CN110790690A - A kind of synthetic method of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid - Google Patents
A kind of synthetic method of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid Download PDFInfo
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- CN110790690A CN110790690A CN201911123930.5A CN201911123930A CN110790690A CN 110790690 A CN110790690 A CN 110790690A CN 201911123930 A CN201911123930 A CN 201911123930A CN 110790690 A CN110790690 A CN 110790690A
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- YLPPWUHTBLHWOM-UHFFFAOYSA-N 3,4-difluoro-2-(phenylsulfanylmethyl)benzoic acid Chemical compound OC(=O)c1ccc(F)c(F)c1CSc1ccccc1 YLPPWUHTBLHWOM-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000010189 synthetic method Methods 0.000 title claims description 13
- GUUVPOWQJOLRAS-UHFFFAOYSA-N Diphenyl disulfide Chemical compound C=1C=CC=CC=1SSC1=CC=CC=C1 GUUVPOWQJOLRAS-UHFFFAOYSA-N 0.000 claims abstract description 16
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims abstract description 14
- JWKULHCJULCSPD-UHFFFAOYSA-N 2-(bromomethyl)-3,4-difluorobenzoic acid Chemical compound OC(=O)c1ccc(F)c(F)c1CBr JWKULHCJULCSPD-UHFFFAOYSA-N 0.000 claims abstract description 14
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims abstract description 11
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 8
- AGUUCAUQWFAFPR-UHFFFAOYSA-N 3,4-difluoro-2-methylbenzoic acid Chemical compound CC1=C(F)C(F)=CC=C1C(O)=O AGUUCAUQWFAFPR-UHFFFAOYSA-N 0.000 claims abstract description 7
- LKYIPGJOXSVWPX-UHFFFAOYSA-M sodium;thiophene-2-carboxylate Chemical compound [Na+].[O-]C(=O)C1=CC=CS1 LKYIPGJOXSVWPX-UHFFFAOYSA-M 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 50
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 239000003638 chemical reducing agent Substances 0.000 claims description 8
- 238000010992 reflux Methods 0.000 claims description 6
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000003513 alkali Substances 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000000706 filtrate Substances 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- RZWQDAUIUBVCDD-UHFFFAOYSA-M sodium;benzenethiolate Chemical compound [Na+].[S-]C1=CC=CC=C1 RZWQDAUIUBVCDD-UHFFFAOYSA-M 0.000 claims 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims 1
- 239000008346 aqueous phase Substances 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical group [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims 1
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- 239000012044 organic layer Substances 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 238000000926 separation method Methods 0.000 claims 1
- 229910052938 sodium sulfate Inorganic materials 0.000 claims 1
- 235000011152 sodium sulphate Nutrition 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 7
- 239000002994 raw material Substances 0.000 abstract description 5
- FIDLLEYNNRGVFR-CTNGQTDRSA-N (3R)-2-[(11S)-7,8-difluoro-6,11-dihydrobenzo[c][1]benzothiepin-11-yl]-11-hydroxy-5-oxa-1,2,8-triazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-9,12-dione Chemical compound OC1=C2N(C=CC1=O)N([C@@H]1COCCN1C2=O)[C@@H]1C2=C(SCC3=C1C=CC(F)=C3F)C=CC=C2 FIDLLEYNNRGVFR-CTNGQTDRSA-N 0.000 abstract description 2
- 238000012805 post-processing Methods 0.000 abstract description 2
- 238000001308 synthesis method Methods 0.000 abstract description 2
- 206010022000 influenza Diseases 0.000 description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000712461 unidentified influenza virus Species 0.000 description 3
- -1 2,3-difluoro-6-bromobenzyl alcohol Chemical compound 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- 235000010233 benzoic acid Nutrition 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
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- 238000010587 phase diagram Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- FZMPLKVGINKUJZ-UHFFFAOYSA-N 1,2-difluoro-4-methylbenzene Chemical compound CC1=CC=C(F)C(F)=C1 FZMPLKVGINKUJZ-UHFFFAOYSA-N 0.000 description 1
