CN116396204B - Preparation method of 4,6, 7-trifluoro-1H-indole-2-carboxylic acid - Google Patents
Preparation method of 4,6, 7-trifluoro-1H-indole-2-carboxylic acid Download PDFInfo
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- CN116396204B CN116396204B CN202310319463.3A CN202310319463A CN116396204B CN 116396204 B CN116396204 B CN 116396204B CN 202310319463 A CN202310319463 A CN 202310319463A CN 116396204 B CN116396204 B CN 116396204B
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- trifluoro
- indole
- toluenesulfonyl
- carboxylic acid
- isatin
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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 22
- 238000002360 preparation method Methods 0.000 title abstract description 7
- -1 N- (p-toluenesulfonyl) -4,6, 7-trifluoro isatin Chemical compound 0.000 claims abstract description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 18
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 17
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 16
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 14
- 229910052796 boron Inorganic materials 0.000 claims abstract description 11
- WQLHXKSIQYHIRB-UHFFFAOYSA-N 4,6,7-trifluoro-1h-indole-2,3-dione Chemical compound FC1=CC(F)=C(F)C2=C1C(=O)C(=O)N2 WQLHXKSIQYHIRB-UHFFFAOYSA-N 0.000 claims abstract description 10
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 claims abstract description 9
- AMGDNQWQBWPRPR-UHFFFAOYSA-N 2,3,5-trifluoroaniline Chemical compound NC1=CC(F)=CC(F)=C1F AMGDNQWQBWPRPR-UHFFFAOYSA-N 0.000 claims abstract description 8
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- HFFLGKNGCAIQMO-UHFFFAOYSA-N trichloroacetaldehyde Chemical compound ClC(Cl)(Cl)C=O HFFLGKNGCAIQMO-UHFFFAOYSA-N 0.000 claims abstract description 8
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 7
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 7
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 7
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 7
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 26
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 17
- HHLFWLYXYJOTON-UHFFFAOYSA-N glyoxylic acid Chemical compound OC(=O)C=O HHLFWLYXYJOTON-UHFFFAOYSA-N 0.000 claims description 14
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 9
- MSXVEPNJUHWQHW-UHFFFAOYSA-N 2-methylbutan-2-ol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 6
- LHGJTWLUIMCSNN-UHFFFAOYSA-L disodium;sulfate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O LHGJTWLUIMCSNN-UHFFFAOYSA-L 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 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
- 239000012043 crude product Substances 0.000 claims description 2
- ZLMJMSJWJFRBEC-OUBTZVSYSA-N potassium-40 Chemical compound [40K] ZLMJMSJWJFRBEC-OUBTZVSYSA-N 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 7
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- 238000004128 high performance liquid chromatography Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000006196 Hemetsberger Knittel synthesis reaction Methods 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical group C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 2
- 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000001514 detection method Methods 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
- UCSVJZQSZZAKLD-UHFFFAOYSA-N ethyl azide Chemical compound CCN=[N+]=[N-] UCSVJZQSZZAKLD-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical compound C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 230000000171 quenching effect Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- CYIFJRXFYSUBFW-UHFFFAOYSA-N 2,4,5-trifluorobenzaldehyde Chemical compound FC1=CC(F)=C(C=O)C=C1F CYIFJRXFYSUBFW-UHFFFAOYSA-N 0.000 description 1
- 238000006159 Bartoli reaction Methods 0.000 description 1
- 238000005679 Batcho-Leimgruber synthesis reaction Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 238000006783 Fischer indole synthesis reaction Methods 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 235000000177 Indigofera tinctoria Nutrition 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- KNVJTCKKCLWSII-UHFFFAOYSA-L O1CCCC1.[Cl-].[Li+].[Cl-].C(C)(C)[Mg+] Chemical compound O1CCCC1.[Cl-].[Li+].[Cl-].C(C)(C)[Mg+] KNVJTCKKCLWSII-UHFFFAOYSA-L 0.000 description 1
- 238000010716 Reissert indole synthesis reaction Methods 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- ZSLKGAAJYMFQFI-UHFFFAOYSA-N acetic acid;azidoethane Chemical compound CC(O)=O.CCN=[N+]=[N-] ZSLKGAAJYMFQFI-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000003763 carbonization Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229940097275 indigo Drugs 0.000 description 1
- COHYTHOBJLSHDF-UHFFFAOYSA-N indigo powder Natural products N1C2=CC=CC=C2C(=O)C1=C1C(=O)C2=CC=CC=C2N1 COHYTHOBJLSHDF-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000000575 pesticide 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
- 238000004537 pulping Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- SIXNTGDWLSRMIC-UHFFFAOYSA-N sodium;toluene Chemical compound [Na].CC1=CC=CC=C1 SIXNTGDWLSRMIC-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a preparation method of 4,6, 7-trifluoro-1H-indole-2-carboxylic acid, belonging to the technical field of organic synthesis. 2,3, 5-trifluoroaniline is substituted and condensed with chloral and hydroxylamine, then sulfuric acid is used for closing a ring to obtain 4,6, 7-trifluoro isatin, p-toluenesulfonyl chloride is used for protecting to obtain N- (p-toluenesulfonyl) -4,6, 7-trifluoro isatin, then N- (p-toluenesulfonyl) -4,6, 7-trifluoro indole is generated by reduction in the presence of sodium borohydride and boron reagent, then isopropyl magnesium chloride-lithium chloride reacts with carbon dioxide to generate carboxylic acid, and finally sodium hydroxide is used for removing p-toluenesulfonyl for protecting to obtain 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.
