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【结 构 式】 
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【分子编号】60678 【品名】(1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one 【CA登记号】 |
【 分 子 式 】C9H14O 【 分 子 量 】138.20956 【元素组成】C 78.21% H 10.21% O 11.58% |
合成路线1
该中间体在本合成路线中的序号：(A)The precursor amino alcohol (XXVIII) was prepared by the following synthetic routes. Claisen orthoester rearrangement of (-)-myrtenol (XXIII) with triethyl orthoacetate at 165-195 C afforded the gamma,delta-unsaturated ester (XXIV). Subsequent ozonolysis of the exocyclic double bond gave rise to keto ester (XXV). Alternatively, keto ester (XXV) was obtained as the major diastereoisomer by alkylation of the lithium enolate of (R)-(+)-nopinone (XXVI) with ethyl bromoacetate in the presence of 1,3-dimethyl-2-imidazolidinone (DMI). Ketone (XXV) was either converted to oxime (XXVI) or to O-methyl oxime (XXVII) by treatment with hydroxylamine or O-methyl hydroxylamine, respectively. Reduction of the hydroxyimino and ester groups of (XXVI) to the key amino alcohol intermediate (XXVIII) was performed by using the combination LiAlH4/AlCl3 or with NaBH4 in the presence of several Lewis acids. The O-methyl oxime (XXVII) was directly reduced to amino alcohol (XXVIII) employing NaBH4 in the presence of boron trifluoride etherate or AlCl3 or, alternatively, with sodium metal in n-propanol. Optionally, the oxime ester (XXVII) was converted to (XXVIII) in a two step procedure, by first reduction of the ester group to alcohol (XXIX) with sodium bis(2-methoxyethoxy)aluminium hydride, and then reduction of the O-methyl oxime with sodium in n-propanol.
| 【1】 Arimura, A.; Honma, T.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Benzothiophenecarboxamide derivs. and PGD2 antagonists comprising them. EP 0944614; JP 2000514824; US 6083974; WO 9825919 . |
| 【2】 Hiramatsu, Y.; Honma, T.; Mitsumori, S. (Shionogi & Co. Ltd.); Novel process for producing bicyclic amino alcohol. EP 1193243; WO 0102334 . |
| 【3】 Okada, T.; Honma, T.; Kakinuma, M.; Hiramatsu, Y. (Shionogi & Co. Ltd.); Process for producing benzothiophenecarboxylic acid amide derivs.. EP 1069123; WO 9950261 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (B) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (A) | 60678 | (1R,5S)-6,6-dimethylbicyclo[3.1.1]heptan-2-one | C9H14O | 详情 | 详情 | |
| (XXIII) | 51423 | [(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanol | C10H16O | 详情 | 详情 | |
| (XXIV) | 52246 | ethyl 2-(6,6-dimethyl-2-methylidenebicyclo[3.1.1]hept-3-yl)acetate | C14H22O2 | 详情 | 详情 | |
| (XXV) | 52247 | ethyl 2-(6,6-dimethyl-2-oxobicyclo[3.1.1]hept-3-yl)acetate | C13H20O3 | 详情 | 详情 | |
| (XXVI) | 52251 | ethyl 2-[2-(hydroxyimino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]acetate | C13H21NO3 | 详情 | 详情 | |
| (XXVII) | 52246 | ethyl 2-(6,6-dimethyl-2-methylidenebicyclo[3.1.1]hept-3-yl)acetate | C14H22O2 | 详情 | 详情 | |
| (XXVIII) | 52250 | 2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)-1-ethanol | C11H21NO | 详情 | 详情 | |
| (XXIX) | 60679 | (1R,3R,5R)-3-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyloxime | C12H21NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVI)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 |