CN114380682A - Synthesis method of 2, 3-difluoro-4-methoxyphenylacetic acid - Google Patents
Synthesis method of 2, 3-difluoro-4-methoxyphenylacetic acid Download PDFInfo
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- CN114380682A CN114380682A CN202111256622.7A CN202111256622A CN114380682A CN 114380682 A CN114380682 A CN 114380682A CN 202111256622 A CN202111256622 A CN 202111256622A CN 114380682 A CN114380682 A CN 114380682A
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- methoxyphenylacetic acid
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- BURJSULJPCCRLL-UHFFFAOYSA-N 2-(2,3-difluoro-4-methoxyphenyl)acetic acid Chemical compound COC1=CC=C(CC(O)=O)C(F)=C1F BURJSULJPCCRLL-UHFFFAOYSA-N 0.000 title claims abstract description 34
- 238000001308 synthesis method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 238000010189 synthetic method Methods 0.000 claims abstract description 11
- VZMFIPVRFWZDPI-UHFFFAOYSA-N 1-bromo-2,3-difluoro-4-methoxybenzene Chemical compound COC1=CC=C(Br)C(F)=C1F VZMFIPVRFWZDPI-UHFFFAOYSA-N 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 239000003513 alkali Substances 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 239000011259 mixed solution Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- -1 borane compound Chemical class 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 238000002156 mixing Methods 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 12
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 12
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- 229940125782 compound 2 Drugs 0.000 claims description 10
- 229940126214 compound 3 Drugs 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- 229940125904 compound 1 Drugs 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 229910000085 borane Inorganic materials 0.000 claims description 8
- 239000003054 catalyst Substances 0.000 claims description 8
- 229940117975 chromium trioxide Drugs 0.000 claims description 7
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 7
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 7
- 238000004440 column chromatography Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 7
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- KEXBLKHKABOPSR-UHFFFAOYSA-N [K]C=C.FB(F)F Chemical compound [K]C=C.FB(F)F KEXBLKHKABOPSR-UHFFFAOYSA-N 0.000 claims description 5
- 229910052786 argon Inorganic materials 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 230000000171 quenching effect Effects 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- WNTGVOIBBXFMLR-UHFFFAOYSA-N bicyclo[3.3.1]nonane Chemical compound C1CCC2CCCC1C2 WNTGVOIBBXFMLR-UHFFFAOYSA-N 0.000 claims description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- SORXVYYPMXPIFD-UHFFFAOYSA-N iron palladium Chemical compound [Fe].[Pd] SORXVYYPMXPIFD-UHFFFAOYSA-N 0.000 claims description 2
- 235000011056 potassium acetate Nutrition 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract description 8
- 238000003786 synthesis reaction Methods 0.000 abstract description 8
- 239000002994 raw material Substances 0.000 abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 abstract description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 3
- 230000009286 beneficial effect Effects 0.000 abstract description 3
- 230000003647 oxidation Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 abstract 2
- 229920002554 vinyl polymer Polymers 0.000 abstract 2
- 125000000524 functional group Chemical group 0.000 abstract 1
- 231100000086 high toxicity Toxicity 0.000 abstract 1
- 238000006197 hydroboration reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 238000006772 olefination reaction Methods 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract 1
- 239000000047 product Substances 0.000 description 8
- 230000000052 comparative effect Effects 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 231100000331 toxic Toxicity 0.000 description 5
- 230000002588 toxic effect Effects 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000007333 cyanation reaction Methods 0.000 description 4
- YWWZCHLUQSHMCL-UHFFFAOYSA-N diphenyl diselenide Chemical compound C=1C=CC=CC=1[Se][Se]C1=CC=CC=C1 YWWZCHLUQSHMCL-UHFFFAOYSA-N 0.000 description 4
- 238000005265 energy consumption Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 150000001336 alkenes Chemical class 0.000 description 3
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- SJFNDMHZXCUXSA-UHFFFAOYSA-M methoxymethyl(triphenyl)phosphanium;chloride Chemical compound [Cl-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(COC)C1=CC=CC=C1 SJFNDMHZXCUXSA-UHFFFAOYSA-M 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 150000003138 primary alcohols Chemical class 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- UBBBLLSKHCENQZ-UHFFFAOYSA-N 2,3-difluoro-4-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(F)=C1F UBBBLLSKHCENQZ-UHFFFAOYSA-N 0.000 description 1
- WGODSCYEKWDSAV-UHFFFAOYSA-N 2-(2-fluoro-4-methoxyphenyl)acetic acid Chemical compound COC1=CC=C(CC(O)=O)C(F)=C1 WGODSCYEKWDSAV-UHFFFAOYSA-N 0.000 description 1
