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【结 构 式】 
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【分子编号】12865 【品名】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 【CA登记号】 |
【 分 子 式 】C28H47N5O6S 【 分 子 量 】581.77728 【元素组成】C 57.81% H 8.14% N 12.04% O 16.5% S 5.51% |
合成路线1
该中间体在本合成路线中的序号：(II)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.
| 【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
该中间体在本合成路线中的序号：(II)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).
| 【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3
该中间体在本合成路线中的序号：(VI)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.
| 【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 |