CN112661632A - Synthetic method of 2-fluoro-4-halogen benzoic acid - Google Patents
Synthetic method of 2-fluoro-4-halogen benzoic acid Download PDFInfo
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- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 239000005711 Benzoic acid Substances 0.000 title claims abstract description 8
- 235000010233 benzoic acid Nutrition 0.000 title claims abstract description 8
- 229910052736 halogen Inorganic materials 0.000 title claims abstract description 8
- 238000010189 synthetic method Methods 0.000 title claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims abstract description 91
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims abstract description 46
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 25
- 239000000126 substance Substances 0.000 claims abstract description 23
- 229910052744 lithium Inorganic materials 0.000 claims abstract description 17
- AFRJJFRNGGLMDW-UHFFFAOYSA-N lithium amide Chemical compound [Li+].[NH2-] AFRJJFRNGGLMDW-UHFFFAOYSA-N 0.000 claims abstract description 15
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 13
- 235000011089 carbon dioxide Nutrition 0.000 claims abstract description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000000605 extraction Methods 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims abstract description 8
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims abstract description 5
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims abstract description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 68
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 32
- 239000002253 acid Substances 0.000 claims description 11
- -1 alkyl lithium Chemical compound 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 8
- 239000002585 base Substances 0.000 claims 3
- 239000003513 alkali Substances 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 229910052731 fluorine Inorganic materials 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 50
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 36
- 239000012074 organic phase Substances 0.000 description 36
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 239000012071 phase Substances 0.000 description 13
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-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 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 12
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 12
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 12
- 238000004321 preservation Methods 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 239000011780 sodium chloride Substances 0.000 description 12
- 238000000926 separation method Methods 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000001914 filtration Methods 0.000 description 8
- 239000012141 concentrate Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 238000005292 vacuum distillation Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229940043279 diisopropylamine Drugs 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 3
- NJYBIFYEWYWYAN-UHFFFAOYSA-N 2,4-difluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1F NJYBIFYEWYWYAN-UHFFFAOYSA-N 0.000 description 3
- SOCTUWSJJQCPFX-UHFFFAOYSA-N dichromate(2-) Chemical compound [O-][Cr](=O)(=O)O[Cr]([O-])(=O)=O SOCTUWSJJQCPFX-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- HVJKLCOHVAENRQ-UHFFFAOYSA-N 1,2,2,6-tetramethylpiperidine Chemical compound CC1CCCC(C)(C)N1C HVJKLCOHVAENRQ-UHFFFAOYSA-N 0.000 description 2
- QDFKKJYEIFBEFC-UHFFFAOYSA-N 1-bromo-3-fluorobenzene Chemical compound FC1=CC=CC(Br)=C1 QDFKKJYEIFBEFC-UHFFFAOYSA-N 0.000 description 2
- 102000003964 Histone deacetylase Human genes 0.000 description 2
- 108090000353 Histone deacetylase Proteins 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000003682 fluorination reaction Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000001590 oxidative effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- WDCYWAQPCXBPJA-UHFFFAOYSA-N 1,3-dinitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC([N+]([O-])=O)=C1 WDCYWAQPCXBPJA-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
Images
Classifications
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- 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
Abstract
The invention provides a synthetic method of 2-fluoro-4-halogen benzoic acid, which comprises the following steps: (a) the substance shown in the formula (I) is subjected to hydrogen extraction by an aminolithium reagent or an alkyllithium reagent (LDA, TMP-Li, n-butyllithium and the like), and then reacts with trialkyl halogenosilane (TMSCl, TESCl, TBSCl and the like) to obtain a compound shown in a formula (II); (b) removing hydrogen from the compound represented by the formula (II) obtained in the step (a) by using an aminolithium reagent or an alkyllithium reagent (LDA, TMP-Li, n-butyllithium and the like), and adding the compound into dry ice/THF for reaction to obtain a compound represented by a formula (III); (c) removing the trialkyl silane protecting group from the compound represented by the formula (III) obtained in the step (b) to obtain a compound represented by the formula (IV). The preparation method provided by the invention has the advantages that the initial raw materials, the process route and the post-treatment process are different, the raw materials are simple and easy to obtain, the cost is low, and the preparation method is suitable for small-scale preparation in a laboratory and industrial production.
Description
Technical Field
The invention relates to the technical field of organic matter synthesis, in particular to a synthesis method of 2-fluoro-4-halogen benzoic acid.
