CN115124410B - Preparation method of 2-fluoro-4-hydroxybenzaldehyde - Google Patents

Preparation method of 2-fluoro-4-hydroxybenzaldehyde Download PDF

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CN115124410B
CN115124410B CN202210971692.9A CN202210971692A CN115124410B CN 115124410 B CN115124410 B CN 115124410B CN 202210971692 A CN202210971692 A CN 202210971692A CN 115124410 B CN115124410 B CN 115124410B
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hydroxybenzaldehyde
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CN115124410A (en
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蒋道来
熊诗传
王放
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Shanghai Kehua Biotechnology Co ltd
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    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
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    • C07—ORGANIC CHEMISTRY
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    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/22—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of halogens; by substitution of halogen atoms by other halogen atoms
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Abstract

The invention discloses a preparation method of 2-fluoro-4-hydroxybenzaldehyde, and belongs to the technical field of organic synthesis. 3-fluorophenol is used as a raw material to protect hydroxyl, then the hydroxyl is subjected to bromination with a brominating reagent, then Grignard reagent exchange and DMF react to generate corresponding aldehyde, and finally deprotection and purification are carried out to obtain 2-fluoro-4-hydroxybenzaldehyde. The invention has the advantages of easily obtained raw materials, low cost, mild and continuous reaction conditions, low equipment requirement and high product purity up to 99.5 percent, and finally, isopropyl is selected as a protecting group by screening different phenolic hydroxyl protecting groups, thereby optimizing the final process.

Description

Preparation method of 2-fluoro-4-hydroxybenzaldehyde
Technical Field
The invention relates to a preparation method of 2-fluoro-4-hydroxybenzaldehyde, belonging to the technical field of organic synthesis.
Background
2-Fluoro-4-hydroxybenzaldehyde, english name: the 2-fluoro-4-hydroxybenzaldehyde, CAS 348-27-6, 2-fluoro-4-hydroxybenzaldehyde is mainly applied to intermediates of physiologically active compounds such as medicines or pesticides, is a wide organic block compound, and has the structure containing fluorine, aldehyde groups and phenolic hydroxyl groups which can be added or replaced with other functional groups.
At present, the fluorine-containing medicine is most actively developed, and more than one product is commercialized or developed. Literature [ Bioorganic AND MEDICINAL CHEMISTRY LETTERS,2010,20,153-156] synthesis of potent JAK2 kinase inhibitors via 2-fluoro-4-hydroxybenzaldehyde as an intermediate; literature [ RSC ADVANCES,2016,6,95177-95188] adamantane-substituted imidazo [1,2-a ] pyridine derivatives were synthesized from 2-fluoro-4-hydroxybenzaldehyde as an intermediate; literature [ Journal of MEDI CINAL CHEMISTRY,2016,59,2497-2511] synthesized novel melanin concentrating hormone receptor antagonists via 2-fluoro-4-hydroxybenzaldehyde as an intermediate. WO2016/22742,2016, A1 likewise uses 2-fluoro-4-hydroxybenzaldehyde as an intermediate for the synthesis of imidazole-containing fused tricyclic drugs.
However, there are few methods for synthesizing 2-fluoro-4-hydroxybenzaldehyde, wherein [ Journal ofFluo RINE CHEMISTRY,1995,70,39-44] reports that 3-fluorophenol is reacted with tert-butyldimethylchlorosilane to protect hydroxyl group, then sec-butyllithium is subjected to ultralow temperature hydrogen extraction and then reacts with DMF to generate aldehyde, and then deprotection is carried out under acidic condition to obtain 2-fluoro-4-hydroxybenzaldehyde. The reaction equation is as follows:
The method has short steps, the total yield reaches 68.4%, but the price of the used reagents is high, the ultralow temperature reaction is required, the equipment requirement is high, and the large-scale production is not facilitated.
