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【结 构 式】 
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【分子编号】20896 【品名】Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester 【CA登记号】64920-29-2 |
【 分 子 式 】C12H14O3 【 分 子 量 】206.24136 【元素组成】C 69.89% H 6.84% O 23.27% |
合成路线1
该中间体在本合成路线中的序号：(VIII)The reductocondensation of ethyl glycinate (I) with 2-indanone (II) by means of sodium cyanoborohydride in methanol gives ethyl N-(2-indanyl)glycinate (III), which is condensed with N-benzyloxycarbonyl-L-alanine (IV) by means of isobutyl chlorocarbonate and triethylamine in THF yielding N-(N-benzyloxycarbonyl-L-alanyl)-N-(2-indanyl)glycine ethyl ester (V). The partial hydrolysis of (V) with NaOH in methanol affords N-(N-benzyloxycarbonyl-L-alanyl)-N-(2-indanyl)glycine (VI), which is deprotected by hydrogenolysis with H2 over Pd/C in ethanol giving N-(L-alanyl)-N-(2-indanyl)glycine (VII). Finally, this compound is reductocondensed with ethyl 2-oxo-4-phenylbutanoate (VIII) by means of sodium cyanoborohydride in ethanol.
| 【1】 Oka, Y.; Nishikawa, K.; Miyake, A. (Takeda Chemical Industries, Ltd.); Bicyclic compounds, their production and use. EP 0051391; GB 2086393; JP 82179141; JP 8277651; US 4385051 . |
| 【2】 Serradell, M.N.; Castaner, J.; CV-3317. Drugs Fut 1984, 9, 5, 324. |
| 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) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (II) | 30550 | 1,3-dihydro-2H-inden-2-one | 615-13-4 | C9H8O | 详情 | 详情 |
| (III) | 30551 | ethyl 2-(2,3-dihydro-1H-inden-2-ylamino)acetate | C13H17NO2 | 详情 | 详情 | |
| (IV) | 61209 | CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine | C11H13NO4 | 详情 | 详情 | |
| (V) | 30552 | ethyl 2-[((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)(2,3-dihydro-1H-inden-2-yl)amino]acetate | C24H28N2O5 | 详情 | 详情 | |
| (VI) | 30553 | 2-[((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)(2,3-dihydro-1H-inden-2-yl)amino]acetic acid | C22H24N2O5 | 详情 | 详情 | |
| (VII) | 30554 | 2-[[(2S)-2-aminopropanoyl](2,3-dihydro-1H-inden-2-yl)amino]acetic acid | C14H18N2O3 | 详情 | 详情 | |
| (VIII) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)The reductocondensation of (II) with tert-butyl glycinate (IX) by means of sodium cyanoborohydride in ethanol gives tert-butyl-N-(2-indanyl)glycinate (X), which is condensed with (IV) by means of isobutyl chlorocarbonate as before yielding tert-butyl-N-[N-(tert-butoxycarbonyl)-L-alanyl]-N-(2-indanyl)glycinate (XI). Deprotection of (XI) by hydrogenolysis with H2 over Pd/C in methanol affords tert-butyl N-(L-alanyl)-N-(2-indanyl)glycinate (XII), which is reductocondensed with (VIII) using H2 and Raney-Ni in ethanol to afford tert-butyl N-[N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl]-N-(2-indanyl)glycinate (XIII). Finally, this compound is saponified with HBr in acetic acid.
