by treatment with tert-butyl isocyanate, the Boc group was cleaved with trifluoroacetic acid to produce resin (XIII).

参考文献中间体

合成目标

【1】 Stalewski, J.; Galyean, R.; Jiang, G.; et al.; GnRH antagonists: A new generation of long acting analogues incorporating p-ureido-phenylalanines at positions 5 and 6. J Med Chem 2001, 44, 3, 453.
【2】 Jiang, G.; Semple, G. (Ferring BV Group Holding); GnRH antagonists being modified in positions 5 and 6. WO 9846634 .

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)	15859	Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid	7764-95-6	C₈H₁₅NO₄	详情	详情
(II)	46750	tert-butyl (1R)-2-amino-1-methyl-2-oxoethylcarbamate		C₈H₁₆N₂O₃	详情	详情
(III)	46751	(2R)-2-aminopropanamide		C₃H₈N₂O	详情	详情
(IV)	16734	(2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid		C₁₀H₁₇NO₄	详情	详情
(V)	46743	(2S)-N-[(1R)-2-amino-1-methyl-2-oxoethyl]-2-pyrrolidinecarboxamide		C₈H₁₅N₃O₂	详情	详情
(VI)	46752	(2S)-6-[[(benzyloxy)carbonyl](isopropyl)amino]-2-[(tert-butoxycarbonyl)amino]hexanoic acid	125323-99-1	C₂₂H₃₄N₂O₆	详情	详情
(VII)	46744	benzyl (5S)-5-amino-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-6-oxohexyl(isopropyl)carbamate		C₂₅H₃₉N₅O₅	详情	详情
(VIII)	23663	(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine		C₁₁H₂₁NO₄	详情	详情
(IX)	46745	benzyl (5S)-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-5-[[(2S)-2-amino-4-methylpentanoyl]amino]-6-oxohexyl(isopropyl)carbamate		C₃₁H₅₀N₆O₆	详情	详情
(X)	46746	(2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]phenyl)propionic acid	173054-11-0	C₂₉H₃₀N₂O₆	详情	详情
(XI)	46747	9H-fluoren-9-ylmethyl 4-[(2R,5S,8S)-8-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-2-[(tert-butoxycarbonyl)amino]-5-isobutyl-13-isopropyl-3,6,14-trioxo-16-phenyl-15-oxa-4,7,13-triazahexadec-1-yl]phenylcarbamate		C₆₀H₇₈N₈O₁₁	详情	详情
(XII)	46748	benzyl (5S,8S,11R)-11-(4-aminobenzyl)-5-[[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]carbonyl]-8-isobutyl-15,15-dimethyl-7,10,13-trioxo-14-oxa-6,9,12-triazahexadec-1-yl(isopropyl)carbamate		C₄₅H₆₈N₈O₉	详情	详情
(XIII)	46749	benzyl (5S)-5-[((2S)-2-[[(2R)-2-amino-3-(4-[[(tert-butylamino)carbonyl]amino]phenyl)propanoyl]amino]-4-methylpentanoyl)amino]-6-[(2S)-2-([[(1R)-2-amino-1-methyl-2-oxoethyl]amino]carbonyl)pyrrolidinyl]-6-oxohexyl(isopropyl)carbamate		C₄₅H₆₉N₉O₈	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

N-Boc-D-alanine (VII) was converted into amide (VIII) via activation as the corresponding mixed anhydride with isobutyl chloroformate. Treatment of amide (VIII) with Lawesson’s reagent gave thioamide (IX). Coupling of (IX) with ethyl bromopyruvate (X) produced the intermediate hydroxythiazoline (XI), which was further dehydrated using trifluoroacetic anhydride to afford the fully protected thiazole amino acid (XII). Removal of the Boc protecting group of (XII) to give (XIII) was achieved by treatment with either trifluoroacetic acid or acetyl chloride in EtOH.

参考文献中间体

合成目标

【1】 Xia, Z.; Smith, C.D.; Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance. J Org Chem 2001, 66, 10, 3459.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	15859	Boc-D-Alanine; (2R)-2-[(tert-butoxycarbonyl)amino]propionic acid	7764-95-6	C₈H₁₅NO₄	详情	详情
(VIII)	46750	tert-butyl (1R)-2-amino-1-methyl-2-oxoethylcarbamate		C₈H₁₆N₂O₃	详情	详情
(IX)	48364	tert-butyl (1R)-2-amino-1-methyl-2-thioxoethylcarbamate		C₈H₁₆N₂O₂S	详情	详情
(X)	25183	ethyl 3-bromo-2-oxopropanoate;ethyl 3-bromopyruvate;Bromopyruvic acid ethyl ester;ethyl 3-bromopyruvate;ethyl bromopyruvate	70-23-5	C₅H₇BrO₃	详情	详情
(XI)	48365	ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-4-hydroxy-4,5-dihydro-1,3-thiazole-4-carboxylate		C₁₃H₂₂N₂O₅S	详情	详情
(XII)	48366	ethyl 2-[(1R)-1-[(tert-butoxycarbonyl)amino]ethyl]-1,3-thiazole-4-carboxylate		C₁₃H₂₀N₂O₄S	详情	详情
(XIII)	48367	ethyl 2-[(1R)-1-aminoethyl]-1,3-thiazole-4-carboxylate		C₈H₁₂N₂O₂S	详情	详情

Extended Information