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【结 构 式】 
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【分子编号】12880 【品名】4-(2-Aminoethyl)morpholine; 2-(4-Morpholinyl)ethylamine; 2-(4-Morpholinyl)-1-ethanamine; N-(2-Aminoethyl)morpholine; N-Morpholine ethanamide 【CA登记号】2038-03-1 |
【 分 子 式 】C6H14N2O 【 分 子 量 】130.19004 【元素组成】C 55.35% H 10.84% N 21.52% O 12.29% |
合成路线1
该中间体在本合成路线中的序号：(II)This compound can be prepared in several different ways: 1) By reaction of p-chlorobenzoyl chloride (I) with N-(2-aminoethyl)morpholine (II) in pyridine. 2) By reaction of p-chlorobenzoyl anhydride (III) with N-(2-aminoethyl)morpholine (II) in pyridine. 3) By reaction of methyl p-chlorobenzoate (IV) with N-(2-aminoethyl)morpholine (II) at 120 C. 4) By reaction of N-(p-chlorobenzoyl)succinimide (V) with N-(2-aminoethyl)morpholine (II) in dioxane. 5) By reaction of p-nitrophenyl p-chlorobenzoate (VI) with N-(2-aminoethyl)morpholine (II) in THF. 6) By reaction of p-chloro-N-(2-chloroethyl)benzamide (VII) with morpholine (VIII) at 100 C. 7) By reaction of p-chlorobenzoylaziridine (IX) with morpholine (VIII) in refluxing toluene. 8) By reaction of p-chlorobenzaldehyde (X) with N-(2-aminoethyl)morpholine (II) in refluxing benzene to give 4-[2-[(p-chlorobenzylidene)amino]ethyl]morpholine (XI), followed by an oxidation with H2O2 in methanol. 9) By reaction of p-chloro-N-(2-morpholinoethyl)thiobenzamide (XII) with lead tetraacetate in refluxing water. 11) By reaction of p-chlorobenzoic acid (XIV) with N-(2-aminoethyl)morpholine (II) by means of dicyclohexylcarbodiimide in pyridine, or by means of chloroformic acid ethyl ester and triethylamine in acetone. 10) By isomerization of (alpha-(p-chlorophenyl)-N-(2-morpholinoethyl)nitrone (XIII) in hot acetic acid - acetic anhydride, followed by a treatment with NaOH.
| 【1】 Bukard, W.; Wyss, P.C. (F. Hoffmann-La Roche AG); Benzamides. BE 0851422; CA 1076112; DE 2706179; FR 2340940; GB 1512194; JP 52100476; NL 7701144; US 4210754; ZA 7700488 . |
| 【2】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Grau, M.; Moclobemide. Drugs Fut 1983, 8, 2, 124. |
| 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) | 10295 | p-Chlorobenzoyl chloride; 4-Chlorobenzoyl chloride | 122-01-0 | C7H4Cl2O | 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) | 30702 | 4-chloro-1-benzenecarboxylic anhydride | C14H8Cl2O3 | 详情 | 详情 | |
| (IV) | 30703 | methyl 4-chlorobenzoate | 1126-46-1 | C8H7ClO2 | 详情 | 详情 |
| (V) | 30704 | 1-(4-chlorobenzoyl)-2,5-pyrrolidinedione | C11H8ClNO3 | 详情 | 详情 | |
| (VI) | 30705 | 4-nitrophenyl 4-chlorobenzoate | C13H8ClNO4 | 详情 | 详情 | |
| (VII) | 30706 | 4-chloro-N-(2-chloroethyl)benzamide | C9H9Cl2NO | 详情 | 详情 | |
| (VIII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (IX) | 30707 | 1-aziridinyl(4-chlorophenyl)methanone | C9H8ClNO | 详情 | 详情 | |
| (X) | 29029 | 4-chlorobenzaldehyde | 104-88-1 | C7H5ClO | 详情 | 详情 |
| (XI) | 30708 | N-[(E)-(4-chlorophenyl)methylidene]-2-(4-morpholinyl)-1-ethanamine; N-[(E)-(4-chlorophenyl)methylidene]-N-[2-(4-morpholinyl)ethyl]amine | C13H17ClN2O | 详情 | 详情 | |
| (XII) | 30709 | 4-chloro-N-[2-(4-morpholinyl)ethyl]benzenecarbothioamide | C13H17ClN2OS | 详情 | 详情 | |
| (XIII) | 30710 | [(Z)-(4-chlorophenyl)methylidene][2-(4-morpholinyl)ethyl]ammoniumolate | C13H17ClN2O2 | 详情 | 详情 | |
| (XIV) | 18359 | p-chlorobenzoic acid; 4-chlorobenzoic acid | 74-11-3 | C7H5ClO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(II)By condensation of 3-chloro-4-methyl-6-phenylpyridazine (I) with N-(2-aminoethyl)morpholine (II) by means of powdered Cu in refluxing n-butanol.
