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【结 构 式】 
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【药物名称】Suvorexant 【化学名称】(R)-5-Chloro-2-[5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepan-1-yl]-1,3-benzoxazole 【CA登记号】1030377-33-3 【 分 子 式 】C23H23ClN6O2 【 分 子 量 】450.921 |
【开发单位】Merck & Co., Inc. (US) 【药理作用】Dual Orexin OX1/OX2 Receptor Antagonist;Treatment of Sleep Disorders |
合成路线1
The synthesis of suvorexant by the medicinal route starts with conjugate addition of monoprotected diamine (I) to methyl vinyl ketone (II) in Et2O, followed by in situ trapping with benzyl chloroformate in the presence of Et3N to yield the fully protected diaminoketone (III), from which the Boc-protecting group is cleaved by means of HCl in EtOAc to provide primary amine (IV). Intramolecular reductive cyclization of amino ketone (IV) in the presence of NaBH(OAc)3 and AcOH in CH2Cl2 affords benzyl 5-methyl-1,4-diazepane-1-carboxylate (V), which is then N-protected with di-tert-butyl dicarbonate in the presence of Et3N in CH2Cl2 to give the diprotected diazepine derivative (VI). Resolution of racemic diazepine (VI) by means of chiral HPLC provides the desired (R)-enantiomer (VII), which is then N-deprotected with HCl in EtOAc to afford benzyl 5(R)-methyl-1,4-diazepane-1-carboxylate (VIII). Coupling of cyclic amine (VIII) or its hydrochloride with 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid (IX) [prepared by condensation of 2-iodo-5-methylbenzoic acid (X) with 1,2,3-triazole (XI) in the presence of Cs2CO3, CuI and t-DAMCH in DMF at 120 °C] using EDC, HOAt and NMM in DMF produces the corresponding amide (XII). N-Deprotection of N-Cbz-amine (XII) by means of H2 over Pd(OH)2/C in EtOAc/MeOH or EtOAc generates the 7(R)-methyldiazepane derivative (XIII), which is finally condensed with 2,5-dichloro-1,3-benzoxazole (XIV) [prepared by the chlorination of 5-chloro-2-mercaptobenzoxazole (XV) with POCl3 and PCl5 in CH2Cl2] in the presence of Et3N in DMF at 75 °C .
| 【1】 Bergman, J.M., Breslin, M.J., Coleman, P.J., Cox, C.D., Mercer, S.P.,Roecker, A.J. (Merck & Co., Inc.) Substituted diazepan compounds as orexin receptor antagonists. CN 101880276, EP 2089382, EP 2392572, JP 201051121, JP 2011068665, JP 2011079848, US 2008132490, US 7951797, US 2011195957, WO 2008069997. |
| 【2】 Cox, C.D., Breslin, M.J., Whitman, D.B. et al. Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J Med Chem 2010, 53(14): 5320-32. |
| 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 |
| (III) | 67930 | benzyl (2-((tert-butoxycarbonyl)amino)ethyl)(3-oxobutyl)carbamate | C19H28N2O5 | 详情 | 详情 | |
| (IV) | 67931 | benzyl (2-aminoethyl)(3-oxobutyl)carbamate | C14H20N2O3 | 详情 | 详情 | |
| (V) | 67932 | benzyl 5-methyl-1,4-diazepane-1-carboxylate | C14H20N2O2 | 详情 | 详情 | |
| (VI) | 67933 | 1-benzyl 4-tert-butyl 5-methyl-1,4-diazepane-1,4-dicarboxylate | C19H28N2O4 | 详情 | 详情 | |
| (VII) | 67934 | (R)-1-benzyl 4-tert-butyl 5-methyl-1,4-diazepane-1,4-dicarboxylate | C19H28N2O4 | 详情 | 详情 | |
| (VIII) | 67935 | benzyl 5(R)-methyl-1,4-diazepane-1-carboxylate | C14H20N2O2 | 详情 | 详情 | |
| (IX) | 67936 | 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid | C10H9N3O2 | 详情 | 详情 | |
| (X) | 34151 | 2-iodo-5-methylbenzoic acid | 52548-14-8 | C8H7IO2 | 详情 | 详情 |
| (XI) | 67937 | 2H-1,2,3-triazole | C2H3N3 | 详情 | 详情 | |
| (XII) | 67938 | (R)-benzyl 5-methyl-4-(5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl)-1,4-diazepane-1-carboxylate | C24H27N5O3 | 详情 | 详情 | |
| (XIII) | 67939 | (R)-(7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone | C16H21N5O | 详情 | 详情 | |
| (XIV) | 67940 | 2,5-dichloro-1,3-benzoxazole；2,5-Dichlorobenzoxazole | 3621-81-6 | C7H3Cl2NO | 详情 | 详情 |