The general route is to protect with 3-fluorophenol hydroxy groups followed by butyl lithium/DMF aldehyde groups followed by deprotection to give 2-fluoro-4-hydroxybenzaldehyde. The method screens out the protecting groups which are low in price and easy to remove through experimental optimization, is moderate in steric hindrance, is beneficial to fluorine ortho-bromination, is mild and continuous in reaction condition, does not need ultralow temperature, has low equipment requirement and high quality, and is suitable for industrial production so as to meet the increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a preparation method of 2-fluoro-4-hydroxybenzaldehyde. 3-fluorophenol is used as a raw material to protect hydroxyl, then the raw material is subjected to bromination with a brominating reagent, then Grignard reagent exchange and DMF react to generate corresponding aldehyde, finally the phenolic hydroxyl protection is removed, and then the 2-fluoro-4-hydroxybenzaldehyde is obtained through purification. The invention has the advantages of easily obtained raw materials, low cost, mild and continuous reaction conditions, low equipment requirement and high product purity up to 99.5 percent, and finally, isopropyl is selected as a protecting group by screening different phenolic hydroxyl protecting groups, thereby optimizing the final process.
The invention relates to a preparation method of 2-fluoro-4-hydroxybenzaldehyde, which has the following reaction equation:
The method comprises the following steps:
The first step: mixing 3-fluorophenol, potassium carbonate and 2-bromopropane in an organic solvent, and heating to react 1-fluoro-3-isopropoxy benzene;
And a second step of: dissolving 1-fluoro-3-isopropoxy benzene in an organic solvent, and reacting with a brominating reagent to obtain 1-bromo-2-fluoro-4-isopropoxy benzene;
and a third step of: dissolving 1-bromo-2-fluoro-4-isopropoxy benzene in tetrahydrofuran, dropwise adding isopropyl magnesium chloride/tetrahydrofuran solution at-10 ℃ to 0 ℃, and adding DMF (dimethyl formamide) for reaction after Grignard exchange to obtain 2-fluoro-4-isopropoxy benzaldehyde;
fourth step: reacting 2-fluoro-4-isopropoxybenzaldehyde with boron trichloride, and deprotecting to obtain 2-fluoro-4-hydroxybenzaldehyde.
Further, in the above technical scheme, the organic solvent in the first step is selected from acetonitrile, acetone, tetrahydrofuran or DMF.
Further, in the above technical scheme, the molar ratio of the 3-fluorophenol, the potassium carbonate and the 2-bromopropane in the first step is 1:1.80-2.30:1.20-1.40.
Further, in the above technical scheme, in the second step, the brominating reagent is selected from tetrabutylammonium tribromide or pyridinium tribromide.
Further, in the above technical scheme, the organic solvent in the second step is selected from 1, 2-dichloroethane or dichloromethane.
Further, in the above technical scheme, in the second step, the molar ratio of the 1-fluoro-3-isopropoxy benzene to the brominating reagent is 1:0.98-1.05.
Further, in the above technical scheme, in the third step, the molar ratio of the 1-bromo-2-fluoro-4-isopropoxybenzene, the isopropyl magnesium chloride and the DMF is 1:1.15-1.20:1.25-1.35.
Further, in the above technical scheme, in the fourth step, the molar ratio of the 2-fluoro-4-isopropoxybenzaldehyde to the boron trichloride is 1:2-5.5.
Advantageous effects of the invention
1. The screening of the phenolic hydroxyl protecting groups is carried out from the protecting groups of methyl, ethyl, isopropyl, tertiary butyl and THP (2-tetrahydropyran), the methyl and ethyl protecting groups have more isomers during bromination, the tertiary butyl protecting groups have the least brominated isomers, but tertiary butyl bromide is more expensive and is not easy to protect, the THP is easy to deprotect during bromination reaction, and the screening of different brominating reagents is carried out to carry out bromination reaction on different phenolic hydroxyl protecting groups, so that the isomers of dibromohydantoin, tetrabutylammonium tribromide or pyridinium tribromide are less, and tetrabutylammonium tribromide is preferred. The isomer can be purified by recrystallization using deprotection with boron trichloride at low temperature. In summary, the price of 2-bromopropane is relatively low, the isomers are relatively few when the isopropyl protecting group is brominated, boron trichloride is adopted during deprotection, the conditions are more heated and combined, and the yield is higher.
