CN115124410A - Preparation method of 2-fluoro-4-hydroxybenzaldehyde - Google Patents
Preparation method of 2-fluoro-4-hydroxybenzaldehyde Download PDFInfo
- Publication number
- CN115124410A CN115124410A CN202210971692.9A CN202210971692A CN115124410A CN 115124410 A CN115124410 A CN 115124410A CN 202210971692 A CN202210971692 A CN 202210971692A CN 115124410 A CN115124410 A CN 115124410A
- Authority
- CN
- China
- Prior art keywords
- fluoro
- hydroxybenzaldehyde
- isopropoxybenzene
- producing
- dmf
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- ONRPXRPUBXXCCM-UHFFFAOYSA-N 2-fluoro-4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C(F)=C1 ONRPXRPUBXXCCM-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 14
- SJTBRFHBXDZMPS-UHFFFAOYSA-N 3-fluorophenol Chemical compound OC1=CC=CC(F)=C1 SJTBRFHBXDZMPS-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000005893 bromination reaction Methods 0.000 claims abstract description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 7
- 230000031709 bromination Effects 0.000 claims abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- AKLUAOGEXFDAFW-UHFFFAOYSA-N 1-bromo-2-fluoro-4-propan-2-yloxybenzene Chemical compound CC(C)OC1=CC=C(Br)C(F)=C1 AKLUAOGEXFDAFW-UHFFFAOYSA-N 0.000 claims description 10
- INDGWZOOYLDIPO-UHFFFAOYSA-N 1-fluoro-3-propan-2-yloxybenzene Chemical compound CC(C)OC1=CC=CC(F)=C1 INDGWZOOYLDIPO-UHFFFAOYSA-N 0.000 claims description 10
- RJOOMVDJWKWFDU-UHFFFAOYSA-N 2-fluoro-4-propan-2-yloxybenzaldehyde Chemical compound CC(C)OC1=CC=C(C=O)C(F)=C1 RJOOMVDJWKWFDU-UHFFFAOYSA-N 0.000 claims description 9
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 7
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical group ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 6
- NAMYKGVDVNBCFQ-UHFFFAOYSA-N 2-bromopropane Chemical compound CC(C)Br NAMYKGVDVNBCFQ-UHFFFAOYSA-N 0.000 claims description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- SFLXUZPXEWWQNH-UHFFFAOYSA-K tetrabutylazanium;tribromide Chemical group [Br-].[Br-].[Br-].CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC SFLXUZPXEWWQNH-UHFFFAOYSA-K 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- JQRYUMGHOUYJFW-UHFFFAOYSA-N pyridine;trihydrobromide Chemical compound [Br-].[Br-].[Br-].C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1.C1=CC=[NH+]C=C1 JQRYUMGHOUYJFW-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 2
- 239000002994 raw material Substances 0.000 abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 9
- 238000010511 deprotection reaction Methods 0.000 abstract description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 abstract description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 5
- 125000006239 protecting group Chemical group 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 4
- 238000012216 screening Methods 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 150000001299 aldehydes Chemical class 0.000 abstract description 3
- 239000007818 Grignard reagent Substances 0.000 abstract description 2
- 150000004795 grignard reagents Chemical group 0.000 abstract description 2
- 239000012074 organic phase Substances 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- 239000005457 ice water Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 229910052731 fluorine Inorganic materials 0.000 description 4
- 229940060037 fluorine Drugs 0.000 description 4
- 235000019000 fluorine Nutrition 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- UWWCZZMOTBWUAB-UHFFFAOYSA-N 1-ethoxy-3-fluorobenzene Chemical compound CCOC1=CC=CC(F)=C1 UWWCZZMOTBWUAB-UHFFFAOYSA-N 0.000 description 2
- MFJNOXOAIFNSBX-UHFFFAOYSA-N 1-fluoro-3-methoxybenzene Chemical compound COC1=CC=CC(F)=C1 MFJNOXOAIFNSBX-UHFFFAOYSA-N 0.000 description 2
