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【结 构 式】 
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【药物名称】AP-22408 【化学名称】4-[2(S)-(Acetamido)-3-[3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5(S)-ylamino]-3-oxopropyl]benzene-1,2-diphosphonic acid 【CA登记号】268741-43-1 【 分 子 式 】C30H41N3O10P2 【 分 子 量 】665.62297 |
【开发单位】Ariad Pharmaceuticals (Originator) 【药理作用】Bone Diseases, Treatment of, Bone Resorption Inhibitors, METABOLIC DRUGS, Treatment of Osteoporosis, Src Kinase Inhibitors |
合成路线1
After protection of (I) as the N-Boc derivative (II), sulfonylation of the phenolic hydroxyl groups using N-phenyl-bis(trifluoromethanesulfonimide) produced the bis(triflate) (III). The triflate groups of (III) were then displaced by diethyl phosphite, yielding phosphonate (IV). Hydrolysis of the methyl ester group with LiOH provided the corresponding carboxylic acid (V).
| 【1】 Bohacek, R.; Yang, M.; Shakespeare, W.; et al.; Structure-based design of an osteoclast-selective, nonpeptide Src homology 2 inhibitor with in vivo antiresorptive activity. Proceedings of the National Academy of Sciences of the United States of America 2000, 97, 17, 9373. |
| 【2】 Bohacek, R.; Sawyer, T.K.; Yang, M.G.; Eyermann, C.J.; Sundaramoorthi, R.; Shakespeare, W.C. (Ariad Pharmaceuticals Inc.); Bicyclic signal transduction inhibitors, compsns. containing them & uses thereof. WO 0027802 . |
| 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) | 29568 | methyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate | C10H13NO4 | 详情 | 详情 | |
| (II) | 43265 | methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,4-dihydroxyphenyl)propanoate | C15H21NO6 | 详情 | 详情 | |
| (III) | 43266 | methyl (2S)-3-(3,4-bis[[(trifluoromethyl)sulfonyl]oxy]phenyl)-2-[(tert-butoxycarbonyl)amino]propanoate | C17H19F6NO10S2 | 详情 | 详情 | |
| (IV) | 43267 | methyl (2S)-3-[3,4-bis(diethoxyphosphoryl)phenyl]-2-[(tert-butoxycarbonyl)amino]propanoate | C23H39NO10P2 | 详情 | 详情 | |
| (V) | 43268 | (2S)-3-[3,4-bis(diethoxyphosphoryl)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid | C22H37NO10P2 | 详情 | 详情 |
合成路线2
Condensation of 6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ol (VI) with (bromomethyl)cyclohexane (VII) in the presence of Cs2CO3 gave ether (VIII). Benzylic oxidation of (VIII) to provide ketone (IX) was effected by treatment with potassium persulfate in the presence of cupric sulfate. Subsequent reduction of (IX) with NaBH4 yielded alcohol (X), which was converted to azide (XI) using diphenylphosphoryl azide and DBU. Catalytic hydrogenation of the azido group of (XI) in the presence of Boc2O produced carbamate (XII). Bromination of (XII) at position 3 was carried out by means of N-bromosuccinimide in acetonitrile. The resulting aryl bromide (XIII) was lithiated with butyllithium in cold THF and subsequently converted to carboxylic acid (XIV) by quenching with CO2 gas. Coupling of acid (XIV) with ammonia by means of EDC and HOBt afforded amide (XV). The Boc group of (XV) was then removed by treatment with trifluoroacetic acid to furnish the racemic amine (XVI).
| 【1】 Bohacek, R.; Sawyer, T.K.; Yang, M.G.; Eyermann, C.J.; Sundaramoorthi, R.; Shakespeare, W.C. (Ariad Pharmaceuticals Inc.); Bicyclic signal transduction inhibitors, compsns. containing them & uses thereof. WO 0027802 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 43269 | 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-ol | C11H14O | 详情 | 详情 | |
| (VII) | 31767 | 1-(bromomethyl)cyclohexane | 2550-36-9 | C7H13Br | 详情 | 详情 |
| (VIII) | 43270 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene; cyclohexylmethyl 6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl ether | C18H26O | 详情 | 详情 | |
| (IX) | 43271 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H24O2 | 详情 | 详情 | |
| (X) | 43272 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ol | C18H26O2 | 详情 | 详情 | |
| (XI) | 43273 | 5-azido-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-2-yl cyclohexylmethyl ether; 5-azido-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene | C18H25N3O | 详情 | 详情 | |
| (XII) | 43274 | tert-butyl 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H35NO3 | 详情 | 详情 | |
| (XIII) | 43275 | tert-butyl 3-bromo-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H34BrNO3 | 详情 | 详情 | |
| (XIV) | 43276 | 9-[(tert-butoxycarbonyl)amino]-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxylic acid | C24H35NO5 | 详情 | 详情 | |
| (XV) | 43277 | tert-butyl 3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C24H36N2O4 | 详情 | 详情 | |
| (XVI) | 43278 | 9-amino-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxamide | C19H28N2O2 | 详情 | 详情 |
合成路线3
An alternative procedure has been reported for the synthesis of the chiral (S)-amine (XXIV). Ketone (IX) was treated with O-methyl hydroxylamine to afford a geometric mixture of O-methyl oximes, from which isomer (XVII) was isolated by silica gel chromatography. Asymmetric reduction of the O-methyl oxime (XVII) with borane in the presence of the chiral auxiliary (XVIII) furnished the desired (S)-amine (XIX), which was further protected as the tert-butyl carbamate (XX) by treatment with Boc2O. Bromide (XXI), carboxylic acid (XXII) and amide (XXIII) were obtained following the same procedures as above. Then, acid cleavage of the Boc group of (XXIII) yielded the chiral amine (XXIV).
