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【结 构 式】 
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【分子编号】12312 【品名】(2S)-3-[1-(tert-Butoxycarbonyl)-1H-imidazol-5-yl]-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propionic acid 【CA登记号】 |
【 分 子 式 】C30H36N4O7 【 分 子 量 】564.6386 【元素组成】C 63.82% H 6.43% N 9.92% O 19.83% |
合成路线1
该中间体在本合成路线中的序号：(I)1) Synthesis of N(tau)-tert-butoxycarbonyl-N(alpha)-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine: The condensation of diethyl succinate (III) with 1-naphthaldehyde (IV) by means of sodium ethoxide in refluxing methanol gives 2-(1-naphthylmethylene)succinic acid diethyl ester (V), which is hydrolyzed to the corresponding acid (VI) with NaOH. The cyclization of (VI) with refluxing SOCl2 affords the anhydride (VII), which is treated with morpholine (VIII) in ethyl acetate, yielding 2-(morpholinocarbonylmethyl)-3-(1-naphthyl)acrylic acid (IX). Hydrogenation of (IX) with H2 over Pd/C in methanol affords the corresponding propionic acid (X), which is then condensed with histidine methyl ester (XI) by means of DCC and HONB as before, giving a racemic mixture that is submitted to optical resolution by repeated crystallization of its salycylic acid salt, thus yielding N-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine methyl ester (XII). Finally, this compound is hydrolyzed with NaOH and protected with tert-butoxycarbonyl anhydride to give (I).
| 【1】 Harada, H.; Iyobe, A.; Tsubaki, A.; Yamaguchi, T.; Kamijo, T.; Kiso, Y.; Iizuka, K.; Hirata, K.; A practical synthesis of an orally potent renin inhibitor, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-[N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naaphthyl)propionyl]-L-histidyl]aminobutyrate. J Chem Soc - Perkins Trans I 1990, 9, 2497-500. |
| 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) | 12312 | (2S)-3-[1-(tert-Butoxycarbonyl)-1H-imidazol-5-yl]-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propionic acid | C30H36N4O7 | 详情 | 详情 | |
| (III) | 12313 | diethyl succinate | 123-25-1 | C8H14O4 | 详情 | 详情 |
| (IV) | 12314 | 1-Naphthaldehyde | 66-77-3 | C11H8O | 详情 | 详情 |
| (V) | 12315 | diethyl 2-[(Z)-1-naphthylmethylidene]succinate | C19H20O4 | 详情 | 详情 | |
| (VI) | 12316 | 2-[(Z)-1-Naphthylmethylidene]succinic acid | C15H12O4 | 详情 | 详情 | |
| (VII) | 12317 | 3-[(Z)-1-Naphthylmethylidene]-2,5(4H)-furandione | C15H10O3 | 详情 | 详情 | |
| (VIII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (IX) | 12319 | (Z)-2-(2-Morpholino-2-oxoethyl)-3-(1-naphthyl)-2-propenoic acid | C19H19NO4 | 详情 | 详情 | |
| (X) | 12320 | 4-Morpholino-2-(1-naphthylmethyl)-4-oxobutyric acid | C19H21NO4 | 详情 | 详情 | |
| (XI) | 12321 | methyl (2S)-2-amino-3-(1H-imidazol-5-yl)propanoate; Methyl-L-histidine | 1499-46-3 | C7H11N3O2 | 详情 | 详情 |
| (XII) | 12322 | methyl (2S)-3-(1H-imidazol-5-yl)-2-[[(2R)-4-morpholino-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propanoate | C26H30N4O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)2) Synthesis of (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester (II): Phenylalanine methyl ester (XIII) is protected with isopropyl chloroformate and triethylamine in THF to give N-(isopropoxycarbonyl)phenylalanine methyl ester (XIV), which is reduced with NaBH4 - LiCl in THF - ethanol, yielding N-(isopropoxycarbonyl)phenylalaninol (XV). The hydrogenation of (XV) with H2 over Rh/Al2O3 in methanol affords N-(isopropoxycarbonyl)cyclohexylalaninol (XVI), which is oxidized with pyridine - SO3 in DMSO to the corresponding aldehyde (XVII). The reaction of (XVII) with NaCN - HCl in CHCl3 - water affords (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid (XVIII), which is finally esterified with isopropanol - HCl to give (II). 3) Synthesis of KRY-1314: By condensation of N(tau)-tert-butoxycarbonyl-N(alpha)-[2(R)-(morpholinocarbonylmethyl)-3-(1-naphthyl)propionyl]histidine (I) with (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid isopropyl ester (II) by means of dicyclohexylcarbodiimide (DCC) and N-hydroxy-5-norbornene-2,3-dicarboximide (HONB) in acetonitrile - triethylamine.
