CN118930473A - A preparation method of 4,6,7-trifluoro-1H-indole-2-carboxylic acid - Google Patents
A preparation method of 4,6,7-trifluoro-1H-indole-2-carboxylic acid Download PDFInfo
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- CN118930473A CN118930473A CN202410993716.XA CN202410993716A CN118930473A CN 118930473 A CN118930473 A CN 118930473A CN 202410993716 A CN202410993716 A CN 202410993716A CN 118930473 A CN118930473 A CN 118930473A
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- FDONAEMTXHBAJT-UHFFFAOYSA-N 4,6,7-trifluoro-1H-indole-2-carboxylic acid Chemical compound OC(=O)c1cc2c(F)cc(F)c(F)c2[nH]1 FDONAEMTXHBAJT-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title description 9
- 238000000034 method Methods 0.000 claims abstract description 22
- RUQZFYKHVDKIKW-UHFFFAOYSA-N (2,3,5-trifluorophenyl)hydrazine Chemical compound NNC1=CC(F)=CC(F)=C1F RUQZFYKHVDKIKW-UHFFFAOYSA-N 0.000 claims abstract description 20
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 20
- -1 methylpyruvic acid-2,3,5-trifluorophenylhydrazone Chemical compound 0.000 claims abstract description 18
- 239000003638 chemical reducing agent Substances 0.000 claims abstract description 17
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 10
- AMGDNQWQBWPRPR-UHFFFAOYSA-N 2,3,5-trifluoroaniline Chemical compound NC1=CC(F)=CC(F)=C1F AMGDNQWQBWPRPR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 8
- 230000002378 acidificating effect Effects 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 74
- 239000000243 solution Substances 0.000 claims description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 32
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 20
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 14
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 13
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 9
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 9
- 238000002156 mixing Methods 0.000 claims description 6
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 6
- 239000011592 zinc chloride Substances 0.000 claims description 6
- 235000005074 zinc chloride Nutrition 0.000 claims description 6
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910021626 Tin(II) chloride Inorganic materials 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- LVZGQWKTUCVPBQ-UHFFFAOYSA-N acetic acid;trifluoroborane Chemical compound CC(O)=O.FB(F)F LVZGQWKTUCVPBQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000004927 clay Substances 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- 238000006481 deamination reaction Methods 0.000 claims description 3
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 3
- 230000008707 rearrangement Effects 0.000 claims description 3
- 238000007670 refining Methods 0.000 claims description 3
- 235000010265 sodium sulphite Nutrition 0.000 claims description 3
- 235000011150 stannous chloride Nutrition 0.000 claims description 3
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 238000006462 rearrangement reaction Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 13
- 239000000126 substance Substances 0.000 abstract description 8
- 238000006193 diazotization reaction Methods 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 11
- 239000012954 diazonium Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- 239000000376 reactant Substances 0.000 description 6
- 239000004289 sodium hydrogen sulphite Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 150000001989 diazonium salts Chemical class 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 241000700721 Hepatitis B virus Species 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- 238000010669 acid-base reaction Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 230000009615 deamination Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000013021 overheating Methods 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000012429 reaction media Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 206010055113 Breast cancer metastatic Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010010356 Congenital anomaly Diseases 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940124433 antimigraine drug Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- UCSVJZQSZZAKLD-UHFFFAOYSA-N ethyl azide Chemical compound CCN=[N+]=[N-] UCSVJZQSZZAKLD-UHFFFAOYSA-N 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 125000004492 methyl ester group Chemical group 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