- MENYRYNFSIBDQN-UHFFFAOYSA-N 5,5-dibromoimidazolidine-2,4-dione Chemical compound BrC1(Br)NC(=O)NC1=O MENYRYNFSIBDQN-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- XANVIFOBBVAKCY-UHFFFAOYSA-N 1-bromo-2-fluoro-4-methoxybenzene Chemical compound COC1=CC=C(Br)C(F)=C1 XANVIFOBBVAKCY-UHFFFAOYSA-N 0.000 description 1
- ZLECMIQMTYRKRG-UHFFFAOYSA-N 1-bromo-4-ethoxy-2-fluorobenzene Chemical compound CCOC1=CC=C(Br)C(F)=C1 ZLECMIQMTYRKRG-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229940123502 Hormone receptor antagonist Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000029828 Melanin-concentrating hormone receptor Human genes 0.000 description 1
- 108010047068 Melanin-concentrating hormone receptor Proteins 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- OZQXEOSNFMMMRD-UHFFFAOYSA-M [Cl-].CC(C)[Mg+].C1CCOC1 Chemical compound [Cl-].CC(C)[Mg+].C1CCOC1 OZQXEOSNFMMMRD-UHFFFAOYSA-M 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- DENRZWYUOJLTMF-UHFFFAOYSA-N diethyl sulfate Chemical compound CCOS(=O)(=O)OCC DENRZWYUOJLTMF-UHFFFAOYSA-N 0.000 description 1
- 229940008406 diethyl sulfate Drugs 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- RKSOPLXZQNSWAS-UHFFFAOYSA-N tert-butyl bromide Chemical compound CC(C)(C)Br RKSOPLXZQNSWAS-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
- C07C41/01—Preparation of ethers
- C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/004—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reaction with organometalhalides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic System
- C07F3/02—Magnesium compounds
-
- 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 discloses a preparation method of 2-fluoro-4-hydroxybenzaldehyde, belonging to the technical field of organic synthesis. Protecting hydroxyl by taking 3-fluorophenol as a raw material, then bromizing with a bromination reagent, then carrying out Grignard reagent exchange and DMF (dimethyl formamide) reaction to generate corresponding aldehyde, and finally carrying out deprotection and purification to obtain 2-fluoro-4-hydroxybenzaldehyde. The method has the advantages of easily obtained raw materials, low cost, mild and continuous reaction conditions, low requirement on equipment and high product purity of 99.5 percent, and optimizes the final process by screening different phenolic hydroxyl protecting groups and finally selecting isopropyl as the protecting group.
Description
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: 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 and the like, is a wide range of organic block compounds, and has a structure containing fluorine, aldehyde group and phenolic hydroxyl group which can be added or substituted for other functional groups.
At present, fluorine-containing medicines are developed most actively, and hundreds of products are commercialized or developed. The literature [ Bioorganic and Medicinal Chemistry Letters,2010,20, 153-; the literature [ RSC Advances,2016,6, 95177-; the synthesis of novel melanin concentrating hormone receptor antagonists via 2-fluoro-4-hydroxybenzaldehyde as an intermediate is described in the Journal of Medi ci-al Chemistry,2016,59, 2497-2511. WO2016/22742,2016, A1 also uses 2-fluoro-4-hydroxybenzaldehyde as intermediate to synthesize fused tricyclic imidazole-containing medicines.
However, the synthesis of 2-fluoro-4-hydroxybenzaldehyde is not limited, among them [ Journal of Fluo rine Chemistry,1995,70,39-44]The method adopts 3-fluorophenol and tert-butyldimethylsilyl chloride to react for protecting hydroxyl, then adopts sec-butyllithium to react with DMF after ultra-low temperature hydrogen extraction to generate aldehyde, and then obtains deprotection 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 used reagents are expensive, require ultralow temperature reaction, have high requirements on equipment and are not beneficial to large-scale production.