| 【1】 Oka, Y.; Nishikawa, K.; Miyake, A. (Takeda Chemical Industries, Ltd.); Bicyclic compounds, their production and use. EP 0051391; GB 2086393; JP 82179141; JP 8277651; US 4385051 . |
| 【2】 Serradell, M.N.; Castaner, J.; CV-3317. Drugs Fut 1984, 9, 5, 324. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 30550 | 1,3-dihydro-2H-inden-2-one | 615-13-4 | C9H8O | 详情 | 详情 |
| (IV) | 61209 | CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine | C11H13NO4 | 详情 | 详情 | |
| (VIII) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
| (IX) | 27841 | tert-butyl 2-aminoacetate;tert-butyl glycinate;Glycine tert-butyl ester | 6456-74-2 | C6H13NO2 | 详情 | 详情 |
| (X) | 30555 | tert-butyl 2-(2,3-dihydro-1H-inden-2-ylamino)acetate | C15H21NO2 | 详情 | 详情 | |
| (XI) | 30556 | tert-butyl 2-[((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)(2,3-dihydro-1H-inden-2-yl)amino]acetate | C26H32N2O5 | 详情 | 详情 | |
| (XII) | 30557 | tert-butyl 2-[[(2S)-2-aminopropanoyl](2,3-dihydro-1H-inden-2-yl)amino]acetate | C18H26N2O3 | 详情 | 详情 | |
| (XIII) | 30558 | ethyl (2S)-2-([(1S)-2-[[2-(tert-butoxy)-2-oxoethyl](2,3-dihydro-1H-inden-2-yl)amino]-1-methyl-2-oxoethyl]amino)-4-phenylbutanoate | C30H40N2O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XIII)A new synthesis of CGS-14824A is given: The reaction of 3-bromo-1-phenylpropane (I) with KCN gives 4-phenylbutyronitrile (II), which is hydrolyzed to the corresponding butyric acid (III). The cyclization of (III) with polyphosphoric acid affords 1-tetralone (IV), which is brominated to 2-bromo-1-tetralone (V) and treated with hydroxylamine to give the oxime (VI). The Beckman rearrangement of (VI) yields 3-bromo-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is treated with sodium azide to afford the azide derivative (VIII). The N-alkylation of (VIII) with ethyl bromoacetate (IX) by means of KOH and tetrabutylammonium bromide in THF gives the N-alkylated azide (X), which is reduced by catalytic hydrogenation to the corresponding amine (XI). The hydrolysis of the ester group of (XI) with NaOH yields the free acetic acid derivative (XII), which is finally reductocondensed with ethyl 2-oxo-4-phenylbutyrate (XIII) by means of sodium cyanoborohydride.
| 【1】 Chaudhuri, N.K.; Patera, R.; Markus, B.; Sung, M.-S.; Synthesis of 14C-labeled 3-([1-ethoxycarbonyl-3-phenyl-(1S)-propyl]amino)-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid hydrochloride ([14C]CGS 14824A). J Label Compd Radiopharm 1987, 24, 10, 1177-84. |
| 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) | 20884 | 1-(3-bromopropyl)benzene | 637-59-2 | C9H11Br | 详情 | 详情 |
| (II) | 20885 | 4-phenylbutanenitrile | 2046-18-6 | C10H11N | 详情 | 详情 |
| (III) | 20886 | Benzenebutyric acid; 4-Phenylbutyric acid | 1821-12-1 | C10H12O2 | 详情 | 详情 |
| (IV) | 20720 | 3,4-dihydro-1(2H)-naphthalenone | 529-34-0 | C10H10O | 详情 | 详情 |
| (V) | 20721 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone | C10H9BrO | 详情 | 详情 | |
| (VI) | 20722 | 2-bromo-3,4-dihydro-1(2H)-naphthalenone oxime | C10H10BrNO | 详情 | 详情 | |
| (VII) | 20723 | 3-bromo-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10BrNO | 详情 | 详情 | |
| (VIII) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
| (IX) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (X) | 20893 | ethyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C14H16N4O3 | 详情 | 详情 | |
| (XI) | 20894 | ethyl 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetate | 109010-60-8 | C14H18N2O3 | 详情 | 详情 |
| (XII) | 20895 | 2-[(3S)-3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]acetic acid | C12H14N2O3 | 详情 | 详情 | |
| (XIII) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The reaction of 2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (I) with PCl5 in hot xylene gives 3,3-dichloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (II), which is treated with sodium acetate and reduced with H2 over Pd/C in acetic acid yielding 3-chloro-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (III). The reaction of (III) with sodium azide in DMSO affords 3-azido-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (IV), which is condensed with benzyl bromoacetate (V) by means of NaH in DMF giving 3-azido-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VI). The treatment of (VI) with Raney-Ni in ethanol-water yields 3-amino-1-(benzyloxycarbonylmethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol affording 3-amino-1-(carboxymethyl)-2,3,4,5-tetrahydro-1H-(1)benzazepin-2-one (VIII). Finally, this compound is condensed with ethyl 3-benzylpyruvate (IX) by means of sodium cyanoborohydride in methanol acetic acid.