2. The whole process avoids ultralow temperature reaction, the reaction condition is mild, the intermediate does not need to be purified through the property analysis of impurities, and finally the obtained product is recrystallized through isopropyl ether to obtain the purity of more than 99.5%.
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.
Example 1
5.6G (0.05 mol,1 eq) of 3-fluorophenol, 20.7g (0.15 mol,3 eq) of ground potassium carbonate and 60mL of acetonitrile are mixed, 8.8g (0.07 mol,1.4 eq) of dimethyl sulfate is slowly dropped at 30-35 ℃, then the temperature is raised to 80-82 ℃ to react for 4 hours, the HPLC detection raw material is left for 2%, water and ethyl acetate are added at room temperature, an organic phase is separated, the organic phase is washed with water and saturated sodium chloride, anhydrous sodium sulfate is dried, and the organic phase is concentrated to obtain 6.03g of 1-fluoro-3-methoxybenzene. HPLC 94.5%, yield 95.6％.1HNMR(400MHz,CDCl3):7.73-7.69(m,1H),7.45-7.41(m,1H),7.15-7.11(m,1H),6.71-6.68(m,1H),3.81(s,3H).
5.0G (0.04 mol,1 eq) of 1-fluoro-3-methoxybenzene are mixed with 50mL of dichloromethane under the protection of nitrogen, the temperature is reduced to 10 ℃, a solution containing 6.4g (0.04 mol,1 eq) of bromine per 5mL of dichloromethane is slowly added dropwise, 3% of the raw material is detected by HPLC, ice water is added, sodium carbonate solid is added in portions to adjust pH to 8-9, the layers are separated, the aqueous phase is extracted by dichloromethane, the organic phase is combined, the organic phase is washed by water and saturated sodium chloride respectively, dried by anhydrous sodium sulfate, the organic phase is concentrated, HPLC is 52%, and the column chromatography is carried out on ethyl acetate: n-heptane=1: 10-1:5 elution to obtain 3.7g of 1-bromo-2-fluoro-4-methoxybenzene in yield 44.9％,HPLC 97.3％.1HNMR(400MHz,CDCl3):7.45-7.40(m,1H),7.01-6.97(m,1H),6.64-6.60(m,1H),3.78(s,3H).
Example 2
5.6G (0.05 mol,1 eq) of 3-fluorophenol, 20.7g (0.15 mol,3 eq) of ground potassium carbonate and 60mL of acetonitrile are mixed, 10.8g (0.07 mol,1.4 eq) of diethyl sulfate is slowly dropped at 30-35 ℃, then the temperature is raised to 80-82 ℃ for reaction for 6 hours, the residual 2% of the raw materials are detected by HPLC, water and ethyl acetate are added at room temperature, the organic phase is separated, the organic phase is washed by water and saturated sodium chloride, anhydrous sodium sulfate is dried, the organic phase is concentrated to obtain 6.7g of 1-fluoro-3-ethoxybenzene, HPLC 93.7%, yield 96.0％.1HNMR(400MHz,CDCl3):7.71-7.68(m,1H),7.44-7.40(m,1H),7.14-7.10(m,1H),6.63-6.60(m,1H),4.02-3.99(m,2H),1.38-1.34(m,3H).