The general route is all protected with a 3-fluorophenol hydroxyl group followed by a butyllithium/DMF aldehyde group followed by deprotection to give 2-fluoro-4-hydroxybenzaldehyde. The method screens out the protective group which is low in price and easy to remove through experimental optimization, has moderate steric hindrance, is beneficial to fluorine ortho-position bromination, has mild and continuous reaction conditions, does not need ultralow temperature, has low requirements on equipment and high quality, is suitable for industrial production, and meets 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. Protecting hydroxyl by taking 3-fluorophenol as a raw material, then brominating with a bromination reagent, then carrying out Grignard reagent exchange to react with DMF to generate corresponding aldehyde, finally removing phenolic hydroxyl protection, and further purifying to obtain 2-fluoro-4-hydroxybenzaldehyde. The method has the advantages of easily obtained raw materials, low cost, mild and continuous reaction conditions, low requirement on equipment and high product purity of 99.5 percent, and optimizes the final process by screening different phenolic hydroxyl protecting groups and finally selecting isopropyl as the protecting group.
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 is as follows: mixing 3-fluorophenol, potassium carbonate and 2-bromopropane in an organic solvent, and heating to react with 1-fluoro-3-isopropoxybenzene;
the second step is that: dissolving 1-fluoro-3-isopropoxybenzene in an organic solvent, and reacting with a bromization reagent to obtain 1-bromo-2-fluoro-4-isopropoxybenzene;
the third step: dissolving 1-bromo-2-fluoro-4-isopropoxybenzene in tetrahydrofuran, dropwise adding an isopropyl magnesium chloride/tetrahydrofuran solution at-10 to 0 ℃, and adding DMF (dimethyl formamide) for reaction after Grignard exchange to obtain 2-fluoro-4-isopropoxybenzaldehyde;
the fourth step: reacting 2-fluoro-4-isopropoxybenzaldehyde with boron trichloride, and deprotecting to obtain 2-fluoro-4-hydroxybenzaldehyde.
Further, in the above technical solution, the organic solvent in the first step is selected from acetonitrile, acetone, tetrahydrofuran or DMF.
Further, in the 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 solution, the brominating reagent in the second step is selected from tetrabutyl ammonium tribromide or pyridinium tribromide.
Further, in the above technical solution, the organic solvent in the second step is selected from 1, 2-dichloroethane or dichloromethane.
Further, in the above technical scheme, the molar ratio of the 1-fluoro-3-isopropoxybenzene to the brominating agent in the second step is 1: 0.98-1.05.
Further, in the technical scheme, the molar ratio of the 1-bromo-2-fluoro-4-isopropoxybenzene, isopropyl magnesium chloride and DMF in the third step is 1: 1.15-1.20: 1.25-1.35.
Further, in the above technical solution, the molar ratio of the 2-fluoro-4-isopropoxybenzaldehyde to boron trichloride in the fourth step is 1: 2-5.5.
Advantageous effects of the invention
1. Through screening of phenolic hydroxyl protecting groups, bromination is carried out on protecting groups of methyl, ethyl, isopropyl, tert-butyl and THP (2-tetrahydropyran), the methyl and ethyl protecting groups have more isomers when being brominated, the tert-butyl protecting group has the least brominated isomer, but the tert-butyl bromide is expensive and is not easy to be protected, the THP is easy to be deprotected during the bromination reaction, and through screening of different bromination reagents, the bromination reaction of different phenolic hydroxyl protecting groups finds that dibromohydantoin, tetrabutyl ammonium tribromide or pyridinium tribromide has less isomers, and tetrabutyl ammonium tribromide is preferred. By deprotection with boron trichloride at low temperature, isomers can be recrystallized and purified. In conclusion, the price of the 2-bromopropane is relatively low, isomers are relatively few when the isopropyl protecting group is brominated, boron trichloride is adopted during deprotection, the conditions are more appropriate to heat, and the yield is higher.
