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【结 构 式】 
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【分子编号】25585 【品名】ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate 【CA登记号】 |
【 分 子 式 】C17H23N3O3 【 分 子 量 】317.38804 【元素组成】C 64.33% H 7.3% N 13.24% O 15.12% |
合成路线1
该中间体在本合成路线中的序号：(VII)Michael addition of acrylonitrile (II) to 2-methyl-3-aminopropionitrile (I) gave dinitrile (III), which was cyclized to piperidone (IV) under Thorpe-Ziegler conditions. After protection of (IV) as the carbamate (V), hydrolysis of the nitrile with 85% H2SO4 provided ketoamide (VI). This was converted to enamine (VII) by condensation with benzylamine in refluxing xylene. Subsequent treatment of (VII) with H2S in DMF, followed by bromine in AcOH furnished isothiazole (VIII). The ethoxycarbonyl group of (VIII) was then replaced for a tert-butoxycarbonyl group by hydrolysis with HBr in AcOH to (IX), and then reaction with Boc2O to give a N,O-di-Boc intermediate, which was further treated with K2CO3 in MeOH to afford (X). After alkylation of the hydroxyl group of (X) with propargyl bromide (XI), the tert-butyl carbamate was removed with ethereal HCl to yield the racemic isothiazolopyridine (XII). Finally, the (S)-(+)-enantiomer of (XII) was resolved by crystallization as the diastereomeric salt with D-(+)-dibenzoyltartaric acid and, after liberation of the base with NaOH, was isolated as the fumarate salt.
| 【1】 Pedersen, H.; et al.; Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline. Bioorg Med Chem 1999, 7, 5, 795. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 | |
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 25580 | 3-amino-2-methylpropanenitrile | C4H8N2 | 详情 | 详情 | |
| (II) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (III) | 25581 | 3-[(2-cyanoethyl)amino]-2-methylpropanenitrile | C7H11N3 | 详情 | 详情 | |
| (IV) | 25582 | 5-methyl-4-oxo-3-piperidinecarbonitrile | C7H10N2O | 详情 | 详情 | |
| (V) | 25583 | ethyl 3-cyano-5-methyl-4-oxo-1-piperidinecarboxylate | C10H14N2O3 | 详情 | 详情 | |
| (VI) | 25584 | ethyl 3-(aminocarbonyl)-5-methyl-4-oxo-1-piperidinecarboxylate | C10H16N2O4 | 详情 | 详情 | |
| (VII) | 25585 | ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate | C17H23N3O3 | 详情 | 详情 | |
| (VIII) | 25586 | ethyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate | C10H14N2O3S | 详情 | 详情 | |
| (IX) | 25587 | 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol | C7H10N2OS | 详情 | 详情 | |
| (X) | 25588 | tert-butyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate | C12H18N2O3S | 详情 | 详情 | |
| (XI) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (XII) | 25589 | 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-yl 2-propynyl ether | C10H12N2OS | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Michael addition of acrylonitrile (II) to 2-methyl-3-aminopropionitrile (I) gave dinitrile (III), which was cyclized to piperidone (IV) under Thorpe-Ziegler conditions. After protection of (IV) as the carbamate (V), hydrolysis of the nitrile with 85% H2SO4 provided ketoamide (VI). This was converted to enamine (VII) by condensation with benzylamine in refluxing xylene. Subsequent treatment of (VII) with H2S in DMF, followed by bromine in AcOH furnished isothiazole (VIII). The ethoxycarbonyl group of (VIII) was then replaced for a tert-butoxycarbonyl group by hydrolysis with HBr in AcOH to (IX), and then reaction with Boc2O to give a N,O-di-Boc intermediate, which was further treated with K2CO3 in MeOH to afford (X). After alkylation of the hydroxyl group of (X) with propargyl bromide (XI), the tert-butyl carbamate was removed with ethereal HCl to yield the racemic isothiazolopyridine (XII). Finally, the (R)-(-)-enantiomer of (XII) was resolved by crystallization as the diastereomeric salt with L-(-)-dibenzoyltartaric acid and, after liberation of the base with NaOH, was isolated as the fumarate salt .