| 【1】 Bohacek, R.; Yang, M.; Shakespeare, W.; et al.; Structure-based design of an osteoclast-selective, nonpeptide Src homology 2 inhibitor with in vivo antiresorptive activity. Proceedings of the National Academy of Sciences of the United States of America 2000, 97, 17, 9373. |
| 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) | 43271 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one | C18H24O2 | 详情 | 详情 | |
| (XVII) | 43279 | 2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-one O-methyloxime | C19H27NO2 | 详情 | 详情 | |
| (XVIII) | 10103 | (2R)-2-Amino-3-methyl-1,1-diphenyl-1-butanol | 56755-20-5 (hydrochloride) | C17H21NO | 详情 | 详情 |
| (XIX) | 43281 | (5S)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylamine; (5S)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-amine | C18H27NO | 详情 | 详情 | |
| (XX) | 43282 | tert-butyl (5S)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H35NO3 | 详情 | 详情 | |
| (XXI) | 43283 | tert-butyl (5S)-3-bromo-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C23H34BrNO3 | 详情 | 详情 | |
| (XXII) | 43284 | (9S)-9-[(tert-butoxycarbonyl)amino]-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxylic acid | C24H35NO5 | 详情 | 详情 | |
| (XXIII) | 43285 | tert-butyl (5S)-3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-ylcarbamate | C24H36N2O4 | 详情 | 详情 | |
| (XXIV) | 43286 | (9S)-9-amino-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxamide | C19H28N2O2 | 详情 | 详情 |
合成路线4
Coupling of carboxylic acid (V) with either the racemic amine (XVI) or the chiral amine (XXIV) in the presence of EDC and HOBt, followed by trifluoroacetic acid-promoted cleavage of the Boc group, furnished the diastereomeric mixture of amides (XXV) or the pure (S,S)-isomer (XXVI), respectively. Isomer (XXVI) was also obtained by separation of the diastereomeric mixture (XXV) by means of preparative reverse-phase HPLC. Acetylation of the amino group of (XXVI) with acetic anhydride gave amide (XXVII). Finally, the ethyl phosphonate esters of (XXVII) were hydrolyzed by means of trimethylsilyl iodide in acetonitrile.
| 【1】 Bohacek, R.; Yang, M.; Shakespeare, W.; et al.; Structure-based design of an osteoclast-selective, nonpeptide Src homology 2 inhibitor with in vivo antiresorptive activity. Proceedings of the National Academy of Sciences of the United States of America 2000, 97, 17, 9373. |
| 【2】 Bohacek, R.; Sawyer, T.K.; Yang, M.G.; Eyermann, C.J.; Sundaramoorthi, R.; Shakespeare, W.C. (Ariad Pharmaceuticals Inc.); Bicyclic signal transduction inhibitors, compsns. containing them & uses thereof. WO 0027802 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 43286 | (9S)-9-amino-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxamide | C19H28N2O2 | 详情 | 详情 | |
| (XVI) | 43278 | 9-amino-3-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene-2-carboxamide | C19H28N2O2 | 详情 | 详情 | |
| (XXIV) | 43268 | (2S)-3-[3,4-bis(diethoxyphosphoryl)phenyl]-2-[(tert-butoxycarbonyl)amino]propionic acid | C22H37NO10P2 | 详情 | 详情 | |
| (XXV) | 43287 | diethyl 4-((2S)-2-amino-3-[[3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-yl]amino]-3-oxopropyl)-2-(diethoxyphosphoryl)phenylphosphonate | C36H55N3O9P2 | 详情 | 详情 | |
| (XXVI) | 43288 | diethyl 4-((2S)-2-amino-3-[[(5S)-3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-yl]amino]-3-oxopropyl)-2-(diethoxyphosphoryl)phenylphosphonate | C36H55N3O9P2 | 详情 | 详情 | |
| (XXVII) | 43289 | diethyl 4-((2S)-2-(acetamido)-3-[[(5S)-3-(aminocarbonyl)-2-(cyclohexylmethoxy)-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-5-yl]amino]-3-oxopropyl)-2-(diethoxyphosphoryl)phenylphosphonate | C38H57N3O10P2 | 详情 | 详情 |