5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid -Drug Synthesis Database

【结构式】

【分子编号】67936

【品名】5-methyl-2-(1,2,3-triazol-2-yl)benzoic acid

【CA登记号】　

【分子式】C₁₀H₉N₃O₂

【分子量】203.20048

【元素组成】C 59.11% H 4.46% N 20.68% O 15.75%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IX)

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 .

参考文献中间体

合成目标

【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

该中间体在本合成路线中的序号：(IX)

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 .

参考文献中间体

合成目标

【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

Extended Information