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【结 构 式】 
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【分子编号】60688 【品名】ethyl (Z)-7-[(1R,2R,3S,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptenoate 【CA登记号】 |
【 分 子 式 】C18H31NO2 【 分 子 量 】293.44968 【元素组成】C 73.67% H 10.65% N 4.77% O 10.9% |
合成路线1
该中间体在本合成路线中的序号：(XLIV)In a further method, the lithium acetylide of 2-(propargyloxy)tetrahydropyran (XXXIV) was alkylated with 1-bromo-3-chloropropane (XXXV) to afford chloride (XXXVI). Displacement of the Cl atom of (XXXVI) with NaCN yielded nitrile (XXXVII), which was further hydrolyzed to carboxylic acid (XXXVIII) under basic conditions. Esterification of (XXXVIII) with concomitant tetrahydropyranyl group cleavage in ethanolic H2SO4 gave hydroxy ester (XXXIX). Conversion of (XXXIX) to the corresponding mesylate, followed by treatment with KI, provided ethyl 7-iodo-5-heptynoate (XL). (R)-(+)-nopinone (XXVI) was then alkylated with the propargyl iodide (XL) in the presence of LDA to afford (XLI). Conversion of (XLI) to oxime (XLII), followed by reduction with TiCl3 and BH3•t-BuNH2, provided amino ester (XLIII). Then, partial hydrogenation of the triple bond of (XLIII) over Lindlar catalyst furnished the precursor aminoalkene ester (XLIV).
| 【1】 Cai, D.; Larsen, R.; Journet, M.; Campos, K. (Merck & Co., Inc.); Process for the preparation of PGD2 antagonist. WO 0232892 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXVI) | 60678 | (1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one | C9H14O | 详情 | 详情 | |
| (XXXIV) | 43835 | 2-propynyl tetrahydro-2H-pyran-2-yl ether; 2-(2-propynyloxy)tetrahydro-2H-pyran | 6089-04-9 | C8H12O2 | 详情 | 详情 |
| (XXXV) | 10358 | 1-Bromo-3-chloropropane | 109-70-6 | C3H6BrCl | 详情 | 详情 |
| (XXXVI) | 60680 | 2-[(6-chloro-2-hexynyl)oxy]tetrahydro-2H-pyran; 6-chloro-2-hexynyl tetrahydro-2H-pyran-2-yl ether | C11H17ClO2 | 详情 | 详情 | |
| (XXXVII) | 60681 | 7-(tetrahydro-2H-pyran-2-yloxy)-5-heptynenitrile | C12H17NO2 | 详情 | 详情 | |
| (XXXVIII) | 60682 | 7-(tetrahydro-2H-pyran-2-yloxy)-5-heptynoic acid | C12H18O4 | 详情 | 详情 | |
| (XXXIX) | 60683 | ethyl 7-hydroxy-5-heptynoate | C9H14O3 | 详情 | 详情 | |
| (XL) | 60684 | ethyl 7-iodo-5-heptynoate | C9H13IO2 | 详情 | 详情 | |
| (XLI) | 60685 | ethyl 7-[(1R,3R,5R)-6,6-dimethyl-2-oxobicyclo[3.1.1]hept-3-yl]-5-heptynoate | C18H26O3 | 详情 | 详情 | |
| (XLII) | 60686 | ethyl 7-[(1R,3R,5R)-2-(hydroxyimino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptynoate | C18H27NO3 | 详情 | 详情 | |
| (XLIII) | 60687 | ethyl 7-[(1R,2R,3R,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptynoate | C18H29NO2 | 详情 | 详情 | |
| (XLIV) | 60688 | ethyl (Z)-7-[(1R,2R,3S,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptenoate | C18H31NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XLIV)Coupling of amino ester (XLIV) with carboxylic acid (IX) by means of EDC and HOBt produced the corresponding amide ester (XLV). In a related procedure, the analogous amino methyl ester (XLVI) was coupled with acid chloride (XV) to yield amide (XLVII). The title compound was then obtained by hydrolysis of the ethyl ester (XLV) with LiOH or by NaOH hydrolysis of diester (XLVII).
| 【1】 Tsuri, T.; Honma, T.; Hiramatsu, Y.; Okada, T.; Hashizume, H.; Mitsumori, S.; Inagaki, M.; Arimura, A.; Yasui, K.; Asanuma, F.; Kishino, J.; Ohtani, M.; Bicyclo[2.2.1]heptane and 6,6-dimethylbicyclo[3.1.1]heptane derivatives: Orally active, potent, and selective prostaglandin D2 receptor antagonists. J Med Chem 1997, 40, 22, 3504. |
| 【2】 Arimura, A.; Honma, T.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Benzothiophenecarboxamide derivs. and PGD2 antagonists comprising them. EP 0944614; JP 2000514824; US 6083974; WO 9825919 . |
| 【3】 Cai, D.; Larsen, R.; Journet, M.; Campos, K. (Merck & Co., Inc.); Process for the preparation of PGD2 antagonist. WO 0232892 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 52240 | 5-hydroxy-1-benzothiophene-3-carboxylic acid | C9H6O3S | 详情 | 详情 | |
| (XV) | 52242 | 3-(chlorocarbonyl)-1-benzothiophen-5-yl acetate | C11H7ClO3S | 详情 | 详情 | |
| (XLIV) | 60688 | ethyl (Z)-7-[(1R,2R,3S,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptenoate | C18H31NO2 | 详情 | 详情 | |
| (XLV) | 60689 | ethyl (Z)-7-((1R,2R,3S,5R)-2-{[(5-hydroxy-1-benzothiophen-3-yl)carbonyl]amino}-6,6-dimethylbicyclo[3.1.1]hept-3-yl)-5-heptenoate | C27H35NO4S | 详情 | 详情 | |
| (XLVI) | 52243 | methyl (Z)-7-[(1R,2R,3S,5R)-2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptenoate | C17H29NO2 | 详情 | 详情 | |
| (XLVII) | 52244 | methyl 7-[2-({[5-(acetyloxy)-1-benzothiophen-3-yl]carbonyl}amino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-5-heptenoate | C28H35NO5S | 详情 | 详情 |