本发明公开了一种4，6，7‑三氟‑1H‑吲哚‑2‑羧酸的制备方法，涉及有机合成技术领域，包括以下步骤：S1、采用2，3，5‑三氟苯胺与亚硝酸钠和无机酸进行重氮化反应后与还原剂反应制备2，3，5‑三氟苯肼；S2、将2，3，5‑三氟苯肼与乙酰乙酸甲酯反应得到甲基丙酮酸‑2，3，5‑三氟苯腙，然后在酸性条件下生成4，6，7‑三氟‑1H‑吲哚‑2‑羧酸甲酯；S3、将4，6，7‑三氟‑1H‑吲哚‑2‑羧酸甲酯在碱性条件下水解生成4，6，7‑三氟‑1H‑吲哚‑2‑羧酸；该4，6，7‑三氟‑1H‑吲哚‑2‑羧酸的制备方法，流程简单，原料易得，产品质量稳定，产品化学纯度达到99％以上，适合于规模化生产。
The invention discloses a method for preparing 4,6,7-trifluoro-1H-indole-2-carboxylic acid, and relates to the technical field of organic synthesis. The method comprises the following steps: S1, carrying out diazotization reaction on 2,3,5-trifluoroaniline, sodium nitrite and inorganic acid, and then reacting with a reducing agent to prepare 2,3,5-trifluorophenylhydrazine; S2, reacting 2,3,5-trifluorophenylhydrazine with methyl acetoacetate to obtain methylpyruvic acid-2,3,5-trifluorophenylhydrazone, and then generating 4,6,7-trifluoro-1H-indole-2-carboxylic acid methyl ester under acidic conditions; S3, hydrolyzing 4,6,7-trifluoro-1H-indole-2-carboxylic acid methyl ester under alkaline conditions to generate 4,6,7-trifluoro-1H-indole-2-carboxylic acid; the method for preparing 4,6,7-trifluoro-1H-indole-2-carboxylic acid has simple process, easily available raw materials, stable product quality, chemical purity of the product reaching more than 99%, and is suitable for large-scale production.
Description
Technical Field
The invention relates to an organic synthesis technology, in particular to a preparation method of 4,6, 7-trifluoro-1H-indole-2-carboxylic acid.
Background
The indole compound is a high-efficiency low-toxicity anti-tumor drug for treating central nervous system diseases, is mainly used for treating advanced non-small cell lung cancer, metastatic breast cancer, ovarian cancer, congenital genetic diseases, metabolic disorders and the like, and can be synthesized into intermediates of anti-inflammatory and analgesic drugs, anti-arrhythmia drugs, anti-migraine drugs, alzheimer disease drugs and the like. The fluorine-containing indole derivative can be used for affinity of various receptors and is widely applied to the fields of medicines and pesticides.
4,6, 7-Trifluoro-1H-indole-2-carboxylic acid is a highly bioactive intermediate, suitable for preparing antiviral precursors and widely studied, which is capable of synthesizing drugs that inhibit the protein encoded by Hepatitis B Virus (HBV) or interfere with the replication cycle function of HBV.
In the existing method for preparing 4,6, 7-trifluoro-1H-indole-2-carboxylic acid, hazardous chemicals such as ethyl azide, sodium borohydride, boron reagent, butyl lithium, sodium cyanide, pd/C, bromine and concentrated sulfuric acid are used, so that the method has the advantages of high potential safety hazard, environment friendliness, unsuitability for large-scale production and low yield.
Disclosure of Invention
The invention aims to provide a preparation method of 4,6, 7-trifluoro-1H-indole-2-carboxylic acid, which aims to solve the defects in the prior art.
In order to achieve the above object, the present invention provides the following technical solutions: a method for preparing 4,6, 7-trifluoro-1H-indole-2-carboxylic acid, comprising the following steps:
S1, dropwise adding a sodium nitrite solution into a mixture of 2,3, 5-trifluoroaniline and inorganic acid to carry out diazonium reaction, adding a reducing agent to carry out reduction reaction after the diazonium reaction is finished, and finally refining to obtain 2,3, 5-trifluorophenylhydrazine;
s2, mixing the 2,3, 5-trifluoro phenylhydrazine obtained in the step with toluene or xylene to obtain a mixed solution, and carrying out reflux reaction on the mixed solution and methyl acetoacetate under an acidic condition to obtain phenylhydrazone;
adding phenylhydrazone, a solvent and a reducing agent into a three-neck flask, and preparing 4,6, 7-trifluoro-1H-indole-2-carboxylic acid methyl ester through rearrangement and deamination;
s3, dissolving the 4,6, 7-trifluoro-1H-indole-2-carboxylic acid methyl ester obtained in the S2, then reacting with a sodium hydroxide solution, and purifying after the reaction is finished to obtain the 4,6, 7-trifluoro-1H-indole-2-carboxylic acid.
Further, the reaction temperature of the diazo reaction of S1 is 0-10 ℃, and the reaction temperature of the reduction reaction of S1 is 0-30 ℃.
