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【结 构 式】 
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【分子编号】66007 【品名】 【CA登记号】 |
【 分 子 式 】C14H17NO8 【 分 子 量 】327.29092 【元素组成】C 51.38% H 5.24% N 4.28% O 39.11% |
合成路线1
该中间体在本合成路线中的序号：(XX)The synthetic precursor (X) is prepared by esterification of N-acetyl-2,3-didehydroneuraminic acid (XV) with MeOH in the presence of HC(OMe)3 and H2SO4 at 40 °C to yield the methyl ester (XVI), which by O-acylation with AcOH by means of H2SO4 in heptane at 40 °C followed by cyclization in the presence of NH3 and Et3N in toluene/H2O furnishes the pyrano[3,4-d]oxazole derivative (XVII). Hydrolysis of the triacetate (XVII) by means of NaOMe in MeOH gives the corresponding triol (XVIII), which is protected again at the vicinal 8,9-hydroxyl groups as the cyclic carbonate (XIX) by means of CO(OMe)2 in MeOH. Then, methylation of the free C-7 hydroxyl group with Me2SO4 in the presence of NaH in THF/DMA gives the corresponding methyl ether (XX), which is submitted to oxazoline ring opening with Me3SiN3 in the presence of (i-PrO)4Ti in t-BuOH to furnish the acetamido azide (XXI). Finally, azide (XXI) is reduced by means of PPh3 in THF or EtOAc (3). Scheme 2.
| 【3】 Nakamura, Y., Murakami, M., Yamaoka, M., Wakayama, M., Umeo, K. (Daiichi Sankyo Co., Ltd.). Method for manufacturing neuraminic acid derivatives. EP 2132191, JP 2010523472, WO 2008126943. |
| 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) | 65998 | C14H20N2O8 | 详情 | 详情 | ||
| (XV) | 66002 | N-Acetyl-2,3-dehydro-2-deoxyneuraminic acid; 2-Deoxy-2,3-Didehydro-D-N--Acetylneuraminic Acid | 24967-27-9 | C11H17NO8 | 详情 | 详情 |
| (XVI) | 66003 | methyl (2R,3R,4S)-3-acetamido-4-hydroxy-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylate | 25875-99-4 | C12H19NO8 | 详情 | 详情 |
| (XVII) | 66004 | Methyl (3aR,4R,7aR)-2-methyl-4-[(1S,2R)-1,2,3-triacetoxypropyl]-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate | 78850-37-0 | C18H23NO10 | 详情 | 详情 |
| (XVIII) | 66005 | methyl (3aS,4R,7aR)-4-[(1R,2R)-1,2,3-trihydroxy-propyl]-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate | 1072449-83-2 | C12H17NO7 | 详情 | 详情 |
| (XIX) | 66006 | C13H15NO8 | 详情 | 详情 | ||
| (XX) | 66007 | C14H17NO8 | 详情 | 详情 | ||
| (XXI) | 66008 | C14H18N4O8 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XX)The azido acetamide intermediate (XXVII) can be prepared by several alternative methods. Alkylation of the benzyl glycoside of N-acetyl-3,6-di-O-benzyl-α-D-glucosamine (XXVIII) with iodomethane and NaH in DMF followed by catalytic benzyl group hydrogenolysis of the resulting 4-methoxy derivative (XXIX) with H2 over Pd/C yields N-acetyl-4-O-methylglucosamine (XXX), which by subsequent incubation with N-acetylneuraminic acid aldolase (N-Ac-NAA) in the presence of sodium pyruvate (XXXI) and NaN3 at pH 10-11 gives the nonuropyranosoic acid derivative (XXXII). Acid (XXXII) is esterified with MeOH in the presence of acidic cation exchange resin (Dowex 50x8) to give methyl ester (XXXIII), which by acetylation with Ac2O in pyridine and successive treatments with HCl and DBU leads to the non-2-enopyranosonate (XXXIV). Finally, compound (XXXIV) is converted to the azido acetamide intermediate (XXVII) by treatment with boron trifluoride etherate and one equivalent of MeOH in CH2Cl2 followed by NaN3 and Dowex 50x8 resin (1, 7, 8). Scheme 4.
Alternatively, solvolysis of the cyclic carbonate (XX) with methanolic NaOMe yields diol (XXXV), which is then acetylated with AcOH by means of Et3N and DMAP in EtOAc to give diacetate (XXXVI). Ring opening of oxazoline (XXXVI) with Me3SiN3 in the presence of (i-PrO)4Ti in t-BuOH furnishes the 4-azido-5,6-dihydropyran derivative (XXVII) (3). Scheme 4.
| 【1】 Honda, T., Kobayashi, Y., Masuda, T., Yamashita, M., Arai, M. (Daiichi Sankyo Co., Ltd.). Neuraminic acid derivatives, their preparation and their medical use. EP 0823428, JP 1998330373, JP 1999279059, JP 199927968. |
| 【3】 Nakamura, Y., Murakami, M., Yamaoka, M., Wakayama, M., Umeo, K. (Daiichi Sankyo Co., Ltd.). Method for manufacturing neuraminic acid derivatives. EP 2132191, JP 2010523472, WO 2008126943. |
| 【7】 Honda, T., Arai, M., Yamashita, M., Masuda, T., Kobayashi, Y. (Daiichi Sankyo Co., Ltd.). Neuraminic acid derivatives, their preparation and their medical use. US 6340702. |
| 【8】 Kobayashi, Y., Honda, T., Yamashita, M. (Daiichi Sankyo Co., Ltd.). Neuraminic acid derivatives, their preparation and their medical use. US 2002137791, US 6451766. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XX) | 66007 | C14H17NO8 | 详情 | 详情 | ||
| (XXVII) | 66014 | C17H24N4O9 | 详情 | 详情 | ||
| (XXVIII) | 66015 | Benzyl 2-Acetamido-3,6-Di-O-Benzyl-2-Deoxy-alpha-D-Glucopyranoside; 2-Acetamido-1,3,6-Tri-O-Benzyl-2-Deoxy-A-D-Glucopyranoside | 55287-49-5 | C29H33NO6 | 详情 | 详情 |
| (XXIX) | 66016 | C30H35NO6 | 详情 | 详情 | ||
| (XXX) | 66017 | Methyl 2-Acetamido-2-deoxy-alpha-D-glucopyranoside | 6082-04-8 | C9H17NO6 | 详情 | 详情 |
| (XXXI) | 66018 | sodium 2-oxopropanoate; Sodium pyruvate; Sodium 2-ketopropionate; 2-Oxo-propanoic acid sodium salt | 113-24-6 | C3H3NaO3 | 详情 | 详情 |
| (XXXII) | 66019 | C12H21NO9 | 详情 | 详情 | ||
| (XXXIII) | 66020 | C13H23NO9 | 详情 | 详情 | ||
| (XXXIV) | 66021 | C19H27NO11 | 详情 | 详情 | ||
| (XXXV) | 66022 | C13H19NO7 | 详情 | 详情 | ||
| (XXXVI) | 66023 | C17H25NO9 | 详情 | 详情 |