tert-butyl (4R)-4-[[(benzyloxy)carbonyl]amino]-4-cyanobutanoate -Drug Synthesis Database

【结构式】

【分子编号】41356

【品名】tert-butyl (4R)-4-[[(benzyloxy)carbonyl]amino]-4-cyanobutanoate

【CA登记号】

【分子式】C₁₇H₂₂N₂O₄

【分子量】318.37276

【元素组成】C 64.13% H 6.97% N 8.8% O 20.1%

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：(XVII)

N-(Benzyloxycarbonyl)-D-glutamic acid (XIV) was converted to the mixed anhydride (XV) with isobutyl chloroformate and then treated with ammonia to give amide (XVI). Dehydration of the amide with POCl3/pyridine produced nitrile (XVII) and further dipolar cycloaddition of NaN3 produced the tetrazole (XVIII). After hydrogenolysis of the benzyloxycarbonyl protecting group of (XVIII), the resulting amine (XIX) was coupled with N-(benzyloxycarbonyl)-L-glutamic acid (XX) via activation as the mixed anhydride with isobutyl chloroformate to give (XXI). The benzyloxycarbonyl group of (XXI) was then deprotected by catalytic hydrogenolysis over Pd/C as above, yielding amine (XXII). This was coupled with the intermediate benzoic acid derivative (XIII) employing benzotriazolyloxy-tris(pyrrolidino)phosphonium hexafluorophosphate to furnish amide (XXIII). The tert-butyl esters of (XXIII) were finally cleaved by treatment with trifluoroacetic acid.

参考文献中间体

合成目标

【1】 Bavetsias, V.; Boyle, F.T.; Hennequin, L.F.A.; Marriott, J.H. (AstraZeneca plc; BTG plc); Anti-cancer cpds. containing cyclopentaquinazoline ring. EP 0758328; GB 2290082; JP 1997512812; US 5747499; WO 9530673 .
【2】 Jackman, A.L.; Melin, C.; Bavetsias, V.; Matusiak, Z.S.; Marriott, J.H.; Kimbel, C.; Boyle, F.T.; Design and synthesis of cyclopenta[g]quinazoline-based antifolates as inhibitors of thymidylate synthase and potential antitumor agents. J Med Chem 2000, 43, 10, 1910.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIII)	41349	4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoic acid		C₂₂H₁₉N₃O₃	详情	详情
(XIV)	41353	(2R)-2-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoic acid	3886-08-6	C₁₇H₂₃NO₆	详情	详情
(XV)	41354			C₂₂H₃₁NO₈	详情	详情
(XVI)	41355	tert-butyl (4R)-5-amino-4-[[(benzyloxy)carbonyl]amino]-5-oxopentanoate		C₁₇H₂₄N₂O₅	详情	详情
(XVII)	41356	tert-butyl (4R)-4-[[(benzyloxy)carbonyl]amino]-4-cyanobutanoate		C₁₇H₂₂N₂O₄	详情	详情
(XVIII)	41357	tert-butyl (4R)-4-[[(benzyloxy)carbonyl]amino]-4-(1H-1,2,3,4-tetraazol-5-yl)butanoate		C₁₇H₂₃N₅O₄	详情	详情
(XIX)	41358	tert-butyl (4R)-4-amino-4-(1H-1,2,3,4-tetraazol-5-yl)butanoate		C₉H₁₇N₅O₂	详情	详情
(XX)	41359	(4S)-4-[[(benzyloxy)carbonyl]amino]-5-(tert-butoxy)-5-oxopentanoic acid		C₁₇H₂₃NO₆	详情	详情
(XXI)	41360	tert-butyl (2S)-2-[[(benzyloxy)carbonyl]amino]-5-[[(1R)-4-(tert-butoxy)-4-oxo-1-(1H-1,2,3,4-tetraazol-5-yl)butyl]amino]-5-oxopentanoate		C₂₆H₃₈N₆O₇	详情	详情
(XXII)	41361	tert-butyl (2S)-2-amino-5-[[(1R)-4-(tert-butoxy)-4-oxo-1-(1H-1,2,3,4-tetraazol-5-yl)butyl]amino]-5-oxopentanoate		C₁₈H₃₂N₆O₅	详情	详情
(XXIII)	41362	tert-butyl (2S)-5-[[(1R)-4-(tert-butoxy)-4-oxo-1-(1H-1,2,3,4-tetraazol-5-yl)butyl]amino]-2-([4-[(2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-cyclopenta[g]quinazolin-6-yl)(2-propynyl)amino]benzoyl]amino)-5-oxopentanoate		C₄₀H₄₉N₉O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XI)