Further, the molar ratio of the 2,3, 5-trifluoroaniline, the inorganic salt, the sodium nitrite and the reducing agent in the S1 is 1:2.0-4.0:1.0-2.0:0.5-3.0.
Further, the inorganic acid in S1 is hydrochloric acid, sulfuric acid or acetic acid, and the reducing agent in S1 is sodium sulfite, sodium bisulphite or tin dichloride.
Further, the reaction temperature of S2 is 100-115 ℃ or 130-150 ℃.
Further, the molar ratio of the 2,3, 5-trifluoro-phenylhydrazine to the methyl acetoacetate in the S2 is 1:1.0-2.0.
Further, the solvent in S2 is ethanol, dimethylformamide or dichloromethane.
Further, the reducing agent in S2 is zinc chloride, acetic acid, hydrochloric acid, activated clay, zinc powder, hydrochloric acid, polyphosphoric acid, zinc chloride, polyphosphoric acid, boron trifluoride acetic acid solution, hydrochloric acid, sulfuric acid and cuprous chloride.
Further, the reaction temperature of the reaction in S3 is 70-100 ℃.
Compared with the prior art, the preparation method of the 4,6, 7-trifluoro-1H-indole-2-carboxylic acid provided by the invention adopts 2,3, 5-trifluoro-aniline, sodium nitrite and inorganic acid to carry out diazotization reaction, then reacts with a reducing agent to obtain 2,3, 5-trifluoro-phenylhydrazine, then reacts with methyl acetoacetate to obtain methyl pyruvic acid-2, 3, 5-trifluoro-phenylhydrazone, then carries out ring closure under an acidic condition to generate 4,6, 7-trifluoro-1H-indole-2-carboxylic acid methyl ester, and finally hydrolyzes under an alkaline condition to generate 4,6, 7-trifluoro-1H-indole-2-carboxylic acid; the method has the advantages of simple flow, easily obtained raw materials, stable product quality, suitability for large-scale production and product chemical purity reaching more than 99 percent.
Drawings
In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for the embodiments will be briefly described below, and it is apparent that the drawings in the following description are only some embodiments described in the present application, and other drawings may be obtained according to these drawings for a person having ordinary skill in the art.
FIG. 1 is a schematic diagram of an overall preparation flow provided in an embodiment of the present invention;
FIG. 2 is a schematic diagram of a preparation flow of S1 according to an embodiment of the present invention;
FIG. 3 is a schematic diagram of a preparation flow of S2 according to an embodiment of the present invention;
fig. 4 is a schematic diagram of a preparation flow of S3 according to an embodiment of the present invention.
Detailed Description
In order to make the technical scheme of the present invention better understood by those skilled in the art, the present invention will be further described in detail with reference to the accompanying drawings.
Examples:
Referring to FIG. 1, a process for preparing 4,6, 7-trifluoro-1H-indole-2-carboxylic acid comprises the steps of:
S1, dropwise adding sodium nitrite solution into a mixture of 2,3, 5-trifluoroaniline and inorganic acid to carry out diazonium reaction, adding a reducing agent to carry out reduction reaction after the diazonium reaction is finished, and finally refining to obtain the 2,3, 5-trifluorophenylhydrazine. The reaction temperature of the diazo reaction is 0-10 ℃, and the reaction temperature of the reduction reaction is 0-30 ℃; the molar ratio of the 2,3, 5-trifluoroaniline, the inorganic salt, the sodium nitrite and the reducing agent is 1:2.0-4.0:1.0-2.0:0.5-3.0; the inorganic acid is hydrochloric acid, sulfuric acid or acetic acid, and the reducing agent is sodium sulfite, sodium bisulphite or tin dichloride.
In the specific embodiment, 50.0 g (corresponding to 0.34 mol) of 2,3, 5-trifluoroaniline is firstly accurately weighed in a room temperature environment, and the method is an organic raw material with special chemical property and structure, and has wide application prospect in the fields of medicine, pesticide and material science; subsequently, 124.0 g (calculated to contain 1.02 mol of pure hydrochloric acid) of a 30% hydrochloric acid solution was measured, which not only served as reaction medium, but also acted as catalyst, which was essential for the subsequent diazotisation reaction.