Background
2-fluoro-4-halogen benzoic acid is an important medical intermediate, and can be used for synthesizing Histone Deacetylase (HDAC) inhibitors (WO2011021209, CN105384792, US 20120120101099 and the like).
For example, 2, 4-difluorobenzoic acid is an important intermediate of medicines and pesticides, can be used for liquid crystal materials, and has the advantages of high value and good market prospect. However, in the current domestic traditional synthesis process of 2, 4-difluorobenzoic acid, dichromate is generally adopted as an oxidant, and the synthesis needs two steps of oxidation and fluorination.
The 2, 4-difluorobenzoic acid is an important intermediate of antifungal drugs, is generally prepared from m-dinitrobenzene as a raw material through 5 steps of reactions such as reduction, diazotization, fluorination, acylation, oxidation and the like, and has the advantages of longer reaction steps, low-temperature control of diazotization reaction and great operation difficulty.
As can be seen from the above description, the current domestic synthesis of 2-fluoro-4-halobenzoic acid series usually adopts dichromate as an oxidant, but dichromate has high toxicity, serious environmental pollution and low product yield.
However, few reports have been made to date on the production of 2-fluoro-4-halobenzoic acids at home and abroad (WO 2011021209). In view of the above, a new synthesis method is needed.
The invention content is as follows:
the invention provides a synthesis method of 2-fluoro-4-halogen benzoic acid, which is different from the original raw materials, process routes and post-treatment processes, and has the advantages of simple and easily obtained raw materials, low cost and simple operation.
The technical scheme of the invention is realized as follows: a synthetic method of 2-fluoro-4-halogen benzoic acid comprises the following steps:
a) the substance shown in the formula (I) is subjected to hydrogen extraction by an aminolithium reagent or an alkyllithium reagent (LDA, TMP-Li, n-butyllithium and the like), and then reacts with trialkyl halogenosilane (TMSCl, TESCl, TBSCl and the like) to obtain a compound shown in a formula (II); wherein the reaction temperature is-60 to-40 ℃;
(b) removing hydrogen from the compound represented by the formula (II) obtained in the step (a) by using an aminolithium reagent or alkyl lithium (LDA, TMP-Li, n-butyl lithium and the like), and adding the compound into dry ice/THF for reaction to obtain a compound represented by a formula (III); wherein the reaction temperature is-60 to-40 ℃;
(c) removing the trialkyl silane protecting group from the compound represented by the formula (III) obtained in the step (b) to obtain a compound represented by the formula (IV).
The post-treatment process of the step (c) comprises the following steps: and (3) desolventizing, extracting, acidifying, filtering and drying the compound shown as the formula (IV) obtained by the reaction.
As a preferred technical scheme, the specific steps are as follows:
dropwise adding the substance shown in the formula (I) into an aminolithium reagent or an alkyllithium reagent (LDA, TMP-Li, n-butyllithium and the like) at the temperature of-60 to-40 ℃, adding trialkylhalosilane (TMSCl, TESCl, TBSCl and the like) at the temperature of-60 to-40 ℃ after hydrogen removal reaction, and carrying out heat preservation reaction at the temperature of-60 to-40 ℃ after the addition to obtain a compound shown in the formula (II);
the post-treatment process of the step (a) comprises the following steps: and (3) carrying out layering desolventizing on the compound shown as the formula (II) obtained by the reaction, extracting with water phase ethyl acetate, mixing concentrates, washing, drying, filtering and desolventizing to obtain the compound.
Dropwise adding the substance shown in the formula (II) into an aminolithium reagent or an alkyl lithium reagent (LDA, TMP-Li, n-butyllithium and the like) at the temperature of-60 to-40 ℃ for hydrogen removal reaction, adding the substance into a dry ice/tetrahydrofuran solution at the temperature of-60 to-40 ℃, and carrying out heat preservation reaction at the temperature of-60 to-40 ℃ after the addition is finished to obtain the compound shown in the formula (III).
The post-treatment process of the step (b) comprises the following steps: and (3) extracting the compound shown as the formula (III) obtained by the reaction with ethyl acetate, washing and desolventizing to obtain the compound.
Dissolving the substance shown in the formula (III) in methanol, dropwise adding strong base at the temperature of 20-50 ℃, and keeping the temperature at 20-50 ℃ after adding the strong base to remove the trialkyl silane protecting group by reaction to obtain the compound shown in the formula (IV).