2. Ultralow temperature reaction is avoided in the whole process, the reaction condition is mild, the intermediate does not need to be purified through the property analysis of impurities, and finally the obtained product has the purity of more than 99.5 percent through the recrystallization of isopropyl ether.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the present invention, one skilled in the art can make various changes and modifications to the invention, and these equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Example 1
5.6g (0.05mol,1eq) of 3-fluorophenol, 20.7g (0.15mol,3eq) of ground potassium carbonate and 60mL of acetonitrile are mixed, 8.8g (0.07mol,1.4eq) of dimethyl sulfate is slowly dropped at 30-35 ℃, then the temperature is raised to 80-82 ℃ for reaction for 4 hours, HPLC detects 2 percent of the raw material remained, water and ethyl acetate are added when the temperature is lowered to room temperature, an organic phase is separated, the organic phase is washed by 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%. 1 HNMR(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).
Under the protection of nitrogen, mixing 5.0g (0.04mol,1eq) of 1-fluoro-3-methoxybenzene with 50mL of dichloromethane, cooling to 10 ℃, slowly dropwise adding a solution containing 6.4g (0.04mol,1eq) of bromine/5 mL of dichloromethane, detecting the residual 3% of raw materials by HPLC, adding ice water, adding sodium carbonate solid in batches to adjust the pH to 8-9, carrying out layering, extracting an aqueous phase with dichloromethane, combining organic phases, washing the organic phases with water and saturated sodium chloride respectively, drying the organic phases by using anhydrous sodium sulfate, concentrating the organic phases, carrying out HPLC (high performance liquid chromatography), and carrying out column chromatography on ethyl acetate: n-heptane ═ 1: 10-1: 5 elution gave 3.7g of 1-bromo-2-fluoro-4-methoxybenzene in 44.9% yield, HPLC 97.3%. 1 HNMR(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 (0.05mol,1eq) of 3-fluorophenol, 20.7g (0.15mol,3eq) of ground potassium carbonate and 60mL of acetonitrile are mixed, 10.8g (0.07mol,1.4eq) of diethyl sulfate is slowly dropped at 30-35 ℃, then the temperature is increased to 80-82 ℃ for reaction for 6 hours, HPLC detects the residual 2 percent of raw materials, and the temperature is reduced to room temperatureWater and ethyl acetate were added to the reaction mixture, and the organic phase was separated, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give 6.7g of 1-fluoro-3-ethoxybenzene, HPLC 93.7%, yield 96.0%. 1 HNMR(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 (0.04mol,1eq) of 1-fluoro-3-ethoxybenzene is mixed with 50mL of dichloromethane, the temperature is reduced to 10 ℃, 7.1g (0.04mol,1eq) of NBS is added in batches, the residual 3 percent of raw materials is detected by HPLC, ice water is added, sodium carbonate solid is added in batches to adjust the pH value to be 8-9 for layering, dichloromethane in an aqueous phase is extracted, an organic phase is combined, the organic phase is washed by water and saturated sodium chloride, anhydrous sodium sulfate is dried, the organic phase is concentrated and is subjected to HPLC 71%, and column chromatography ethyl acetate/n-heptane 1/10 is eluted to obtain 5.3g of 1-bromo-2-fluoro-4-ethoxybenzene, the yield is 60.3 percent, and the HPLC is 96.8 percent. 1 H 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 (0.05mol,1eq) of 3-fluorophenol, 15.9g (0.115mol,2.3eq) of ground potassium carbonate and 60mL of acetonitrile are mixed, 8.7g (0.07mol,1.4eq) of 2-bromopropane is slowly dropped at 30-35 ℃, then the temperature is increased to 80-82 ℃ for reaction for 14 hours, HPLC detects the residual 2 percent of raw materials, water and ethyl acetate are added after the temperature is reduced to room temperature, an 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-isopropoxybenzene, the HPLC is 95.7 percent, and the yield is 97.1 percent. 1 HNMR(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).
