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【结 构 式】 
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【分子编号】29540 【品名】2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide 【CA登记号】 |
【 分 子 式 】C17H27N3O 【 分 子 量 】289.421 【元素组成】C 70.55% H 9.4% N 14.52% O 5.53% |
合成路线1
该中间体在本合成路线中的序号：(X)The reaction of succinic anhydride (I) with the lithium salt of the chiral oxazolidinone (II) in THF gives 3-(hydroxysucccinyl)-4(S)-isopropyloxazolidin-2-one (III), which is treated successively with oxalyl chloride, CH2N2 and HBr to yield the bromomethyl derivative (IV). The cyclization of (IV) with thiourea in refluxing isopropanol affords the 2-aminothiazol derivative (V), which is protected with 2,2,2-trichloroethyl chloroformate by means of DIEA and DMAP in dichloromethane giving the carbamate (VI). The reaction of (VI) with tert-butyl 2-bromoacetate (VII) by means of sodium hexamethyldisilazane (NaHMDS) in THF yields the chiral butyrate (VIII), which is hydrolyzed with TFA in dichloromethane to the chiral butyric acid (IX). The condensation of (IX) with the intermediate amine (X) by means of BOP-PF6 and DIEA in DMF affords the corresponding amide (XI), which is treated with magnesium methoxide in methanol to eliminate the oxazolidinone group (the chiral inductor) providing the methyl ester (XII). The hydrolysis of (XII) with NaOH, followed by condensation with amine (XIII) (J Org Chem 1988, 53: 6109; J Med Chem 1993, 36: 449) gives the protected intermediate (XIV), which is finally deprotected by reaction with Zn/HCl in aqueous dioxane.
| 【1】 Simoneau, B.; Lavallee, P.; Anderson, P.C.; et al.; Discovery of non-peptidic P2-P3 butanediamide renin inhibitors with high oral efficacy. Bioorg Med Chem 1999, 7, 3, 489. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 | |
| 13664 | 1,1,1-Trichloro-2-[(chlorocarbonyl)oxy]ethane; 2,2,2-Trichloroethyl chloroformate | 17341-93-4 | C3H2Cl4O2 | 详情 | 详情 | |
| (I) | 11291 | Dihydro-2,5-furandione; Succinic anhydride | 108-30-5 | C4H4O3 | 详情 | 详情 |
| (II) | 29533 | [(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]lithium | C6H10LiNO2 | 详情 | 详情 | |
| (III) | 29534 | 4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxobutyric acid | C10H15NO5 | 详情 | 详情 | |
| (IV) | 29535 | 5-bromo-1-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-1,4-pentanedione | C11H16BrNO4 | 详情 | 详情 | |
| (V) | 29536 | (4S)-3-[3-(2-amino-1,3-thiazol-4-yl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one | C12H17N3O3S | 详情 | 详情 | |
| (VI) | 29537 | 2,2,2-trichloroethyl 4-[3-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-3-oxopropyl]-1,3-thiazol-2-ylcarbamate | C15H18Cl3N3O5S | 详情 | 详情 | |
| (VII) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (VIII) | 29538 | tert-butyl (3R)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-3-[(2-[[(2,2,2-trichloroethoxy)carbonyl]amino]-1,3-thiazol-4-yl)methyl]butanoate | C21H28Cl3N3O7S | 详情 | 详情 | |
| (IX) | 29539 | (3R)-4-[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]-4-oxo-3-[(2-[[(2,2,2-trichloroethoxy)carbonyl]amino]-1,3-thiazol-4-yl)methyl]butyric acid | C17H20Cl3N3O7S | 详情 | 详情 | |
| (X) | 29540 | 2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide | C17H27N3O | 详情 | 详情 | |
| (XI) | 29541 | 2,2,2-trichloroethyl 4-((2R)-4-[(cyclohexylmethyl)(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)amino]-2-[[(4S)-4-isopropyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl]-4-oxobutyl)-1,3-thiazol-2-ylcarbamate | C34H45Cl3N6O7S | 详情 | 详情 | |
| (XII) | 29542 | methyl (2R)-4-[(cyclohexylmethyl)(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)amino]-4-oxo-2-[(2-[[(2,2,2-trichloroethoxy)carbonyl]amino]-1,3-thiazol-4-yl)methyl]butanoate | C29H38Cl3N5O6S | 详情 | 详情 | |
| (XIII) | 29543 | (2S,3R,4S)-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol | C14H29NO2 | 详情 | 详情 | |
| (XIV) | 29544 | 2,2,2-trichloroethyl 4-[(2R)-2-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-4-[(cyclohexylmethyl)(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)amino]-4-oxobutyl]-1,3-thiazol-2-ylcarbamate | C42H63Cl3N6O7S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)The intermediate amine (X) has been obtained as follows: The reaction of ethyl 2-bromoacetate (XV) with cyclohexylmethylamine (XVI) by means of Et3N in THF gives the N-(cyclohexylmethyl)glycine ethyl ester (XVII), which is protected with (Boc)2O in dichloromethane yielding (XVIII). The hydrolysis of (XVIII) with NaOH in water gives the corresponding free acid (XIX), which is condensed with 2-[2-(methylamino)ethyl]pyridine (XX) by means of BOP-PF6 and DIEA in DMF to provide the amide (XXI). Finally, this compound is deprotected with HCl in dioxane/water to obtain the ddesired intermediate (X).
