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【结 构 式】 
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【分子编号】53055 【品名】2-benzyl 4-ethyl 4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2,4-dicarboxylate 【CA登记号】n/a |
【 分 子 式 】C21H29NO6 【 分 子 量 】391.4644 【元素组成】C 64.43% H 7.47% N 3.58% O 24.52% |
合成路线1
该中间体在本合成路线中的序号：(IV)Alkylation of ethyl 1-benzyloxycarbonyl-3-oxopyrrolidine-4-carboxylate (I) with iodomethane and K2CO3 produced the 4-methylpyrrolidine (II). The keto group of (III) was then protected as the corresponding ketal (IV) with 2,2-dimethyl-1,3-propanodiol (III). Replacement of the benzyloxycarbonyl protecting group of (IV) with a benzyl group (V) was accomplished by catalytic hydrogenolysis, followed by alkylation of the resulting pyrrolidine with benzyl chloride. The ester group of (V) was then reduced to the primary alcohol (VI) using LiAlH4. After conversion of alcohol (VI) to the corresponding mesylate, displacement with NaN3 provided the alkyl azide (VII). This was reduced to the primary amine (VIII) by catalytic hydrogenation over Raney-Ni. Resolution of the racemic amine (VIII) was carried out via acylation with N-tosyl-L-proline (IX), followed by chromatographic separation of the diastereomeric amides. Base-promoted hydrolysis of the chiral auxiliary from the desired diastereoisomer (X) provided the (R)-amine, which was further protected as the N-Boc derivative (XI). The N-benzyl group of (XI) was then removed by catalytic hydrogenolysis over Pd/C to yield the target pyrrrolidine (XII).
| 【1】 Yoon, S.J.; Chung, Y.H.; Lee, C.W.; Choi, D.R.; Lee, J.S.; Yang, W.Y.; Kim, N.D.; Jin, Y.H.; Song, W.J.; Kim, I.H.; Shin, J.H. (Dong-Wha Pharmaceuticals Industry Co. Ltd); Optically active quinoline carboxylic acid derivs. having 7-pyrrolidine substitutes causing optical activity and a process for preparing thereof. WO 0071541 . |
| 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) | 53053 | 1-benzyl 3-ethyl 4-oxo-1,3-pyrrolidinedicarboxylate | n/a | C15H17NO5 | 详情 | 详情 |
| (II) | 53054 | 1-benzyl 3-ethyl 3-methyl-4-oxo-1,3-pyrrolidinedicarboxylate | n/a | C16H19NO5 | 详情 | 详情 |
| (III) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (IV) | 53055 | 2-benzyl 4-ethyl 4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2,4-dicarboxylate | n/a | C21H29NO6 | 详情 | 详情 |
| (V) | 53056 | ethyl 2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-4-carboxylate | n/a | C20H29NO4 | 详情 | 详情 |
| (VI) | 53057 | (2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl)methanol | n/a | C18H27NO3 | 详情 | 详情 |
| (VII) | 50358 | (5S,6R)-6-(2-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-5-methyltetrahydro-2H-pyran-2-one | C14H28O3Si | 详情 | 详情 | |
| (VIII) | 53059 | (2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl)methanamine; (2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl)methylamine | n/a | C18H28N2O2 | 详情 | 详情 |
| (IX) | 53060 | (2S)-1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinecarboxylic acid | n/a | C12H15NO4S | 详情 | 详情 |
| (X) | 53061 | (2S)-N-{[(4R)-2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methyl}-1-[(4-methylphenyl)sulfonyl]-2-pyrrolidinecarboxamide | n/a | C30H41N3O5S | 详情 | 详情 |
| (XI) | 53062 | tert-butyl [(4R)-2-benzyl-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methylcarbamate | n/a | C23H36N2O4 | 详情 | 详情 |
| (XII) | 53063 | tert-butyl [(4S)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methylcarbamate | n/a | C16H30N2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)In a similar procedure, ester (IV) was reduced to the corresponding alcohol (XIII) using LiAlH4. After conversion of (XIII) to the corresponding mesylate (XIV), displacement by NaN3 provided azide (XV). Reduction of (XV) to the primary amine (XVI) was effected by treatment with PPh3 in moist acetonitrile. Resolution of the racemic amine (XVI) was achieved by acylation with N-tosyl-L-proline (IX) followed by chromatographic separation. The desired isomer (XVII) was hydrolyzed with KOH in isopropanol, and the resultant amine was further protected as the N-Boc derivative (XVIII). Catalytic hydrogenolysis of (XVIII) then provided the target pyrrolidine (XII).
| 【1】 Lee, C.-W.; et al.; Synthesis antibacterial activities of DW286, a new fluoronaphthyridone antibiotic as an enantiomer. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-553. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 53055 | 2-benzyl 4-ethyl 4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2,4-dicarboxylate | n/a | C21H29NO6 | 详情 | 详情 |
| (IX) | 50360 | 2-amino-6-(4-[(E)-3-[4-(3,5-difluorophenyl)-1-piperazinyl]-1-propenyl]-5-methyl-1H-pyrazol-1-yl)-4-pyrimidinol | C21H23F2N7O | 详情 | 详情 | |
| (XII) | 53063 | tert-butyl [(4S)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]dec-4-yl]methylcarbamate | n/a | C16H30N2O4 | 详情 | 详情 |
| (XIII) | 53064 | benzyl 4-(hydroxymethyl)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate | n/a | C19H27NO5 | 详情 | 详情 |
| (XIV) | 53065 | benzyl 4,8,8-trimethyl-4-{[(methylsulfonyl)oxy]methyl}-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate | n/a | C20H29NO7S | 详情 | 详情 |
| (XV) | 53066 | benzyl 4-(azidomethyl)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate | n/a | C19H26N4O4 | 详情 | 详情 |
| (XVI) | 53067 | benzyl 4-(aminomethyl)-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate | n/a | C19H28N2O4 | 详情 | 详情 |
| (XVII) | 53068 | benzyl (4R)-4,8,8-trimethyl-4-{[({(2S)-1-[(4-methylphenyl)sulfonyl]pyrrolidinyl}carbonyl)amino]methyl}-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate | n/a | C31H41N3O7S | 详情 | 详情 |
| (XVIII) | 53069 | benzyl (4R)-4-{[(tert-butoxycarbonyl)amino]methyl}-4,8,8-trimethyl-6,10-dioxa-2-azaspiro[4.5]decane-2-carboxylate | n/a | C24H36N2O6 | 详情 | 详情 |