- VURNBRZIFABCRU-UHFFFAOYSA-N 2-(3-fluoro-4-methoxyphenyl)acetic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1F VURNBRZIFABCRU-UHFFFAOYSA-N 0.000 description 1
- UNWQNFJBBWXFBG-UHFFFAOYSA-N 2-fluoro-4-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(F)=C1 UNWQNFJBBWXFBG-UHFFFAOYSA-N 0.000 description 1
- SOQCZBSZZLWDGU-UHFFFAOYSA-N 3-fluoro-4-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1F SOQCZBSZZLWDGU-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 206010037211 Psychomotor hyperactivity Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 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
- 201000011510 cancer Diseases 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
-
- 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
- C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of 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
- C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
Abstract
The invention discloses a synthetic method of 2, 3-difluoro-4-methoxyphenylacetic acid, and relates to the field of chemical industry. The synthesis method takes 4-bromo-2, 3-difluoroanisole which is easily obtained in the market as a raw material, introduces vinyl on a benzene ring, then carries out a functional group conversion strategy from the vinyl to an ethanol group and then to an acetate group, and prepares the 2, 3-difluoro-4-methoxyphenylacetic acid through three steps of olefination, hydroboration and oxidation; the synthesis method is simple and convenient to operate, good in stability, free of high-toxicity reagents, ideal in total yield of the route and high in industrial production potential; not only makes up for the vacancy reported in the synthesis of 2, 3-difluoro-4-methoxyphenylacetic acid in the prior art, but also is beneficial to the further popularization and application of the compound.
Description
Technical Field
The invention relates to the field of chemical industry, in particular to a synthetic method of 2, 3-difluoro-4-methoxyphenylacetic acid.
Background
2, 3-difluoro-4-methoxy phenylacetic acid is an important fluoro phenylacetic acid compound, can be used as a key intermediate, participates in the synthesis of drug compounds which can inhibit the overactivity or overexpression signal transduction pathway in cancer tissues and treat hyperproliferation, tumor diseases and the like, and is a drug molecular building block with higher utilization value.
With respect to the synthesis of 2, 3-difluoro-4-methoxyphenylacetic acid, there is no prior art report, which to some extent limits the use of this compound. The similar compound, 3-fluoro-4-methoxyphenylacetic acid, in the prior art, 3-fluoro-4-methoxybenzaldehyde is usually used as a raw material, sodium cyanide is used for cyanation, and then a target product is obtained through cyanohydrolysis, the sodium cyanide used in the method belongs to a highly toxic reagent, and not only seriously pollutes the surrounding environment in the using process, but also has great threat to the body health of experimenters (Prog Clin Biol Res,1989,291(1):357 and 360.). Preparing another similar compound, namely 2-fluoro-4-methoxyphenylacetic acid, by using fluoro-4-methoxybenzaldehyde as a raw material and performing chloroform treatment to obtain an intermediate 3,3, 3-trichloro-1- (2-fluoro-4-methoxyphenyl) propan-1-ol, and then performing conversion of an acetate group under the action of diphenyl diselenide to obtain a target compound (Chemmedchem,2011,6 (11)); although the yield of the method is ideal, the used diphenyl diselenide belongs to a highly toxic product, and the method also seriously threatens the health of experimenters and is not beneficial to industrial expanded production.
As described above, in the synthesis of similar compounds, the preparation of acetate groups is the key to the synthesis, and currently: 1) aldehyde aromatic hydrocarbon is taken as a raw material, and acetic acid groups are obtained through cyanation and hydrolysis of cyano groups; 2) the aldehyde aromatic hydrocarbon raw material is treated by chloroform and is converted into acetate under the action of diphenyl diselenide; wherein, the former cyanozation uses sodium cyanide as a reagent, although the conversion rate is high, the reagent belongs to a highly toxic product, can be poisoned and killed by inhaling a trace amount, and the use of the reagent is gradually limited; the diphenyl diselenide used by the reagent also belongs to a highly toxic reagent, and the reagent is not easy to realize large-scale production expansion, and has potential safety hazards in preparation of a small amount of products in a laboratory; therefore, an ideal synthesis method of aromatic acetoxy is lacked in the prior art.
Aiming at the defects of the synthesis method of 2, 3-difluoro-4-methoxyphenylacetic acid in the prior art and various defects in the synthesis of similar compounds in the prior art, the development of a synthesis route of 2, 3-difluoro-4-methoxyphenylacetic acid, which has the advantages of simple operation, ideal yield, low energy consumption and low cost of used reagents, is necessary.
