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【结 构 式】

【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%

与该中间体有关的原料药合成路线共 2 条

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
Extended Information