4-methyl-2-pyrimidinylhydrosulfide; 4-methyl-2-pyrimidinethiol -Drug Synthesis Database

【结构式】

【分子编号】49196

【品名】4-methyl-2-pyrimidinylhydrosulfide; 4-methyl-2-pyrimidinethiol

【CA登记号】

【分子式】C₅H₆N₂S

【分子量】126.18212

【元素组成】C 47.59% H 4.79% N 22.2% S 25.41%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

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

合成目标

【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

该中间体在本合成路线中的序号：(I)

Alkylation of 2-mercapto-4-methylpyrimidine (I) with iodomethane and NaOH affords 2-methylthio-4-methylpyrimidine (II). Condensation of (II) with methyl 4-fluorobenzoate (III) in the presence of sodium hexamethyldisilazide produces ketone (IV), which is further oxidized to dione (V) with DMSO/HBr. Ring closure of dione (V) with glyoxal dimethyl acetal (VI) in the presence of ammonium acetate leads to imidazole (VII). Acid-catalyzed transketalization of (VII) with the dihydroxy ester (VIII) yields the 1,3-dioxane derivative (IX) as a 3:2 mixture of cis- and trans- isomers. After chromatographic separation of the desired trans- isomer, oxidation of the methylthio group with mCPBA furnishes sulfone (X)

参考文献中间体

合成目标

【1】 McKenna, J.M.; Halley, F.; Souness, J.E.; McLay, I.M.; Pickett, S.D.; Collis, A.J.; Page, K.; Ahmed, I.; An algorithm-directed two-component library synthesized via solid-phase methodology yielding potent and orally bioavailable p38 MAP kinase inhibitors. J Med Chem 2002, 45, 11, 2173.

中间体序号	中间体编号	品名	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)	62737	methyl 4-fluorobenzoate	C₈H₇FO₂	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)	62738	4-[2-(dimethoxymethyl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-(methylsulfanyl)pyrimidine; {4-(4-fluorophenyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]-1H-imidazol-2-yl}(methoxy)methyl methyl ether	C₁₇H₁₇FN₄O₂S	详情	详情
(VIII)	33803	methyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate	C₆H₁₂O₄	详情	详情
(IX)	62739	methyl 2-{4-(4-fluorophenyl)-5-[2-(methylsulfanyl)-4-pyrimidinyl]-1H-imidazol-2-yl}-5-methyl-1,3-dioxane-5-carboxylate	C₂₁H₂₁FN₄O₄S	详情	详情
(X)	62740	methyl 2-{4-(4-fluorophenyl)-5-[2-(methylsulfonyl)-4-pyrimidinyl]-1H-imidazol-2-yl}-5-methyl-1,3-dioxane-5-carboxylate	C₂₁H₂₁FN₄O₆S	详情	详情

Extended Information