The two raw materials are transferred into a dry and clean three-neck flask, and a stirring device is started to fully and uniformly mix the two raw materials to form a uniform reaction system. In order to ensure that the subsequent reaction can be carried out under the optimal condition, a cooling device is adopted to slowly reduce the temperature of the reaction liquid to a low temperature range of 0-5 ℃, and the step is important to control the reaction rate and reduce the generation of byproducts.
Under the low-temperature environment, 130.0 g (converted to contain 0.374 mol of sodium nitrite) of 20% sodium nitrite solution is slowly added into a three-neck flask in a dropwise adding mode, and in the dropwise adding process, the change of a reaction system is closely focused, so that moderate dropping speed is ensured, and side reactions caused by overhigh local concentration are avoided.
After the dripping is completed, keeping the temperature of the reaction system at a low temperature for about 2 hours, giving enough time for the reactants to perform sufficient diazotization reaction, and successfully preparing the target product, namely diazonium salt solution after the diazotization reaction is completed. The solution presents special color and property, and provides important raw materials and intermediates for subsequent organic synthesis reaction.
At room temperature, 97.0 g of sodium bisulphite (the amount of which is precisely calculated to be 0.935 mol) is accurately weighed, which is a salt commonly used in chemical synthesis and has specific chemical properties and reactivity, and the sodium bisulphite is slowly added into 250 g of purified water prepared in advance, and a stirring device is started, so that solid particles can be quickly and uniformly dissolved in water, and a clear and transparent sodium bisulphite solution is formed.
In order to adjust the pH of the solution to a specific range, a 30% strength sodium hydroxide solution was used as the regulator. The pH of the sodium bisulphite solution was adjusted to 6 by dropwise addition of sodium hydroxide solution and monitoring the pH of the solution in real time, which is critical for the subsequent diazotisation reaction and the stability of its product.
Immediately after the solution reached the desired pH, the sodium bisulfite solution was cooled to a low temperature of 0-5 ℃ to slow down the reaction rate and facilitate adequate contact and reaction of the reactants, followed by dropwise addition of the already carefully prepared diazonium salt solution to the cooled sodium bisulfite solution. In order to maintain the PH of the reaction system at ph=6, sodium hydroxide solution was simultaneously added dropwise to neutralize acidic substances generated by the addition of diazonium salt.
After the completion of the dropping process, the reaction system was returned to room temperature and kept at that condition for 6 to 8 hours to ensure that the diazotization reaction and the subsequent chemical reactions thereof were sufficiently and thoroughly carried out. Through the series of precise operations and fine regulation, the mixed solution in the expectation is finally obtained, and the solution not only provides important raw materials and intermediates for the subsequent chemical synthesis step, but also fully shows the necessity and importance of precise control on the reaction conditions in the chemical experiment.
In the mixed solution system, the pH value of the solution is accurately adjusted to 3 by accurately controlling the adding amount of the concentrated hydrochloric acid. The key point of the step is that non-target compounds in the mixed solution are separated out in the form of salt or the solubility of the non-target compounds is changed by utilizing the acid-base reaction principle, and the target compounds 2,3, 5-trifluoro-phenylhydrazine can be kept relatively stable or slightly changed.
And then fully mixing the solution by mechanical stirring to ensure that the acid-base reaction is uniformly carried out and promote the effective precipitation of solids. After the completion of the stirring, the solid-liquid two phases were successfully separated by a fine filtration operation, to obtain a solid mixture containing the objective product and possible impurities.
Next, in order to further extract pure 2,3, 5-trifluorophenylhydrazine from the solid, the resulting solid was redissolved in a suitable amount of deionized water to form a new aqueous system. Subsequently, a sodium hydroxide solution was slowly added dropwise to this aqueous system, and the pH of the solution was continuously monitored until it reached around 8. This step aims at advantageously changing the solubility of the target compound 2,3, 5-trifluoro-phenylhydrazine by adjusting the alkaline environment of the solution, thereby facilitating the subsequent extraction and separation.
After the pH adjustment is completed, dichloromethane is selected as an extractant, and the dichloromethane has good selectivity and solubility to a target product. The target product is efficiently transferred from the aqueous phase to the organic phase by multiple extraction operations. Then, the methylene dichloride solution containing the target product is concentrated, most of the solvent is evaporated, and finally the relatively pure 2,3, 5-trifluoro phenylhydrazine product is obtained, the weight of the product is 16.87 g, and the corresponding yield is about 80%.
1H NMR(400MHz,DMSO-d6)，δ：6.11-6.12(d，2H)，4.0(s，1H)，2.0(s，2H).m/z：163[M+H].
S2, mixing the 2,3, 5-trifluoro phenylhydrazine obtained in the step with toluene or xylene to obtain a mixed solution, and carrying out reflux reaction on the mixed solution and methyl acetoacetate under an acidic condition to obtain phenylhydrazone; adding phenylhydrazone, a solvent and a reducing agent into a three-neck flask, and preparing 4,6, 7-trifluoro-1H-indole-2-carboxylic acid methyl ester through rearrangement and deamination;
The reaction temperature of S2 is 100-115 ℃ or 130-150 ℃; the molar ratio of 2,3, 5-trifluoro phenylhydrazine to methyl acetoacetate is 1:1.0-2.0; the solvent is ethanol, dimethylformamide or dichloromethane; the reducing agent is zinc chloride, acetic acid, hydrochloric acid, activated clay, zinc powder, hydrochloric acid, polyphosphoric acid, zinc chloride, polyphosphoric acid, boron trifluoride acetic acid solution, hydrochloric acid, sulfuric acid and cuprous chloride.
In a specific embodiment, methyl pyruvic acid-2, 3, 5-trifluoro phenylhydrazone is prepared by reacting 2,3, 5-trifluoro phenylhydrazine with methyl acetoacetate under the condition of room temperature. First, 20.0 grams (i.e., 0.123 mol) of 2,3, 5-trifluorophenylhydrazine, an important organic synthetic intermediate, has a unique fluorine substituent, and imparts its special chemical properties. 2,3, 5-trifluoro-phenylhydrazine was then added to a 500 ml three-necked flask containing 100ml of toluene solvent. Toluene is used as a reaction solvent, so that reactants can be effectively dissolved, and a proper reaction environment can be provided.
After stirring sufficiently to ensure uniform dispersion of 2,3, 5-trifluorophenylhydrazine in toluene, 17.18 g (i.e., 0.148 mole) of methyl acetoacetate was accurately measured and slowly added to the reaction system via a dropping funnel. This step requires careful control of the drop rate to ensure that the reaction proceeds smoothly and to avoid side reactions caused by local overheating or too fast a reaction.
After the completion of the dropwise addition, the whole system was heated uniformly to a reflux state. Reflux is a heating mode commonly used in chemical experiments, and can effectively utilize the steam heat of a solvent to keep a reaction system within a constant temperature range, thereby being beneficial to the reaction. Under this condition, the reaction mixture was allowed to react for 5 hours with heat preservation to ensure that the reaction was sufficiently carried out, and after the completion of the reaction, most of the solvent and unreacted raw materials in the reaction system were removed by a concentration technique such as distillation under reduced pressure, to finally obtain crude methyl pyruvic acid-2, 3, 5-trifluorophenylhydrazone having a weight of 30.0 g. Although the product at this stage is crude and contains some impurities, it has provided an important raw material basis for the subsequent purification steps.
The crude methyl pyruvic acid-2, 3, 5-trifluoro phenylhydrazone obtained in the previous step, 200ml of ethanol as a solvent and 5.0 g of ZnC l 2 (as a catalyst) were sequentially added to a 500 ml three-necked flask. The addition of ethanol not only provides the necessary dissolution environment for the reaction, but also helps promote adequate contact and reaction of the reactants. Subsequently, the reaction mixture was thoroughly stirred using a magnetic stirrer to ensure uniform mixing of all the components to form a uniform reaction system, during which the reactants were observed to gradually dissolve in ethanol to form a pale yellow or pale brown solution. Then, the reaction system was gradually warmed to a reflux state. The reflux operation helps to maintain the temperature in the reaction system stable and to accelerate the reaction rate. And (3) maintaining the reflux state, and simultaneously carrying out heat preservation treatment on the reaction until the raw materials are completely reacted. In this process, the temperature change of the reaction system and the progress of the reaction are required to be closely focused, and if necessary, the reaction end point can be confirmed by sampling analysis.
