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【结 构 式】 
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【分子编号】52246 【品名】ethyl 2-(6,6-dimethyl-2-methylidenebicyclo[3.1.1]hept-3-yl)acetate 【CA登记号】 |
【 分 子 式 】C14H22O2 【 分 子 量 】222.32748 【元素组成】C 75.63% H 9.97% O 14.39% |
合成路线1
该中间体在本合成路线中的序号：(VIII)In an alternative method, (-)-myrtenol (VI) was heated with triethyl orthoacetate to produce an intermediate allyl vinyl ether (VII), which underwent Claisen rearrangement to the unsaturated ester (VIII). Ozonization of the olefin (VIII), followed by reductive treatment with trimethyl phosphite, furnished ketone (IX). Conversion of ketone (IX) into the required amine (XI) was effected via previous formation of either the oxime (XII) or the O-methyl oxime (X). Simultaneous reduction of the O-methyl oxime and ester functions of (X) was carried out by using NaBH4 in the presence of AlCl3 or, alternatively, with sodium metal and n-propanol, to produce the desired (2R,3R)-amino alcohol (XI) as the major diastereoisomer. Isolation of (XI) from the reaction mixture was achieved through formation of the corresponding benzoate salt. Amino alcohol (XI) was also obtained by reduction of oxime (XII) with NaBH4 in the presence of either boron trifluoride ethearate or TiCl4. Optionally, (X) was reduced in a two-step process by first conversion to alcohol (XIII) and subsequent reduction of the oxime function. Acid chloride (XIV) was prepared from 5-hydroxybenzothiophene-3-carboxylic acid (I) by sulfonylation of the phenolic hydroxyl with benzenesulfonyl chloride, followed by treatment with SOCl2. Condensation of acid chloride (XIV) with amine (XI) produced the corresponding amide (XV). The alcohol function of (XV) was oxidized to aldehyde (XVI) using NaOCl in the presence of catalytic amounts of TEMPO and KBr. Then Wittig condensation of aldehyde (XVI) with (4-carboxybutyl)triphenylphosphonium bromide (XVII), followed by basic hydrolysis of the phenylsulfonyl protecting group, gave rise to the title compound.
| 【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】 Arimura, A. (Shionogi & Co. Ltd.); Remedies for itching containing PGD2 antagonists. EP 1084711; WO 9962555 . |
| 【4】 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 |
|---|---|---|---|---|---|---|
| (I) | 52240 | 5-hydroxy-1-benzothiophene-3-carboxylic acid | C9H6O3S | 详情 | 详情 | |
| (VI) | 51423 | [(1R,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methanol | C10H16O | 详情 | 详情 | |
| (VII) | 52245 | (6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl 1-(ethyloxy)ethenyl ether; 2-({[1-(ethyloxy)ethenyl]oxy}methyl)-6,6-dimethylbicyclo[3.1.1]hept-2-ene | C14H22O2 | 详情 | 详情 | |
| (VIII) | 52246 | ethyl 2-(6,6-dimethyl-2-methylidenebicyclo[3.1.1]hept-3-yl)acetate | C14H22O2 | 详情 | 详情 | |
| (IX) | 52247 | ethyl 2-(6,6-dimethyl-2-oxobicyclo[3.1.1]hept-3-yl)acetate | C13H20O3 | 详情 | 详情 | |
| (X) | 52248 | ethyl 2-{6,6-dimethyl-2-[(methyloxy)imino]bicyclo[3.1.1]hept-3-yl}acetate | C14H23NO3 | 详情 | 详情 | |
| (XI) | 52250 | 2-(2-amino-6,6-dimethylbicyclo[3.1.1]hept-3-yl)-1-ethanol | C11H21NO | 详情 | 详情 | |
| (XII) | 52251 | ethyl 2-[2-(hydroxyimino)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]acetate | C13H21NO3 | 详情 | 详情 | |
| (XIII) | 52249 | 3-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-one O-methyloxime | C12H21NO2 | 详情 | 详情 | |
| (XIV) | 52252 | 3-(chlorocarbonyl)-1-benzothiophen-5-yl benzenesulfonate | C15H9ClO4S2 | 详情 | 详情 | |
| (XV) | 52253 | 3-({[3-(2-hydroxyethyl)-6,6-dimethylbicyclo[3.1.1]hept-2-yl]amino}carbonyl)-1-benzothiophen-5-yl benzenesulfonate | C26H29NO5S2 | 详情 | 详情 | |
| (XVI) | 52254 | 3-({[6,6-dimethyl-3-(2-oxoethyl)bicyclo[3.1.1]hept-2-yl]amino}carbonyl)-1-benzothiophen-5-yl benzenesulfonate | C26H27NO5S2 | 详情 | 详情 | |
| (XVII) | 37404 | (3-carboxypropyl)(triphenyl)phosphonium bromide | 17857-14-6 | C22H22BrO2P | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXVII)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3
该中间体在本合成路线中的序号：(XXIV)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 |