methyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate -Drug Synthesis Database

【结构式】

【分子编号】33803

【品名】methyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate

【CA登记号】

【分子式】C₆H₁₂O₄

【分子量】148.15888

【元素组成】C 48.64% H 8.16% O 43.2%

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：(VI)

The known diarylimidazole (I) was protected as the N-[2-(trimethylsilyl)ethoxy]methyl derivative (II) by treatment with 2-(trimethylsilyl)ethoxymethyl chloride and NaH. Lithiation of (II) with BuLi at -78 C, followed by quenching with N-formylmorpholine (III) provided aldehyde (IV). This was converted to the dimethyl acetal (V) upon treatment with trimethyl orthoformate and p-toluenesulfonic acid. Further condensation of (V) with methyl 2,2-bis(hydroxymethyl)propionate (VI) produced the dioxane derivative (VII) as a mixture of cis and trans isomers. Basic hydrolysis of the methyl ester group of (VII) afforded the corresponding carboxylic acid. The desired trans isomer (VIII) was then isolated by selective precipitation of the acidified methanolic solution. Finally, coupling of (VIII) with morpholine (IX) using EDC and HOBt furnished the title amide.

参考文献中间体

合成目标

【1】 McLay, I.M.; Halley, F.; Souness, J.E.; et al.; The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-anthritic efficacy. Bioorg Med Chem 2001, 9, 2, 537.
【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)	33798	4-[4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridine		C₁₄H₁₀FN₃	详情	详情
(II)	33799	[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-1-yl]methyl 2-(trimethylsilyl)ethyl ether; 4-(4-(4-fluorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazol-5-yl)pyridine		C₂₀H₂₄FN₃OSi	详情	详情
(III)	33800	4-morpholinecarbaldehyde	4394-85-8	C₅H₉NO₂	详情	详情
(IV)	33801	4-(4-fluorophenyl)-5-(4-pyridinyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-2-carbaldehyde		C₂₁H₂₄FN₃O₂Si	详情	详情
(V)	33802	[2-(dimethoxymethyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-1-yl]methyl 2-(trimethylsilyl)ethyl ether; 4-(2-(dimethoxymethyl)-4-(4-fluorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazol-5-yl)pyridine		C₂₃H₃₀FN₃O₃Si	详情	详情
(VI)	33803	methyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate		C₆H₁₂O₄	详情	详情
(VII)	33804	methyl 2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carboxylate		C₂₁H₂₀FN₃O₄	详情	详情
(VIII)	33805	2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carboxylic acid		C₂₀H₁₈FN₃O₄	详情	详情
(IX)	10388	Morpholine	110-91-8	C₄H₉NO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VIII)

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