methyl 2-{4-(4-fluorophenyl)-5-[2-(methylsulfonyl)-4-pyrimidinyl]-1H-imidazol-2-yl}-5-methyl-1,3-dioxane-5-carboxylate -Drug Synthesis Database

【结构式】

【分子编号】62740

【品名】methyl 2-{4-(4-fluorophenyl)-5-[2-(methylsulfonyl)-4-pyrimidinyl]-1H-imidazol-2-yl}-5-methyl-1,3-dioxane-5-carboxylate

【CA登记号】

【分子式】C₂₁H₂₁FN₄O₆S

【分子量】476.4855032

【元素组成】C 52.94% H 4.44% F 3.99% N 11.76% O 20.15% S 6.73%

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：(X)

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

合成路线2

该中间体在本合成路线中的序号：(X)

Attachment of the sulfonylpyrimidine (X) to a Merrifield thiol resin in the presence of NaH in DMF provides resin-bounded compound (XI). Then, saponification of the methyl ester group of (XI) yields carboxylic acid (XII). After formation of the corresponding acid chloride (XIII), coupling with N-methylpiperazine (XIV) gives rise to amide (XV). Sulfide group oxidation in (XV) leads to the sulfonylpyrimidine resin (XVI). Finally, cleavage from the resin in the presence of cyclopropylmethylamine (XVII) in hot NMP affords the target 2-aminopyrimidine derivative

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	CAS号	分子式	供应商	用于合成
(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
(XI)	62741	methyl 2-[4-(4-fluorophenyl)-5-(2-sulfanyl-4-pyrimidinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carboxylate		C₂₀H₁₉FN₄O₄S	详情	详情
(XII)	62742	2-[4-(4-fluorophenyl)-5-(2-sulfanyl-4-pyrimidinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carboxylic acid		C₁₉H₁₇FN₄O₄S	详情	详情
(XIII)	62743	2-[4-(4-fluorophenyl)-5-(2-sulfanyl-4-pyrimidinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carbonyl chloride		C₁₉H₁₆ClFN₄O₃S	详情	详情
(XIV)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	详情	详情
(XV)	62744	{2-[4-(4-fluorophenyl)-5-(2-sulfanyl-4-pyrimidinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxan-5-yl}(4-methyl-1-piperazinyl)methanone		C₂₄H₂₇FN₆O₃S	详情	详情
(XVI)	62745	{2-[5-[2-(dioxo-lambda~6~-sulfanyl)-4-pyrimidinyl]-4-(4-fluorophenyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxan-5-yl}(4-methyl-1-piperazinyl)methanone		C₂₄H₂₇FN₆O₅S	详情	详情
(XVII)	59524	Aminomethylcyclopropane; Cyclopropanemethylamine	2516-47-4	C₄H₉N	详情	详情

Extended Information