| 【1】 Laborit, H.; Pyridazine derivatives. ZA 7300671 . |
| 【2】 Laborit, H.; Pyridazine derivatives in alleviating depressive states. CH 546769; DE 2229215; ES 403998; FR 2141697; GB 1345880; US 4169158 . |
| 【3】 Castaner, J.; Minaprine. Drugs Fut 1977, 2, 12, 811. |
合成路线3
该中间体在本合成路线中的序号：(II)The reaction of 3-chloro-4-cyano-6-phenylpyridazine (I) with (4-morpholino)ethylamine (II) in refluxing n-butanol gives title compound.
| 【1】 Eastland, G. Jr.; SR-95191. Drugs Fut 1987, 12, 2, 137. |
合成路线4
该中间体在本合成路线中的序号：(XVII)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5
该中间体在本合成路线中的序号：(II)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 |
合成路线6
该中间体在本合成路线中的序号：(II)The title compound was prepared by condensation of 5-chloro-2-(methylsulfanyl)-8,9-dihydro-7H-thiopyrano[3,2-d]-1,2,4-triazolo[1,5-a]pyrimidine (I) with N-(2-aminoethyl)morpholine (II) in the presence of Et3N in refluxing isopropanol.
| 【1】 Reiter, J.; Berecz, G.; Zsila, G.; Petocz, L.; Gigler, G.; Fekete, M.; Szecsey, M.; Szirt, E.; Rohacs, L.; Gorgenyl, F.; Csorgo, M. (Egis Pharmaceuticals Ltd.); 1,2,4-Triazolo[1,5-a]pyrimidine derivs.. EP 0500136; GB 2254611; JP 1993148267 . |
| 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) | 37349 | 5-chloro-8,9-dihydro-7H-thiopyrano[3,2-d][1,2,4]triazolo[1,5-a]pyrimidin-2-yl methyl sulfide; 5-chloro-2-(methylsulfanyl)-8,9-dihydro-7H-thiopyrano[3,2-d][1,2,4]triazolo[1,5-a]pyrimidine | C9H9ClN4S2 | 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 |
合成路线7
该中间体在本合成路线中的序号：(II)The condensation of 6,7-dichloroquinoline-5,8-dione (I) with 4-(2-aminoethyl)morpholine (II) provided a 2:1 mixture of the title 7-amino quinoline and its 6-amino regioisomer (III), which were separated by column chromatography.
| 【1】 Cooley, K.A.; Southwick, E.C.; Ducruet, A.P.; Joo, B.; Vogt, A.; Wipf, P.; Aslan, D.C.; Lazo, J.S.; Discovery and biological evaluation of a new family of potent inhibitors of the dual specificity protein phosphatase Cdc25. J Med Chem 2001, 44, 24, 4042. |
| 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) | 53106 | 6,7-dichloro-5,8-quinolinedione | n/a | C9H3Cl2NO2 | 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) | 53108 | 7-chloro-6-{[2-(4-morpholinyl)ethyl]amino}-5,8-quinolinedione | n/a | C15H16ClN3O3 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(II)The condensation of 6,7-dichloroquinoline-5,8-dione (I) with 4-(2-aminoethyl)morpholine (II) provided a 1:2 mixture of the title 6-amino quinoline and its 7-amino regioisomer (III), which were separated by column chromatography.
