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【结 构 式】 
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【分子编号】14799 【品名】dimethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl)benzoyl]amino]pentanedioate 【CA登记号】 |
【 分 子 式 】C27H33N5O7 【 分 子 量 】539.58852 【元素组成】C 60.1% H 6.16% N 12.98% O 20.76% |
合成路线1
该中间体在本合成路线中的序号：(XIII)1) The condensation of ethyl cyanoacetate (I) with 2-bromoacetaldehyde diethylacetal (II) by means of K2CO3 gives the alkylated cyanoacetate (III), which is cyclized with guanidine (IV) and sodium ethoxide to the pyrimidinone (V). The acidic cyclization of (V) by means of 0.5 N HCl affords the pyrrolopyrimidinone (VI), which is acylated with pivaloyl chloride (VII) to the heterocyclic amide (VIII). The iodination of (VIII) with N-iodosuccinimide (NIS) gives the diiodo derivative (IX), which by selective deiodination with Zn/acetic acid yields the 5-iodo derivative (X). The condensation of (X) with N-(4-ethynylbenzoyl)-L-glutamic acid dimethyl ester (XI) by means of tetrakis(triphenylphosphine)palladium and CuI affords the expected condensation product (XII), which is reduced with H2 over Pd/C in methanol/dichloromethane to the saturated compound (XIII). Finally, this compound is saponified with NaOH.
| 【1】 Castaner, J.; Graul, A.; Tracy, M.; Penetrexed Disodium. Drugs Fut 1998, 23, 5, 498. |
| 【2】 Taylor, E.C.; Design and synthesis of inhibitors of folate-dependent enzymes as antitumor agents. Adv Exp Med Biol 1993, 338, 387-408. |
| 【3】 Taylor, E.C.; Kuhnt, D.G.; Shih, C.; Grindey, G.B. (Eli Lilly and Company; Princeton University); N-(Pyrrolo[2,3-d]pyrimidin-3-ylacyl)-glutamic acid derivs. AU 9167791; EP 0432677; JP 1996003166; US 5028608 . |
| 【4】 Jannatipour, M.; Kuhnt, D.; Shih, C.; Rinzel, S.M.; Grindey, G.B.; Taylor, E.C.; Moran, R.G.; Barredo, J.; A dideazatetrahydrofolate analogue lacking a chiral center at C-6, N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl) ethyl]benzoyl-L-glutamic acid, is an inhibitor of thymidylate synthase. J Med Chem 1992, 35, 23, 4450-4. |
| 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) | 11877 | Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate | 105-56-6 | C5H7NO2 | 详情 | 详情 |
| (II) | 12113 | 2-Bromo-1-ethoxyethyl ethyl ether; 2-Bromo-1,1-diethoxyethane; Bromoacetaldehyde diethylacetal | 2032-35-1 | C6H13BrO2 | 详情 | 详情 |
| (III) | 14789 | ethyl 2-cyano-4,4-diethoxybutanoate | C11H19NO4 | 详情 | 详情 | |
| (IV) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (V) | 14791 | 2,6-diamino-5-(2,2-diethoxyethyl)-4(3H)-pyrimidinone | C10H18N4O3 | 详情 | 详情 | |
| (VI) | 14792 | 2-amino-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one | 7355-55-7 | C6H6N4O | 详情 | 详情 |
| (VII) | 13597 | 2,2-Dimethylpropanoyl chloride; Pivaloyl chloride | 3282-30-2 | C5H9ClO | 详情 | 详情 |
| (VIII) | 14794 | 2,2-dimethyl-N-(4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)propanamide | C11H14N4O2 | 详情 | 详情 | |
| (IX) | 14795 | N-(5,6-diiodo-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide | C11H12I2N4O2 | 详情 | 详情 | |
| (X) | 14796 | N-(5-iodo-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide | C11H13IN4O2 | 详情 | 详情 | |
| (XI) | 14797 | dimethyl (2S)-2-[(4-ethynylbenzoyl)amino]pentanedioate | C16H17NO5 | 详情 | 详情 | |
| (XII) | 14798 | dimethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl)benzoyl]amino]pentanedioate | C27H29N5O7 | 详情 | 详情 | |
| (XIII) | 14799 | dimethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl)benzoyl]amino]pentanedioate | C27H33N5O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)
| 【1】 Taylor EC, Kuhnt D, Shih C.et aL. 1992. A dideazatetrahydrofolate analogh lacking a chiral center at C-6: N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d] pyrimidinn-5,yl) ethyl[benaoyl]-L-glutamic acid is an inhibitor of thymidylate synthase.J Med Chem, 35: 4450一44154 |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| （III) | 14795 | N-(5,6-diiodo-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide | C11H12I2N4O2 | 详情 | 详情 | |
| (I) | 14792 | 2-amino-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one | 7355-55-7 | C6H6N4O | 详情 | 详情 |
| (II) | 14794 | 2,2-dimethyl-N-(4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)propanamide | C11H14N4O2 | 详情 | 详情 | |
| (IV) | 14796 | N-(5-iodo-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-2,2-dimethylpropanamide | C11H13IN4O2 | 详情 | 详情 | |
| (V) | 14797 | dimethyl (2S)-2-[(4-ethynylbenzoyl)amino]pentanedioate | C16H17NO5 | 详情 | 详情 | |
| (VI) | 14798 | dimethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethynyl)benzoyl]amino]pentanedioate | C27H29N5O7 | 详情 | 详情 | |
| (VII) | 14799 | dimethyl (2S)-2-[[4-(2-[2-[(2,2-dimethylpropanoyl)amino]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl]ethyl)benzoyl]amino]pentanedioate | C27H33N5O7 | 详情 | 详情 |