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【结 构 式】 
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【药物名称】BMS-337197 【化学名称】N-[2-[2-[3-Methoxy-4-(5-oxazolyl)phenylamino]oxazol-5-yl]phenyl]-N-methyl-2-(4-morpholinyl)acetamide hydrochloride 【CA登记号】267645-83-0 (free base) 【 分 子 式 】C26H28ClN5O5 【 分 子 量 】525.99656 |
【开发单位】Bristol-Myers Squibb (Originator) 【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Inosine 5'-Monophosphate Dehydrogenase (IMPDH) Inhibitors |
合成路线1
Intermediate (VII) is prepared by the following route. Oxidation of 2-methoxy-4-nitrotoluene (I) by means of chromic acid in the presence of Ac2O affords acylal (II), which is further hydrolyzed to aldehyde (III) under acidic conditions. Treatment of benzaldehyde (III) with TOSMIC reagent in the presence of K2CO3 gives rise to the phenyl oxazole derivative (IV). Nitro group reduction in (IV) with H2 and Pd/C yields aniline (V). This is then converted into isothiocyanate (VII) employing 1,1'-thiocarbonyldi-2(2H)-pyridone (VI).
| 【1】 Liu, C.; Leftheris, K.; Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H. (Bristol-Myers Squibb Co.); Cpds. derived from an amine nucleus that are inhibitors of IMPDH enzyme. EP 1126843; US 6399773; WO 0025780 . |
| 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) | 39654 | methyl 2-methyl-5-nitrophenyl ether; 2-methoxy-1-methyl-4-nitrobenzene | 13120-77-9 | C8H9NO3 | 详情 | 详情 |
| (II) | 39655 | (acetoxy)(2-methoxy-4-nitrophenyl)methyl acetate | C12H13NO7 | 详情 | 详情 | |
| (III) | 39656 | 2-methoxy-4-nitrobenzaldehyde | C8H7NO4 | 详情 | 详情 | |
| (IV) | 39657 | methyl 5-nitro-2-(1,3-oxazol-5-yl)phenyl ether; 5-(2-methoxy-4-nitrophenyl)-1,3-oxazole | C10H8N2O4 | 详情 | 详情 | |
| (V) | 39658 | C10H10N2O2 | 详情 | 详情 | ||
| (VI) | 61696 | 1-{[2-oxo-1(2H)-pyridinyl]carbothioyl}-2(1H)-pyridinone | C11H8N2O2S | 详情 | 详情 | |
| (VII) | 61697 | 3-methoxy-4-(1,3-oxazol-5-yl)phenyl isothiocyanate; 5-(4-isothiocyanato-2-methoxyphenyl)-1,3-oxazole | C11H8N2O2S | 详情 | 详情 |
合成路线2
2-Bromoaniline (VIII) is acylated by bromoacetyl chloride (IX) in pyridine to produce the corresponding bromoacetanilide (X). Subsequent displacement of the aliphatic bromide of (X) with morpholine (XI) furnishes the morpholinoacetanilide (XII). Alkylation at the amide N of (XII) with iodomethane and NaH leads to the N-methyl amide (XIII). Stille coupling of aryl bromide (XIII) with tributyl (1-ethoxyvinyl)tin (XIV) yields the enol ether (XV). Bromination of enol ether (XV) with N-bromosuccinimide in moist THF produces the bromo acetophenone (XVI), which is further reacted with NaN3 to give the azido ketone (XVII). The target amino oxazole compound is finally obtained by condensation of azido ketone (XVII) with isothiocyanate (VII) in the presence of PPh3 in hot dioxane.
