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【结 构 式】 
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【分子编号】67954 【品名】(R)-5-chloro-2-(5-methyl-1,4-diazepan-1-yl)benzo[d]oxazole 【CA登记号】 |
【 分 子 式 】C13H16ClN3O 【 分 子 量 】265.742 【元素组成】C 58.76% H 6.07% Cl 13.34% N 15.81% O 6.02% |
合成路线1
该中间体在本合成路线中的序号：(XXIX)Process route to suvorexant starts with treatment of dichlorobenzoxazole (XIV) with N-Boc-ethylenediamine (I) in the presence of Et3N to provide 82% yield of 2-aminobenzoxazole (XXV), which by reaction with methyl vinyl ketone (II) in the presence of DBU in acetonitrile provides intermediate (XXVI) in a high yield. Clean deprotection of (XXVI) is achieved with methanesulfonic acid in THF to give 94% of aminoketone in the form of salt (XXVII). Reductive cyclization of this salt by means of Na(OAc)3BH in the presence of NaOAc in CH2Cl2 provides 98% yield of racemic diazepane (XXVIII). An extensive screening of classical resolution methods for racemate (XXVIII) led to optimal conditions based on resolution with dibenzoyl-L-tartaric acid in THF/CH2Cl2, giving 39% yield (74% ee). Recrystallization of this salt in a 4:1 mixture of i-PrAc/MeOH then provided a 70% yield (96% ee). Treatment of the tartrate salt with NaOH provided the free base (XXIX), which is finally condensed with acid chloride (XXIV) in the presence of Et3N, giving a 95% yield of suvorexant .
| 【1】 Baxter, C.A., Cleator, E., Brands, K.M.J. et al. The first large-scale synthesis of MK-4305: A dual orexin receptor antagonist for the treatment of sleep disorder. Org Proc Res Dev 2011, 15(2): 367-75. |
| 【2】 Wallace, D.J. Development of the manufacturing route for suvorexant - A dual orexin antagonist for sleep disorder. 244th ACS Natl Meet Exp (Aug 19-23, Philadelphia) 2012, Abst ORGN-271. |
| 【3】 Baxter, C.A. Development of the manufacturing route for suvorexant - A dual orexin antagonist for sleep disorder. Balticum Organicum Syntheticum Intl Conf Org Synth (July 1-4, Tallinn) 2012, p 16. |
| 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) | 13241 | N-Boc-ethylenediamine;tert-butyl (2-aminoethyl)carbamate；tert-butyl 2-aminoethylcarbamate; tert-Butyl n-(2-aminoethyl)carbamate | 57260-73-8 | C7H16N2O2 | 详情 | 详情 |
| (II) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (XIV) | 67940 | 2,5-dichloro-1,3-benzoxazole；2,5-Dichlorobenzoxazole | 3621-81-6 | C7H3Cl2NO | 详情 | 详情 |
| (XXIV) | 67949 | 5-methyl-2-(1,2,3-triazol-2-yl)benzoyl chloride | C10H8ClN3O | 详情 | 详情 | |
| (XXV) | 67950 | tert-butyl (2-((5-chlorobenzo[d]oxazol-2-yl)amino)ethyl)carbamate | C14H18ClN3O3 | 详情 | 详情 | |
| (XXVI) | 67951 | tert-butyl (2-((5-chlorobenzo[d]oxazol-2-yl)(3-oxobutyl)amino)ethyl)carbamate | C18H24ClN3O4 | 详情 | 详情 | |
| (XXVII) | 67952 | 4-((2-aminoethyl)(5-chlorobenzo[d]oxazol-2-yl)amino)butan-2-one dimethanesulfonate | C13H16ClN3O3.2CH4O3S | 详情 | 详情 | |
| (XXVIII) | 67953 | 5-chloro-2-(5-methyl-1,4-diazepan-1-yl)benzo[d]oxazole | C13H16ClN3O | 详情 | 详情 | |
| (XXIX) | 67954 | (R)-5-chloro-2-(5-methyl-1,4-diazepan-1-yl)benzo[d]oxazole | C13H16ClN3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXIX)Alternatively, asymmetric reductive amination of aminoketone (XXVII) using a novel Ru-based transfer hydrogenation catalyst (XXX) results in the diazepane (XXIX) in 97% yield .
| 【1】 Wallace, D.J. Development of the manufacturing route for suvorexant - A dual orexin antagonist for sleep disorder. 244th ACS Natl Meet Exp (Aug 19-23, Philadelphia) 2012, Abst ORGN-271. |
| 【2】 Baxter, C.A. Development of the manufacturing route for suvorexant - A dual orexin antagonist for sleep disorder. Balticum Organicum Syntheticum Intl Conf Org Synth (July 1-4, Tallinn) 2012, p 16. |
| 【3】 Strotman, N.A., Baxter, C.A., Brands, K.M.J. et al. Reaction development and mechanistic study of a ruthenium catalyzed intramolecular asymmetric reductive amination en route to the dual orexin inhibitor suvorexant (MK-4305). J Am Chem Soc 2011, 133(21): 8362-71. |
| 【4】 Cleator, E. Discovery of an asymmetric synthesis of suvorexant. 244th ACS Natl Meet Exp (Aug 19-23, Philadelphia) 2012, Abst ORGN-13. |
| 【5】 Kocienski, P. Synthesis of suvorexant. Synfacts 2011, (8): 822. |