| 【1】 Cooley, K.A.; Southwick, E.C.; Ducruet, A.P.; Joo, B.; Vogt, A.; Wipf, P.; Aslan, D.C.; Lazo, J.S.; Discovery and biological evaluation of a new family of potent inhibitors of the dual specificity protein phosphatase Cdc25. J Med Chem 2001, 44, 24, 4042. |
| 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) | 53106 | 6,7-dichloro-5,8-quinolinedione | n/a | C9H3Cl2NO2 | 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) | 53107 | 6-chloro-7-{[2-(4-morpholinyl)ethyl]amino}-5,8-quinolinedione | n/a | C15H16ClN3O3 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(III)By cyclization of ethyl acetoacetate (I) with 2-trifluoromethylbenzaldehyde (II) and N-(2-aminoethyl)morpholine (III) in refluxing ethanol
| 【1】 Blancafort, P.; Serradell, M.N.; Castaner, J.; Thorpe, P.J.; Flordipine. Drugs Fut 1983, 8, 9, 770. |
| 【2】 Loev, B.; Shroff, J.R. (USV Pharmaceutical Corp.); BE 888327; DE 3109794; FR 2480284; GB 2073739; JP 81158762; US 4258042 . |
| 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) | 11819 | ethyl acetoacetate; ethyl 3-oxobutanoate；Acetoacetic ester;Ethyl beta-ketobutyrate;ethyl 3-oxobutyrate | 141-97-9 | C6H10O3 | 详情 | 详情 |
| (II) | 30332 | 2-(trifluoromethyl)benzaldehyde | 447-61-0 | C8H5F3O | 详情 | 详情 |
| (III) | 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 |
合成路线10
该中间体在本合成路线中的序号：(XI)Vilsmeier formylation of ethyl 4-methylpyrrole-2-carboxylate (VIII) affords aldehyde (IX). The ethyl ester group of (IX) is subsequently hydrolyzed under alkaline conditions to provide acid (X). Coupling of (X) with 4-(2-aminoethyl)morpholine (XI) gives amide (XII). Then, condensation between aldehyde (XII) and lactam (VII) in the presence of piperidine leads to adduct (XIII). The 4-chloro group of (XIII) is finally displaced with 3-chloro-4-fluoroaniline (XIV) in hot NMP to provide the title compound
| 【1】 Wei, C.C.; Tang, P.C.; McMahon, G.; Sun, L.; Hirth, K.P.; Liang, C.; Cui, J. (Sugen, Inc.); 4-Substd. 7-aza-indolin-2-ones and their use as protein kinase inhibitors. EP 1244672; WO 0146196 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 60048 | 4-chloro-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one | C6H4ClN3O | 详情 | 详情 | |
| (VIII) | 60049 | ethyl 4-methyl-1H-pyrrole-2-carboxylate | C8H11NO2 | 详情 | 详情 | |
| (IX) | 60050 | ethyl 5-formyl-4-methyl-1H-pyrrole-2-carboxylate | C9H11NO3 | 详情 | 详情 | |
| (X) | 60051 | 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid | C7H7NO3 | 详情 | 详情 | |
| (XI) | 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 |
| (XII) | 59999 | 5-formyl-4-methyl-N-[2-(4-morpholinyl)ethyl]-1H-pyrrole-2-carboxamide | C13H19N3O3 | 详情 | 详情 | |
| (XIII) | 59998 | 5-[(4-chloro-6-oxo-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-5-ylidene)methyl]-4-methyl-N-[2-(4-morpholinyl)ethyl]-1H-pyrrole-2-carboxamide | C19H21ClN6O3 | 详情 | 详情 | |
| (XIV) | 18688 | 3-Chloro-4-fluorophenylamine; 3-Chloro-4-fluoroaniline | 367-21-5 | C6H5ClFN | 详情 | 详情 |