Description
Technical Field
The invention relates to a preparation method of 4,6, 7-trifluoro-1H-indole-2-carboxylic acid, belonging to the technical field of organic synthesis.
Background
The fluorine-containing indole derivative can be used for affinity multiple receptors, is widely applied to the fields of medicines and pesticides, is a basic skeleton or an important component part of a plurality of natural products, increases the lipophilicity of molecules along with the introduction of fluorine atoms, increases the penetration capacity of biological tissues, improves the biological absorption and transmission speed of the fluorine-containing indole derivative, and introduces carboxylic acid, wherein the activity of the carboxylic acid with even carbon is higher.
4,6,7-Trifluoro-1H-indole-2-carboxylic acid, CAS:1699249-56-3, english name: 4,6, 7-trifluoro-1H-indole-2-carboxilic acid. The 4,6,7-trifluoro-1H-indole-2-carboxylic acid is an intermediate with high biological activity, and is suitable for preparing antiviral precursors and is widely studied. European patent WO2019/86142,2019, A1 et al uses 4,6,7-trifluoro-1H-indole-2-carboxylic acid synthesis to inhibit proteins encoded by Hepatitis B Virus (HBV) or interfere with HBV replication cycle functional drugs.
Typical indole syntheses include Hemetsberger indole synthesis, bartoli indole synthesis, batcho-Leimgruber indole synthesis, cadogan-Sundberg indole synthesis, fischer indole synthesis, hegedus indole synthesis and Reissert indole synthesis.
The patent WO2019/86142A1, WO 2019/86146A 1, WO2020/89455A1 and the like are prepared by adopting Hemetsberger indole synthesis methods, 2,4, 5-trifluorobenzaldehyde is used as a raw material, nucleophilic substitution is carried out on the raw material and ethyl azide, then the raw material is subjected to cyclization under xylene reflux, finally sodium hydroxide aqueous solution is hydrolyzed and then acidized, the total yield is about 18%, the method is used for the explosive substance of the ethyl azide, and the method has larger potential safety hazard, is not suitable for large-scale production and has lower yield. The reaction equation is as follows:
Aiming at the problems existing in the synthesis method of the 4,6, 7-trifluoro-1H-indole-2-carboxylic acid, the method is an explosion-proof product of the ethyl azide acetate, so that a more concise and effective synthesis route is necessary to be developed to adapt to the requirement of industrialized amplification and meet the increasing market requirement.
Disclosure of Invention
In order to overcome the technical defects, the invention discloses a preparation method of 4,6, 7-trifluoro-1H-indole-2-carboxylic acid.
The preparation method of the invention comprises the following steps: 2,3, 5-trifluoroaniline is substituted and condensed with chloral and hydroxylamine, then sulfuric acid is used for closing a ring to obtain 4,6, 7-trifluoro isatin, p-toluenesulfonyl chloride is used for protecting to obtain N- (p-toluenesulfonyl) -4,6, 7-trifluoro isatin, then N- (p-toluenesulfonyl) -4,6, 7-trifluoro indole is generated by reduction in the presence of sodium borohydride and boron reagent, then isopropyl magnesium chloride-lithium chloride reacts with carbon dioxide to generate carboxylic acid, and finally sodium hydroxide is used for removing p-toluenesulfonyl for protecting to obtain 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.