Disclosure of Invention
The invention aims to provide a method for synthesizing 2, 3-difluoro-4-methoxyphenylacetic acid, which solves the problems in the background technology.
A synthetic method of 2, 3-difluoro-4-methoxyphenylacetic acid comprises the following steps of:
preferably, the compound 1 is 4-bromo-2, 3-difluoroanisole; the compound 4 is 2, 3-difluoro-4-methoxyphenylacetic acid.
Preferably, the synthesis method of the 2, 3-difluoro-4-methoxyphenylacetic acid comprises the following specific steps:
(1) dissolving a compound 1 in a first solvent at the temperature of 20-25 ℃, adding alkali 1 and vinyl potassium trifluoroborate, and adding a catalyst under the protection of argon to prepare a reaction solution; heating the reaction solution to 75 ℃ under the protection of argon, stirring at 300-400 rpm for reaction for 15h, concentrating to obtain a residue, dissolving the residue with water, extracting with ethyl acetate, separating, washing with saturated saline solution, drying with anhydrous magnesium sulfate, concentrating, mixing with a sample, and performing column chromatography to obtain a compound 2;
(2) dissolving the compound 2 in a second solvent at 0 ℃, dropwise adding a borane compound at 2-3 ml/min, and stirring at room temperature at 300-400 rpm for 3 hours to obtain a mixed solution; cooling the mixed solution to 0 ℃, respectively dripping the aqueous solution of alkali 2 and hydrogen peroxide into the mixed solution at a rate of 4-5 ml/min, and stirring and reacting at a temperature of 20-25 ℃ at a speed of 300-400 rpm for 12 hours; adjusting the temperature to 0 ℃, adding saturated sodium thiosulfate aqueous solution with the mass 3 times that of the mixed solution for quenching, extracting with ethyl acetate, concentrating, mixing with a sample, and passing through a column to obtain a compound 3;
(3) adding the compound 3 into a third solvent at the temperature of 20-25 ℃, sequentially adding chromium trioxide and periodic acid to prepare a reaction mixed solution, and stirring and reacting at the temperature of 0-5 ℃ at 300-400 rpm for 3 hours; adding water with the same mass as the reaction mixed solution, extracting with ethyl acetate, drying, concentrating, mixing with a sample, and passing through a column to obtain a target compound 4.
Preferably, in the step (1): the alkali 1 is one or more of triethylamine, cesium carbonate, potassium carbonate, sodium carbonate, potassium acetate and n-butylamine; the first solvent is one or more of tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane and toluene, and is mixed with water according to the mass ratio of 2: 1, mixing to obtain the product; the catalyst is one or more of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, tetrakis (triphenylphosphine) palladium, 1-bis (diphenylphosphino) dicyclopentadieny iron palladium dichloride and bis (triphenylphosphine) palladium dichloride.
Preferably, in the step (1): the ratio of the compound 1 to the first solvent is 7-15 mL/g; the mol ratio of the compound 1 to the vinyl potassium trifluoroborate, the alkali 1 and the catalyst is 1: (1.0-1.5): (2.0-3.5): (0.003-0.01).
Preferably, in the step (2): the borane compound is one or a mixture of diborane, borane tetrahydrofuran and 9-boron bicyclo [3.3.1] nonane; the second solvent is one or a mixture of tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether; the alkali 2 is one or a mixture of sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium carbonate.
Preferably, in the step (2): the ratio of the compound 2 to the second solvent is 3.5-5.0 mL/g; the aqueous solution of the alkali 2 is alkali liquor with the mass fraction of 8-15%; the molar ratio of the compound 2 to borane, alkali 2 and hydrogen peroxide is 1: (1.5-3.0): (3.0-8.5): (3.0-10.5).
Preferably, in the step (3): the third solvent is one or more of acetone, acetonitrile, dichloromethane, ethyl acetate and water, and is mixed with the water according to a mass ratio of 2: 1, mixing to obtain the product.
Preferably, in the step (3): the ratio of the compound 3 to the third solvent is 7-15 mL/g; the molar ratio of the compound 3 to the chromium trioxide and periodic acid is 1: (0.05-0.15): (2.0-3.0).
