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【结 构 式】

【药物名称】ES-6864

【化学名称】N-[N-[3-(Morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propionyl]-3-(4-thiazolyl)-L-alanyl]cyclostatin-(2-morpholinoethyl)amide
　　　　　　4(S)-[N-[3-(Morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propionyl]-3-(4-thiazolyl)-L-alanylamino]-5-cyclohexyl-3(S)-hydroxypentanoic acid 2-morpholinoethylamide

【CA登记号】116326-39-7

【 分 子 式 】C42H58N6O7S

【 分 子 量 】791.03056

【开发单位】Sankyo (Originator)

【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Renin Inhibitors

合成路线1合成路线2合成路线3合成路线4

合成路线1

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
【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2

The starting product (I) is obtained as follows: The acylation of 4(S)-isopropyloxazolidin-2-one (IV) with 3-(1-naphthyl)propionyl chloride (III) by means of butyllithium in THF-hexane yields 4(S)-isopropyl-3-[3-(1-naphthyl)propionyl]oxazolidin-2-one (V), which is condensed with benzyl bromoacetate (VI) by means of lithium diisopropylamide in THF to afford 3-[3-(benzyloxycarbonyl)-2(R)-(1-naphthylmethyl)propionyl]-4(S)-isoprop yloxazolidin-2-one (VII). The hydrogenolysis of (VII) with H2 over Pd/C in ethanol gives the carboxylic acid (VIII), which is condensed with morpholine (IX) by means of triethylamine and diethylphosphoryl cyanide in THF yielding 4(S)-isopropyl-3-[3-(morpholinocarbonyl)-2(R)-(1-naphthylmethyl)propion yl]oxazolidin-2-one (X). Finally, this compound is hydrolyzed with LiOH in THF - water to afford the acid (I).

参考文献 中间体
【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
(III) 12866 3-(1-Naphthyl)propanoyl chloride C13H11ClO 详情 详情
(IV) 12867 (4S)-4-Isopropyl-1,3-oxazolidin-2-one; (R)-4-Isopropyl-2-oxazolidinone 17016-83-0 C6H11NO2 详情 详情
(V) 12868 (4S)-4-Isopropyl-3-[3-(1-naphthyl)propanoyl]-1,3-oxazolidin-2-one C19H21NO3 详情 详情
(VI) 12869 benzyl 2-bromoacetate 5437-45-6 C9H9BrO2 详情 详情
(VII) 12870 benzyl (3R)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-3-(1-naphthylmethyl)-4-oxobutanoate C28H29NO5 详情 详情
(VIII) 12871 (3R)-4-[(4S)-4-Isopropyl-2-oxo-1,3-oxazolidin-3-yl]-3-(1-naphthylmethyl)-4-oxobutyric acid C21H23NO5 详情 详情
(IX) 10388 Morpholine 110-91-8 C4H9NO 详情 详情
(X) 12873 Boc-L-phenylalanine;N-[(1,1-Dimethylethoxy)carbonyl]-L-phenylalanine;N-(tert-Butoxycarbonyl)-L-phenylalanine;(R)-2-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid;N-Boc-Lhomophenylalanine；(2R)-1-[(4S)-4-Isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-(4-morpholinyl)-2-(1-naphthylmethyl)-1,4-butanedione C25H30N2O5 详情 详情

合成路线3

The starting product (II) is obtained as follows: The condensation of N-(tert-butoxycarbonyl)-L-phenylalanine (XI) with magnesium diethylmalonate (XII) by means of N,N'-carbonyldiimidazole in THF - DMSO gives 4(S)-(tert-butoxycarbonylamino)-3-oxo-4-phenylpentanoic acid ethyl ester (XIII), which by an asymetric hydrogenation with H2 and (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl-Ruthenium complex in ethanol is converted into 4(S)-(tert-butoxycarbonylamino)-4(S)-hydroxy-5-phenylpentanoic acid ethyl ester (XIV). The hydrolysis of (XIV) with KOH in water - dioxane gives the corresponding free acid (XV), which is hydrogenated with H2 over Rh/Al2O3 in ethanol to yield N-(tert-butoxycarbonyl)cyclostatine (XVI).The condensation of (XVI) with 2-morpholinoethylamine (XVII) by means of triethylamine and diethylphosphoryl cyanide in THF affords the corresponding amide (XVIII), which is finally condensed with N-(tert-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine (XIX) by means of a previous hydrolysis with HCl, followed by the condensation step with diethylphosphoryl cyanide in THF, to give the cyclostatine derivative (II).

参考文献 中间体
【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
(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
(XI) 12874 (2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine 13734-34-4 C14H19NO4 详情 详情
(XII) 12875 Bromo[2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]magnesium C7H11BrMgO4 详情 详情
(XIII) 12876 ethyl (4S)-4-[(tert-butoxycarbonyl)amino]-3-oxo-5-phenylpentanoate C18H25NO5 详情 详情
(XIV) 12877 ethyl (3S,4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-phenylpentanoate C18H27NO5 详情 详情
(XV) 12878 (3S,4S)-4-[(tert-Butoxycarbonyl)amino]-3-hydroxy-5-phenylpentanoic acid 72155-46-5 C16H23NO5 详情 详情
(XVI) 12879 (3S,4S)-4-[(tert-Butoxycarbonyl)amino]-5-cyclohexyl-3-hydroxypentanoic acid C16H29NO5 详情 详情
(XVII) 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
(XVIII) 12881 tert-butyl (1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-4-[[2-(4-morpholinyl)ethyl]amino]-4-oxobutylcarbamate C22H41N3O5 详情 详情
(XIX) 12882 (2S)-2-[(tert-Butoxycarbonyl)amino]-3-(1,3-thiazol-4-yl)propionic acid C11H16N2O4S 详情 详情

合成路线4

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
【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