The preparation method of the 4,6, 7-trifluoro-1H-indole-2-carboxylic acid comprises the following steps:
the first step: dropwise adding a mixture of 2,3, 5-trifluoroaniline and concentrated hydrochloric acid into an aqueous solution containing chloral and sodium sulfate heptahydrate, adding hydroxylamine to react to obtain an intermediate N- (2, 3, 5-difluorophenyl) -2- (hydroxyimino) acetamide, and then adding the intermediate N- (2, 3, 5-difluorophenyl) -2- (hydroxyimino) acetamide into toluene, 50% glyoxylic acid and concentrated sulfuric acid in batches to close the ring to obtain 4,6, 7-trifluoro isatin;
And a second step of: mixing 4,6, 7-trifluoro isatin with tetrahydrofuran, cooling, adding strong base, and then adding p-toluenesulfonyl chloride to obtain N- (p-toluenesulfonyl) -4,6, 7-trifluoro isatin;
And a third step of: mixing N- (p-toluenesulfonyl) -4,6, 7-trifluoro isatin with tetrahydrofuran, cooling, adding sodium borohydride, and then dropwise adding a boron reagent for reaction to obtain N- (p-toluenesulfonyl) -4,6, 7-trifluoro indole;
Fourth step: mixing N- (p-toluenesulfonyl) -4,6, 7-trifluoro-indole with tetrahydrofuran, cooling, adding isopropyl magnesium chloride-lithium chloride and carbon dioxide to the 2-position to generate carboxylic acid, performing post-treatment to obtain a crude product, and then deprotecting in sodium hydroxide aqueous solution to obtain 4,6, 7-trifluoro-1H-indole-2-carboxylic acid.
Further, in the above technical scheme, in the first step, the hydroxylamine is selected from hydroxylamine sulfate or hydroxylamine hydrochloride.
Further, in the above technical scheme, in the first step, the molar ratio of the 2,3, 5-trifluoroaniline, chloral, sodium sulfate heptahydrate, hydroxylamine, 50% glyoxylic acid to 98% sulfuric acid is 1:1.15-1.25:9.0-10.0:3.1-3.2:5.5-7.5:10.5-11.5.
Further, in the above technical scheme, in the second step, the strong base is selected from potassium tert-butoxide or 40% sodium tert-amyl alcohol toluene solution.
Further, in the above technical scheme, in the second step, the molar ratio of the 4,6, 7-trifluoro isatin, the strong base to the p-toluenesulfonyl chloride is 1:1.15-1.20:1.20-1.25.
Further, in the above technical scheme, in the third step, the boron reagent is a mixture of BF 3-Et2 O and B (C 6F5)3, wherein the molar ratio of BF 3-Et2 O to B (C 6F5)3 is 1:0.01-0.05).
Further, in the above technical scheme, in the third step, the molar ratio of the N- (p-toluenesulfonyl) -4,6, 7-trifluoro isatin, sodium borohydride and boron reagent is 1:2.10-2.40:1.02-1.10.
Further, in the above technical scheme, in the fourth step, the isopropyl magnesium chloride-lithium chloride is a 1.3M tetrahydrofuran solution of isopropyl magnesium chloride-lithium chloride.
Further, in the above technical scheme, in the fourth step, the molar ratio of the N- (p-toluenesulfonyl) -4,6, 7-trifluoroindole, isopropyl magnesium chloride-lithium chloride to carbon dioxide is 1:1.05-1.10:5.0-6.0.
Advantageous effects of the invention
1. The method avoids the application of Hemetsberger indole synthesis method and reduces the potential safety hazard. The yield of the generated isatin is stable by increasing the amount of sodium sulfate and using a heterogeneous system composed of toluene, glyoxylic acid and concentrated sulfuric acid for closing the ring, excessive dehydration and carbonization in sulfuric acid are avoided, and the yield is improved.