Mixing 5.6g (0.04mol,1eq) of 1-fluoro-3-isopropoxybenzene with 50mL of dichloromethane under the protection of nitrogen, cooling to 10 ℃, adding 11.4g (0.04mol,1eq) of dibromohydantoin in batches, detecting the residual 2 percent of raw materials by HPLC, adding ice water, adding sodium carbonate in batches to adjust the pH to 9, demixing, and adding waterThe phases were extracted with dichloromethane, the organic phases were combined, washed with water and saturated sodium chloride, dried over anhydrous sodium sulfate, and then the organic phase was concentrated, HPLC 88%, column chromatography ethyl acetate/n-heptane ═ 1/10 to give 7.6g of 1-bromo-2-fluoro-4-isopropoxybenzene, yield 81.3%, HPLC 98.1%. 1 HNMR(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).
Comparative results of protection on hydroxyl test:
bromination reaction test comparison results:
the overall yield of isopropyl protection is determined to be the highest, the price is the lowest and the conditions are mild by the table.
Example 4
Under the protection of nitrogen, 15.4g (0.1mol,1eq) of 1-fluoro-3-isopropoxybenzene was mixed with 100mL of 1, 2-dichloroethane, the temperature was controlled to 0-10 ℃, 35.2g (0.099mol,1eq) of 90% pyridinium tribromide was added in portions, the addition was completed, the reaction was carried out for 2 hours, and HPLC detected that 2% of starting material remained. Adding ice water, adding saturated aqueous solution of sodium carbonate to adjust pH to 9, layering, extracting the aqueous phase with 1, 2-dichloroethane, combining the organic phases, washing the organic phase with water and saturated sodium chloride once respectively, drying over anhydrous sodium sulfate, concentrating the organic phase to obtain 22.4g of 1-bromo-2-fluoro-4-isopropoxybenzene, and carrying out HPLC 91% without purification.
Under the protection of nitrogen, 15.4g (0.1mol,1eq) of 1-fluoro-3-isopropoxybenzene is mixed with 100mL of 1, 2-dichloroethane, the temperature is controlled to be 0-10 ℃, 49.2g (0.1mol,1eq) of 98% tetrabutylammonium tribromide/50 mL of dichloromethane is added dropwise, the reaction is carried out for 2 hours after the addition is finished, and HPLC detects 1% of the raw material. Adding ice water, adding saturated aqueous solution of sodium carbonate to regulate pH to 9, demixing, extracting the aqueous phase with 1, 2-dichloroethane, combining the organic phases, washing the organic phase with water and saturated sodium chloride once respectively, drying over anhydrous sodium sulfate, concentrating the organic phase to obtain 23.1g of 1-bromo-2-fluoro-4-isopropoxybenzene, performing HPLC (high performance liquid chromatography) on 95.2%, and directly performing the next step without purification.
Example 5
Under the protection of nitrogen, 22.4g of 1-bromo-2-fluoro-4-isopropoxybenzene obtained in example 4 and 200mL of tetrahydrofuran are mixed, cooled to-5 ℃, and 60mL of 2.0mol/L isopropyl magnesium chloride tetrahydrofuran solution is slowly added dropwise while controlling the temperature to be-5 ℃ to 0 ℃, and then heated to 5-10 ℃ for reaction for 1 hour. The temperature is reduced to-15 ℃,20 mL of tetrahydrofuran solution containing 9.5g of DMF is added dropwise, then the temperature is slowly raised to room temperature for reaction for 2 hours, 2N hydrochloric acid is quenched, MTBE is extracted, organic phases are combined, washed by saturated sodium chloride, dried by anhydrous sodium sulfate, and concentrated and then distilled under reduced pressure to obtain 17.2g of 2-fluoro-4-isopropoxybenzaldehyde, the HPLC purity of which is 91.2 percent, and the 2-fluoro-4-isopropoxybenzaldehyde is directly used in the next step without purification.