The selective monobenzylation of the hydroxysuccinic acid (I) with trifluoroacetic anhydride and benzyl alcohol gives the monoester (II), which is esterified again with 4-methoxybenzyl chloride (PMB-Cl) and K2CO3 in hot DMF yielding the asymetric diester (III). The reaction of (III) with trifluoromethanesulfonic anhydride, CH3SNa and 15-crown-5 affords the methylsulfanyl derivative (IV), which is selectively debenzylated to give the hemiester (V). The condensation of (V) with the intermediate aminomethyl amide (VI) by means of EDAC and HOBT yields the expected amide (VII), which is oxidized with MCPBA or Oxone to afford the methylsulfanyl derivative (VIIIa-b). Unfortunately, during the preceding oxidation, during a variety of conditions, inevitably lead to epimerization of the stereocenter bearing the methylsulfonyl group. Finally (VIIIa-b) is deprotected by hydrogenolysis with Pd/C and formic acid in methanol. The intermediate aminomethyl amide (VI) has been obtained by condensation of N-benzyloxycarbonyl-L-alanine (X) with glycinamide (IX) by means of CDI and TEA in THF to give the dipeptide (XI), which is submitted to an acidic Hofmann rearrangement using I,I-bis(trifluoroacetoxy)iodobenzene (PIFA) yielding the desired aminomethyl amide (VI).

参考文献中间体

合成目标

【1】 Sutton, A.E.; Clardy, J.; The total synthesis of pantocin B. Org Lett 2000, 2, 3, 319.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIIIa)	41533	benzyl (5S,12S)-5-methyl-12-(methylsulfonyl)-3,6,10-trioxo-1-phenyl-2-oxa-4,7,9-triazatridecan-13-oate		C₂₄H₂₉N₃O₈S	详情	详情
(VIIIb)	41534	benzyl (5S,12R)-5-methyl-12-(methylsulfonyl)-3,6,10-trioxo-1-phenyl-2-oxa-4,7,9-triazatridecan-13-oate		C₂₄H₂₉N₃O₈S	详情	详情
(I)	11058	(S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid	97-67-6	C₄H₆O₅	详情	详情
(II)	41527	(3S)-4-(benzyloxy)-3-hydroxy-4-oxobutyric acid		C₁₁H₁₂O₅	详情	详情
(III)	41528	1-benzyl 4-(4-methoxybenzyl) (2S)-2-hydroxybutanedioate		C₁₉H₂₀O₆	详情	详情
(IV)	41529	1-benzyl 4-(4-methoxybenzyl) (2R)-2-(methylsulfanyl)butanedioate		C₂₀H₂₂O₅S	详情	详情
(V)	41530	(3R)-4-(benzyloxy)-3-(methylsulfanyl)-4-oxobutyric acid		C₁₂H₁₄O₄S	详情	详情
(VI)	41531	benzyl (1S)-2-[(aminomethyl)amino]-1-methyl-2-oxoethylcarbamate		C₁₂H₁₇N₃O₃	详情	详情
(VII)	41532	benzyl (5S,12R)-5-methyl-12-(methylsulfanyl)-3,6,10-trioxo-1-phenyl-2-oxa-4,7,9-triazatridecan-13-oate		C₂₄H₂₉N₃O₆S	详情	详情
(IX)	61209	CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine		C₁₁H₁₃NO₄	详情	详情
(X)	41435	N'-[3-(tert-butyl)-5-methoxy-2-(methoxymethoxy)phenyl]-N-(3-pyridinyl)-N-(4-pyridinylmethyl)urea		C₂₅H₃₀N₄O₄	详情	详情
(XI)	41356	tert-butyl (4R)-4-[[(benzyloxy)carbonyl]amino]-4-cyanobutanoate		C₁₇H₂₂N₂O₄	详情	详情

Extended Information