2. The Grignard exchange of the isopropyl magnesium chloride and lithium chloride is basically the same as the yield of the hydrogen drawing reaction of n-butyl lithium, so that a safer isopropyl magnesium chloride-lithium chloride complex is adopted.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples should be construed as merely illustrative of the present invention and not limiting the scope of the present invention. Various changes and modifications to the present invention may be made by one skilled in the art after reading the description herein, and such equivalent changes and modifications are intended to fall within the scope of the present invention as defined in the appended claims. Synthesis of 4,6, 7-trifluoro-1H-indole-2-carboxylic acid
Example 1
1340G (5 mol) of sodium sulfate heptahydrate and 600mL of water are put into a reaction bottle, after stirring uniformly, 88.4g (0.6 mol) of chloral is added, the temperature is raised to room temperature, a mixture of 73.6g (0.5 mol) of pre-prepared 2,3, 5-trifluoroaniline and 900g (5 mol) of 5% hydrochloric acid is added dropwise, 107.7g (1.55 mol) of hydroxylamine hydrochloride is added batchwise, the temperature is raised to 80-85 ℃, the reaction is carried out for 2-3 hours, TLC detection is carried out for almost no raw materials, the reaction is immediately cooled to room temperature, the filtration is carried out, the filter cake is rinsed by water, the wet intermediate N- (2, 3, 5-difluorophenyl) -2- (hydroxyimino) acetamide (without purification) is obtained, then the intermediate is added batchwise into a heterogeneous system consisting of 1500mL of toluene, 444.2g (3 mol) of 50% glyoxylic acid and 500g (5 mol) of 98% concentrated sulfuric acid, the mixture is heated to 95-100 ℃ for 3 hours, the reaction is separated into a layer of acid, an organic phase is washed by saturated sodium carbonate aqueous solution and water phase, the aqueous phase is concentrated by vacuum, 7.79% of indofluoroheptane is obtained, the HPLC is carried out, the method comprises the steps of concentrating the aqueous phase, and the aqueous phase is carried out, and the aqueous phase is concentrated by HPLC, and the method is carried out. 1HNMR(400MHz,DMSO-d6 ) 11.79 (s, 1H), 6.69 (s, 1H).
Example 2
1340G (5 mol) of sodium sulfate heptahydrate and 600mL of water are put into a reaction bottle, after stirring uniformly, 92.1g (0.625 mol) of chloral is added, the temperature is raised to room temperature, a mixture of 73.6g (0.5 mol) of pre-prepared 2,3, 5-trifluoroaniline and 900g (5 mol) of 5% hydrochloric acid is added dropwise, then 131.3g (0.8 mol) of hydroxylamine sulfate is added batchwise, the temperature is raised to 80-85 ℃, the reaction is carried out for 2-3 hours, TLC detection is carried out for almost no raw materials, the reaction is immediately cooled to room temperature, the filtration is carried out, the filter cake is rinsed by water, the wet intermediate N- (2, 3, 5-difluorophenyl) -2- (hydroxyimino) acetamide (without purification) is obtained, then the intermediate is added batchwise into a heterogeneous system consisting of 1500mL of toluene, 444.2g (3 mol) of 50% glyoxylic acid and 500g (5 mol) of 98% concentrated sulfuric acid, the mixture is heated to 95-100 ℃ for 3 hours, the layering is carried out after the separation, an organic phase is washed by saturated sodium carbonate aqueous solution and water phase, the aqueous phase is concentrated by a vacuum, and 3.84% of indigo is obtained by HPLC (HPLC), 1.84.84%, 1.84% and 3.84% of thermal HPLC is obtained.
Example 3
Under the protection of nitrogen, 40.2g (0.2 mol) of 4,6, 7-trifluoro isatin and 240mL of tetrahydrofuran are put into a reaction bottle, cooled to-15 ℃, 25.8g (0.23 mol) of potassium tert-butoxide is slowly added in batches at the temperature of-15 to-5 ℃, stirred for half an hour, a mixed solution of 45.8g (0.24 mol) of p-toluenesulfonyl chloride and 60mL of tetrahydrofuran is added, the temperature is slowly increased to 5-10 ℃ for reacting for 1 hour, water and acetic acid are added at the temperature of 5-10 ℃, the mixture is kept stand for layering, an organic phase is reserved, the organic phase is decompressed and concentrated to be non-flowing liquid, and 63.5g of N- (p-toluenesulfonyl) -4,6, 7-trifluoro isatin is obtained by adding ethyl acetate and N-heptane for recrystallization, and the yield 89.3％,HPLC99.4％.1HNMR(400MHz,DMSO-d6):7.75-7.68(m,2H),7.35(d,2H),6.68(s,1H),2.35(s,3H).