The post-treatment process of the step (c) comprises the following steps: and (3) desolventizing, extracting, acidifying, filtering and drying the compound shown as the formula (IV) obtained by the reaction.
Preferably, the molar ratio of the substance shown in the formula (I), the lithium amide reagent or the alkyl lithium reagent and the trialkyl halosilane is 1: 1.0-1.5: 1.0 to 2.0.
According to a preferable technical scheme, 15-25 g of a substance shown in a formula (I) is added into every 100mL of tetrahydrofuran; the molar concentration of the n-hexane solution of n-butyllithium is 1.5-2.5 mol/l.
Preferably, the molar ratio of the substance represented by the formula (II), the aminolithium reagent or the alkyllithium reagent and the dry ice is 1: 1.0-1.5: 5.0 to 20.0
Preferably, 15 to 25g of the substance represented by the formula (II) is added to 100mL of tetrahydrofuran. The molar concentration of the n-hexane solution of n-butyllithium is 1.5-2.5 mol/l.
Preferably, the molar ratio of the substance represented by the formula (III) to the base is 1: 2.0 to 4.0.
Preferably, 15 to 25g of the compound represented by the formula (III) is added to 100mL of methanol.
The invention has the following beneficial effects:
the preparation method provided by the invention has the advantages that the initial raw materials, the process route and the post-treatment process are different, the raw materials are simple and easy to obtain, the cost is low, and the operation is simple.
The post-treatment of the invention does not need to use column chromatography to purify and separate products, because the selection of the raw materials and the process route of the invention ensures that the post-treatment is simpler and more convenient, the purification is easy, the use of column chromatography purification is avoided, the production cost is saved, meanwhile, the time is greatly shortened, and the invention is suitable for industrialized mass production and is also suitable for small-scale preparation in laboratories.
Description of the drawings:
in order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without inventive exercise.
FIG. 1 is a process scheme of the present invention;
FIG. 2 is a schematic representation of 2-fluoro-4-halobenzoic acid prepared in accordance with example 11HNMR atlas.
The specific implementation mode is as follows:
the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1:
referring to FIG. 1, 2, 6, 6-tetramethylpiperidine (7.6g, 74.8mmol) was dissolved in tetrahydrofuran (45mL) under nitrogen, and the reaction was cooled to-40 to-60 ℃. A2.5M solution of n-butyllithium in n-hexane (29.9mL, 74.8mmol) was slowly added dropwise to the mixture. After the dripping is finished, the reaction is continued for 0.5 hour under the condition of heat preservation. M-bromofluorobenzene (10.0g, 57.5mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 1 hour. Chlorotrimethylsilane (8.1g, 74.8mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 1 hour. The reaction mixture was quenched by dropping it at 20 ℃ or below into 1N hydrochloric acid (83g, 82.8mmol), stirred for 30 minutes after dropping, and then allowed to stand for separation. The organic phase was separated and concentrated under reduced pressure, the aqueous phase was back-extracted with dichloromethane (50mL), and the organic phase was combined with the concentrate and washed with saturated aqueous sodium chloride (50 mL). The separated organic phase is sequentially added with anhydrous sodium sulfate for drying, filtering and vacuum distillation to obtain 13.5g of a compound II.
Under the protection of nitrogen, 2, 6, 6-tetramethylpiperidine (8.6g, 61.0mmol) was dissolved in tetrahydrofuran (50mL) and cooled to-40-60 ℃. A2.5M solution of n-butyllithium in n-hexane (24.4mL, 61.0mmol) was slowly added dropwise to tetrahydrofuran. After completion of the dropwise addition, Compound II (10.0g, 40.7mmol) was slowly added dropwise to the reaction mixture. After the dripping is finished, the reaction is kept warm for 1 hour. The reaction solution was added dropwise to a solution of dry ice (29.5g, 670mmol) in tetrahydrofuran (40mL) at-40 to-60 ℃ and the reaction was continued for 1 hour with maintaining the temperature after completion of the addition. The reaction mixture was quenched by dropping it at 20 ℃ or below into 1N hydrochloric acid (134.0g, 134.2mmol), stirred for 30 minutes after dropping, and then allowed to stand for separation. The organic phase was separated, the aqueous phase was back-extracted with ethyl acetate (50mL), the organic phases were combined and washed with saturated aqueous sodium chloride (50 mL). The organic phase was separated and distilled under reduced pressure to give 11.8g of Compound III.
Under nitrogen protection, compound III (11.8g, 40.5mmol) was put into methanol (60mL), aqueous sodium hydroxide solution (6.5g, 162.0mmol, dissolved in 15.1g of water) was slowly added dropwise at 20-50 ℃ and the reaction was allowed to proceed for 6 hours under heat preservation. After the reaction is finished, the reaction solution is cooled to below 30 ℃, hydrochloric acid (10.1g, 101.3mmol) is added dropwise, then methanol is removed under reduced pressure, tert-butyl methyl ether (30mL x 2) is sequentially added into the water phase for back extraction, the water phase is acidified by hydrochloric acid (8.1g, 81.0mmol), the temperature is reduced to 0-10 ℃, and the mixture is filtered and dried under reduced pressure to obtain 5.6g of a compound IV.
FIG. 2 is a schematic representation of 2-fluoro-4-halobenzoic acid prepared in accordance with the procedure of this example1HNMR atlas.
1H-NMR(500MHz，DMSO-d6)δ(ppm):13.7(brs，1H)，7.70-7.83(m，2H，H(3)and H(5))，8.07(t，1H，J＝8.08，H(6)).。
Example 2:
referring to FIG. 1, 2, 6, 6-tetramethylpiperidine (13.0g, 91.9mmol) was dissolved in tetrahydrofuran (45mL) under nitrogen, and the reaction was cooled to-40 to-60 ℃. A1.5M solution of n-butyllithium in n-hexane (46.0mL, 91.9mmol) was slowly added dropwise to the mixture. After the dripping is finished, the reaction is continued for 0.5 hour under the condition of heat preservation. M-chlorobenzenebenzene (10.0g, 76.6mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 1 hour. Triethylchlorosilane (13.9g, 91.9mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 1 hour. The reaction mixture was quenched by adding dropwise to 1N hydrochloric acid (132.0g, 132.3mmol) at 20 ℃ or lower, stirred for 30 minutes after completion of the addition, and then allowed to stand for separation. The organic phase was separated and concentrated under reduced pressure, the aqueous phase was back-extracted with dichloromethane (50mL), and the organic phase was combined with the concentrate and washed with saturated aqueous sodium chloride (50 mL). The separated organic phase is sequentially added with anhydrous sodium sulfate for drying, filtering and vacuum distillation to obtain 21.1g of a compound II.
Tetrahydrofuran (45mL) was cooled to-40-60 ℃ under nitrogen. A1.5M solution of n-butyllithium in n-hexane (32.6mL, 48.8mmol) was slowly added dropwise to tetrahydrofuran. After completion of the dropwise addition, Compound II (10.0g, 40.8mmol) was slowly added dropwise to the reaction mixture. After the dripping is finished, the reaction is kept warm for 1 hour. The reaction solution is dripped into a tetrahydrofuran (45mL) solution of dry ice (35.8g, 814mmol) at the temperature of minus 40 to minus 60 ℃, and the temperature is kept for reaction for 1 hour after dripping. The reaction mixture was quenched by dropping it at 20 ℃ or below into 1N hydrochloric acid (48g, 48.8mmol), stirred for 30 minutes after dropping, and then allowed to stand for separation. The organic phase was separated, the aqueous phase was back-extracted with ethyl acetate (50mL), the organic phases were combined and washed with saturated aqueous sodium chloride (50 mL). The organic phase was separated and distilled under reduced pressure to give 11.5g of Compound III.
Under nitrogen protection, compound III (11.5g, 39.8mmol) was put into methanol (50mL), and an aqueous solution of potassium hydroxide (6.6g, 118.5mmol, dissolved in 15.4g of water) was slowly added dropwise at 20-50 ℃ to carry out a reaction for 6 hours with heat preservation. After the reaction is finished, the reaction solution is cooled to below 30 ℃, hydrochloric acid (7.9g, 79.0mmol) is added dropwise, then methanol is removed under reduced pressure, tert-butyl methyl ether (30mL x 2) is sequentially added into the water phase for back extraction, the water phase is acidified by hydrochloric acid (5.9g, 59.3mmol), the temperature is reduced to 0-10 ℃, and the mixture is filtered and dried under reduced pressure to obtain 4.9g of a compound IV.