Under the protection of nitrogen, 5.6g (0.04 mol,1 eq) of 1-fluoro-3-ethoxybenzene are mixed with 50mL of dichloromethane, the temperature is reduced to 10 ℃, 7.1g (0.04 mol,1 eq) of NBS is added in portions, 3 percent of HPLC detection raw material is remained, ice water is added, sodium carbonate solid is added in portions to adjust pH=8-9 for layering, aqueous dichloromethane is used for extraction, organic phases are combined, the organic phase is washed with saturated sodium chloride, anhydrous sodium sulfate is dried, the organic phase is concentrated, HPLC 71 percent, column chromatography ethyl acetate/n-heptane=1/10 is used for eluting to obtain 5.3g of 1-bromo-2-fluoro-4-ethoxybenzene, the yield is improved 60.3％,HPLC 96.8％.1H NMR(400MHz,CDCl3):7.44-7.38(m,1H),6.91-6.87(m,1H),6.60-6.58(m,1H),4.01-3.98(m,2H),1.40-1.37(m,3H).
Example 3
5.6G (0.05 mol,1 eq) of 3-fluorophenol, 15.9g (0.115 mol,2.3 eq) of ground potassium carbonate and 60mL of acetonitrile are mixed, 8.7g (0.07 mol,1.4 eq) of 2-bromopropane are slowly dropped at 30-35 ℃, then the temperature is raised to 80-82 ℃ to react for 14 hours, the residual 2% of the raw materials are detected by HPLC, the temperature is lowered to room temperature, water and ethyl acetate are added, the organic phase is separated, the organic phase is washed by water and saturated sodium chloride, anhydrous sodium sulfate is dried, the organic phase is concentrated to obtain 7.5g of 1-fluoro-3-isopropoxyphenyl, HPLC 95.7 percent is obtained, the yield is improved 97.1％.1HNMR(400MHz,CDCl3):7.64-7.60(m,1H),7.40-7.35(m,1H),7.10-7.06(m,1H),6.59-6.55(m,1H),4.51-4.46(m,1H),1.37-1.33(m,6H).
5.6G (0.04 mol,1 eq) of 1-fluoro-3-isopropoxyphenyl are mixed with 50mL of dichloromethane under the protection of nitrogen, cooled to 10 ℃, 11.4g (0.04 mol,1 eq) of dibromohydantoin are added in portions, HPLC is carried out to detect the residual 2% of the raw material, ice water is added, sodium carbonate solid is added in portions to adjust the pH to be 9, the layers are separated, the aqueous phase is extracted by dichloromethane, the organic phases are combined, the organic phases are washed by water and saturated sodium chloride, anhydrous sodium sulfate is dried, then the organic phases are concentrated, HPLC 88% is carried out, and column chromatography ethyl acetate/n-heptane=1/10 is eluted to obtain 7.6g of 1-bromo-2-fluoro-4-isopropoxyphenyl with the yield 81.3％,HPLC98.1％.1HNMR(400MHz,CDCl3):7.44-7.32(m,1H),6.87-6.84(m,1H),6.58-6.55(m,1H),4.46-4.42(m,1H),1.33-1.29(m,6H).
Comparison of the protection test on hydroxyl:
Bromination reaction test comparative results:
the highest overall yield of isopropyl protection, lowest price and mild conditions can be determined through the table.
Example 4
15.4G (0.1 mol,1 eq) of 1-fluoro-3-isopropoxy benzene are mixed with 100ml of 1, 2-dichloroethane under nitrogen, the temperature is controlled between 0 and 10℃and 35.2g (0.099 mol,1 eq) of 90% pyridinium tribromide are added in portions, after the addition is complete, the reaction is carried out for 2 hours and HPLC detects 2% of the starting material remaining. Ice water was added, saturated aqueous sodium carbonate was added to adjust ph=9, the layers were separated, the aqueous phase was extracted with 1, 2-dichloroethane, the organic phases were combined, each washed once with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give 22.4g of 1-bromo-2-fluoro-4-isopropoxybenzene, HPLC91% and the next step was directly performed without purification.