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a synthetic method of 2, 3-difluoro-4-methoxy phenylacetic acid, which adopts easily obtained 4-bromo-2, 3-difluoroanisole as a raw material, and is coupled with vinyl potassium trifluoroborate in the presence of alkali and a catalyst to realize the conversion from bromine to olefin, and then the conversion from hydrogen peroxide to ethanol is carried out under the action of borane, alkali and a catalyst to convert the olefin of hydrogen peroxide, and finally, under the catalysis of chromium trioxide, the 2, 3-difluoro-4-methoxy phenylacetic acid is obtained by periodate oxidation; the synthetic method has the advantages that the reagent used in the synthetic method is low in toxicity, strict dehydration is not required in the reaction, the operation is simpler, and the required energy consumption and manpower are lower; in the alcohol alkylation step, the alkene intermediate and borane generate alkyl boron, the reaction selectivity is high, few byproducts are generated, and then the alkyl boron reacts with hydrogen peroxide under an alkaline condition to obtain primary alcohol, the process follows the inverse Markov rule, the rearrangement phenomenon is avoided, and the purification is easier; in the oxidation step, under the catalysis of chromium trioxide, periodic acid can oxidize primary alcohol into carboxylic acid with high yield under mild reaction conditions, the reaction operation is simple and convenient, the used reagent is cheap and easy to obtain, and the high-temperature condition is not adopted, so that the control is easier.
Drawings
Figure 1 is a nuclear magnetic spectrum of compound 4.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention and the accompanying drawings of the specification, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the 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
A synthetic method of 2, 3-difluoro-4-methoxyphenylacetic acid comprises the following steps:
(1) potassium carbonate (103.65g, 750mmol, 2.5eq) and potassium vinyltrifluoroborate (48.22g, 360mmol, 1.2eq) were added sequentially to compound 1(66.8g, 300.97mmol, 1.0eq) in tetrahydrofuran (668mL) and H at 20 deg.C2O (334mL), then Pd (dppf) Cl is added under the protection of argon2.CH2Cl2(1.2g, 1.5mmol, 0.005eq) to prepare a reaction solution; stirring the reaction solution at 75 ℃ under the protection of argon at 350rpm for 15h, concentrating to obtain a residue, adding water (284mL) into the residue, extracting with ethyl acetate to obtain an organic phase, washing the organic phase with saturated saline water for 3 times, drying with anhydrous magnesium sulfate, concentrating, mixing the sample, and performing column chromatography to obtain 48.39g of compound 2;
(2) dropwise adding a 1M borane tetrahydrofuran solution (550mL, 550mmol, 2.1eq) into a tetrahydrofuran (220mL) solution of a compound 2(45.77g, 262mmol, 1.0eq) at 3mL/min at 0 ℃, and stirring at 350rpm for 3h at 20 ℃ to obtain a mixed solution; the mixture was cooled to 0 ℃ and 3M aqueous sodium hydroxide (700mL, 2100mmol, 8.0eq) and 30% H were added2O2(297mL, 2620mmol, 10.0eq) were added dropwise to the mixture at 4mL/min, followed by stirring at 350rpm for 12h at 20 ℃ and saturated sodium thiosulfate 3 times the mass of the mixture at 0 ℃ for 30min, followed by extraction with ethyl acetate, separation, concentration, sample stirring, and column chromatography to give 36.32g of Compound 3.
(3) Compound 3(17.13g, 87.73mmol, 1.0eq), acetonitrile (170mL) and water (85mL) were mixed at 20 ℃, then chromium trioxide (0.88g, 8.8mmol, 0.1eq) and periodic acid (50.01g, 219.33mmol, 2.5eq) were added, stirred at 0 ℃ for 3h, water (323mL) was added, and extracted with ethyl acetate and dried, concentrated to give a crude product, which was purified by column chromatography to give 15.84g of compound 4, i.e. 2, 3-difluoro-4-methoxyphenylacetic acid.
Comparative example 1
A synthetic method of 2, 3-difluoro-4-methoxyphenylacetic acid comprises the following steps:
(1) dropping a tetrahydrofuran (143mL) solution of potassium tert-butoxide (26g, 232mmol, 4.0eq) into a tetrahydrofuran (45mL) solution of p-toluenesulfonylmethylisocyanogen (22.65g, 116mmol, 2eq) at-78 ℃, stirring at 350rpm for 15min with maintaining the temperature, dropping a tetrahydrofuran (63mL) solution of compound 5(10g, 58mmol, 1eq) at 3mL/min, stirring at 350rpm for 1.5h with maintaining the temperature, then adding methanol (65mL), raising to reflux reaction for 0.5h, spin-drying the reaction solution, dissolving the residue in water (323mL), extracting with ethyl acetate, combining the organic phases, drying, mixing, and passing through a column to obtain 2.0g of compound 6.