1H-NMR(500MHz，DMSO-d6)δ(ppm):13.7(brs，1H)，7.70-7.83(m，2H，H(3)and H(5))，8.07(t，1H，J＝8.08，H(6)).。
Example 3:
referring to FIG. 1, diisopropylamine (21.7g, 214.5mmol) was dissolved in tetrahydrofuran (120mL) under nitrogen, and the reaction was cooled to-40 to-60 ℃. A2.5M solution of n-butyllithium in n-hexane (85.5mL, 214.5mmol) was slowly added dropwise to the mixture. After the dripping is finished, the reaction is continued for 0.5 hour under the condition of heat preservation. M-chlorobenzenebenzene (20.0g, 153.2mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 1 hour. Tert-butyldimethylsilyl chloride (34.8g, 230.8mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 1 hour. The reaction mixture was quenched by dropping it at 20 ℃ or below into 1N hydrochloric acid (253.5g, 253.5mmol), stirred for 30 minutes after dropping, and then allowed to stand for separation. The organic phase was separated and concentrated under reduced pressure, the aqueous phase was back-extracted with dichloromethane (100mL), and the organic phase was combined with the concentrate and washed with saturated aqueous sodium chloride (100 mL). The separated organic phase is sequentially added with anhydrous sodium sulfate for drying, filtering and vacuum distillation to obtain 36.4g of a compound II.
In tetrahydrofuran (120mL) under the protection of nitrogen, the mixture is cooled to-40 to-60 ℃. A2.5M solution of n-butyllithium in n-hexane (32.7mL, 81.7mmol) was slowly added dropwise to tetrahydrofuran. After completion of the dropwise addition, Compound II (20.0g, 81.7mmol) was slowly added dropwise to the reaction mixture. After the dripping is finished, the reaction is kept warm for 1 hour. The reaction solution was added dropwise to a solution of dry ice (18.0g, 405mmol) in tetrahydrofuran (54mL) at-40 to-60 ℃ and the reaction was continued for 1 hour with keeping the temperature after completion of the addition. The reaction mixture was quenched by dropping it at 20 ℃ or below into 1N hydrochloric acid (130.0g, 130.0mmol), stirred for 30 minutes after dropping, and then allowed to stand for separation. The organic phase was separated, the aqueous phase was back-extracted with ethyl acetate (100mL), the organic phases were combined and washed with saturated aqueous sodium chloride (100 mL). The organic phase was separated and distilled under reduced pressure to give 22.6g of Compound III.
Under nitrogen protection, compound III (22.6g, 78.3mmol) was put into methanol (115.0mL), aqueous sodium hydroxide (6.3g, 156.6mmol, dissolved in 14.6g of water) was slowly added dropwise at 20-50 ℃ and the reaction was incubated for 6 hours. After the reaction is finished, the reaction solution is cooled to below 30 ℃, hydrochloric acid (11.7g, 117.5mmol) is added dropwise, then methanol is removed under reduced pressure, tert-butyl methyl ether (80mL x 2) is sequentially added into the water phase for back extraction, the water phase is acidified by hydrochloric acid (7.8g, 78.3mmol), the temperature is reduced to 0-10 ℃, and the compound IV is filtered, dried under reduced pressure and obtained 8.8 g.
1H-NMR(500MHz，DMSO-d6)δ(ppm):13.7(brs，1H)，7.70-7.83(m，2H，H(3)and H(5))，8.07(t，1H，J＝8.08，H(6)).。
Example 4:
referring to FIG. 1, diisopropylamine (8.7g, 86.3mmol) was dissolved in tetrahydrofuran (65mL) under nitrogen, and the reaction was cooled to-40 to-60 ℃. A2.5M solution of n-butyllithium in n-hexane (33.4mL, 83.4mmol) was slowly added dropwise to the mixture. After the dripping is finished, the reaction is continued for 0.5 hour under the condition of heat preservation. Compound I (10.0g, 57.5mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 1 hour. Chlorotrimethylsilane (6.0g, 54.8mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 1 hour. The reaction mixture was quenched by dropping it at 20 ℃ or below into 1N hydrochloric acid (95g, 94.8mmol), stirred for 30 minutes after dropping, and then allowed to stand for separation. The organic phase was separated and concentrated under reduced pressure, the aqueous phase was back-extracted with dichloromethane (50mL), and the organic phase was combined with the concentrate and washed with saturated aqueous sodium chloride (50 mL). The separated organic phase is sequentially added with anhydrous sodium sulfate for drying, filtering and vacuum distillation to obtain 13.1g of a compound II.
Under the protection of nitrogen, 2, 6, 6-tetramethylpiperidine (8.3g, 59.0mmol) was dissolved in tetrahydrofuran (65mL) and cooled to-40-60 ℃. A2.5M solution of n-butyllithium in n-hexane (22.8mL, 57.0mmol) was slowly added dropwise to tetrahydrofuran. After completion of the dropwise addition, Compound II (10.0g, 40.7mmol) was slowly added dropwise to the reaction mixture. After the dripping is finished, the reaction is kept warm for 1 hour. The reaction solution was added dropwise to a solution of dry ice (17.9g, 407mmol) in tetrahydrofuran (65mL) at-40 to-60 ℃ and the reaction was continued for 1 hour with maintaining the temperature after completion of the addition. The reaction mixture was quenched by dropping it at 20 ℃ or below into 1N hydrochloric acid (127.0g, 127.6mmol), stirred for 30 minutes after dropping, and then allowed to stand for separation. The organic phase was separated, the aqueous phase was back-extracted with ethyl acetate (50mL), the organic phases were combined and washed with saturated aqueous sodium chloride (50 mL). The organic phase was separated and distilled under reduced pressure to give 11.6g of Compound III.
Under nitrogen protection, compound III (11.6g, 39.8mmol) was put into methanol (50mL), aqueous sodium hydroxide solution (5.6g, 139.3mmol, dissolved in 13.1g of water) was slowly added dropwise at 20-50 ℃ and the reaction was allowed to proceed for 6 hours under heat preservation. After the reaction is finished, the reaction solution is cooled to below 30 ℃, hydrochloric acid (10.0g, 99.5mmol) is added dropwise, then methanol is removed under reduced pressure, tert-butyl methyl ether (30mL x 2) is sequentially added into the water phase for back extraction, the water phase is acidified by hydrochloric acid (6.0g, 59.7mmol), the temperature is reduced to 0-10 ℃, and the compound IV is filtered, dried under reduced pressure and obtained 6.0 g.
1H-NMR(500MHz，DMSO-d6)δ(ppm):13.7(brs，1H)，7.70-7.83(m，2H，H(3)and H(5))，8.07(t，1H，J＝8.08，H(6)).。
Example 5
Referring to FIG. 1, diisopropylamine (6.4g, 63.3mmol) was dissolved in tetrahydrofuran (65mL) under nitrogen and cooled to-40-60 ℃. A2.5M solution of n-butyllithium in n-hexane (25.3mL, 63.3mmol) was slowly added dropwise to tetrahydrofuran. After the dripping is finished, the reaction is continued for 0.5 hour under the condition of heat preservation. M-bromofluorobenzene (10.0g, 57.5mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 1 hour. Chlorotrimethylsilane (6.2g, 57.5mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 1 hour. The reaction mixture was quenched by dropping it at 20 ℃ or below into 1N hydrochloric acid (95g, 94.8mmol), stirred for 30 minutes after dropping, and then allowed to stand for separation. The organic phase was separated and concentrated under reduced pressure, the aqueous phase was back-extracted with dichloromethane (50mL), and the organic phase was combined with the concentrate and washed with saturated aqueous sodium chloride (50 mL). The separated organic phase is sequentially added with anhydrous sodium sulfate for drying, filtering and vacuum distillation to obtain 12.1g of a compound II.
Diisopropylamine (5.8g, 57.0mmol) was dissolved in tetrahydrofuran (65mL) under nitrogen and cooled to-40-60 ℃. A2.5M solution of n-butyllithium in n-hexane (22.8mL, 57.0mmol) was slowly added dropwise to tetrahydrofuran. After completion of the dropwise addition, Compound II (10.0g, 40.7mmol) was slowly added dropwise to the reaction mixture. After the dripping is finished, the reaction is kept warm for 1 hour. The reaction solution was added dropwise to a solution of dry ice (17.9g, 407mmol) in tetrahydrofuran (65mL) at-40 to-60 ℃ and the reaction was continued for 1 hour with maintaining the temperature after completion of the addition. The reaction mixture was quenched by dropping it at 20 ℃ or below into 1N hydrochloric acid (127.0g, 127.6mmol), stirred for 30 minutes after dropping, and then allowed to stand for separation. The organic phase was separated, the aqueous phase was back-extracted with ethyl acetate (50mL), the organic phases were combined and washed with saturated aqueous sodium chloride (50 mL). The organic phase was separated and distilled under reduced pressure to give 11.7g of Compound III.