| 【1】 Watthey, J.W.H. (Novartis AG); Benzazepin-2-ones, process for their preparation, pharmaceutical preparations containing these compounds and the compounds for therapeutical use. EP 0072352; GB 2103614; JP 8338260 . |
| 【2】 Castaner, J.; Serradell, M.N.; CGS-14824 A. Drugs Fut 1984, 9, 5, 317. |
| 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) | 30511 | 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H11NO | 详情 | 详情 | |
| (II) | 30512 | 3,3-dichloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H9Cl2NO | 详情 | 详情 | |
| (III) | 30513 | 3-chloro-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10ClNO | 详情 | 详情 | |
| (IV) | 20891 | 3-azido-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one | C10H10N4O | 详情 | 详情 | |
| (V) | 12869 | benzyl 2-bromoacetate | 5437-45-6 | C9H9BrO2 | 详情 | 详情 |
| (VI) | 30514 | benzyl 2-(3-azido-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C19H18N4O3 | 详情 | 详情 | |
| (VII) | 30515 | benzyl 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetate | C19H20N2O3 | 详情 | 详情 | |
| (VIII) | 30516 | 2-(3-amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)acetic acid | C12H14N2O3 | 详情 | 详情 | |
| (IX) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VI)The condensation of ethyl indoline-2-carboxylate (I) with N-benzyloxycarbonylalanine (II) by means of CH2Cl2 gives ethyl N-(benzyloxycarbonylalanyl)indoline-2-carboxylate (III), which is hydrolyzed partially with LiOH in DMF water yielding N-(benzyloxycarbonylalanyl)indoline-2-carboxylic acid (IV). Debenzylation of (IV) by hydrogenation with H2 over Pd/C in aqueous ethanol affords N-alanylindoline-2-carboxylic acid, which is finally reductocondensed with ethyl 2-oxo-3-phenylbutyrate (VI) by means of NaOH and sodium cyanoborohydride or H2 and RaNi in ethanol.
| 【1】 Renfroe, H.B.; Stanton, J.L.; Sele, A. (Novartis AG); 1-Carboxy-azaalkyl-indolin-2-carboxylic acids, process for preparing them, pharmaceutical compositions containing them and their therapeutical use. DD 201888; EP 0051301; GB 2086390 . |
| 【2】 Serradell, M.N.; Castaner, J.; CGS-13928C. Drugs Fut 1985, 10, 3, 190. |
| 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) | 29042 | ethyl (2S)-1-methyl-2,3-dihydro-1H-indole-2-carboxylate | C12H15NO2 | 详情 | 详情 | |
| (II) | 61209 | CBZ-L-Alanine; (2S)-2-[[(Benzyloxy)carbonyl]amino]propionic acid; N-((Phenylmethoxy)carbonyl)-alanine; Carbobenzyloxy-L-alanine | C11H13NO4 | 详情 | 详情 | |
| (III) | 29043 | ethyl (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-2,3-dihydro-1H-indole-2-carboxylate | C22H24N2O5 | 详情 | 详情 | |
| (IV) | 29044 | (2S)-1-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-2,3-dihydro-1H-indole-2-carboxylic acid | C20H20N2O5 | 详情 | 详情 | |
| (V) | 29045 | (2S)-1-[(2S)-2-aminopropanoyl]-2,3-dihydro-1H-indole-2-carboxylic acid | C12H14N2O3 | 详情 | 详情 | |
| (VI) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)The cyclization of 1-benzyloxycarbonyl-4-oxoproline methyl ester (I) with ethanedithiol (II) by means of p-toluenesulfonic acid in refluxing acetic acid gives methyl 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate (III), which is deprotected with 20% HBr to give methyl 1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate (IV). The condensation of (IV) with N-benzyloxycarbonyl alanine N-hydroxysuccinimide ester (V) affords the corresponding dipeptide methyl ester (VI), which is hydrolyzed with NaOH to the free acid (VII), and deprotected with 20% HBr as before to 7-alanyl-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid (VIII). Finally, this compound is condensed with ethyl 2-oxo-4-phenylbutyrate (IX) by means of sodium cyanoborohydride in methanol.
| 【1】 Smith, E.M.; Neustadt, B.R.; Gold, E.H. (Schering Corp.); 7-Carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids. JP 1989163197; US 4470972 . |
| 【2】 Prous, J.; Castaner, J.; Spirapril. Drugs Fut 1987, 12, 9, 860. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 27314 | benzyl hydrogen sulfate | C7H8O4S | 详情 | 详情 | |
| (I) | 27312 | 1-benzyl 2-methyl (2R)-4-oxo-1,2-cyclopentanedicarboxylate | C15H16O5 | 详情 | 详情 | |
| (II) | 27313 | 1,2-ethanedithiol | 540-63-6 | C2H6S2 | 详情 | 详情 |
| (III) | 27315 | 7-benzyl 8-methyl (8R)-1,4-dithiaspiro[4.4]nonane-7,8-dicarboxylate | C17H20O4S2 | 详情 | 详情 | |
| (IV) | 27316 | methyl (8S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate | C8H13NO2S2 | 详情 | 详情 | |
| (V) | 27317 | benzyl (1S)-2-[(2,5-dioxo-1-pyrrolidinyl)oxy]-1-methyl-2-oxoethylcarbamate | C15H16N2O6 | 详情 | 详情 | |
| (VI) | 27318 | methyl (8S)-7-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate | C19H24N2O5S2 | 详情 | 详情 | |
| (VII) | 27319 | (8S)-7-((2S)-2-[[(benzyloxy)carbonyl]amino]propanoyl)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid | C18H22N2O5S2 | 详情 | 详情 | |
| (VIII) | 27320 | (8S)-7-[(2S)-2-aminopropanoyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid | C10H16N2O3S2 | 详情 | 详情 | |
| (IX) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IX)The condensation of (IX) with alanine benzyl ester (X) with sodium cyanoboohydride as before gives N-[1-(ethoxycarbonyl)-3-phenylpropyl]alanine benzyl ester (XI), which is submitted to fractional crystallization with maleic acid yielding N-[1(S)-(ethoxycarbonyl)-3-phenylpropyl]-(S)-alanine benzyl ester (XII), which is debenzylated by hydrogenation with H2 over Pd/C in ethanol yielding the free acid (XIII). Finally, this compound is condensed with spirane (IV) through the N-hydroxysuccinimide ester, in the usual way.
| 【1】 Smith, E.M.; Neustadt, B.R.; Gold, E.H. (Schering Corp.); 7-Carboxyalkylaminoacyl-1,4-dithia-7-azaspiro[4.4]-nonane-8-carboxylic acids. JP 1989163197; US 4470972 . |
| 【2】 Prous, J.; Castaner, J.; Spirapril. Drugs Fut 1987, 12, 9, 860. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 23808 | Fumaric acid; (E)-2-butenedioic acid | 110-17-8 | C4H4O4 | 详情 | 详情 |
| (IV) | 27316 | methyl (8S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate | C8H13NO2S2 | 详情 | 详情 | |
| (IX) | 20896 | Ethyl 2-oxo-4-phenylbutanoate; 2-Oxo-4-phenylbutyric acid ethyl ester | 64920-29-2 | C12H14O3 | 详情 | 详情 |
| (X) | 10143 | benzyl (2S)-2-aminopropanoate | C10H13NO2 | 详情 | 详情 | |
| (XI) | 27321 | ethyl 2-[[(1S)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C22H27NO4 | 详情 | 详情 | |
| (XII) | 15665 | ethyl (2S)-2-[[(1S)-2-(benzyloxy)-1-methyl-2-oxoethyl]amino]-4-phenylbutanoate | C22H27NO4 | 详情 | 详情 | |
| (XIII) | 11360 | (2S)-2-[[(1S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]propionic acid; (S)-N-(1-Ethoxycarbonyl-3-phenylpropyl)-(S)-alanine | 82717-96-2 | C15H21NO4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)By reductocondensation of ethyl 2-oxo-4-phenylbutyrate (I) with alanylproline (II) by means of sodium cyanoborohydride or H2 over Raney-Ni or Pd/C in water.
| 【1】 Patchett, A.A.; et al.; A new class of angiotensin-converting anzyme inhibitors. Nature 1980, 288, 280-283. |
| 【2】 Hopkins, S.J.; Serradell, M.N.; Blancafort, P.; Castaner, J.; Enalapril maleate. Drugs Fut 1982, 7, 8, 556. |