| (XV) | 67941 | 5-chloro-2-mercaptobenzoxazole | 22876-19-3 | C7H4ClNOS | 详情 | 详情 |
合成路线2
Enantioselective synthesis of suvorexant is based on enzymatic transamination and described as follows. Cyclization of 2-amino-4-chlorophenol (XVI) with trimethyl orthoformate HC(OMe)3 in the presence of p-TsOH in THF provides 5-chlorobenzoxazole (XVII), which subsequently reacts with LiHMDS in THF followed by bromination of the resulting anion with NBS to afford 2-bromo-5-chlorobenzoxazole (XVIII). Condensation of crude bromo derivative (XVIII) with ethanolamine (XIX) in acetonitrile gives 2-(5-chloro-2-benzoxazolylamino)ethanol (XX), which is subjected to aza-Michael addition with methyl vinyl ketone (II) in the presence of NaOH in DMF to yield the β-amino ketone (XXI). Activation of crude alcohol (XXI) with MsCl in the presence of Et3N in i-PrOAc provides keto mesylate (XXII), which by transamination and cyclization with i-PrNH2 in the presence of CDX-017 enzyme and pyridoxal phosphate in DMSO, and subsequent acidification with HCl, provides the (R)-azepane derivative (XXIII). Finally, Schotten-Baumann acylation of amine (XXIII) with 5-methyl-2-(1,2,3-triazol-2-yl)benzoyl chloride (XXIV) in the presence of K2CO3 in i-PrOAc/H2O affords suvorexant. Chloride (XXIV) was prepared from 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid (IX) by treatment with (COCl)2 in the presence of DMF in i-PrOAc .
| 【1】 Mangion, I.K., Sherry, B.D., Yin, J., Fleitz, F.J. Enantioselective synthesis of a dual orexin receptor antagonist. Org Lett 2012, 14(13): 3458-61. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 30324 | 3-buten-2-one; methyl vinyl ketone | 78-94-4 | C4H6O | 详情 | 详情 |
| (IX) | 67936 | 5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid | C10H9N3O2 | 详情 | 详情 | |
| (XVI) | 67942 | 2-amino-4-chlorophenol | 95-85-2 | C6H6ClNO | 详情 | 详情 |
| (XVII) | 67943 | 5-chlorobenzo[d]oxazole | 17200-29-2 | C7H4ClNO | 详情 | 详情 |
| (XVIII) | 67944 | 2-bromo-5-chlorobenzo[d]oxazole | C7H3BrClNO | 详情 | 详情 | |
| (XIX) | 10259 | Ethanol amine;Ethanolamine;2-Aminoethanol; 2-Amino-1-ethanol；2-Aminoethyl alcohol | 141-43-5 | C2H7NO | 详情 | 详情 |
| (XX) | 67945 | 2-(5-chloro-2-benzoxazolylamino)ethanol | C9H9ClN2O2 | 详情 | 详情 | |
| (XXI) | 67946 | 4-((5-chlorobenzo[d]oxazol-2-yl)(2-hydroxyethyl)amino)butan-2-one | C13H15ClN2O3 | 详情 | 详情 | |
| (XXII) | 67947 | 2-((5-chlorobenzo[d]oxazol-2-yl)(3-oxobutyl)amino)ethyl methanesulfonate | C14H17ClN2O5S | 详情 | 详情 | |
| (XXIII) | 67948 | (R)-5-chloro-2-(5-methyl-1,4-diazepan-1-yl)benzo[d]oxazole hydrochloride | C13H16ClN3O.HCl | 详情 | 详情 | |
| (XXIV) | 67949 | 5-methyl-2-(1,2,3-triazol-2-yl)benzoyl chloride | C10H8ClN3O | 详情 | 详情 |
合成路线3
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4
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. |
合成路线5
Preparation of racemic suvorexant was used as a proof of the direct amination of benzoxazoles using 2,2,6,6-tetramethylpiperidine-Noxoammonium tetrafluoroborate as organic oxidant. In this case, chlorobenzoxazole (XVII) was aminated by racemic diazepane rac-(XIII) using Sc(OTf)3 and TEMPOBF4 to provide racemic suvorexant in 84% yield .
| 【1】 Wertz, S., Kodama, S., Studer, A. Amination of benzoxazoles and 1,3,4-oxadiazoles using 2,2,6,6-tetramethylpiperidine-N-oxoammonium tetrafluoroborate as an organic oxidant. Angew Chem Int Ed 2011, 50(48): 11511-5. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| rac-(XIII) | 67955 | (7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone | C16H21N5O | 详情 | 详情 | |
| (XVII) | 67943 | 5-chlorobenzo[d]oxazole | 17200-29-2 | C7H4ClNO | 详情 | 详情 |
| (XXXII) | 67956 | (4-(5-chlorobenzo[d]oxazol-2-yl)-7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone | C23H23ClN6O2 | 详情 | 详情 |