Under nitrogen protection, compound III (11.6g, 39.8mmol) was put into methanol (50mL), and an aqueous solution of potassium hydroxide (7.8g, 139.3mmol, dissolved in 18.2g of water) was slowly added dropwise at 20 to 50 ℃ to carry out a reaction for 6 hours with heat preservation. After the reaction is finished, the reaction solution is cooled to below 30 ℃, hydrochloric acid (10.0g, 99.5mmol) is added dropwise, then methanol is removed under reduced pressure, tert-butyl methyl ether (30mL x 2) is sequentially added into the water phase for back extraction, the water phase is acidified by hydrochloric acid (6.0g, 59.7mmol), the temperature is reduced to 0-10 ℃, and the compound IV is filtered, dried under reduced pressure and obtained 5.8 g.
1H-NMR(500MHz，DMSO-d6)δ(ppm):13.7(brs，1H)，7.70-7.83(m，2H，H(3)and H(5))，8.07(t，1H，J＝8.08，H(6)).。
Example 6
Referring to FIG. 1, tetrahydrofuran (65mL) was cooled to-40 to-60 ℃ under nitrogen. A1.5M solution of n-butyllithium in n-hexane (76.6mL, 114.9mmol) was slowly added dropwise to tetrahydrofuran. After the dripping is finished, the reaction is continued for 0.5 hour under the condition of heat preservation. M-chlorobenzenebenzene (10.0g, 76.6mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 1 hour. Triethylchlorosilane (16.2g, 107.2mmol) was slowly added dropwise to the reaction solution. After the dripping is finished, the reaction is kept warm for 1 hour. The reaction mixture was quenched by adding dropwise to 1N hydrochloric acid (126.4g, 126.4mmol) at 20 ℃ or lower, stirred for 30 minutes after completion of the addition, and then allowed to stand to separate into layers. The organic phase was separated and concentrated under reduced pressure, the aqueous phase was back-extracted with dichloromethane (50mL), and the organic phase was combined with the concentrate and washed with saturated aqueous sodium chloride (50 mL). The separated organic phase was sequentially added with anhydrous sodium sulfate, dried, filtered, and distilled under reduced pressure to obtain 17.9g of compound II.
Under the protection of nitrogen, 2, 6, 6-tetramethylpiperidine (5.8g, 40.8mmol) was dissolved in tetrahydrofuran (45mL) and cooled to-40-60 ℃. A2.5M solution of n-butyllithium in n-hexane (16.3mL, 40.8mmol) was slowly added dropwise to tetrahydrofuran. After completion of the dropwise addition, Compound II (10.0g, 40.8mmol) was slowly added dropwise to the reaction mixture. After the dripping is finished, the reaction is kept warm for 1 hour. The reaction solution was added dropwise to a solution of dry ice (17.9g, 407mmol) in tetrahydrofuran (65mL) at-40 to-60 ℃ and the reaction was continued for 1 hour with maintaining the temperature after completion of the addition. The reaction mixture was quenched by dropping it at 20 ℃ or below into 1N hydrochloric acid (98.0g, 98.0mmol), stirred for 30 minutes after dropping, and then allowed to stand for separation. The organic phase was separated, the aqueous phase was back-extracted with ethyl acetate (50mL), the organic phases were combined and washed with saturated aqueous sodium chloride (50 mL). The organic phase was separated and distilled under reduced pressure to give 10.9g of Compound III.
Under nitrogen protection, compound III (8.7g, 30.0mmol) was put into methanol (40mL), aqueous sodium hydroxide (2.4g, 60.0mmol, dissolved in 5.6g of water) was slowly added dropwise at 20-50 ℃ and the reaction was incubated for 6 hours. After the reaction is finished, the reaction solution is cooled to below 30 ℃, hydrochloric acid (4.5g, 45.0mmol) is added dropwise, then methanol is removed under reduced pressure, tert-butyl methyl ether (30mL x 2) is sequentially added into the water phase for back extraction, the water phase is acidified by hydrochloric acid (2.7g, 27.0mmol), the temperature is reduced to 0-10 ℃, and the compound IV is filtered, dried under reduced pressure and 3.3g is obtained.