| 【1】 Liu, C.; Leftheris, K.; Pitts, W.J.; Iwanowicz, E.J.; Dhar, T.G.M.; Gu, H.H. (Bristol-Myers Squibb Co.); Cpds. derived from an amine nucleus that are inhibitors of IMPDH enzyme. EP 1126843; US 6399773; WO 0025780 . |
| 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) | 61697 | 3-methoxy-4-(1,3-oxazol-5-yl)phenyl isothiocyanate; 5-(4-isothiocyanato-2-methoxyphenyl)-1,3-oxazole | C11H8N2O2S | 详情 | 详情 | |
| (VIII) | 27739 | 2-bromoaniline | 615-36-1 | C6H6BrN | 详情 | 详情 |
| (IX) | 27903 | 2-Bromoacetyl chloride | 22118-09-8 | C2H2BrClO | 详情 | 详情 |
| (X) | 61698 | 2-bromo-N-(2-bromophenyl)acetamide | C8H7Br2NO | 详情 | 详情 | |
| (XI) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XII) | 61699 | N-(2-bromophenyl)-2-(4-morpholinyl)acetamide | C12H15BrN2O2 | 详情 | 详情 | |
| (XIII) | 61700 | N-(2-bromophenyl)-N-methyl-2-(4-morpholinyl)acetamide | C13H17BrN2O2 | 详情 | 详情 | |
| (XIV) | 19760 | ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane | 97674-02-7 | C16H34OSn | 详情 | 详情 |
| (XV) | 61850 | N-[2-(1-ethoxyvinyl)phenyl]-N-methyl-2-(4-morpholinyl)acetamide | C17H24N2O3 | 详情 | 详情 | |
| (XVI) | 61851 | N-[2-(2-bromoacetyl)phenyl]-N-methyl-2-(4-morpholinyl)acetamide | C15H19BrN2O3 | 详情 | 详情 | |
| (XVII) | 61852 | N-[2-(2-azidoacetyl)phenyl]-N-methyl-2-(4-morpholinyl)acetamide | C15H19N5O3 | 详情 | 详情 |
合成路线3
In a related synthetic strategy, acylation of 2-bromoaniline (I) with acetoxyacetyl chloride (II) affords the acetoxy acetanilide (III). Alkylation of amide (III) with iodomethane and NaH leads to the N-methyl amide (IV). Then, Stille coupling of aryl bromide (IV) with tributyl (1-ethoxyvinyl)tin (V) gives rise to the enol ether (VI). Bromination of (VI) with N-bromosuccinimide in moist THF, followed by displacement of the resultant bromo ketone (VII) with NaN3 provides azido ketone (VIII). The key oxazole (X) is then obtained by condensation of azido ketone (VIII) with isothiocyanate (IX) in the presence of PPh3. Alkaline hydrolysis of the acetate ester (X) yields alcohol (XI), which is converted to mesylate (XII) by means of methanesulfonyl chloride and triethylamine. The mesylate group is finally displaced with morpholine (XIII) to furnish the title compound.
| 【1】 Dhar, T.G.M.; Guo, J.; Shen, Z.; et al.; A modified approach to 2-(N-aryl)-1,3-oxazoles: application to the synthesis of the IMPDH inhibitor BMS-337197 and analogues. Org Lett 2002, 4, 12, 2091. |
| 【2】 Dhar, T.G.M.; et al.; Discovery of N-[2-[2-[[3-methoxy-4-(5-oxazolyl)phenyl]-amino]-5-oxazolyl]phenyl]-N-methyl-4-morpholineacetamide as a novel and potent inhibitor of inosine monophosphate dehydrogenase with excellent in vivo activity. J Med Chem 2002, 45, 11, 2127. |
| 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) | 27739 | 2-bromoaniline | 615-36-1 | C6H6BrN | 详情 | 详情 |
| (II) | 10456 | Acetoxiacetil chloride; 2-chloro-2-oxoethyl acetate | 13831-31-7 | C4H5ClO3 | 详情 | 详情 |
| (III) | 61853 | 2-(2-bromoanilino)-2-oxoethyl acetate | C10H10BrNO3 | 详情 | 详情 | |
| (IV) | 61854 | 2-[2-bromo(methyl)anilino]-2-oxoethyl acetate | C11H12BrNO3 | 详情 | 详情 | |
| (V) | 19760 | ethyl 1-(tributylstannyl)vinyl ether; tributyl(1-ethoxyvinyl)stannane | 97674-02-7 | C16H34OSn | 详情 | 详情 |
| (VI) | 61855 | 2-[2-(1-ethoxyvinyl)(methyl)anilino]-2-oxoethyl acetate | C15H19NO4 | 详情 | 详情 | |
| (VII) | 61856 | 2-[2-(2-bromoacetyl)(methyl)anilino]-2-oxoethyl acetate | C13H14BrNO4 | 详情 | 详情 | |
| (VIII) | 61857 | 2-[2-(2-azidoacetyl)(methyl)anilino]-2-oxoethyl acetate | C13H14N4O4 | 详情 | 详情 | |
| (IX) | 61697 | 3-methoxy-4-(1,3-oxazol-5-yl)phenyl isothiocyanate; 5-(4-isothiocyanato-2-methoxyphenyl)-1,3-oxazole | C11H8N2O2S | 详情 | 详情 | |
| (X) | 61858 | 2-[2-{2-[3-methoxy-4-(1,3-oxazol-5-yl)anilino]-1,3-oxazol-5-yl}(methyl)anilino]-2-oxoethyl acetate | C24H22N4O6 | 详情 | 详情 | |
| (XI) | 61859 | 2-hydroxy-N-(2-{2-[3-methoxy-4-(1,3-oxazol-5-yl)anilino]-1,3-oxazol-5-yl}phenyl)-N-methylacetamide | C22H20N4O5 | 详情 | 详情 | |
| (XII) | 61860 | 2-[2-{2-[3-methoxy-4-(1,3-oxazol-5-yl)anilino]-1,3-oxazol-5-yl}(methyl)anilino]-2-oxoethyl methanesulfonate | C23H22N4O7S | 详情 | 详情 | |
| (XIII) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |