(2R)-4-(4-Morpholinyl)-2-(1-naphthylmethyl)-4-oxobutyric acid -Drug Synthesis Database

【结构式】

【分子编号】12864

【品名】(2R)-4-(4-Morpholinyl)-2-(1-naphthylmethyl)-4-oxobutyric acid

【CA登记号】

【分子式】C₁₉H₂₁NO₄

【分子量】327.38008

【元素组成】C 69.71% H 6.47% N 4.28% O 19.55%

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：(III)

By condensation of N-[3-(morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propionyl-L-histidine methyl ester (I) with isopropyl 3(S)-amino-4-cyclohexyl-2(R)-hydroxybutyrate (II) by means of diphenyl phosphoryl azide (DPA) in DMF. The starting products are prepared as follows: The condensation of 3-(morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propionic acid (III) and histidine methyl ester (IV) by means of DPA in DMF gives the substituted histidine ester (I). The hydrogenation of N-(tert-butoxycarbonyl)-L-phenylalanine (V) with H2 over Rh/Al2O3 gives N-(tert-butoxycarbonyl)-L-cyclohexylalanine (VI), which is reduced with borane to the corresponding alaninol (VII). Controlled oxidation of (VII) with SO3-pyridine in benzene-DMSO affords N-(tert-butoxycarbonyl)-L-cyclohexylalaninal (VIII), which by treatment with KCN followed by hydrolysis with concentrated HCl yields 3-amino-4-cyclohexyl-2-hydroxybutyric acid (IX). Finally, this compound is esterified with isopropanol and hydrochloric acid to the starting ester (II).

参考文献中间体

合成目标

【1】 108th Annu Meet Pharm Soc Jpn (April 4-7, Hiroshima) 1988, Abst 5e06 11-3.
【2】 Khandewal, Y.; Rajgopalan, R.; Dohadwalla, A.N.; Rupp, R.H.; De Souza, N.J. (Aventis SA); 7-Acyloxy-6-aminoacyloxypolyoxylabdanes, process for their preparation and their use. DE 3623300; EP 0252482; JP 1988023878 .
【3】 Castaner, J.; Prous, J.; KRI-1314. Drugs Fut 1988, 13, 12, 1042.

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)	23045	methyl (2S)-3-(1H-imidazol-4-yl)-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propanoate		C₂₆H₃₀N₄O₅	详情	详情
(II)	12323	isopropyl (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutanoate		C₁₃H₂₅NO₃	详情	详情
(III)	12864	(2R)-4-(4-Morpholinyl)-2-(1-naphthylmethyl)-4-oxobutyric acid		C₁₉H₂₁NO₄	详情	详情
(IV)	23048	methyl (2S)-2-amino-3-(1H-imidazol-4-yl)propanoate		C₇H₁₁N₃O₂	详情	详情
(V)	12874	(2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine	13734-34-4	C₁₄H₁₉NO₄	详情	详情
(VI)	23050	(2S)-2-[(tert-butoxycarbonyl)amino]-3-cyclohexylpropionic acid		C₁₄H₂₅NO₄	详情	详情
(VII)	23051	tert-butyl (1S)-2-cyclohexyl-1-(hydroxymethyl)ethylcarbamate		C₁₄H₂₇NO₃	详情	详情
(VIII)	15853	tert-butyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate		C₁₄H₂₅NO₃	详情	详情
(IX)	12329	(2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid		C₁₀H₁₉NO₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

A new synthesis of ES-6864 has been reported: The condensation of 3-(morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propionic acid (I) with N-[N-(tert-butoxycarbonyl)-3-(4-thiazolyl)-L-alanyl]cyclosatine 2-morpholinoethylamide (II) by means of a previous hydrolysis with HCl followed by the condensation step with diethylphosphoryl cyanide gives ES-6864.