1H-NMR(500MHz，DMSO-d6)δ(ppm):13.7(brs，1H)，7.70-7.83(m，2H，H(3)and H(5))，8.07(t，1H，J＝8.08，H(6)).。
While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that the foregoing and other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention. Those skilled in the art can make various changes, modifications and equivalent arrangements, which are equivalent to the embodiments of the present invention, without departing from the spirit and scope of the present invention, and which may be made by utilizing the techniques disclosed above; meanwhile, any changes, modifications and variations of the above-described embodiments, which are equivalent to those of the technical spirit of the present invention, are within the scope of the technical solution of the present invention.
Claims (10)
1. A synthetic method of 2-fluoro-4-halogen benzoic acid is characterized by comprising the following steps:
(a) the substance shown in the formula (I) is subjected to hydrogen extraction by an aminolithium reagent or an alkyl lithium reagent and then reacts with trialkyl halogenosilane to obtain a compound shown in the formula (II);
(b) after the compound shown in the formula (II) obtained in the step (a) is subjected to hydrogen extraction by an aminolithium reagent or alkyl lithium, adding the compound into dry ice/THF for reaction to obtain a compound shown in a formula (III);
(c) removing a trialkyl silane protecting group from the compound shown in the formula (III) obtained in the step (b) to obtain a compound shown in a formula (IV);
wherein the substance of formula (I):
a compound of formula (II):
a compound represented by the formula (III):
a compound of formula (IV):
wherein X is F, Cl or Br; r is TMS, TES or TBS.
2. The method for synthesizing 2-fluoro-4-halobenzoic acid according to claim 1, wherein the method comprises the following steps:
a) dropwise adding the substance shown in the formula (I) into an aminolithium reagent or an alkyl lithium reagent at the temperature of-60 to-40 ℃ for hydrogen removal reaction, adding trialkyl halogenosilane at the temperature of-60 to-40 ℃, and keeping the temperature at-60 to-40 ℃ for reaction to obtain a compound shown in the formula (II);
b) dropwise adding the substance shown in the formula (II) into an aminolithium reagent or an alkyl lithium reagent at the temperature of-60 to-40 ℃ for hydrogen removal reaction, adding the substance into a dry ice/tetrahydrofuran solution at the temperature of-60 to-40 ℃, and keeping the temperature at-60 to-40 ℃ for reaction after the addition is finished to obtain the compound shown in the formula (III).
c) Dissolving the substance shown in the formula (III) in methanol, dropwise adding strong base at the temperature of 20-50 ℃, and keeping the temperature at 20-50 ℃ after adding the strong base to remove the trialkyl silane protecting group by reaction to obtain the compound shown in the formula (IV).
3. The method of claim 1 or 2, wherein the aminolithium reagent or alkyl lithium comprises LDA, TMP-Li or n-butyllithium.
4. The method of claim 1 or 2, wherein the trialkyl halosilane comprises TMSCl, TESCl, or TBSCl.
5. The method for synthesizing 2-fluoro-4-halobenzoic acid according to claim 2, wherein in step a), the molar ratio of the substance represented by formula (i), the lithium amide reagent or the alkyl lithium reagent, and the trialkyl halosilane is 1: 1.0-1.5: 1.0 to 2.0.
6. The method for synthesizing 2-fluoro-4-halobenzoic acid according to claim 2, wherein in step a), 15-25 g of the substance represented by formula (i) is added to 100mL of tetrahydrofuran; the molar concentration of the n-hexane solution of n-butyllithium is 1.5-2.5 mol/l.
7. The method for synthesizing 2-fluoro-4-halobenzoic acid according to claim 2, wherein in step b), the molar ratio of the substance represented by formula (ii), the lithium amide reagent or the alkyl lithium reagent and the dry ice is 1: 1.0-1.5: 5.0 to 20.0.
8. The method for synthesizing 2-fluoro-4-halobenzoic acid according to claim 2, wherein 15 to 25g of the substance represented by formula (II) is added to 100mL of tetrahydrofuran in step b), and the n-hexane solution of n-butyllithium is used at a molar concentration of 1.5 to 2.5 mol/L.
9. The method for synthesizing 2-fluoro-4-halobenzoic acid according to claim 2, wherein in step c), the molar ratio of the substance represented by formula (iii) to the base is 1: 2.0 to 4.0.
10. The method for synthesizing 2-fluoro-4-halobenzoic acid according to claim 2, wherein 15-25 g of the substance represented by formula (III) is added to 100mL of methanol in step c), and the concentration of the alkali solution is 27.0-33.0% by weight.
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