- UBCHPRBFMUDMNC-UHFFFAOYSA-N 1-(1-adamantyl)ethanamine Chemical compound C1C(C2)CC3CC2CC1(C(N)C)C3 UBCHPRBFMUDMNC-UHFFFAOYSA-N 0.000 description 1
- 229940123734 Endonuclease inhibitor Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010024264 Lethargy Diseases 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 208000036071 Rhinorrhea Diseases 0.000 description 1
- 206010039101 Rhinorrhoea Diseases 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 102000013530 TOR Serine-Threonine Kinases Human genes 0.000 description 1
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- DKNWSYNQZKUICI-UHFFFAOYSA-N amantadine Chemical compound C1C(C2)CC3CC2CC1(N)C3 DKNWSYNQZKUICI-UHFFFAOYSA-N 0.000 description 1
- 229960003805 amantadine Drugs 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- RZVPBGBYGMDSBG-GGAORHGYSA-N baloxavir marboxil Chemical compound COC(=O)OCOc1c2C(=O)N3CCOC[C@H]3N([C@H]3c4ccc(F)c(F)c4CSc4ccccc34)n2ccc1=O RZVPBGBYGMDSBG-GGAORHGYSA-N 0.000 description 1
- 229940008411 baloxavir marboxil Drugs 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940124579 cold medicine Drugs 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940042406 direct acting antivirals neuraminidase inhibitors Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000001225 nuclear magnetic resonance method Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229960003752 oseltamivir Drugs 0.000 description 1
- VSZGPKBBMSAYNT-RRFJBIMHSA-N oseltamivir Chemical compound CCOC(=O)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](N)C1 VSZGPKBBMSAYNT-RRFJBIMHSA-N 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
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- ARAIBEBZBOPLMB-UFGQHTETSA-N zanamivir Chemical compound CC(=O)N[C@@H]1[C@@H](N=C(N)N)C=C(C(O)=O)O[C@H]1[C@H](O)[C@H](O)CO ARAIBEBZBOPLMB-UFGQHTETSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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Abstract
本发明公开了一种巴洛沙韦关键中间体即3,4‑二氟‑2‑((苯硫基)甲基)苯甲酸的制备方法。本发明以3,4‑二氟‑2‑甲基苯甲酸为原料与偶氮二异丁腈(AIBN)和N‑溴代琥珀酰亚胺(NBS)在四氯化碳溶液中回流反应得到2‑溴甲基‑3,4‑二氟苯甲酸,然后与苯硫酚钠或者与二苯二硫醚反应得到3,4‑二氟‑2‑((苯硫基)甲基)苯甲酸。该方法合成只需两步就能得到目标产物,原料易得,后处理简便,产率高。The invention discloses a preparation method of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid, a key intermediate of baloxavir. In the present invention, 3,4-difluoro-2-methylbenzoic acid is used as raw material to react with azobisisobutyronitrile (AIBN) and N-bromosuccinimide (NBS) in carbon tetrachloride solution to obtain 2-bromomethyl-3,4-difluorobenzoic acid, then react with sodium thiophenate or diphenyl disulfide to obtain 3,4-difluoro-2-((phenylthio)methyl)benzoic acid . The synthesis method of the method can obtain the target product in only two steps, the raw materials are readily available, the post-processing is simple and the yield is high.
Description
技术领域technical field
本发明涉及3,4-二氟-2-((苯硫基)甲基)苯甲酸的合成方法。The present invention relates to a synthesis method of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid.
背景技术Background technique
流行性感冒是呼吸道受流感病毒急性感染后所致的一种疾病,其症状包括发烧、精神萎靡、流涕等。抗病毒药可用于季节性流感的预防和治疗,目前有包括M2(金刚胺与金刚乙胺)和神经氨酸酶抑制剂(奥司他韦与扎那米韦)等药物用于流感的化学预防,有效率为70-90%。巴洛沙韦(Baloxavir marboxil)是一款创新的Cap依赖型核酸内切酶抑制剂,也是世上少数可以抑制流感病毒增殖的新药。对比通常的感冒药,这项疗法的优势在于生效快,疗效持续时间长,用药量少。Influenza is a disease caused by acute infection of the respiratory tract by influenza virus, and its symptoms include fever, lethargy, and runny nose. Antiviral drugs can be used for the prevention and treatment of seasonal influenza, and currently there are drugs including M2 (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir) for influenza chemistries Prevention, the effective rate is 70-90%. Baloxavir marboxil is an innovative Cap-dependent endonuclease inhibitor and one of the few new drugs in the world that can inhibit the proliferation of influenza virus. Compared with the usual cold medicine, the advantage of this therapy is that it takes effect quickly, the effect lasts for a long time, and the dosage is small.
