9H-fluoren-9-ylmethyl (4S)-4-[(tert-butoxycarbonyl)amino]-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxopentylcarbamate -Drug Synthesis Database

【结构式】

【分子编号】43424

【品名】9H-fluoren-9-ylmethyl (4S)-4-[(tert-butoxycarbonyl)amino]-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxopentylcarbamate

【CA登记号】

【分子式】C₂₉H₃₃N₃O₈

【分子量】551.59644

【元素组成】C 63.15% H 6.03% N 7.62% O 23.2%

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：(XLIII)

Treatment of N-phthaloyl-L-phenylalanine acid chloride (VI) with 2,6-dicyanopiperidine (XXXIII) [obtained by reaction of glutaric dialdehyde (XXXIV) with NaCN and ammonium chloride in water] by means of potassium tert-butoxide in ice/carbon tetrachloride gives the tetrahydropyridine derivative (XXXV), which is then subjected to cyclization with H2SO4 and trifluoroacetic acid anhydride to yield the benzazepine derivative (XXXVI). Hydrolysis of the cyano group of (XXXVI) with water yields the carboxylic acid (XXXVII), from which the desired diastereomer (XXXVIII) is separated by chromatography. Removal of the phthaloyl moiety of compound (XXXVIII) by treatment with hydrazine monohydrate and Et3N in refluxing MeOH affords the amino derivative (XXXIX), which is then condensed with 2(R)-bromopropionic acid (XXXI) by means of N-hydroxysuccinimide (HOSu) and 1,3-dicyclohexylcarbodiimide (DCC) in THF resulting in amide (XL). Finally, MDL-100240 is obtained by reaction of (XL) with thioacetic acid and KOH in acetone. Treatment of acid chloride (VI) with ammonia provides amide (XLI), which by reaction with glutaric dialdehyde (XXXIV) in refluxing CH2Cl2 affords the pyridine derivative (XLII). Cyclization of (XLII) with either trifluoromethanesulfonic acid in CH2Cl2 or H2SO4 and trifluoroacetic acid anhydride yields the pyridobenzodiazepine derivative (XLIII), which is finally converted into intermediate (XXXVIII) by introduction of a carboxylic group by reaction with either H2SO4 and formic acid or H2SO4 and carbon monoxide.

参考文献中间体

合成目标

【1】 del Fresno, M.; Bayes, M.; Castaner, R.M.; Sorbera, L.A.; MDL-100240. Drugs Fut 2002, 27, 5, 458.
【2】 Flynn, G.A.; Beight, D.W.; Genin, M.J.; Bannister, T.D. (Aventis Pharmaceuticals, Inc.); Novel processes for preparing intermediates of inhibitors of enkephalinase and angiotensin converting enzyme and intermediates thereof. WO 9619492 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	52756	(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl chloride		C₁₇H₁₂ClNO₃	详情	详情
(XXXII)	53417	(2R)-2-bromo-3-phenylpropanoic acid	n/a	C₉H₉BrO₂	详情	详情
(XXXIII)	53419	2,6-piperidinedicarbonitrile	41980-31-8	C₇H₉N₃	详情	详情
(XXXIV)	53423	pentanedial	111-30-8	C₅H₈O₂	详情	详情
(XXXV)	53420	1-[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]-1,2,3,4-tetrahydro-2-pyridinecarbonitrile	n/a	C₂₃H₁₉N₃O₃	详情	详情
(XXXVI)	53421	(7S)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carbonitrile	n/a	C₂₃H₁₉N₃O₃	详情	详情
(XXXVII)	53422	(7S)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylic acid	n/a	C₂₃H₂₀N₂O₅	详情	详情
(XXXVIII)	49788	(4S,7S,12bR)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylic acid		C₂₃H₂₀N₂O₅	详情	详情
(XXXIX)	53427	(4S,7S,12bR)-7-amino-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylic acid	n/a	C₁₅H₁₈N₂O₃	详情	详情
(XL)	53428	(4S,7S,12bR)-7-{[(2R)-2-bromo-3-phenylpropanoyl]amino}-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylic acid	n/a	C₂₄H₂₅BrN₂O₄	详情	详情
(XLI)	53425	(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanamide	n/a	C₁₇H₁₄N₂O₃	详情	详情
(XLII)	53426	2-{(1S)-1-benzyl-2-oxo-2-[1(4H)-pyridinyl]ethyl}-1H-isoindole-1,3(2H)-dione	n/a	C₂₂H₁₈N₂O₃	详情	详情
(XLIII)	43424	9H-fluoren-9-ylmethyl (4S)-4-[(tert-butoxycarbonyl)amino]-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxopentylcarbamate		C₂₉H₃₃N₃O₈	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVII)

For the preparation of tripeptide intermediate (XVIII), N-Cbz-threonine (XII) was coupled with proline benzyl ester (XIII) to give dipeptide (XIV). Subsequent hydrogenolysis of the benzyl groups of (XIV) in the presence of Pd/C furnished threonyl proline (XV). Coupling of (XV) with the succinimidyl ester (XVII) prepared from the protected ornithine (XVI) then provided tripeptide intermediate (XVIII).

参考文献中间体

合成目标

【1】 Chen, H.-J.; Klein, L.L.; Li, L.; et al.; Total synthesis and antifungal evaluation of cyclic aminohexapeptides. Bioorg Med Chem Lett 2000, 8, 7, 1677.

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)	43420	(2S,3R)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxybutyric acid	19728-63-3	C₁₂H₁₅NO₅	详情	详情
(XIII)	20930	benzyl (2S)-2-pyrrolidinecarboxylate	16652-71-4	C₁₂H₁₅NO₂	详情	详情
(XIV)	43421	benzyl (2S)-1-((2S,3R)-2-[[(benzyloxy)carbonyl]amino]-3-hydroxybutanoyl)-2-pyrrolidinecarboxylate		C₂₄H₂₈N₂O₆	详情	详情
(XV)	43422	(2S)-1-[(2S,3R)-2-amino-3-hydroxybutanoyl]-2-pyrrolidinecarboxylic acid		C₉H₁₆N₂O₄	详情	详情
(XVI)	43423	(2S)-2-[(tert-butoxycarbonyl)amino]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]pentanoic acid		C₂₅H₃₀N₂O₆	详情	详情
(XVII)	43424	9H-fluoren-9-ylmethyl (4S)-4-[(tert-butoxycarbonyl)amino]-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxopentylcarbamate		C₂₉H₃₃N₃O₈	详情	详情
(XVIII)	43425	(2S)-1-[(2S,3R)-2-[((2S)-2-[(tert-butoxycarbonyl)amino]-5-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]pentanoyl)amino]-3-hydroxybutanoyl]-2-pyrrolidinecarboxylic acid		C₃₄H₄₄N₄O₉	详情	详情

Extended Information