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【结 构 式】 
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【药物名称】Posizolid, AZD-2563 【化学名称】3-[4-[1-[2(S),3-Dihydroxypropionyl]-1,2,3,6-tetrahydropyridin-4-yl]-3,5-difluorophenyl]-5(R)-(isoxazol-3-yloxymethyl)oxazolidin-2-one 【CA登记号】252260-02-9, 252260-00-7 (diastereomer) 【 分 子 式 】C21H21F2N3O7 【 分 子 量 】465.41422 |
【开发单位】AstraZeneca (Originator) 【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Oxazolidinones |
合成路线1
The condensation of the protected 3,5-difluoroaniline (I) with 1-benzyl-4-piperidone (II) by means of BuLi in THF gives 4-(1-benzyl-4-hydroxypiperidin-4-yl)-3,5-difluoroaniline (III), which is dehydrated with refluxing conc. HCl to yield the tetrahydropyridine (IV). The reaction of (IV) with benzyl chloroformate in acetone/water affords the carbamate (V), which is cyclized with (R)-glycidyl butyrate (VI) by means of BuLi in THF to provide the oxazolidinone (VII). The condensation of (VII) with isoxazol-3-ol (VIII) by means of PPh3 and DIAD in THF gives the expected ether adduct (IX), which is debenzylated by reaction with 1-chloroethyl chloroformate in dichloromethane, yielding the free tetrahydropyridine derivative (X). The condensation of (X) with (S)-2,3-O-isopropylideneglyceric acid (XI) by means of DEC or DCC and TEA in dichloromethane affords the corresponding acyl tetrahydropyridine (XII), which is finally deprotected with HCl in THF to provide the target dihydroxy compound.
| 【1】 Gravestock, M.B. (AstraZeneca plc); Oxazolidinone derivs., process for their preparation and pharmaceutical compsns. containing them. EP 1082323; JP 2002517498; WO 9964417 . |
| 【2】 Gravestock, M.B.; Warren, K.E.H.; Ennis, D.S.; Currie, A.C.; Ainge, D. (AstraZeneca AB; AstraZeneca plc); Chemical processes and intermedies. WO 0140236 . |
| 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) | 59481 | 1-(3,5-difluorophenyl)-2,2,5,5-tetramethyl-1,2,5-azadisilolidine | C12H19F2NSi2 | 详情 | 详情 | |
| (II) | 15720 | 1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one | 3612-20-2 | C12H15NO | 详情 | 详情 |
| (III) | 59482 | 4-(4-amino-2,6-difluorophenyl)-1-benzyl-4-piperidinol | C18H20F2N2O | 详情 | 详情 | |
| (IV) | 59483 | 4-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)-3,5-difluorophenylamine; 4-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)-3,5-difluoroaniline | C18H18F2N2 | 详情 | 详情 | |
| (V) | 59484 | benzyl 4-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)-3,5-difluorophenylcarbamate | C26H24F2N2O2 | 详情 | 详情 | |
| (VI) | 17017 | (2S)oxiranylmethyl butyrate | C7H12O3 | 详情 | 详情 | |
| (VII) | 59485 | (5R)-3-[4-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl]-5-(hydroxymethyl)-1,3-oxazolidin-2-one | C22H22F2N2O3 | 详情 | 详情 | |
| (VIII) | 59486 | 3-isoxazolol | C3H3NO2 | 详情 | 详情 | |
| (IX) | 59487 | (5R)-3-[4-(1-benzyl-1,2,3,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl]-5-[(3-isoxazolyloxy)methyl]-1,3-oxazolidin-2-one | C25H23F2N3O4 | 详情 | 详情 | |
| (X) | 59488 | (5R)-3-[3,5-difluoro-4-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]-5-[(3-isoxazolyloxy)methyl]-1,3-oxazolidin-2-one | C18H17F2N3O4 | 详情 | 详情 | |
| (XI) | 59489 | (4S)-2,2-dimethyl-1,3-dioxolane-4-carboxylic acid | C6H10O4 | 详情 | 详情 | |
| (XII) | 59490 | (5R)-3-[4-(1-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]carbonyl}-1,2,3,6-tetrahydro-4-pyridinyl)-3,5-difluorophenyl]-5-[(3-isoxazolyloxy)methyl]-1,3-oxazolidin-2-one | C24H25F2N3O7 | 详情 | 详情 |