Example 4
Under the protection of nitrogen, 40.2g (0.2 mol) of 4,6, 7-trifluoro isatin and 160mL of tetrahydrofuran are put into a reaction bottle, the temperature is reduced to minus 15 ℃, 67.3g (0.24 mol) of 40 percent tertiary amyl alcohol sodium toluene solution is slowly dropped at the temperature of minus 15 to minus 5 ℃, the mixture is stirred for half an hour, the mixed solution of 47.6g (0.25 mol) of p-toluenesulfonyl chloride and 60mL of tetrahydrofuran is added, the temperature is slowly increased to 5 to 10 ℃ for reacting for 1 hour, the temperature is controlled to 5 to 10 ℃, water and acetic acid are added at the temperature of 5 to 10 ℃, the mixture is stood for layering, the organic phase is reserved, the organic phase is decompressed and concentrated to a non-flowing liquid, the ethyl acetate and N-heptane are added for recrystallization, and the N- (p-toluenesulfonyl) -4,6, 7-trifluoro isatin-red is obtained with the yield of 91.6 percent and the HPLC of 99.1 percent.
Example 5
Under the protection of nitrogen, 53.3g (0.15 mol) of N- (p-toluenesulfonyl) -4,6, 7-trifluoro-indigo red and 440mL of tetrahydrofuran are put into a reaction bottle, cooled to-5-0 ℃, 12.5g (0.33 mol) of sodium borohydride is added in batches, 24.1g (0.17 mol) of BF 3-Et2 O and B (C 6F5)3) (1.75 g,3.4 mmol) are dropwise added in the temperature range, the temperature is slowly raised to room temperature, the reaction is carried out for 7 hours, cooled to 0 ℃, water and hydrochloric acid are dropwise added for quenching, an organic phase is reserved, the aqueous phase is extracted by adding ethyl acetate, the organic phase is combined, the saturated saline is used for washing, the organic phase is dried by anhydrous magnesium sulfate, the organic phase is concentrated to an unfluid liquid, methanol is added, the organic phase is cooled to-5-0 ℃, 41.4g of BF 329 g (0.33 mol) of BF 3-Et2 O is adopted to replace 24.24 g (0.24 mmol) and the yield 84.8％,HPLC 98.5％.1HNMR(400MHz,DMSO-d6):7.87(d,2H),7.45(d,1H),7.39(d,2H),6.59-6.32(m,2H),2.31(s,3H). g (3.57 mmol) of BF is obtained under the same conditions that the yield is that the yield 84.8％,HPLC 98.5％.1HNMR(400MHz,DMSO-d6):7.87(d,2H),7.45(d,1H),7.39(d,2H),6.59-6.32(m,2H),2.31(s,3H). g (3.24 g) is obtained by pulping N- (p-toluenesulfonyl) -4.24.4 g and the yield is 3.57 mmol (3.57 mmol).
Example 6
Under the protection of nitrogen, 32.5g (0.1 mol) of N- (p-toluenesulfonyl) -4,6, 7-trifluoro indole and 180mL of tetrahydrofuran are put into a reaction bottle, the temperature is reduced to minus 15 ℃ under stirring, 85mL (0.11 mol) of 1.3M isopropyl magnesium chloride-lithium chloride tetrahydrofuran solution is dropwise added under the control of the temperature of minus 15 ℃ and minus 5 ℃, the mixture is stirred for 2 hours at minus 10 ℃ to 0 ℃, 26.4g of carbon dioxide is then introduced, the mixture is stirred for 4 hours at minus 10 ℃ to 0 ℃, the mixture is slowly warmed to room temperature, an ammonium chloride aqueous solution is added for quenching, an organic phase is reserved, the mixture is slowly warmed to 35 ℃,100 mL of water and 47g of 30% sodium hydroxide aqueous solution are added, the mixture is subsequently warmed to 45 ℃ to 55 ℃ for reaction for 5 hours, the mixture is concentrated under reduced pressure for evaporating the solvent, methyl tertiary butyl ether is added for extracting impurities, the water phase is slowly adjusted to pH=2.5 to 3.5 by 1% concentrated sulfuric acid, solid precipitation is carried out, the filter cake is filtered, 200mL of ethyl acetate is heated for dissolving, a small amount of water is separated, and the water is washed once by a small amount of water, an organic phase is decompressed and concentrated under reduced pressure, N-heptane is added, and 4,6, 7-trifluoro indole-1-6-1-HPLC is obtained by adding the N-1-trifluoro indole: 99.7% and yield 70.3%. 1HNMR(400MHz,DMSO-d6 ) 13.2 (s, 1H), 12.2 (s, 1H), 7.14 (s, 1H), 6.40 (s, 1H).