目前关于巴洛沙韦关键中间体3,4-二氟-2-((苯硫基)甲基)苯甲酸的相关报道只有两条,其中WO2017221869公开了一种合成方法:At present, there are only two relevant reports on baloxavir key intermediate 3,4-difluoro-2-((phenylthio)methyl)benzoic acid, wherein WO2017221869 discloses a synthetic method:
此方法第一步用到正丁基锂(n-BuLi),试剂易燃,操作需非常小心,且反应需在-40℃下进行。该路线实际操作中因区域选择性问题导致产品纯化麻烦。The first step of this method uses n-butyllithium (n-BuLi), the reagent is flammable, the operation needs to be very careful, and the reaction needs to be carried out at -40 °C. In the actual operation of this route, product purification is troublesome due to the problem of regioselectivity.
CN109721585公开了该中间体的另一种合成方法:CN109721585 discloses another synthetic method of this intermediate:
此路线第一步需要使用溴化氢,第三步需要惰性气体保护并在-35℃反应。该路线相较于专利WO2017221869的方法,操作简便,但需三步反应才能合成得到,且原料2,3-二氟-6-溴苯甲醇不易商业化获得。The first step of this route requires the use of hydrogen bromide, and the third step requires the protection of inert gas and the reaction at -35 °C. Compared with the method of patent WO2017221869, this route is easy to operate, but requires three-step reaction to be synthesized, and the
鉴于近年来流感发病率逐年提升,流感病毒抗药性不断增强,抗流感药物也越来越受到科学家的关注,因此实现一条更安全、便捷、高效、低成本的合成3,4-二氟-2-((苯硫基)甲基)苯甲酸的路线是十分必要的。In view of the increasing incidence of influenza in recent years, the increasing resistance of influenza viruses, and the increasing attention of scientists on anti-influenza drugs, a safer, more convenient, efficient and low-cost synthetic 3,4-difluoro-2 The route of -((phenylthio)methyl)benzoic acid is quite necessary.
发明内容SUMMARY OF THE INVENTION
针对现有技术存在的上述问题,我们设计了一条原料便宜易得,步骤简便,收率高的反应路线。该路线只需要两步反应就能得到产物,反应路线不涉及低温、惰性气体保护等不便要求,后处理简便,产率高,且原料3,4-二氟-2-甲基苯甲酸是合成ATP竞争性的mTOR选择性抑制剂XL388的重要中间体,它亦可由3,4-二氟甲苯通过一步反应方便制得。In view of the above problems existing in the prior art, we have designed a reaction route with cheap and easily available raw materials, simple steps and high yield. This route only needs two-step reaction to obtain the product, the reaction route does not involve inconvenient requirements such as low temperature and inert gas protection, the post-processing is simple and the yield is high, and the raw material 3,4-difluoro-2-methylbenzoic acid is synthesized An important intermediate of XL388, an ATP-competitive mTOR-selective inhibitor, which can also be easily prepared by one-step reaction from 3,4-difluorotoluene.
具体操作步骤如下:The specific operation steps are as follows:
步骤1:将3,4-二氟-2-甲基苯甲酸、偶氮二异丁腈和N-溴代琥珀酰亚胺在室温下加入到四氯化碳溶液中,开启搅拌,升温回流(60-80℃),反应2-12h后,停止反应,减压除去溶剂,将残余物加入乙酸乙酯和水,分液,乙酸乙酯用水洗数次,饱和食盐水洗涤,无水硫酸钠干燥,减压除去溶剂,得到2-溴甲基-3,4-二氟苯甲酸。Step 1: Add 3,4-difluoro-2-methylbenzoic acid, azobisisobutyronitrile and N-bromosuccinimide to the carbon tetrachloride solution at room temperature, turn on stirring, heat up and reflux (60-80°C), after 2-12 hours of reaction, the reaction was stopped, the solvent was removed under reduced pressure, the residue was added with ethyl acetate and water, and the layers were separated. Dry over sodium and remove the solvent under reduced pressure to give 2-bromomethyl-3,4-difluorobenzoic acid.
