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【结 构 式】 
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【分子编号】34151 【品名】2-iodo-5-methylbenzoic acid 【CA登记号】52548-14-8 |
【 分 子 式 】C8H7IO2 【 分 子 量 】262.04685 【元素组成】C 36.67% H 2.69% I 48.43% O 12.21% |
合成路线1
该中间体在本合成路线中的序号：(I)The reaction of 2-iodo-5-methylbenzoic acid (I) with 4-hydroxyacetophenone (II) by means of K2CO3 in nitrobenzene at 150 C gives 2-(4-acetylphenoxy)-5-methylbenzoic acid (III), which by reduction with LiAlH4 in refluxing THF is converted into 2-[4-(1-hydroxyethyl)phenoxy]-5-methylbenzyl alcohol (IV). The reaction of (IV) with SOCl2 in refluxing CHCl3 affords 2-[4-(1-chloroethyl)phenoxy]-5-methylbenzyl chloride (V), which is treated with NaCN in refluxing dioxane ethanol-water yielding the dinitrile (VI). The hydrolysis of (VI) with KOH in refluxing ethanol-water gives 2-[4-[2-(carboxymethyl)-4-methylphenoxy]phenyl]propionic acid (VII), which is finally cyclized by treatment with polyphosphoric acid (PPA) at 120 C.
| 【1】 Uno, H.; Nagai, Y.; Nakamura, H.; Dibenz[b,f]oxepin and dibenzo[b,f]thiepin derivatives, process for preparation thereof, method of using the same, and compositions thereof. EP 0003893; ES 477791; JP 1393170C; JP 54122284; US 4238620 . |
| 【2】 Serradell, M.N.; Arrigoni-Martelli, E.; Castaner, J.; AD-1590. Drugs Fut 1984, 9, 6, 399. |
| 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) | 34151 | 2-iodo-5-methylbenzoic acid | 52548-14-8 | C8H7IO2 | 详情 | 详情 |
| (II) | 18123 | 1-(4-hydroxyphenyl)-1-ethanone; 4'-Hydroxyacetophenone | 99-93-4 | C8H8O2 | 详情 | 详情 |
| (III) | 34152 | 2-(4-acetylphenoxy)-5-methylbenzoic acid | C16H14O4 | 详情 | 详情 | |
| (IV) | 34153 | 1-[4-[2-(hydroxymethyl)-4-methylphenoxy]phenyl]-1-ethanol | C16H18O3 | 详情 | 详情 | |
| (V) | 34154 | 1-[4-(1-chloroethyl)phenoxy]-2-(chloromethyl)-4-methylbenzene; 4-(1-chloroethyl)phenyl 2-(chloromethyl)-4-methylphenyl ether | C16H16Cl2O | 详情 | 详情 | |
| (VI) | 34155 | 2-[4-[4-methyl-2-(2-nitriloethyl)phenoxy]phenyl]propanenitrile | C18H16N2O | 详情 | 详情 | |
| (VII) | 34156 | 2-[4-[2-(2-hydroxy-2-oxoethyl)-4-methylphenoxy]phenyl]propionic acid | C18H18O5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reduction of 2-iodo-5-methylbenzoic acid (I) with BH3/THF in THF gives 2-iodo-5-methylbenzyl alcohol (II), which is treated with refluxing 48% HBr to yield the benzyl bromide (III). Reaction of (III) with NaCN in ethanol/water afford the phenylacetonitrile (IV), which is hydrolyzed with NaOH in refluxing EtOH/water to provide the phenylacetic acid (V). Reaction of (V) with SOCl2 in refluxing dichloromethane gives the corresponding acyl chloride (VI), which is treated with dimethylamine in diethyl ether/THF to yield 2-(2-iodo-5-methylphenyl)-N,N-dimethylacetamide (VII). Condensation of (VII) with 2-chloro-6-fluoroaniline (VIII) by means of Cu powder, Cu2I2 and K2CO3 in refluxing xylene affords 2-[2-(2-chloro-6-fluorophenylamino)-5-methylphenyl]-N,N-dimethylacetamide (IX), which is finally hydrolyzed with NaOH in refluxing butanol/water.
| 【1】 Bayes, M.; Silvestre, J.S.; Sorbera, L.A.; Castaner, J.; Lumiracoxib. Drugs Fut 2002, 27, 8, 740. |
| 【2】 Fujimoto, R.A.; Mugrage, B.B.; Van Duzer, J.H.; McQuire, L.W.; Xu, D. (Novartis AG); Certain 5-alkyl-2-arylaminophenylacetic acids and derivs.. JP 2001514244; US 6291523; WO 9911605 . |
| 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) | 34151 | 2-iodo-5-methylbenzoic acid | 52548-14-8 | C8H7IO2 | 详情 | 详情 |
| (II) | 53844 | (2-iodo-5-methylphenyl)methanol | n/a | C8H9IO | 详情 | 详情 |
| (III) | 53845 | 2-(bromomethyl)-1-iodo-4-methylbenzene | n/a | C8H8BrI | 详情 | 详情 |
| (IV) | 53846 | 2-(2-iodo-5-methylphenyl)acetonitrile | n/a | C9H8IN | 详情 | 详情 |
| (V) | 53847 | 2-(2-iodo-5-methylphenyl)acetic acid | n/a | C9H9IO2 | 详情 | 详情 |
| (VI) | 53848 | 2-(2-iodo-5-methylphenyl)acetyl chloride | n/a | C9H8ClIO | 详情 | 详情 |
| (VII) | 53849 | 2-(2-iodo-5-methylphenyl)-N,N-dimethylacetamide | n/a | C11H14INO | 详情 | 详情 |
| (VIII) | 53837 | 2-Chloro-6-fluoroaniline | 363-51-9 | C6H5ClFN | 详情 | 详情 |
| (IX) | 53850 | 2-[2-(2-chloro-6-fluoroanilino)-5-methylphenyl]-N,N-dimethylacetamide | n/a | C17H18ClFN2O | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)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 |