The foregoing is only a preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art, who is within the scope of the present invention, should be covered by the protection scope of the present invention by making equivalents and modifications to the technical solution and the inventive concept thereof.
Claims (6)
1. A method for preparing 4,6, 7-trifluoro-1H-indole-2-carboxylic acid, which is characterized by comprising the following steps:
The first step: dropwise adding a mixture of 2,3, 5-trifluoroaniline and concentrated hydrochloric acid into an aqueous solution containing chloral and sodium sulfate heptahydrate, adding hydroxylamine to react to obtain an intermediate N- (2, 3, 5-trifluorophenyl) -2- (hydroxyimino) acetamide, and then adding the intermediate N- (2, 3, 5-trifluorophenyl) -2- (hydroxyimino) acetamide into toluene, 50% glyoxylic acid and 98% sulfuric acid in batches to close the ring to obtain 4,6, 7-trifluoro isatin;
And a second step of: mixing 4,6, 7-trifluoro isatin with tetrahydrofuran, cooling, adding strong base, and then adding p-toluenesulfonyl chloride to obtain N- (p-toluenesulfonyl) -4,6, 7-trifluoro isatin;
And a third step of: mixing N- (p-toluenesulfonyl) -4,6, 7-trifluoro isatin with tetrahydrofuran, cooling, adding sodium borohydride, and then dropwise adding a boron reagent for reaction to obtain N- (p-toluenesulfonyl) -4,6, 7-trifluoro indole; the boron reagent is a mixture of BF 3-Et2 O and B (C 6F5)3, wherein the molar ratio of BF 3-Et2 O to B (C 6F5)3 is 1:0.01-0.05;
Fourth step: mixing N- (p-toluenesulfonyl) -4,6, 7-trifluoro-indole with tetrahydrofuran, cooling, adding isopropyl magnesium chloride-lithium chloride and carbon dioxide to the 2-position to generate carboxylic acid, performing post-treatment to obtain a crude product, and then deprotecting in sodium hydroxide aqueous solution to obtain 4,6, 7-trifluoro-1H-indole-2-carboxylic acid.
2. The process for producing 4,6, 7-trifluoro-1H-indole-2-carboxylic acid according to claim 1, wherein: in the first step, the molar ratio of the 2,3, 5-trifluoroaniline, chloral, sodium sulfate heptahydrate, hydroxylamine, 50% glyoxylic acid and 98% sulfuric acid is 1:1.15-1.25:9.0-10.0:3.1-3.2:5.5-7.5:10.5-11.5.
3. The process for producing 4,6, 7-trifluoro-1H-indole-2-carboxylic acid according to claim 1, wherein: in the second step, the strong base is selected from potassium tert-butoxide or 40% sodium tert-amyl alcohol toluene solution.
4. The process for producing 4,6, 7-trifluoro-1H-indole-2-carboxylic acid according to claim 1, wherein: in the second step, the mole ratio of the 4,6, 7-trifluoro isatin, the strong base and the p-toluenesulfonyl chloride is 1:1.15-1.20:1.20-1.25.
5. The process for producing 4,6, 7-trifluoro-1H-indole-2-carboxylic acid according to claim 1, wherein: in the third step, the molar ratio of the N- (p-toluenesulfonyl) -4,6, 7-trifluoro isatin, sodium borohydride and boron reagent is 1:2.10-2.40:1.02-1.10.
6. The process for producing 4,6, 7-trifluoro-1H-indole-2-carboxylic acid according to claim 1, wherein: in the fourth step, the molar ratio of the N- (p-toluenesulfonyl) -4,6, 7-trifluoro-indole, isopropyl magnesium chloride-lithium chloride and carbon dioxide is 1:1.05-1.10:5.0-6.0.
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