Yang Shiwei, Chen Shiyun, Wang Cheng, Zhang Shibo, Li Shuaifei, Yuan Xinsong, Peng Fuyun, He Yong
Department of Chemistry and Chemical Engineering, Hefei Normal University, Hefei, China.
Department of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei, China.
Front Chem. 2022 Aug 17;10:860292. doi: 10.3389/fchem.2022.860292. eCollection 2022.
We herein describe an optimal approach for the efficient synthesis of -desmethylvenlafaxine succinate monohydrate (DVS) with high yield and high purity through 5-step reactions, including benzyl protection of the phenolic hydroxyl group, cyclohexanone condensation, deprotection, cyano reduction, dimethylation, and succinic acid salt formation from -hydroxybenzene acetonitrile as a starting material. 4-Benzyloxyphenylacetonitrile (Intermediate I) was prepared by the hydroxyl protection of the bromide benzyl--hydroxyphenylacetonitrile catalyzed by potassium carbonate with 99.83% purity and 98.92% yields. The 1, 2-nucleophilic addition of intermediate I to cyclohexanone promoted by sodium hydroxide with the homogeneous catalyst (n-Bu)NBr to the preparation of 1-[Cyano(4-benzyloxyphenyl)methyl]cyclohexanol (Intermediate II) was obtained by 99.13% purity and 99.71% yields. Cyclohexanone residues and benzyl bromide residues were trace, and tetrabutylammonium bromide residues were UNDER 0.7 ppm, which further improves the residual standards for genotoxic impurities (GIs). 1-[2-amino-1-(4-hydroxyphenyl)ethyl]cyclohexanol hydrochloride (Intermediate III) was prepared by 10% palladium-carbon under 2.0 MPa up to 98.32% purity and 94.20% yields. -desmethylvenlafaxine (ODV) was synthesized by dimethylation of intermediate III with 37% formaldehyde solution and 85% formic acid solution. The highest purity was up to 99.20% and the yield was up to 84.77%. -desmethylvenlafaxine succinate monohydrate (DVS) was formed from succinic acid and -desmethylvenlafaxine (ODV) and crystallized in a mixed solvent of acetone and water (3:1) to obtain 99.92% purity and 90.27% yields. The 5-step total yields of desvenlafaxine succinate monohydrate is 71.09%, and its crystal form has characteristic peaks at 5, 10, 21, and 26 min by XRD powder diffraction, which is consistent with the crystalline form I. Compared with conventional synthesis strategy, we revealed a novel and green process with a high total yield, high atomic economy, low environmental pollution, high operational safety, and high residual standards for genotoxic impurities (GIs), which improves drug safety.
我们在此描述了一种以对羟基苯乙腈为起始原料，通过五步反应高效合成琥珀酸去甲文拉法辛一水合物（DVS）的优化方法，该方法具有高产率和高纯度，包括酚羟基的苄基保护、环己酮缩合、脱保护、氰基还原、甲基化以及琥珀酸盐形成。4 - 苄氧基苯乙腈（中间体I）通过碳酸钾催化溴化苄基 - 对羟基苯乙腈的羟基保护反应制备，纯度为99.83%，产率为98.92%。在氢氧化钠和均相催化剂（正丁基）4NBr的促进下，中间体I与环己酮进行1,2 - 亲核加成反应，制备得到1 - [氰基（4 - 苄氧基苯基）甲基]环己醇（中间体II），纯度为99.13%，产率为99.71%。环己酮残留和苄基溴残留为痕量，四丁基溴化铵残留低于（UNDER）0.7 ppm，这进一步提高了遗传毒性杂质（GIs）的残留标准。1 - [2 - 氨基 - 1 - （4 - 羟基苯基）乙基]环己醇盐酸盐（中间体III）由10%钯 - 碳在2.0 MPa压力下制备，纯度高达98.32%，产率为94.20%。去甲文拉法辛（ODV）通过中间体III与37%甲醛溶液和85%甲酸溶液的甲基化反应合成。最高纯度可达99.20%，产率可达84.77%。琥珀酸去甲文拉法辛一水合物（DVS）由琥珀酸和去甲文拉法辛（ODV）形成，并在丙酮和水（3:1）的混合溶剂中结晶，得到纯度为99.92%，产率为90.27%。琥珀酸去甲文拉法辛一水合物的五步总产率为71.09%，其晶体形式通过XRD粉末衍射在5、10、21和26分钟处有特征峰，与晶型I一致。与传统合成策略相比，我们揭示了一种新颖的绿色工艺，具有高总产率、高原子经济性、低环境污染、高操作安全性以及高遗传毒性杂质（GIs）残留标准，从而提高了药物安全性。