步骤2:方法一:将2-溴甲基-3,4-二氟苯甲酸与苯硫酚钠在室温下混合,加入有机溶液A,室温搅拌2-6h后停止反应,加入有机溶剂B和水,有机溶剂B用水洗涤数次,饱和食盐水洗涤,无水硫酸钠干燥,加入少量活性炭室温搅拌10min,过滤,滤液减压抽除溶剂,得到3,4-二氟-2-((苯硫基)甲基)苯甲酸。方法二:将二苯二硫醚加入双口瓶中,充氮气,加入还原剂C和溶剂D或者加入还原剂C、碱和溶剂D,升温至30-80℃回反应10-30min,再加入2-溴甲基-3,4-二氟苯甲酸,继续反应2-6h,TLC跟踪反应完毕后,反应液加入有机溶剂E和氢氧化钠溶液萃取,将氢氧化钠溶液用盐酸溶液和乙酸乙酯萃取,干燥减压抽除有机溶剂,得到3,4-二氟-2-((苯硫基)甲基)苯甲酸。Step 2: Method 1: Mix 2-bromomethyl-3,4-difluorobenzoic acid and sodium thiophenate at room temperature, add organic solution A, stir at room temperature for 2-6 hours, and stop the reaction, add organic solvent B and Water, organic solvent B was washed several times with water, washed with saturated brine, dried over anhydrous sodium sulfate, added with a small amount of activated carbon and stirred at room temperature for 10 min, filtered, and the filtrate was vacuumed to remove the solvent to obtain 3,4-difluoro-2-((benzene thio)methyl)benzoic acid. Method 2: Add diphenyl disulfide into a double-necked bottle, fill with nitrogen, add reducing agent C and solvent D or add reducing agent C, alkali and solvent D, heat up to 30-80 ° C and react for 10-30 min, then add 2-Bromomethyl-3,4-difluorobenzoic acid, continue to react for 2-6h, after the completion of TLC tracking reaction, the reaction solution is added with organic solvent E and sodium hydroxide solution for extraction, and the sodium hydroxide solution is extracted with hydrochloric acid solution and acetic acid Ethyl ester extraction, drying and vacuum extraction to remove the organic solvent to obtain 3,4-difluoro-2-((phenylthio)methyl)benzoic acid.
具体实施方式:Detailed ways:
下面结合具体实施例对本发明作进一步说明,但本发明的保护范围并不限于此。The present invention will be further described below with reference to specific embodiments, but the protection scope of the present invention is not limited thereto.
实施例1:2-溴甲基-3,4-二氟苯甲酸的制备Example 1: Preparation of 2-bromomethyl-3,4-difluorobenzoic acid
在25ml单口烧瓶中加入3,4-二氟-2-甲基苯甲酸(0.500g,2.905mmol)、N-溴代琥珀酰亚胺(0.517g,2.905mmol)、偶氮二异丁腈(0.050g,0.304mmol)、四氯化碳10ml,80℃回流反应2h,TLC跟踪至反应完毕。冷却反应液,减压抽除溶剂得到白色固体,固体溶于30ml乙酸乙酯,水洗(20mlx2),饱和食盐水20ml洗涤,无水硫酸钠干燥,减压抽除乙酸乙酯,得到2-溴甲基-3,4-二氟苯甲酸0.711g,收率为97.5%。3,4-Difluoro-2-methylbenzoic acid (0.500g, 2.905mmol), N-bromosuccinimide (0.517g, 2.905mmol), azobisisobutyronitrile ( 0.050 g, 0.304 mmol), 10 ml of carbon tetrachloride, refluxed at 80°C for 2 h, followed by TLC until the completion of the reaction. The reaction solution was cooled, and the solvent was removed under reduced pressure to obtain a white solid. The solid was dissolved in 30 ml of ethyl acetate, washed with water (20 ml×2), washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and the ethyl acetate was removed under reduced pressure to obtain 2-bromo Methyl-3,4-difluorobenzoic acid 0.711 g, yield 97.5%.
实施例2:2-溴甲基-3,4-二氟苯甲酸的制备Example 2: Preparation of 2-bromomethyl-3,4-difluorobenzoic acid
在25ml单口烧瓶中加入3,4-二氟-2-甲基苯甲酸(0.500g,2.905mmol)、N-溴代琥珀酰亚胺(0.550g,3.090mmol)、偶氮二异丁腈(0.050g,0.304mmol)、四氯化碳10ml,70℃回流反应5h,TLC跟踪至反应完毕,冷却反应液,减压抽除溶剂得白色固体,固体溶于30ml乙酸乙酯,水洗涤(20mlx2),饱和食盐水20ml洗涤,无水硫酸钠干燥,减压抽除乙酸乙酯,得到2-溴甲基-3,4-二氟苯甲酸0.707g,收率为97.0%。3,4-Difluoro-2-methylbenzoic acid (0.500g, 2.905mmol), N-bromosuccinimide (0.550g, 3.090mmol), azobisisobutyronitrile ( 0.050g, 0.304mmol), 10ml of carbon tetrachloride, refluxed at 70°C for 5h, followed by TLC until the reaction was completed, cooled the reaction solution, and removed the solvent under reduced pressure to obtain a white solid. The solid was dissolved in 30ml of ethyl acetate and washed with water (20ml×2 ), washed with 20 ml of saturated brine, dried over anhydrous sodium sulfate, and removed ethyl acetate under reduced pressure to obtain 0.707 g of 2-bromomethyl-3,4-difluorobenzoic acid with a yield of 97.0%.
实施例3:3,4-二氟-2-((苯硫基)甲基)苯甲酸的制备Example 3: Preparation of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid
在25ml单口烧瓶中加入2-溴甲基-3,4-二氟苯甲酸(0.200g,0.797mmol)、苯硫酚钠(0.110g,0.832mmol)、乙酸乙酯6ml,室温下搅拌4h,加入乙酸乙酯25ml,水洗(20mlx2),饱和食盐水洗(20ml),加入10mg活性炭,常温搅拌10min后过滤,滤液加入无水硫酸钠干燥,减压抽除溶剂,得到3,4-二氟-2-((苯硫基)甲基)苯甲酸176mg,收率为78.8%。2-Bromomethyl-3,4-difluorobenzoic acid (0.200g, 0.797mmol), sodium thiophenate (0.110g, 0.832mmol) and 6ml of ethyl acetate were added to a 25ml one-necked flask, and stirred at room temperature for 4h, 25ml of ethyl acetate was added, washed with water (20mlx2), washed with saturated brine (20ml), added with 10mg of activated carbon, stirred at room temperature for 10min, filtered, the filtrate was dried by adding anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 3,4-difluoro- 2-((phenylthio)methyl)benzoic acid 176 mg, yield 78.8%.
实施例4:3,4-二氟-2-((苯硫基)甲基)苯甲酸的制备Example 4: Preparation of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid
在25ml单口烧瓶中加入2-溴甲基-3,4-二氟苯甲酸(0.200g,0.797mmol)、苯硫酚钠(0.106g,0.802mmol)、丙酮6ml,室温下搅拌4h,加入乙酸乙酯25ml,水洗(20mlx2),饱和食盐水洗(20ml),加入10mg活性炭,常温搅拌10min后过滤,滤液加入无水硫酸钠干燥,减压抽除溶剂,得到3,4二氟-2-((苯硫基)甲基)苯甲酸183mg,收率为81.9%,本发明采用核磁共振法对3,4-二氟-2-((苯硫基)甲基)苯甲酸进行表征,见说明书附图1。HPLC纯度为99.35%,其液相图见附图2。2-Bromomethyl-3,4-difluorobenzoic acid (0.200g, 0.797mmol), sodium thiophenate (0.106g, 0.802mmol) and 6ml of acetone were added to a 25ml single-necked flask, stirred at room temperature for 4h, and acetic acid was added 25ml of ethyl ester, washed with water (20mlx2), washed with saturated brine (20ml), added 10mg of activated carbon, stirred at room temperature for 10min and filtered, the filtrate was dried by adding anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 3,4-difluoro-2-( (Phenylthio)methyl)benzoic acid 183mg, the yield is 81.9%, the present invention adopts nuclear magnetic resonance method to characterize 3,4-difluoro-2-((phenylthio)methyl)benzoic acid, see description Figure 1. The HPLC purity is 99.35%, and its liquid phase diagram is shown in accompanying