Example 6
Under the protection of nitrogen, 17.2g of 2-fluoro-4-isopropoxybenzaldehyde obtained in example 5 and 200mL of dichloromethane were mixed, 49.2g of boron trichloride was introduced at-15 ℃ to 0 ℃ and the temperature was controlled to-15 ℃ to-10 ℃ to react for 2 hours. Pouring ice water into the mixture, adding sodium carbonate solid to adjust the pH value to be 6-7, then adding concentrated hydrochloric acid to adjust the pH value to be 1-2, obviously layering, extracting an aqueous phase by using dichloromethane, washing an organic phase by using saturated salt water, drying by using anhydrous sodium sulfate, concentrating, then carrying out reduced pressure distillation to obtain 13.3g of a crude product of the 2-fluoro-4-hydroxybenzaldehyde, adding 80g of isopropyl ether, heating to 60-65 ℃ for recrystallization to obtain 10.7g of 2-fluoro-4-hydroxybenzaldehyde, wherein the HPLC purity is 99.6%, and the yield is 76.4%. ESI-MS, M/z 139[ M-H ]]。 1 H NMR(400MHz,CDCl3):10.34(s,1H),9.45(s,1H),7.54-7.41(m,2H),6.88-6.85(m,1H).
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (8)
1. A preparation method of 2-fluoro-4-hydroxybenzaldehyde is characterized by comprising the following steps:
the first step is as follows: mixing 3-fluorophenol, potassium carbonate and 2-bromopropane in an organic solvent, and heating to react to obtain 1-fluoro-3-isopropoxybenzene;
the second step is that: dissolving 1-fluoro-3-isopropoxybenzene in an organic solvent, and reacting with a bromination reagent to obtain 1-bromo-2-fluoro-4-isopropoxybenzene;
the third step: dissolving 1-bromo-2-fluoro-4-isopropoxybenzene in tetrahydrofuran, dropwise adding an isopropyl magnesium chloride/tetrahydrofuran solution at-10 to 0 ℃, and adding DMF (dimethyl formamide) for reaction after Grignard exchange to obtain 2-fluoro-4-isopropoxybenzaldehyde;
the fourth step: reacting 2-fluoro-4-isopropoxybenzaldehyde with boron trichloride, and deprotecting to obtain 2-fluoro-4-hydroxybenzaldehyde.
2. The method for producing 2-fluoro-4-hydroxybenzaldehyde according to claim 1, characterized in that: in the first step, the organic solvent is selected from acetonitrile, acetone, tetrahydrofuran or DMF.
3. The method for producing 2-fluoro-4-hydroxybenzaldehyde according to claim 1, characterized in that: in the first step, the molar ratio of the 3-fluorophenol, the potassium carbonate and the 2-bromopropane is 1: 1.80-2.30: 1.20-1.40.
4. The process for producing 2-fluoro-4-hydroxybenzaldehyde according to claim 1, characterized in that: in the second step, the brominating agent is selected from tetrabutyl ammonium tribromide or pyridinium tribromide.
5. The process for producing 2-fluoro-4-hydroxybenzaldehyde according to claim 1, characterized in that: in the second step, the organic solvent is selected from 1, 2-dichloroethane or dichloromethane.
6. The process for producing 2-fluoro-4-hydroxybenzaldehyde according to claim 1, characterized in that: in the second step, the molar ratio of the 1-fluoro-3-isopropoxybenzene to the brominating agent is 1: 0.98-1.05.
7. The process for producing 2-fluoro-4-hydroxybenzaldehyde according to claim 1, characterized in that: in the third step, the molar ratio of the 1-bromo-2-fluoro-4-isopropoxybenzene, isopropyl magnesium chloride and DMF is 1: 1.15-1.20: 1.25-1.35.