| 【1】 Harada, H.; Iyobe, A.; Tsubaki, A.; Yamaguchi, T.; Kamijo, T.; Kiso, Y.; Iizuka, K.; Hirata, K.; A practical synthesis of an orally potent renin inhibitor, isopropyl (2R,3S)-4-cyclohexyl-2-hydroxy-3-[N-[(2R)-2-morpholinocarbonylmethyl-3-(1-naaphthyl)propionyl]-L-histidyl]aminobutyrate. J Chem Soc - Perkins Trans I 1990, 9, 2497-500. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 26492 | 2-[(chlorocarbonyl)oxy]propane | 108-23-6 | C4H7ClO2 | 详情 | 详情 | |
| (I) | 12312 | (2S)-3-[1-(tert-Butoxycarbonyl)-1H-imidazol-5-yl]-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propionic acid | C30H36N4O7 | 详情 | 详情 | |
| (II) | 12323 | isopropyl (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutanoate | C13H25NO3 | 详情 | 详情 | |
| (XIII) | 12324 | methyl (2R)-2-amino-3-phenylpropanoate | 21685-51-8 | C10H13NO2 | 详情 | 详情 |
| (XIV) | 12325 | methyl (2S)-2-[(isopropoxycarbonyl)amino]-3-phenylpropanoate | C14H19NO4 | 详情 | 详情 | |
| (XV) | 12326 | isopropyl N-[(1S)-1-benzyl-2-hydroxyethyl]carbamate | C13H19NO3 | 详情 | 详情 | |
| (XVI) | 12327 | isopropyl N-[(1S)-2-cyclohexyl-1-(hydroxymethyl)ethyl]carbamate | C13H25NO3 | 详情 | 详情 | |
| (XVII) | 12328 | isopropyl N-[(1S)-2-cyclohexyl-1-formylethyl]carbamate | C13H23NO3 | 详情 | 详情 | |
| (XVIII) | 12329 | (2R,3S)-3-Amino-4-cyclohexyl-2-hydroxybutyric acid | C10H19NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VI)3-Phenylindan-1-one (III) is prepared by either condensation between cinnamic acid (I) and benzene in the presence of AlCl3 or by Friedel-Crafts cyclization of 3,3-diphenylpropionic acid (II) in hot polyphosphoric acid. Claisen condensation of indanone (III) with diethyl carbonate affords keto ester (IV), which is further converted to enamino ester (V) upon treatment with ammonium acetate in boiling EtOH. Clauson-Kaas condensation of aminoindene (V) with 2,5-dimethoxytetrahydrofuran (VI) provides a mixture of isomeric pyrrolyl indenes (VII) and (VIII). Subsequent reduction of this mixture with NaBH4/NiCl2 affords the epimeric mixture of indanes (IX). Alkaline hydrolysis of esters (IX) proceeds with epimerization at C-2 to furnish the trans-trans acid (X). After activation of acid (X) as the corresponding mixed anhydride with ethyl chloroformate, coupling with pyrrolidine yields the target amide.
| 【1】 Rault, S.; Jarry, C.; Bovy, P.R.; Sopkova, J.; Dallemagne, P.; Guillon, J.; Leger, J.-M.; Synthesis of a novel class of non-peptide NK-2 receptor ligand, derived from 1-phenyl-3-pyrrol-1-ylidan-2-carboxamides. Bioorg Med Chem 2002, 10, 4, 1043. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IXa) | 57778 | ethyl (1S,2S,3S)-1-phenyl-3-(1H-pyrrol-1-yl)-2,3-dihydro-1H-indene-2-carboxylate | C22H21NO2 | 详情 | 详情 | |
| (IXb) | 57779 | ethyl (1S,2R,3S)-1-phenyl-3-(1H-pyrrol-1-yl)-2,3-dihydro-1H-indene-2-carboxylate | C22H21NO2 | 详情 | 详情 | |
| (I) | 37680 | (2E)-3-phenyl-2-propenoic acid; trans-Cinnamic acid; trans-3-Phenylacrylic acid | 140-10-3 | C9H8O2 | 详情 | 详情 |
| (II) | 57773 | 3-Phenyl-1-indanone | 16618-72-7 | C15H12O | 详情 | 详情 |
| (III) | 36717 | 3,3-diphenylpropionic acid | 606-83-7 | C15H14O2 | 详情 | 详情 |
| (IV) | 57774 | ethyl (2R,3S)-1-oxo-3-phenyl-2,3-dihydro-1H-indene-2-carboxylate | C18H16O3 | 详情 | 详情 | |
| (V) | 57775 | ethyl (1S)-3-amino-1-phenyl-1H-indene-2-carboxylate | C18H17NO2 | 详情 | 详情 | |
| (VI) | 12312 | (2S)-3-[1-(tert-Butoxycarbonyl)-1H-imidazol-5-yl]-2-[[(2R)-4-(4-morpholinyl)-2-(1-naphthylmethyl)-4-oxobutanoyl]amino]propionic acid | C30H36N4O7 | 详情 | 详情 | |
| (VII) | 57776 | ethyl 1-phenyl-3-(1H-pyrrol-1-yl)-1H-indene-2-carboxylate | C22H19NO2 | 详情 | 详情 | |
| (VIII) | 57777 | ethyl 3-phenyl-1-(1H-pyrrol-1-yl)-1H-indene-2-carboxylate | C22H19NO2 | 详情 | 详情 | |
| (X) | 57780 | (1S,2R,3S)-1-phenyl-3-(1H-pyrrol-1-yl)-2,3-dihydro-1H-indene-2-carboxylic acid | C20H17NO2 | 详情 | 详情 |