| 【1】 Simoneau, B.; Lavallee, P.; Anderson, P.C.; et al.; Discovery of non-peptidic P2-P3 butanediamide renin inhibitors with high oral efficacy. Bioorg Med Chem 1999, 7, 3, 489. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 29540 | 2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide | C17H27N3O | 详情 | 详情 | |
| (XV) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (XVI) | 29545 | cyclohexylmethanamine; cyclohexylmethylamine | 3218-02-8 | C7H15N | 详情 | 详情 |
| (XVII) | 29546 | ethyl 2-[(cyclohexylmethyl)amino]acetate | C11H21NO2 | 详情 | 详情 | |
| (XVIII) | 29547 | ethyl 2-[(tert-butoxycarbonyl)(cyclohexylmethyl)amino]acetate | C16H29NO4 | 详情 | 详情 | |
| (XIX) | 29548 | 2-[(tert-butoxycarbonyl)(cyclohexylmethyl)amino]acetic acid | C14H25NO4 | 详情 | 详情 | |
| (XX) | 29549 | N-methyl-2-(2-pyridinyl)-1-ethanamine; N-methyl-N-[2-(2-pyridinyl)ethyl]amine | 5579-84-0 | C8H12N2 | 详情 | 详情 |
| (XXI) | 29550 | tert-butyl cyclohexylmethyl(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)carbamate | C22H35N3O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)The condensation of dimethyl malonate (I) with 2-cloroallyl chloride (II) by means of sodium methoxide in hot methanol gives the alkylmalonate (III), which is treated with tert-butyl bromoacetate (IV), NaOH and benzyltriethylammonium chloride to yield the tricarboxylic ester (V). Partial decarboxylation of (V) with KOH in hot methanol/water affords the succinic acid derivative (VI), which is submitted to enzymatic hydrolysis with Alcalase 2.4L to provide the chiral monoester (VII). The condensation of monoacid (VII) with amine (VIII) by means of HOBT, DCC, and DIEA in THF gives the amide (IX), which is treated with TFA to eliminate the tert-butyl protecting group yielding the acid (X). The condensation of (X) with amine (XI) by means of NMM and pivaloyl chloride affords the amide (XII), which is treated with 2-methoxypropene (XIII) and TsOH in dichloromethane to protect the vicinal hydroxy groups giving the dioxolane (XIV). The bromination of the allyl double bond of (XIV) with NBS in tert-butyl methyl ether/water gives 3-bromo-2-oxopropyl derivative (XV).
| 【1】 Beaulieu, P.L.; et al.; Practical synthesis of BILA 2157 BS, a potent and orally active renin inhibitor: Use of an enzayme-catalyzed hydrolysis for the preparation of homochiral succinic acid derivatives. J Org Chem 1999, 64, 18, 6622. |
| 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) | 19373 | dimethyl malonate；Methyl malonate;Propanedioic acid dimethyl ester | 108-59-8 | C5H8O4 | 详情 | 详情 |
| (II) | 31608 | 2,3-dichloro-1-propene | 78-88-6 | C3H4Cl2 | 详情 | 详情 |
| (III) | 31609 | dimethyl 2-(2-chloro-2-propenyl)malonate | C8H11ClO4 | 详情 | 详情 | |
| (IV) | 17430 | 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate | 5292-43-3 | C6H11BrO2 | 详情 | 详情 |
| (V) | 31610 | 1-(tert-butyl) 2,2-dimethyl 4-chloro-4-pentene-1,2,2-tricarboxylate | C14H21ClO6 | 详情 | 详情 | |
| (VI) | 31611 | 4-(tert-butyl) 1-methyl 2-(2-chloro-2-propenyl)succinate | C12H19ClO4 | 详情 | 详情 | |
| (VII) | 31612 | (2S)-2-[2-(tert-butoxy)-2-oxoethyl]-4-chloro-4-pentenoic acid | C11H17ClO4 | 详情 | 详情 | |
| (VIII) | 29543 | (2S,3R,4S)-2-amino-1-cyclohexyl-6-methyl-3,4-heptanediol | C14H29NO2 | 详情 | 详情 | |
| (IX) | 31613 | tert-butyl (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoate | C25H44ClNO5 | 详情 | 详情 | |
| (X) | 31614 | (3S)-5-chloro-3-([[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]amino]carbonyl)-5-hexenoic acid | C21H36ClNO5 | 详情 | 详情 | |
| (XI) | 29540 | 2-[(cyclohexylmethyl)amino]-N-methyl-N-[2-(2-pyridinyl)ethyl]acetamide | C17H27N3O | 详情 | 详情 | |
| (XII) | 31615 | (2S)-2-(2-chloro-2-propenyl)-N(4)-(cyclohexylmethyl)-N(1)-[(1S,2R,3S)-1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide | C38H61ClN4O5 | 详情 | 详情 | |
| (XIII) | 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 |
| (XIV) | 31616 | (2S)-2-(2-chloro-2-propenyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide | C41H65ClN4O5 | 详情 | 详情 | |
| (XV) | 31617 | (2R)-2-(3-bromo-2-oxopropyl)-N(1)-[(1S)-2-cyclohexyl-1-[(4R,5S)-5-isobutyl-2,2-dimethyl-1,3-dioxolan-4-yl]ethyl]-N(4)-(cyclohexylmethyl)-N(4)-(2-[methyl[2-(2-pyridinyl)ethyl]amino]-2-oxoethyl)butanediamide | C41H65BrN4O6 | 详情 | 详情 |