RPR-203494, -Drug Synthesis Database

【结构式】

【药物名称】RPR-203494

【化学名称】trans-N-Cyclopropyl-4-[4-(4-fluorophenyl)-2-[5-methyl-5-(4-morpholinylcarbonyl)-1,3-dioxan-2-yl]-1H-imidazol-5-yl]pyrimidin-2-amine

【CA登记号】218160-26-0

【分子式】C₂₆H₂₉FN₆O₄

【分子量】508.55723

【开发单位】Aventis Pharma (Originator)

【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, p38 Protein Kinase Inhibitors, TNF-alpha Release Inhibitors

合成路线1 合成路线2

合成路线1

4-Methyl-2-(methylsulfanyl)pyrimidine (II) was prepared by methylation of mercaptopyrimidine (I) with dimethylformamide dimethylacetal (1). Condensation of the lithium anion of (II) with ethyl 4-fluorobenzoate (III) produced the diaryl ethanone (IV), which was further oxidized to diketone (V) by using HBr in DMSO. The target imidazole intermediate (VII) was then obtained by condensation of diketone (V) with glyoxal dimethylacetal (VI) in the presence of ammonium acetate.

参考文献中间体

【1】 Collis, A.J.; Wilsher, N.E.; Foster, M.L.; Redford, E.J.; McLay, I.M.; Page, K.M.; Maslen, C.; Halley, F.; Souness, J.E.; RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potency. Bioorg Med Chem Lett 2001, 11, 5, 693.
【2】 Halley, F.; Porter, B.; Bamborough, P.L.; Lewis, R.A.; Ratcliffe, A.J.; Wallace, P.A.; McLay, I.M.; McKenna, J.M.; Lythgoe, D.J.; Collis, A.J. (Rhone-Poulenc Rorer Ltd.); Imidazolyl-cyclic acetals. EP 0988301; WO 9856788 .

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)	49196	4-methyl-2-pyrimidinylhydrosulfide; 4-methyl-2-pyrimidinethiol		C₅H₆N₂S	详情	详情
(II)	49197	4-methyl-2-(methylsulfanyl)pyrimidine; methyl 4-methyl-2-pyrimidinyl sulfide		C₆H₈N₂S	详情	详情
(III)	22830	ethyl 4-fluorobenzoate	451-46-7	C₉H₉FO₂	详情	详情
(IV)	49198	1-(4-fluorophenyl)-2-[2-(methylsulfanyl)-4-pyrimidinyl]-1-ethanone		C₁₃H₁₁FN₂OS	详情	详情
(V)	49199	1-(4-fluorophenyl)-2-[2-(methylsulfanyl)-4-pyrimidinyl]-1,2-ethanedione		C₁₃H₉FN₂O₂S	详情	详情
(VI)	49200	2,2-dimethoxyacetaldehyde		C₄H₈O₃	详情	详情
(VII)	49201	4-(4-fluorophenyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]-1H-imidazole-2-carbaldehyde		C₁₅H₁₁FN₄OS	详情	详情

合成路线2

Condensation of 2,2-bis(hydroxymethyl)propionic acid (VIII) with morpholine (IX) in the presence of DCC and HOBt gave amide (X). The cyclic ketal (XI) was then obtained by acid-catalyzed condensation of imidazole aldehyde (VII) with diol (X) using azeotropic removal of water. Oxidation of the sulfide group of (XI) with meta-chloroperbenzoic acid furnished sulfone (XII). The methylsulfonyl group of (XII) was finally displaced with cyclopropylamine (XIII) to provide the title compound

参考文献中间体

【1】 Collis, A.J.; Wilsher, N.E.; Foster, M.L.; Redford, E.J.; McLay, I.M.; Page, K.M.; Maslen, C.; Halley, F.; Souness, J.E.; RPR203494 a pyrimidine analogue of the p38 inhibitor RPR200765A with an improved in vitro potency. Bioorg Med Chem Lett 2001, 11, 5, 693.
【2】 Halley, F.; Porter, B.; Bamborough, P.L.; Lewis, R.A.; Ratcliffe, A.J.; Wallace, P.A.; McLay, I.M.; McKenna, J.M.; Lythgoe, D.J.; Collis, A.J. (Rhone-Poulenc Rorer Ltd.); Imidazolyl-cyclic acetals. EP 0988301; WO 9856788 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	49201	4-(4-fluorophenyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]-1H-imidazole-2-carbaldehyde		C₁₅H₁₁FN₄OS	详情	详情
(VIII)	49202	3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid		C₅H₁₀O₄	详情	详情
(IX)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情
(X)	49203	3-hydroxy-2-(hydroxymethyl)-2-methyl-1-(4-morpholinyl)-1-propanone		C₉H₁₇NO₄	详情	详情
(XI)	49204	(2-[4-(4-fluorophenyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]-1H-imidazol-2-yl]-5-methyl-1,3-dioxan-5-yl)(4-morpholinyl)methanone		C₂₄H₂₆FN₅O₄S	详情	详情
(XII)	49205	(2-[4-(4-fluorophenyl)-5-[2-(methylsulfonyl)-4-pyrimidinyl]-1H-imidazol-2-yl]-5-methyl-1,3-dioxan-5-yl)(4-morpholinyl)methanone		C₂₄H₂₆FN₅O₆S	详情	详情
(XIII)	12263	Cyclopropylamine; Cyclopropanamine	765-30-0	C₃H₇N	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)