8. The process for producing 2-fluoro-4-hydroxybenzaldehyde according to claim 1, characterized in that: in the fourth step, the molar ratio of the 2-fluoro-4-isopropoxybenzaldehyde to boron trichloride is 1: 2- -5.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210971692.9A CN115124410A (en) | 2022-08-13 | 2022-08-13 | Preparation method of 2-fluoro-4-hydroxybenzaldehyde |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210971692.9A CN115124410A (en) | 2022-08-13 | 2022-08-13 | Preparation method of 2-fluoro-4-hydroxybenzaldehyde |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115124410A true CN115124410A (en) | 2022-09-30 |
Family
ID=83386116
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210971692.9A Pending CN115124410A (en) | 2022-08-13 | 2022-08-13 | Preparation method of 2-fluoro-4-hydroxybenzaldehyde |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115124410A (en) |
Citations (7)
| 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 |
| US20090131433A1 (en) * | 2005-06-22 | 2009-05-21 | Pfizer Inc. | Histamine-3 receptor antagonists |
| 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 |
-
2022
- 2022-08-13 CN CN202210971692.9A patent/CN115124410A/en active Pending
Patent Citations (7)
| 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 |
| US20090131433A1 (en) * | 2005-06-22 | 2009-05-21 | Pfizer Inc. | Histamine-3 receptor antagonists |
| 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)
| Title |
|---|
| L. REGINALD MILLS ET AL.: "Design of an Electron-Withdrawing Benzonitrile Ligand for Ni-Catalyzed Cross-Coupling Involving Tertiary Nucleophiles", 《J. AM. CHEM. SOC.》, vol. 143, 1 July 2021 (2021-07-01), pages 11 * |
| LUKAS HINTERMANN ET AL.: "Solvent-Controlled Leaving-Group Selectivity in Aromatic Nucleophilic Substitution", 《ORG. LETT.》, vol. 10, no. 21, 9 October 2008 (2008-10-09), pages 3 * |
| MICHEL MONCLUS ET AL.: "Asymmetric synthesis of fluorinated L-tyrosine and meta-L-tyrosines", 《JOURNAL OF FLUORINE CHEMISTRY》, vol. 70, 31 December 1995 (1995-12-31), pages 40 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| FI80708C (en) | Process for selective methylation of derivatives of erythromycin A | |
| CN114524795B (en) | Improved rhodozyrtone preparation method | |
| CN115124410A (en) | Preparation method of 2-fluoro-4-hydroxybenzaldehyde | |
| US5130472A (en) | Total synthesis of erbstatin analogs | |
| CN114195712B (en) | Intermediate capable of being used for preparing procaterol hydrochloride and preparation method thereof | |
| CN114105872B (en) | Intermediate for preparing procaterol hydrochloride and preparation method thereof | |
| CN110845512B (en) | Total synthesis method of triterpenoid natural product (+) -Arisugacins F/G | |
| Ando et al. | The total syntheses of chamaecynone, isochamaecynone, and dihydroisochamaecynone. | |
| EP0089037B1 (en) | Process for preparing optically active (s)-2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran and salts thereof | |
| Matsumoto et al. | The total synthesis of (+)-totarol and (+)-podototarin. | |
| Piers et al. | Some substituted 9-phenylxanthen-9-yl protecting groups | |
| CN113387804B (en) | Synthesis method of alpha-asarone acetate and alpha-octanol | |
| US4495103A (en) | Preparation of optically active 4-demethoxydaunomycinone | |
| Gutzke et al. | Synthesis of quercetin-2-C14 | |
| JPS61152673A (en) | Production of dibenzo(b,e)oxepine derivative | |
| JPS595595B2 (en) | Method for producing 15-hydroxyimino-E-homoebrunane derivative | |
| KR19990015053A (en) | Method for preparing 2- (4-halomethylphenyl) propionic acid | |
| KR100448642B1 (en) | Method for producing phenyl propionic acid derivatives from 2-phenylpropionic acid by simple processing steps with high yield and purity | |
| US4417064A (en) | Biphenyl compounds and method of preparing same | |
| WO1998015516A1 (en) | Process for the preparation of a pharmaceutical intermediate | |
| KR100448640B1 (en) | Method for producing phenyl propionic acid derivatives with high yield and purity | |
| CN114539042A (en) | Novel synthesis process of 5-fluoro-2-hydroxyacetophenone | |
| JP3131056B2 (en) | Process for producing 2,3-dimethylnaphthalene and intermediates thereof | |
| WO2021058425A1 (en) | Method of making and/or isolating isoidide, comprising selective esterification of a mixture of dianhydrohexitol isomers | |
| CN117603167A (en) | Preparation method of high-purity D-ribonic lactone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |