CN113429303A - 一种工业化生产盐酸文拉法辛的方法 - Google Patents
一种工业化生产盐酸文拉法辛的方法 Download PDFInfo
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- CN113429303A CN113429303A CN202110845026.6A CN202110845026A CN113429303A CN 113429303 A CN113429303 A CN 113429303A CN 202110845026 A CN202110845026 A CN 202110845026A CN 113429303 A CN113429303 A CN 113429303A
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- venlafaxine hydrochloride
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- QYRYFNHXARDNFZ-UHFFFAOYSA-N venlafaxine hydrochloride Chemical compound [H+].[Cl-].C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 QYRYFNHXARDNFZ-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 229960002416 venlafaxine hydrochloride Drugs 0.000 title claims abstract description 33
- 238000000034 method Methods 0.000 title claims abstract description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 16
- 238000007069 methylation reaction Methods 0.000 claims description 13
- 239000002994 raw material Substances 0.000 claims description 13
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 12
- 239000013078 crystal Substances 0.000 claims description 12
- 235000019253 formic acid Nutrition 0.000 claims description 12
- 239000007868 Raney catalyst Substances 0.000 claims description 11
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 11
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 239000003638 chemical reducing agent Substances 0.000 claims description 9
- 238000006722 reduction reaction Methods 0.000 claims description 9
- PACGLQCRGWFBJH-UHFFFAOYSA-N 2-(4-methoxyphenyl)acetonitrile Chemical compound COC1=CC=C(CC#N)C=C1 PACGLQCRGWFBJH-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical compound N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 8
- 238000006482 condensation reaction Methods 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- ORAXBZFDDWPRRD-UHFFFAOYSA-N 3-(4-methoxyphenyl)propanenitrile Chemical compound COC1=CC=C(CCC#N)C=C1 ORAXBZFDDWPRRD-UHFFFAOYSA-N 0.000 claims description 3
- 229920000858 Cyclodextrin Polymers 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 3
- 230000009471 action Effects 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
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- 230000008569 process Effects 0.000 description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
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- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 4
- NRPFNQUDKRYCNX-UHFFFAOYSA-N 4-methoxyphenylacetic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
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- 230000000694 effects Effects 0.000 description 4
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- ZGFPIGGZMWGPPW-UHFFFAOYSA-N formaldehyde;formic acid Chemical compound O=C.OC=O ZGFPIGGZMWGPPW-UHFFFAOYSA-N 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229960002748 norepinephrine Drugs 0.000 description 4
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000003747 Grignard reaction Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 238000005576 amination reaction Methods 0.000 description 3
- 230000001430 anti-depressive effect Effects 0.000 description 3
- 229940005513 antidepressants Drugs 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000010531 catalytic reduction reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 229960004688 venlafaxine Drugs 0.000 description 3
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 3
- NTKXIDDUCSFBBF-UHFFFAOYSA-N 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol;hydrochloride Chemical compound Cl.C1=CC(OC)=CC=C1C(CN)C1(O)CCCCC1 NTKXIDDUCSFBBF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VJMAITQRABEEKP-UHFFFAOYSA-N [6-(phenylmethoxymethyl)-1,4-dioxan-2-yl]methyl acetate Chemical compound O1C(COC(=O)C)COCC1COCC1=CC=CC=C1 VJMAITQRABEEKP-UHFFFAOYSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
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- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 208000020016 psychiatric disease Diseases 0.000 description 2
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
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- 238000003467 Ivanov reaction Methods 0.000 description 1
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 1
- SUQHIQRIIBKNOR-UHFFFAOYSA-N N,N-didesmethylvenlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN)C1(O)CCCCC1 SUQHIQRIIBKNOR-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical class NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- 229940121991 Serotonin and norepinephrine reuptake inhibitor Drugs 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
- C07C53/08—Acetic acid
- C07C53/10—Salts thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Chemical Kinetics & Catalysis (AREA)
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- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种工业化生产盐酸文拉法辛的方法，涉及药物有机合成技术领域，本发明以对甲氧基苯乙腈和环己酮为起始原料，经缩合反应、还原反应和甲基化反应制备盐酸文法法辛，整个合成路线的原料易得，反应条件温和，操作简便易行，收率高，环境友好，制备方法的重复性好，能够制得高收率、高纯度的盐酸文拉法辛，从而适用于工业化生产。
Description
技术领域：
本发明涉及药物有机合成技术领域，具体涉及一种工业化生产盐酸文拉法辛的方法。
背景技术：
抑郁症，作为现代经济高速发展的“副产物”，已越来越广泛地影响人们的生活。有资料显示，我国70％的人处于亚健康状态，与心理相关的疾病患者约占人群的5％-10％，精神疾患和心理障碍已成为多发病、常见病。世界卫生组织(WHO)发表的《世界卫生报告》显示，抑郁症已成为世界第四大疾患，到2020年抑郁症可能成为仅次于心脏病的第二大疾病。
WHO数据显示，全球的抑郁症患者超过3亿。我国抑郁症患病率达2.1％，抑郁症已成为一个全球关注的问题，同时也推动着抗抑郁药物的市场扩容。米内网数据显示，2019年中国公立医疗机构终端抗抑郁化药销售额突破90亿元，同比增长超10％。随着人们就诊观念的改变和医生对抑郁症识别率提高，抗抑郁药物市场的巨大潜力将进一步被开发。
盐酸文拉法辛(venlafaxine hydrochloride)为苯乙胺类衍生物，是二环类非典型抗抑郁药，由美国Wyeth-Ayerst公司研制，1994年4月首次在美国上市，1997年在我国开始应用。盐酸文拉法辛是第一个5-羟色胺(5-HT)和去甲肾上腺素(NE)再摄取双重抑制剂(SNRIs)，是不同于其他抗抑郁药物的、具有独特化学结构和神经药理活性的新型抗抑郁药。文拉法辛以消旋方式存在，左右旋体的药理活性有差异，当右旋体主要抑制5-HT时，左旋体同时抑制5-HT和NE的再摄取。它对肾上腺素能、M1胆碱能及组胺H1受体无明显亲和力，因此其不良反应较少，且由于其对β受体的快速下调作用而起效快。与其他抗抑郁药相比，盐酸文拉法辛具有有效率和痊愈率高、疗效快、药物相互作用少等明显优势，已成为治疗抑郁症的一线药物。
盐酸文拉法辛(式I)，化学名为(±)-1-[2-(二甲胺基)-1-(4-甲氧基苯基)乙基]环己醇盐酸盐，其结构如下：
目前很多专利和文献公开了盐酸文拉法辛的不同合成方法。其中，化合物1-(2-氨基-1-(4-甲氧基苯基)乙基)环己醇(式II)是一个非常重要的关键中间体，有很多专利以它作为原料合成盐酸文拉法辛。
JMC文献报道的合成工艺路线以4-甲氧基苯乙腈为原料，经缩合反应、还原反应、甲基化反应得盐酸文拉法辛，收率为37.8％。该路线的缺点是必须在-78℃条件下使用正丁基锂，反应条件苛刻，设备要求高。
专利CN99113785公开的合成工艺路线是以4-甲氧基苯乙酸为原料，经氯化反应、胺化反应、Ivanov反应、加成反应及还原反应得到盐酸文拉法辛，收率为38％。该路线需要用到腐蚀性试剂氯化亚砜，且在应用格氏试剂时条件也较苛刻，限制了其工业化应用。
专利EP00945958公开的合成工艺路线是以4-甲氧基苯乙酸原料，经酯化反应、Claisen缩合反应、胺化反应、催化氢化反应、格氏反应得到盐酸文拉法辛，收率为38％。该路线反应步骤多，操作较复杂，成本较高，难以工业化生产。
专利EP01303347公开的合成工艺路线是以4-甲氧基苯甲醛为原料，经格氏反应、氧化反应、溴化反应、氰化反应、催化还原反应及甲基化反应得到盐酸文拉法辛，收率为24.2％。该工艺路线较长，收率较低，工业化应用价值不大。
专利EP01303347公开的合成工艺路线是以对甲氧基苯乙腈为原料，经Knoevenagel反应、氧化反应、催化还原反应及甲基化反应得到盐酸文拉法辛，收率未见报道。
中国药科大学学报，周金培，报道的合成工艺路线是以苯甲醚为原料，经Friedel-Crafts酰化反应、胺化反应、还原溴代反应及格氏反应得到盐酸文拉法辛，收率为11％。该路线反应步骤长，收率低，生产成本高，且需使用格氏试剂，难以工业化生产。
浙江大学公开的硕士论文是以对甲氧基苯乙腈为原料，经缩合反应、催化还原反应及甲基化反应得到盐酸文拉法辛。该路线收率较高，但甲基化反应起始原料1-(2-氨基-1-(4-甲氧基苯基)乙基)环己醇盐酸盐需要先解离，再进行甲基化反应制备文拉法辛，操作繁琐，影响收率，增加成本。
综合对比以上合成路线，其中最后一条路线的步骤较短，操作简便，原料易得等诸多优势，易于进行工业化生产，但是需要克服甲基化原料1-(2-氨基-1-(4-甲氧基苯基)乙基)环己醇盐酸盐解离和收率低的问题。
发明内容：
本发明所要解决的技术问题在于提供一种工业化生产盐酸文拉法辛的方法，利用该方法制得的盐酸文拉法辛的纯度≥99.5％、总收率≥67.3％，适合工业化生产。
本发明所要解决的技术问题采用以下的技术方案来实现：
本发明的一个目的是提供一种工业化生产盐酸文拉法辛的方法，以对甲氧基苯乙腈和环己酮为原料，在催化剂的作用下经缩合反应制得中间体1，中间体1在氨甲醇的存在下与还原剂、酸经还原反应和成盐反应制得中间体2，中间体2与甲醛、甲酸经甲基化反应制得盐酸文拉法辛。
合成路线如下：
所述对甲氧基苯乙腈、环己酮的摩尔比为1:(1-2)，优选1:(1.2-1.4)。
所述催化剂为PEG、环糊精、苄基三乙基氯化铵、四丁基溴化铵、四丁基氯化铵中的一种或多种，优选PEG。季铵碱为基因毒性杂质，环糊精水溶性差不易除去。
所述缩合反应的反应溶剂为甲苯、甲醇、四氢呋喃、水中的一种或多种，优选甲苯。
所述中间体1、氨甲醇的摩尔比为1:(1-4)，优选1:2。氨甲醇的加入是为了防止中间体2减少副反应发生，降低中间体2的收率和纯度。
副反应的发生机理：
所述中间体1、还原剂的质量比为1:(0.1-1)，优选1:0.4。
所述还原剂为氢化铝锂、钯碳、雷尼镍中的一种或多种，优选雷尼镍。
所述还原反应的反应温度为20-60℃，优选40-50℃。
所述酸为甲酸、乙酸、盐酸、柠檬酸中的一种，优选乙酸。
所述中间体2、甲酸、甲醛的摩尔比为1:(4-15):(2-10)，优选1:(5-7):(3-4)。
所述甲醛为37％甲醛水溶液。
所述甲酸为88％甲酸水溶液。
所述甲基化反应的反应时间为10-30h，优选15-20h。
所述甲基化反应的后处理溶剂为甲苯、乙酸乙酯、二氯甲烷中的一种，优选乙酸乙酯。采用单一的后处理溶剂，便于回收套用，环保性强，成本低。
本发明的另一个目的是提供一种中间体2的单晶，化学结构式为：
本发明的有益效果是：
(1)本发明以对甲氧基苯乙腈和环己酮为起始原料，经缩合反应、还原反应和甲基化反应制备盐酸文法法辛，整个合成路线的原料易得，反应条件温和，操作简便易行，收率高，环境友好，制备方法的重复性好，能够制得高收率、高纯度的盐酸文拉法辛，从而适用于工业化生产。
(2)本发明制得一种中间体2单晶，经单晶结构分析证明其属单斜晶系。文拉法辛有一个手性中心，当右旋体主要抑制5-HT时，左旋体同时抑制5-HT和NE的再摄取，盐酸文拉法辛成药是消旋体，中间体2已经确定了手性比例，而获得单晶更能直观准确的确定结构，确保后面合成的盐酸文拉法辛结构是准确的，从而确保临床用药安全。
附图说明：
图1为中间体1的HPLC图；
图2为中间体1的氢谱图；
图3为中间体1的碳谱图；
图4为中间体2盐酸盐的HPLC图；
图5为中间体2乙酸盐的HPLC图；
图6为中间体2乙酸盐的单晶图；
图7为中间体2的氢谱图；
图8为中间体2的碳谱图；
图9为中间体2的DSC-TGA图；
图10为盐酸文拉法辛的HPLC图；
图11为盐酸文拉法辛的氢谱图；
图12为盐酸文拉法辛的碳谱图。
具体实施方式：
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施例和图示，进一步阐述本发明。
实施例1
中间体1的合成：
向2L三口瓶中加入甲苯600ml，300.00g对甲氧基苯乙腈，270.00g环己酮和30.00gPEG，滴加50％氢氧化钠40.00g，在50℃下搅拌约5h。反应完毕，降温至0-10℃，过滤，滤饼加入2L纯化水打浆，过滤，滤饼置55℃鼓风干燥箱中干燥，得到中间体1。
1H-NMR(400MHz,CDCl3)δ7.27(m,2H),6.90(m,2H),3.81(s,3H),3.73(s,1H),1.73(m,1H),1.56(m,9H),1.17(m,1H).13C NMR(101MHz,CDCl3)δ159.73,130.63,123.70,119.85,114.07,72.72,55.33,49.34,34.98,34.87,25.19,21.56,21.50.
调整对甲氧基苯乙腈与环己酮的摩尔比或者选择不同的催化剂以及反应溶剂，研究中间体1的合成工艺，结果如表1所示。
表1
实施例2
中间体2的合成：
将300.00g中间体1、150.00g雷尼镍、180mL氨甲醇和3000mL无水甲醇加入到高压釜中，在压力2.0MPa、温度50±5℃下氢化反应3h。反应完毕，抽滤，回收雷尼镍，滤液减压回收甲醇，浓缩至干，加入2.1L乙酸乙酯溶解，室温下滴加73.5g冰乙酸，约10min滴加完毕，继续搅拌有大量固体析出，室温搅拌2h，抽滤，滤饼用乙酸乙酯1L淋洗，得到中间体2。
1H-NMR(600MHz,DMSO-d6)δ7.15(d,J＝8.6Hz,2H),6.85(d,J＝8.6Hz,2H),3.73s,3H),3.27(dd,J＝12.7,5.6Hz,1H),2.96(dd,J＝12.7,8.8Hz,1H),2.72(dd,J＝8.8,5.6Hz，1H),1.77s,3H),1.51(m,4H),1.34(m,3H),1.09(m,2H),0.96(m,1H).
13C-NMR(101MHz,DMSO-d6)δ174.06,158.41,132.51,131.04,113.82,72.44,55.43,41.05,37.24,33.85,26.03,23.74,21.90,21.69
中间体2的晶体衍射检测：
取1g中间体2和5ml甲醇溶解加入单晶培养器中，得到中间体2单晶。
单晶呈无色透明针状，检测所用晶体大小为0.14*0.15*0.26mm。
采用RigakuMM007-Saturn724+(Small Molecule Single Crystal X-rayDiffractometer)衍射仪收集衍射强度数据。配备MicroMax007微焦斑转靶Mo靶发生器，焦斑尺寸0.07*0.07mm2，最高功率800W。ConfocalMax-Flux光学系统。SATURN724+CCD探测器，有效区域：70mm*70mm，像素：2048*2048。检测样品喷氮低温装置，可长时间将样品保持在93K～473K之间任意温度进行测试，不需液氮。采用直接法(Shelxs97)解析晶体结构，精修后最终可靠因子R＝0.0514(4761)，wR2＝0.1489(5809)(w＝1/σ|F|2)，S＝1.090。
晶体学参数：属单斜晶系，空间群为P212121/c，晶胞参数：a＝6.717(12)，b＝9.391(18)，
a＝γ＝β＝90.00°，晶胞体积V＝1739(6)，晶胞内不对称单位数Z＝4。
调整中间体1与雷尼镍的质量比或者中间体1与氨甲醇的摩尔比或者选择不同的还原剂以及酸，研究中间体2的合成工艺，结果如表2所示。
表2
| 序号 | 条件 | 收率 | 纯度 |
| 1 | 氢化铝锂 | 84.3％ | 97.2％ |
| 2 | 钯碳 | 82.5％ | 95.5％ |
| 3 | 雷尼镍 | 91.4％ | 98.9％ |
| 4 | 乙酸 | 90.2％ | 99.1％ |
| 5 | 甲酸 | 85.4％ | 99.1％ |
| 6 | 盐酸 | 84.3％ | 94.6％ |
| 7 | 中间体1:雷尼镍＝1:0.1 | 70.2％ | 95.2％ |
| 8 | 中间体1:雷尼镍＝1:0.4 | 89.4％ | 98.9％ |
| 9 | 中间体1:雷尼镍＝1:1 | 83.3％ | 96.3％ |
| 10 | 中间体1:氨甲醇＝1:1 | 83.7％ | 98.3％ |
| 11 | 中间体1:氨甲醇＝1:2 | 89.5％ | 99.1％ |
| 12 | 中间体1:氨甲醇＝1:4 | 88.5％ | 99.0％ |
| 13 | 不加氨甲醇 | 56.2％ | 86.2％ |
实施例3
盐酸文拉法辛的合成
向反应瓶中加入200.00g中间体2、1000mL纯化水、200mL甲酸、150mL甲醛，加热至回流，搅拌反应20h，减压回收溶剂至干，加入400mL纯化水，用400mL*2乙酸乙酯萃取2次，水层用饱和氢氧化钠调节pH约10，用800mL*2乙酸乙酯萃取二次，合并有机层，用400mL饱和食盐水洗一次，有机层用无水硫酸钠干燥，过滤，滤液，在10±5℃下缓慢加入30％盐酸异丙醇120mL，搅拌析晶2h，过滤，滤饼用400mL乙酸乙酯淋洗，湿滤饼用异丙醇1.2L重结晶，得到盐酸文拉法辛。
1H-NMR(400MHz,DMSO-d6)δ9.75(s,1H),7.27(d,J＝8.8Hz,2H),6.90(d,J＝8.8Hz,2H),4.61(s,1H),3.75(s,3H),3.67(m,1H),3.48(s,1H),3.11(s,1H),2.67(d,J＝4.0Hz,3H),2.58(d,J＝4.0Hz,3H),1.59(m,2H),1.44(m,3H),1.33(s,1H),1.22(m,2H),1.04(m,2H).
13C-NMR(101MHz,DMSO-d6)δ158.25,130.73,130.56,113.59,72.07,58.12,54.96,49.93,43.08,42.76,36.08,33.09,25.25,21.34,20.94.
调整中间体2与甲酸、甲醛的摩尔比或者选择不同的后处理溶剂以及反应时间，研究盐酸文拉法辛的合成工艺，结果如表3所示。
表3
| 序号 | 条件 | 收率 | 纯度 |
| 1 | 中间体2:甲酸:甲醛＝1:4:2 | 65.3％ | 99.5％ |
| 2 | 中间体2:甲酸:甲醛＝1:5:3 | 83.6％ | 99.8％ |
| 3 | 中间体2:甲酸:甲醛＝1:7:4 | 85.7％ | 99.9％ |
| 4 | 中间体2:甲酸:甲醛＝1:15:10 | 80.1％ | 99.3％ |
| 5 | 甲苯 | 86.4％ | 99.1％ |
| 6 | 乙酸乙酯 | 85.7％ | 99.9％ |
| 7 | 二氯甲烷 | 80.3％ | 99.9％ |
| 8 | 10h | 72.1％ | 98.2％ |
| 9 | 20h | 84.6％ | 99.9％ |
| 10 | 30h | 83.5％ | 99.7％ |
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (10)
1.一种工业化生产盐酸文拉法辛的方法，其特征在于：以对甲氧基苯乙腈和环己酮为原料，在催化剂的作用下经缩合反应制得中间体1，中间体1在氨甲醇的存在下与还原剂、酸经还原反应和成盐反应制得中间体2，中间体2与甲醛、甲酸经甲基化反应制得盐酸文拉法辛；
合成路线如下：
2.根据权利要求1所述的方法，其特征在于：所述对甲氧基苯乙腈、环己酮的摩尔比为1:(1-2)；所述催化剂为PEG、环糊精、苄基三乙基氯化铵、四丁基溴化铵、四丁基氯化铵中的一种或多种；所述缩合反应的反应溶剂为甲苯、甲醇、四氢呋喃、水中的一种或多种。
3.根据权利要求2所述的方法，其特征在于：所述对甲氧基苯乙腈、环己酮的摩尔比为1:(1.2-1.4)；所述催化剂为PEG；所述缩合反应的反应溶剂为甲苯。
4.根据权利要求1所述的方法，其特征在于：所述中间体1、氨甲醇的摩尔比为1:(1-4)；所述中间体1、还原剂的质量比为1:(0.1-1)；所述还原剂为氢化铝锂、钯碳、雷尼镍中的一种或多种；所述酸为甲酸、乙酸、盐酸、柠檬酸中的一种。
5.根据权利要求4所述的方法，其特征在于：所述中间体1、氨甲醇的摩尔比为1:2；所述中间体1、还原剂的质量比为1:0.4；所述还原剂为雷尼镍；所述酸为乙酸。
6.根据权利要求1所述的方法，其特征在于：所述中间体2、甲酸、甲醛的摩尔比为1:(4-15):(2-10)。
7.根据权利要求6所述的方法，其特征在于：所述中间体2、甲酸、甲醛的摩尔比为1:(5-7):(3-4)。
8.根据权利要求1所述的方法，其特征在于：所述还原反应的反应温度为20-60℃；所述甲基化反应的反应时间为10-30h，后处理溶剂为甲苯、乙酸乙酯、二氯甲烷中的一种。
9.根据权利要求8所述的方法，其特征在于：所述还原反应的反应温度为40-50℃；所述甲基化反应的反应时间为15-20h，后处理溶剂为乙酸乙酯。
10.一种利用权利要求1所述的方法制备的中间体2单晶，化学结构式为：
属单斜晶系，空间群为P212121/c，晶胞参数为：a＝6.717(12)，b＝9.391(18)，
a＝γ＝β＝90.00°，晶胞体积V＝1739(6)，晶胞内不对称单位数Z＝4。
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