参考文献中间体

合成目标

【1】 Nishi, T.; Nagahori, H.; Saito, F.; et al.; Syntheses and biological activities of renin inhibitors containing statine analogues. Chem Pharm Bull 1990, 38, 1, 103-9.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	42235	Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC	2942-58-7	C₅H₁₀NO₃P	详情	详情
(I)	12864	(2R)-4-(4-Morpholinyl)-2-(1-naphthylmethyl)-4-oxobutyric acid		C₁₉H₂₁NO₄	详情	详情
(II)	12865	tert-butyl (1S)-2-[((1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-4-[[2-(4-morpholinyl)ethyl]amino]-4-oxobutyl)amino]-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethylcarbamate		C₂₈H₄₇N₅O₆S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VIII)

The condensation of N-tert-butoxycarbonyl-cyclostatin (I) with 2-morpholinoethylamine (II) by means of diethyl cyanophosphonate in THF gives the corresponding amide (III), which is deprotected with HCl in dioxane yielding cyclostatin 2-morpholinoethylamide (IV). The condensation of (IV) with N-tert-butoxycarbonyl-3-(4-thiazolyl)-L-alanine (V) by means of diethyl cyanophosphonate as before affords the protected dipeptide (VI), which is treated with HCl in dioxane to obtain the free dipeptide 3-(4-thiazolyl)-L-alanyl-cyclostatin 2-morpholinoethylamide (VII). Finally, this compound is condensed with 3-(morpholinocarbonyl)-2(R)-(4-thiazolyl)propionic acid (VIII) by means of diethyl cyanophosphonate as before.

参考文献中间体

合成目标

【1】 Kataoko, M.; Yabe, Y.; Iijima, Y.; Takahagi, H.; Koike, H.; Kokubu, T.; Hiwada, K.; Morisawa, Y. (Sankyo Co., Ltd.); New renin-inhibitory oligopeptides, their preparation and their use. EP 0274259; JP 1989063559; US 5378690 .
【2】 Prous, J.; Castaner, J.; ES-6864. Drugs Fut 1989, 14, 9, 852.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	42235	Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC	2942-58-7	C₅H₁₀NO₃P	详情	详情
(I)	21275	4-[(tert-butoxycarbonyl)amino]-5-cyclohexyl-3-hydroxypentanoic acid		C₁₆H₂₉NO₅	详情	详情
(II)	12880	4-(2-Aminoethyl)morpholine; 2-(4-Morpholinyl)ethylamine; 2-(4-Morpholinyl)-1-ethanamine; N-(2-Aminoethyl)morpholine; N-Morpholine ethanamide	2038-03-1	C₆H₁₄N₂O	详情	详情
(III)	21277	tert-butyl 1-(cyclohexylmethyl)-2-hydroxy-4-[[2-(4-morpholinyl)ethyl]amino]-4-oxobutylcarbamate		C₂₂H₄₁N₃O₅	详情	详情
(IV)	21278	4-amino-5-cyclohexyl-3-hydroxy-N-[2-(4-morpholinyl)ethyl]pentanamide		C₁₇H₃₃N₃O₃	详情	详情
(V)	12882	(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(1,3-thiazol-4-yl)propionic acid		C₁₁H₁₆N₂O₄S	详情	详情
(VI)	12865	tert-butyl (1S)-2-[((1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-4-[[2-(4-morpholinyl)ethyl]amino]-4-oxobutyl)amino]-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethylcarbamate		C₂₈H₄₇N₅O₆S	详情	详情
(VII)	21281	4-[[(2S)-2-amino-3-(1,3-thiazol-4-yl)propanoyl]amino]-5-cyclohexyl-3-hydroxy-N-[2-(4-morpholinyl)ethyl]pentanamide		C₂₃H₃₉N₅O₄S	详情	详情
(VIII)	12864	(2R)-4-(4-Morpholinyl)-2-(1-naphthylmethyl)-4-oxobutyric acid		C₁₉H₂₁NO₄	详情	详情

Extended Information