| 【1】 Pedersen, H.; et al.; Synthesis and muscarinic receptor pharmacology of a series of 4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridine bioisosteres of arecoline. Bioorg Med Chem 1999, 7, 5, 795. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11229 | 1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate | 541-41-3 | C3H5ClO2 | 详情 | 详情 | |
| 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 | |
| (I) | 25580 | 3-amino-2-methylpropanenitrile | C4H8N2 | 详情 | 详情 | |
| (II) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (III) | 25581 | 3-[(2-cyanoethyl)amino]-2-methylpropanenitrile | C7H11N3 | 详情 | 详情 | |
| (IV) | 25582 | 5-methyl-4-oxo-3-piperidinecarbonitrile | C7H10N2O | 详情 | 详情 | |
| (V) | 25583 | ethyl 3-cyano-5-methyl-4-oxo-1-piperidinecarboxylate | C10H14N2O3 | 详情 | 详情 | |
| (VI) | 25584 | ethyl 3-(aminocarbonyl)-5-methyl-4-oxo-1-piperidinecarboxylate | C10H16N2O4 | 详情 | 详情 | |
| (VII) | 25585 | ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate | C17H23N3O3 | 详情 | 详情 | |
| (VIII) | 25586 | ethyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate | C10H14N2O3S | 详情 | 详情 | |
| (IX) | 25587 | 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-ol | C7H10N2OS | 详情 | 详情 | |
| (X) | 25588 | tert-butyl 3-hydroxy-7-methyl-6,7-dihydroisothiazolo[4,5-c]pyridine-5(4H)-carboxylate | C12H18N2O3S | 详情 | 详情 | |
| (XI) | 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 |
| (XII) | 25589 | 7-methyl-4,5,6,7-tetrahydroisothiazolo[4,5-c]pyridin-3-yl 2-propynyl ether | C10H12N2OS | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XXIII)In an alternative method, the aldehyde lactone (XXIII) was subjected to Wadsworth-Emmons reaction with phosphonate (IV) to afford enone (XXIV). Stereoselective ketone reduction, followed by catalytic hydrogenation of the resultant allylic alcohol (XXV), provided (XXVI). Both the benzoate ester and the lactone groups of (XXIV) were hydrolyzed by KOH, yielding trihydroxy acid (XXVII), which was further cyclized to lactone (XIV) in boiling toluene. The hydroxyl groups of (XIV) were then protected with ethyl vinyl ether in the presence of trichloroacetic acid to produce the bis-acetal (XXVIII). Reduction of the lactone function of (XXVIII) to the corresponding lactol (XXIX), followed by Wittig reaction with the phosphorane generated from phosphonium salt (XV) and potassium t-butoxide, furnished olefin (XXX). After acidic hydrolysis of the acetal protecting groups of (XXX), the carboxylate function was converted to the corresponding isopropyl ester by treatment with 2-iodopropane and cesium carbonate.
| 【1】 Henegar, K.E. (Pharmacia Corp.); Process and intermediates to prepare latanoprost. WO 0187816 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 59558 | dimethyl 2-oxo-4-phenylbutylphosphonate | C12H17O4P | 详情 | 详情 | |
| (XIV) | 59562 | (3aR,4R,5R,6aS)-5-hydroxy-4-[(3R)-3-hydroxy-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-one | C18H24O4 | 详情 | 详情 | |
| (XV) | 13616 | (4-Carboxybutyl)triphenylphosphonium bromide | 17814-85-6 | C23H24BrO2P | 详情 | 详情 |
| (XXIII) | 25585 | ethyl 5-(aminocarbonyl)-4-(benzylamino)-3-methyl-3,6-dihydro-1(2H)-pyridinecarboxylate | C17H23N3O3 | 详情 | 详情 | |
| (XXIV) | 59578 | (1S,2S,3aR,6aS)-5-methylene-1-[(1E)-3-phenethyl-1,3-butadienyl]-2-(2-phenyl-2-propenyl)octahydropentalene | C30H34 | 详情 | 详情 | |
| (XXV) | 59572 | (3aR,4R,5R,6aS)-4-[(E,3S)-3-hydroxy-5-phenyl-1-pentenyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate | C25H26O5 | 详情 | 详情 | |
| (XXVI) | 59573 | (3aR,4R,5R,6aS)-4-[(3R)-3-hydroxy-5-phenylpentyl]-2-oxohexahydro-2H-cyclopenta[b]furan-5-yl benzoate | C25H28O5 | 详情 | 详情 | |
| (XXVII) | 59574 | 2-{(1R,2R,3R,5S)-3,5-dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl}acetic acid | C18H26O5 | 详情 | 详情 | |
| (XXVIII) | 59575 | (3aR,4R,5R,6aS)-5-(1-ethoxyethoxy)-4-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-one | C26H40O6 | 详情 | 详情 | |
| (XXIX) | 59576 | (3aR,4R,5R,6aS)-5-(1-ethoxyethoxy)-4-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]hexahydro-2H-cyclopenta[b]furan-2-ol | C26H42O6 | 详情 | 详情 | |
| (XXX) | 59577 | (Z)-7-{(1R,2R,3R,5S)-3-(1-ethoxyethoxy)-2-[(3R)-3-(1-ethoxyethoxy)-5-phenylpentyl]-5-hydroxycyclopentyl}-5-heptenoic acid | C31H50O7 | 详情 | 详情 |