实施例5:3,4-二氟-2-((苯硫基)甲基)苯甲酸的制备Example 5: Preparation of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid
在25ml双口瓶中加入二苯二硫醚0.348g(1.59mmol)和硼氢化钠0.110g(2.91mmol),室温置换氮气三次,加入乙醇10ml,升温至70℃回流反应30min后,加入2-溴甲基-3,4-二氟苯甲酸0.760g(3.03mmol),反应四小时,冷却至室温,反应液中加入1mol/L氢氧化钠溶液(30ml)和乙酸乙酯(50ml),分液,再用1mol/L氢氧化钠溶液洗涤有机相(30mlx2次),合并碱液,用12mol/L浓盐酸溶液(约7ml)调节pH至3-4,乙酸乙酯萃取(25mlx3次),合并乙酸乙酯,无水硫酸钠干燥,减压除去溶剂,得到3,4-二氟-2-((苯硫基)甲基)苯甲酸0.647g,收率76.2%。Add 0.348g (1.59mmol) of diphenyl disulfide and 0.110g (2.91mmol) of sodium borohydride to a 25ml double-necked bottle, replace nitrogen three times at room temperature, add 10ml of ethanol, warm up to 70°C and reflux for 30min, add 2- 0.760g (3.03mmol) of bromomethyl-3,4-difluorobenzoic acid was reacted for four hours, cooled to room temperature, 1mol/L sodium hydroxide solution (30ml) and ethyl acetate (50ml) were added to the reaction solution, and the mixture was separated Then, wash the organic phase with 1mol/L sodium hydroxide solution (30ml×2 times), combine the lye, adjust the pH to 3-4 with 12mol/L concentrated hydrochloric acid solution (about 7ml), extract with ethyl acetate (25ml×3 times), The ethyl acetate was combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 0.647 g of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid with a yield of 76.2%.
实施例6:3,4-二氟-2-((苯硫基)甲基)苯甲酸的制备Example 6: Preparation of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid
在25ml双口瓶中加入二苯二硫醚0.870g(3.98mmol),室温置换氮气三次,加入8ml四氢呋喃,硼氢化钠0.275g(7.27mmol)、氢氧化钠0.916g和水10ml,升温至70℃回流反应5min后,加入2-溴甲基-3,4-二氟苯甲酸2.00g(7.97mmol),反应四小后,反应液中加入1mol/L氢氧化钠溶液(30ml)和乙酸乙酯(50ml),分液,再用1mol/L氢氧化钠溶液洗涤有机相(30mlx2次),合并碱液,用12mol/L浓盐酸溶液(约7ml)调节pH至3-4,乙酸乙酯萃取(25mlx3次),合并乙酸乙酯,无水硫酸钠干燥,减压除去溶剂,得到3,4-二氟-2-((苯硫基)甲基)苯甲酸2.149g,收率96.2%。Add 0.870g (3.98mmol) of diphenyl disulfide to a 25ml two-necked bottle, replace nitrogen three times at room temperature, add 8ml of tetrahydrofuran, 0.275g (7.27mmol) of sodium borohydride, 0.916g of sodium hydroxide and 10ml of water, heat up to 70 After 5 minutes of reflux reaction at ℃, 2.00 g (7.97 mmol) of 2-bromomethyl-3,4-difluorobenzoic acid was added. After 4 hours of reaction, 1 mol/L sodium hydroxide solution (30 ml) and ethyl acetate were added to the reaction solution. Ester (50ml), separated, then washed the organic phase with 1mol/L sodium hydroxide solution (30ml×2 times), combined the lye, adjusted pH to 3-4 with 12mol/L concentrated hydrochloric acid solution (about 7ml), ethyl acetate Extraction (25ml×3 times), combined ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 2.149g of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid, yield 96.2% .
附图说明:图1是 3,4-二氟-2-((苯硫基)甲基)苯甲酸核磁氢谱Description of the drawings: Figure 1 is a hydrogen NMR spectrum of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid
图2是3,4-二氟-2-((苯硫基)甲基)苯甲酸高效液相图。Figure 2 is a high performance liquid phase diagram of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid.
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