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【结 构 式】 
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【分子编号】52756 【品名】(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl chloride 【CA登记号】 |
【 分 子 式 】C17H12ClNO3 【 分 子 量 】313.73992 【元素组成】C 65.08% H 3.86% Cl 11.3% N 4.46% O 15.3% |
合成路线1
该中间体在本合成路线中的序号：(VI)Reaction of 3,4-dihydro-2H-pyran (I) with potassium cyanide, HCl/HOAc and KOH in H2O, followed by treatment with ammonium carbonate in H2O provides hydantoin (II). Hydrolysis of compound (II) with LiOH in H2O at 135 C gives the racemic lithium salt (III), which by treatment with methyl trifluoroacetate and Li2CO3 in a refluxing mixture of BuOH/MeOH followed by enzymatic resolution with acylase I leads to the optically pure (S)-enantiomer (IV). Compound (IV) is converted into its corresponding methyl ester (V) using trimethyl orthoformate and HCl in refluxing MeOH. The ester (V) is then coupled with N-phthaloyl-L-phenylalanine acid chloride (VI) by means of NMM in DMF/CH2Cl2 to provide the alpha-amino-omega-hydroxyhexanoic acid derivative (VII). Compound (VI) is prepared separately from L-phenylalanine (VIII) by reaction with phthalic anhydride (IX) in refluxing toluene or DMF to yield compound (X), which is treated with oxalyl chloride in refluxing toluene in the presence of DMF or in DMF/CH2Cl2. Oxidation of (VII) under Swern conditions [(COCl)2, DMSO and Et3N] followed by treatment with Oxone (potassium peroxymonosulfate) provides aldehyde (XI), which is then subjected to cyclization by means of TFA in CH2Cl2 to furnish the tetrahydropyridine derivative (XII).
| 【1】 del Fresno, M.; Bayes, M.; Castaner, R.M.; Sorbera, L.A.; MDL-100240. Drugs Fut 2002, 27, 5, 458. |
| 【2】 Flynn, G.A.; Warshawsky, A.M.; Mehdi, S.; Bey, P.; Beight, D.W.; Giroux, E.L.; Burkholder, T.P. (Merrell Pharmaceuticals, Inc.); Novel mercaptoacetylamide derivs. useful as inhibitors of enkephalinase and ACE. EP 0481522; JP 1992282382; US 5430145 . |
| 【3】 Horgan, S.W.; Burkhouse, D.W.; Cregge, R.J.; et al.; Process development in the synthesis of the ACE intermediate MDL 28,726. Org Process Res Dev 1999, 3, 4, 241. |
| 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) | 13684 | 3,4-Dihydro-2H-pyran;2,3-Dihydro-4H-pyran; 5,6-Dihydro-4H-pyran;Dihydropyran | 110-87-2 | C5H8O | 详情 | 详情 |
| (II) | 50628 | 5-(4-hydroxybutyl)-2,4-imidazolidinedione | C7H12N2O3 | 详情 | 详情 | |
| (III) | 53406 | lithium 2-amino-6-hydroxyhexanoate | n/a | C6H12LiNO3 | 详情 | 详情 |
| (IV) | 53407 | lithium (2S)-2-amino-6-hydroxyhexanoate | n/a | C6H12LiNO3 | 详情 | 详情 |
| (V) | 22488 | methyl (2S)-2-amino-6-hydroxyhexanoate | C7H15NO3 | 详情 | 详情 | |
| (VI) | 52756 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl chloride | C17H12ClNO3 | 详情 | 详情 | |
| (VII) | 37294 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]amino]-6-hydroxyhexanoate | C24H26N2O6 | 详情 | 详情 | |
| (VIII) | 13952 | (S)-(-)-Phenylalanine; L-Phenylalanine | 63-91-2 | C9H11NO2 | 详情 | 详情 |
| (IX) | 11900 | 2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride | 85-44-9 | C8H4O3 | 详情 | 详情 |
| (X) | 37293 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropionic acid | 5123-55-7 | C17H13NO4 | 详情 | 详情 |
| (XI) | 37295 | methyl (2S)-2-[[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]amino]-6-oxohexanoate | C24H24N2O6 | 详情 | 详情 | |
| (XII) | 37296 | methyl (2S)-1-[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylate | C24H22N2O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Treatment of 2-cyclohexenone (XXI) with SO2Cl2 and 2,6-lutidine in dichloromethane provides 2-chloro-2-cyclohexenone (XXII), which is reduced with (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]-oxazaborole and borane dimethyl sulfide complex in THF/MeOH giving (R)-2-chloro-2-cyclohexen-1-ol (XXIII). Reaction of (XXIII) with trichloroacetonitrile by means of NaH in diethyl ether gives the cyclohexenol derivative (XXIV), which is converted into acetamide (XXV) by heating at 140 C in chlorobenzene. Hydrolysis of (XXV) with K2CO3 in water/methanol affords (S)-2-chloro-2-cyclohexen-1-amine (XXVI), which is then condensed with N-phthaloyl-L-phenylalanine acid chloride (VI) in ethyl acetate to yield amide (XXVII). Finally, ozonolysis of amide (XXVII) in CH2Cl2/MeOH, followed by reduction with tributylphosphine and treatment with TFA in refluxing CH2Cl2 provides the previously described intermediate (XII).
| 【1】 del Fresno, M.; Bayes, M.; Castaner, R.M.; Sorbera, L.A.; MDL-100240. Drugs Fut 2002, 27, 5, 458. |
| 【2】 Flynn, G.A. (Merrell Pharmaceuticals, Inc.); Novel process for preparing (S)-1-[2(S)-(1,3-dihydro-1,3-dioxo-isoindo-2-yl)-1-oxo-3-phenylpropyl]-1,2,3,4-tetrahydro-2-pyridine-carboxylic acid methyl ester and intermediates thereof. WO 9514663 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 28292 | (S)-Methyl oxazaborolidine; (3aS)-1-methyl-3,3-diphenyltetrahydro-3H-pyrrolo[1,2-c][1,3,2]oxazaborole | 112022-81-8 | C18H20BNO | 详情 | 详情 | |
| (VI) | 52756 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl chloride | C17H12ClNO3 | 详情 | 详情 | |
| (XII) | 37296 | methyl (2S)-1-[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]-1,2,3,4-tetrahydro-2-pyridinecarboxylate | C24H22N2O5 | 详情 | 详情 | |
| (XXI) | 26253 | 2-cyclohexen-1-one；Cyclohex-2-enone；2-cyclohexenone | 930-68-7 | C6H8O | 详情 | 详情 |
| (XXII) | 53409 | 2-chloro-2-cyclohexen-1-one | n/a | C6H7ClO | 详情 | 详情 |
| (XXIII) | 53410 | (1R)-2-chloro-2-cyclohexen-1-ol | n/a | C6H9ClO | 详情 | 详情 |
| (XXIV) | 53411 | (1R)-2-chloro-2-cyclohexen-1-yl 2,2,2-trichloroethanimidoate | n/a | C8H9Cl4NO | 详情 | 详情 |
| (XXV) | 53412 | 2,2,2-trichloro-N-[(1S)-2-chloro-2-cyclohexen-1-yl]acetamide | n/a | C8H9Cl4NO | 详情 | 详情 |
| (XXVI) | 53413 | (1S)-2-chloro-3-cyclohexen-1-amine; (1S)-2-chloro-3-cyclohexen-1-ylamine | n/a | C6H10ClN | 详情 | 详情 |
| (XXVII) | 53414 | (2S)-N-[(1S)-2-chloro-3-cyclohexen-1-yl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanamide | n/a | C23H21ClN2O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)Treatment of N-phthaloyl-L-phenylalanine acid chloride (VI) with 2,6-dicyanopiperidine (XXXIII) [obtained by reaction of glutaric dialdehyde (XXXIV) with NaCN and ammonium chloride in water] by means of potassium tert-butoxide in ice/carbon tetrachloride gives the tetrahydropyridine derivative (XXXV), which is then subjected to cyclization with H2SO4 and trifluoroacetic acid anhydride to yield the benzazepine derivative (XXXVI). Hydrolysis of the cyano group of (XXXVI) with water yields the carboxylic acid (XXXVII), from which the desired diastereomer (XXXVIII) is separated by chromatography. Removal of the phthaloyl moiety of compound (XXXVIII) by treatment with hydrazine monohydrate and Et3N in refluxing MeOH affords the amino derivative (XXXIX), which is then condensed with 2(R)-bromopropionic acid (XXXI) by means of N-hydroxysuccinimide (HOSu) and 1,3-dicyclohexylcarbodiimide (DCC) in THF resulting in amide (XL). Finally, MDL-100240 is obtained by reaction of (XL) with thioacetic acid and KOH in acetone. Treatment of acid chloride (VI) with ammonia provides amide (XLI), which by reaction with glutaric dialdehyde (XXXIV) in refluxing CH2Cl2 affords the pyridine derivative (XLII). Cyclization of (XLII) with either trifluoromethanesulfonic acid in CH2Cl2 or H2SO4 and trifluoroacetic acid anhydride yields the pyridobenzodiazepine derivative (XLIII), which is finally converted into intermediate (XXXVIII) by introduction of a carboxylic group by reaction with either H2SO4 and formic acid or H2SO4 and carbon monoxide.
| 【1】 del Fresno, M.; Bayes, M.; Castaner, R.M.; Sorbera, L.A.; MDL-100240. Drugs Fut 2002, 27, 5, 458. |
| 【2】 Flynn, G.A.; Beight, D.W.; Genin, M.J.; Bannister, T.D. (Aventis Pharmaceuticals, Inc.); Novel processes for preparing intermediates of inhibitors of enkephalinase and angiotensin converting enzyme and intermediates thereof. WO 9619492 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 52756 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl chloride | C17H12ClNO3 | 详情 | 详情 | |
| (XXXII) | 53417 | (2R)-2-bromo-3-phenylpropanoic acid | n/a | C9H9BrO2 | 详情 | 详情 |
| (XXXIII) | 53419 | 2,6-piperidinedicarbonitrile | 41980-31-8 | C7H9N3 | 详情 | 详情 |
| (XXXIV) | 53423 | pentanedial | 111-30-8 | C5H8O2 | 详情 | 详情 |
| (XXXV) | 53420 | 1-[(2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanoyl]-1,2,3,4-tetrahydro-2-pyridinecarbonitrile | n/a | C23H19N3O3 | 详情 | 详情 |
| (XXXVI) | 53421 | (7S)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carbonitrile | n/a | C23H19N3O3 | 详情 | 详情 |
| (XXXVII) | 53422 | (7S)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylic acid | n/a | C23H20N2O5 | 详情 | 详情 |
| (XXXVIII) | 49788 | (4S,7S,12bR)-7-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylic acid | C23H20N2O5 | 详情 | 详情 | |
| (XXXIX) | 53427 | (4S,7S,12bR)-7-amino-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylic acid | n/a | C15H18N2O3 | 详情 | 详情 |
| (XL) | 53428 | (4S,7S,12bR)-7-{[(2R)-2-bromo-3-phenylpropanoyl]amino}-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylic acid | n/a | C24H25BrN2O4 | 详情 | 详情 |
| (XLI) | 53425 | (2S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropanamide | n/a | C17H14N2O3 | 详情 | 详情 |
| (XLII) | 53426 | 2-{(1S)-1-benzyl-2-oxo-2-[1(4H)-pyridinyl]ethyl}-1H-isoindole-1,3(2H)-dione | n/a | C22H18N2O3 | 详情 | 详情 |
| (XLIII) | 43424 | 9H-fluoren-9-ylmethyl (4S)-4-[(tert-butoxycarbonyl)amino]-5-[(2,5-dioxo-1-pyrrolidinyl)oxy]-5-oxopentylcarbamate | C29H33N3O8 | 详情 | 详情 |