After the reaction was completed, the reaction system was naturally cooled to room temperature. At this point, the reaction products and possibly by-products will precipitate as solids or as precipitates. The solid product can be separated from the solvent and unreacted raw materials in the reaction liquid by the filtration operation. The solid obtained after filtration was 4,6, 7-trifluoro-1H-indole-2-carboxylic acid methyl ester, which was dried and weighed to 18.0 g, corresponding to a yield of about 80%.
1H NMR(400MHz,DMSO-d6)，δ：12.2(s，1H)，7.14(s，1H)，6.40(s，1H)，3.5(s，3H).m/z：230[M+H].
S3, dissolving the 4,6, 7-trifluoro-1H-indole-2-carboxylic acid methyl ester obtained in the S2, then reacting with sodium hydroxide solution, purifying after the reaction is finished to obtain the 4,6, 7-trifluoro-1H-indole-2-carboxylic acid, wherein the reaction temperature of the reaction is 70-100 ℃.
In a specific embodiment, 18.0 g of crude methyl 4,6, 7-trifluoro-1H-indole-2-carboxylate was precisely weighed as a starting material at room temperature, and then added to a 250 ml three-necked flask together with 50 ml of ethanol. Ethanol is used as a solvent, which not only contributes to the dissolution of the raw materials, but also provides a good reaction medium.
Next, 40.0 g (i.e., 0.25 mol) of 25% sodium hydroxide solution was slowly added to the reaction system. Sodium hydroxide acts as a strong base and serves to catalyze the hydrolysis in this reaction, converting methyl ester groups to carboxylic acid groups. Continuous stirring is required during the addition to ensure adequate mixing of the sodium hydroxide solution with the reactants and to control the rate of addition to avoid localized overheating.
After stirring uniformly, the reaction system is gradually heated to a reflux state. The refluxing operation helps to keep the temperature in the reaction system constant and promotes the hydrolysis reaction. And (3) maintaining the reflux state, and simultaneously carrying out heat preservation treatment on the reaction until the raw materials are completely reacted. In the reaction process, the reaction progress needs to be periodically sampled and detected to ensure that the reaction is fully carried out.
After the reaction is completed, the reaction system is naturally cooled to room temperature, and concentrated to remove most of the ethanol solvent. Subsequently, the residue was extracted with dichloromethane to separate an organic layer. Then, the pH value of the aqueous layer was adjusted by adding an appropriate amount of hydrochloric acid, and the produced 4,6, 7-trifluoro-1H-indole-2-carboxylic acid was precipitated as a salt. The solids were collected by filtration and washed with water thoroughly to remove residual impurities and solvents.
Finally, the filter cake was dried in an oven to constant weight to give 15.2 g of pure 4,6, 7-trifluoro-1H-indole-2-carboxylic acid in about 90% yield.
1H NMR(400MHz,DMSO-d6)，δ：13.2(s，1H)，12.2(s，1H)，7.14(s，1H)，6.40(s，1H).m/z：216[M+H].
While certain exemplary embodiments of the present invention have been described above by way of illustration only, it will be apparent to those of ordinary skill in the art that modifications may be made to the described embodiments in various different ways without departing from the spirit and scope of the invention. Accordingly, the drawings and description are to be regarded as illustrative in nature and not as restrictive of the scope of the invention, which is defined by the appended claims.
Claims (9)
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| WO1998000401A1 (en) * | 1996-06-28 | 1998-01-08 | Merck & Co., Inc. | Fibrinogen receptor antagonist prodrugs |
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| WO2023137007A1 (en) * | 2022-01-11 | 2023-07-20 | Enanta Pharmaceuticals, Inc. | Processes for the preparation of 4,6,7-trifluoro-1h-indole-2-carboxylic acid |
| WO2023177854A1 (en) * | 2022-03-18 | 2023-09-21 | Enanta Pharmaceuticals, Inc. | Processes for the preparation of substituted spirooxindole derivatives |
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| WO1998000401A1 (en) * | 1996-06-28 | 1998-01-08 | Merck & Co., Inc. | Fibrinogen receptor antagonist prodrugs |
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