15.4G (0.1 mol,1 eq) of 1-fluoro-3-isopropoxy benzene are mixed with 100mL of 1, 2-dichloroethane under nitrogen protection, the temperature is controlled to be 0 to 10 ℃, 49.2g (0.1 mol,1 eq) of 98% tetrabutylammonium tribromide per 50mL of dichloromethane are added dropwise, and after the addition, the reaction is carried out for 2 hours, and the raw material is detected to be 1% by HPLC. Ice water was added, saturated aqueous sodium carbonate was added to adjust ph=9, the layers were separated, the aqueous phase was extracted with 1, 2-dichloroethane, the organic phases were combined, each washed once with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give 23.1g of 1-bromo-2-fluoro-4-isopropoxybenzene, HPLC 95.2% and the next step was performed directly without purification.
Example 5
22.4G of 1-bromo-2-fluoro-4-isopropoxybenzene and 200mL of tetrahydrofuran are mixed under the protection of nitrogen, cooled to-5 ℃, and 2.0mol/L isopropyl magnesium chloride tetrahydrofuran solution 60mL is slowly added dropwise at the temperature of-5 ℃ to 0 ℃ under the control of the temperature, and then the temperature is raised to 5-10 ℃ for reaction for 1 hour. Cooling to-15 ℃, dropwise adding 20mL of tetrahydrofuran solution containing 9.5g of DMF, then slowly heating to room temperature for reaction for 2 hours, quenching with 2N hydrochloric acid, extracting with MTBE, combining organic phases, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating the organic phases, and then distilling under reduced pressure to obtain 17.2g of 2-fluoro-4-isopropoxybenzaldehyde with 91.2% of HPLC purity, wherein the 2-fluoro-4-isopropoxybenzaldehyde is directly used in the next step without purification.
Example 6
17.2G of the product of example 5, 2-fluoro-4-isopropoxybenzaldehyde and 200mL of methylene chloride are mixed under the protection of nitrogen, 49.2g of boron trichloride is introduced under the temperature of-15 ℃ to 0 ℃ and the temperature of-15 ℃ to-10 ℃ is controlled to react for 2 hours. Pouring ice water, adding sodium carbonate solid to adjust pH to be 6-7, then adding concentrated hydrochloric acid to adjust pH to be 1-2, carrying out obvious layering, extracting an aqueous phase with dichloromethane, carrying out saturated saline washing on an organic phase, drying with anhydrous sodium sulfate, concentrating, carrying out reduced pressure distillation to obtain 13.3g of crude 2-fluoro-4-hydroxybenzaldehyde, adding 80g of isopropyl ether, heating to 60-65 ℃ and recrystallizing to obtain 10.7g of 2-fluoro-4-hydroxybenzaldehyde, wherein the HPLC purity is 99.6%, and the yield 76.4％.ESI-MS:m/z＝139[M-H].1H NMR(400MHz,CDCl3):10.34(s,1H),9.45(s,1H),7.54-7.41(m,2H),6.88-6.85(m,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 (4)

1. The preparation method of the 2-fluoro-4-hydroxybenzaldehyde is characterized by comprising the following steps:
the first step: mixing 3-fluorophenol, potassium carbonate and 2-bromopropane in an organic solvent, and heating to react to obtain 1-fluoro-3-isopropoxy benzene;
And a second step of: dissolving 1-fluoro-3-isopropoxy benzene in an organic solvent, and reacting with a brominating reagent to obtain 1-bromo-2-fluoro-4-isopropoxy benzene; the organic solvent is selected from 1, 2-dichloroethane or dichloromethane; the brominating reagent is selected from tetrabutylammonium tribromide or pyridinium tribromide; the molar ratio of the 1-fluoro-3-isopropoxy benzene to the brominating reagent is 1:0.98-1.05;
And a third step of: dissolving 1-bromo-2-fluoro-4-isopropoxy benzene in tetrahydrofuran, dropwise adding isopropyl magnesium chloride/tetrahydrofuran solution at-10 ℃ to 0 ℃, and adding DMF (dimethyl formamide) for reaction after Grignard exchange to obtain 2-fluoro-4-isopropoxy benzaldehyde; the molar ratio of the 1-bromo-2-fluoro-4-isopropoxy benzene, the isopropyl magnesium chloride and the DMF is 1:1.15-1.20:1.25-1.35;
Fourth step: reacting 2-fluoro-4-isopropoxybenzaldehyde with boron trichloride, and recrystallizing isopropyl ether after deprotection to obtain 2-fluoro-4-hydroxybenzaldehyde.
2. The method for preparing 2-fluoro-4-hydroxybenzaldehyde according to claim 1, wherein: in the first step, the organic solvent is selected from acetonitrile, acetone, tetrahydrofuran or DMF.
3. The method for preparing 2-fluoro-4-hydroxybenzaldehyde according to claim 1, wherein: in the first step, the mole ratio of the 3-fluorophenol, the potassium carbonate and the 2-bromopropane is 1:1.80-2.30:1.20-1.40.
4. The method for preparing 2-fluoro-4-hydroxybenzaldehyde according to claim 1, wherein: in the fourth step, the molar ratio of the 2-fluoro-4-isopropoxybenzaldehyde to the boron trichloride is 1:2-5.5.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0352839A (en) * 1989-07-19 1991-03-07 Hokko Chem Ind Co Ltd Production of p-or m-tert-butoxybenzaldehyde
CN102574788A (en) * 2009-09-24 2012-07-11 弗·哈夫曼-拉罗切有限公司 Indole derivatives as crac modulators
CN105814046A (en) * 2013-12-09 2016-07-27 Ucb生物制药私人有限公司 Imidazopyridine derivatives as modulators of TNF activity
CN105859536A (en) * 2016-05-06 2016-08-17 蚌埠中实化学技术有限公司 Method for preparing 3, 4-difluorobenzaldehyde
WO2022051596A1 (en) * 2020-09-03 2022-03-10 Orexia Therapeutics Limited Bicyclic-heterocycle derivatives and their uses as orexin-2 receptor agonists
CN114671747A (en) * 2022-04-08 2022-06-28 浙江永太科技股份有限公司 Synthesis method of 4-chloro-2-fluorobenzaldehyde

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE488496T1 (en) * 2005-06-22 2010-12-15 Pfizer Prod Inc HISTAMINE 3 RECEPTOR ANTAGONISTS

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0352839A (en) * 1989-07-19 1991-03-07 Hokko Chem Ind Co Ltd Production of p-or m-tert-butoxybenzaldehyde
CN102574788A (en) * 2009-09-24 2012-07-11 弗·哈夫曼-拉罗切有限公司 Indole derivatives as crac modulators
CN105814046A (en) * 2013-12-09 2016-07-27 Ucb生物制药私人有限公司 Imidazopyridine derivatives as modulators of TNF activity
CN105859536A (en) * 2016-05-06 2016-08-17 蚌埠中实化学技术有限公司 Method for preparing 3, 4-difluorobenzaldehyde
WO2022051596A1 (en) * 2020-09-03 2022-03-10 Orexia Therapeutics Limited Bicyclic-heterocycle derivatives and their uses as orexin-2 receptor agonists
CN114671747A (en) * 2022-04-08 2022-06-28 浙江永太科技股份有限公司 Synthesis method of 4-chloro-2-fluorobenzaldehyde

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Asymmetric synthesis of fluorinated L-tyrosine and meta-L-tyrosines;Michel Monclus et al.;《Journal of Fluorine Chemistry》;19951231;第70卷;第40页 *
Design of an Electron-Withdrawing Benzonitrile Ligand for Ni-Catalyzed Cross-Coupling Involving Tertiary Nucleophiles;L. Reginald Mills et al.;《J. Am. Chem. Soc.》;20210701;第143卷;S11 *
Solvent-Controlled Leaving-Group Selectivity in Aromatic Nucleophilic Substitution;Lukas Hintermann et al.;《Org. Lett.》;20081009;第10卷(第21期);S3-S4 *

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