(2) Adding the compound 6(2g, 8.7mmol, 1eq) into water (20ml), dropwise adding 4M NaOH aqueous solution (9ml, 34.8mmol, 4eq) at 1ml/min, and raising to reflux reaction for 2 h; the reaction solution was cooled, the reaction mixture was adjusted to pH 1 with 1M HCl solution, extracted with ethyl acetate, the organic phases combined and spin dried to give 1.26g of the title compound 4.
Comparative example 2
A synthetic method of 2, 3-difluoro-4-methoxyphenylacetic acid comprises the following steps:
(1) under the protection of nitrogen, (methoxymethyl) triphenyl phosphonium chloride (25.85g, 75.4mmol, 1.3eq) is dissolved in dry tetrahydrofuran (78ml), cooled to 0 ℃, 1.5ml/min is added with 1M tetrahydrofuran solution (75.4ml, 75.4mmol, 1.3eq) of lithium bis (trimethylsilyl) amide dropwise, the mixture is kept for reaction for 0.5h, 1.5ml/min is added with tetrahydrofuran solution (30ml) of compound 5(10g, 58mmol, 1eq) dropwise, the reaction is continued for 1h at 0 ℃ after the addition is finished, saturated ammonium chloride (170ml) is added for quenching, ethyl acetate extraction is carried out again, organic phases are combined, anhydrous sodium sulfate is dried, concentrated, sample mixed and column chromatography is carried out to obtain 8.93g of compound 7.
(2) At room temperature, under the protection of nitrogen, trimethylchlorosilane (3.2ml, 25mmol, 1eq) is added into an anhydrous acetonitrile (30ml) solution of a compound 7(5g, 25mmol, 1eq) and sodium iodide (4.3g, 28.5mmol, 1.14eq) to prepare a mixed solution, the mixed solution is stirred at 350rpm for 20min at room temperature, a saturated sodium thiosulfate aqueous solution with the mass 3 times that of the mixed solution is added, ethyl acetate is used for extraction, organic phases are combined, anhydrous sodium sulfate is dried, concentrated, stirred and subjected to column chromatography, and the target compound 8 cannot be obtained.
Examples of effects
The following table 1 shows the results of analysis using the compounds of examples 1 and 2 of the present invention and comparative examples 1 and 2.
TABLE 1
Comparative example 1 preparation of Compound 6 by cyanation of p-toluenesulfonylmethyl isonitrile with 2, 3-difluoro-4-methoxybenzaldehyde as the starting Material and subsequent hydrolysis to prepare 2, 3-difluoro-4-methoxyphenylacetic acid and cyanation with p-toluenesulfonylmethyl isonitrile to prepare Compound 6, which avoids the use of highly toxic reagents but requires reaction at-78 deg.C, is complicated in operation and high in energy consumption, and more importantly, in the preparation of Compound 6, the ring-closing by-product is obtained
The reaction yield is only 15%, and the product is difficult to purify.
In comparative example 2, (methoxymethyl) triphenyl phosphonium chloride is used for the witting reaction, the yield of the prepared intermediate 7 is ideal, but the stability of the intermediate 8 is extremely poor, the product cannot be separated, and the synthesis of the target compound is difficult to continue.
Comparing example 1 with comparative examples 1 and 2, it can be clearly found that the reagents used in the process of synthesizing 2, 3-difluoro-4-methoxyphenylacetic acid in the present application are low in toxicity, simple and convenient to operate, ideal in yield, free from strict dehydration in the reaction, high in reaction activity, low in required energy consumption, not adopting high temperature conditions, easier to control, and more potential for industrial scale production.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Claims (9)
1. A synthetic method of 2, 3-difluoro-4-methoxyphenylacetic acid is characterized in that the synthetic method of the 2, 3-difluoro-4-methoxyphenylacetic acid comprises the following steps of:
2. the method for synthesizing 2, 3-difluoro-4-methoxyphenylacetic acid as claimed in claim 1, wherein compound 1 is 4-bromo-2, 3-difluoroanisole; the compound 4 is 2, 3-difluoro-4-methoxyphenylacetic acid.
3. The method for synthesizing 2, 3-difluoro-4-methoxyphenylacetic acid as claimed in claim 2, wherein the method for synthesizing 2, 3-difluoro-4-methoxyphenylacetic acid comprises the following steps:
(1) dissolving a compound 1 in a first solvent at the temperature of 20-25 ℃, adding alkali 1 and vinyl potassium trifluoroborate, and adding a catalyst under the protection of argon to prepare a reaction solution; heating the reaction solution to 75 ℃ under the protection of argon, stirring at 300-400 rpm for reaction for 15h, concentrating to obtain a residue, dissolving the residue with water, extracting with ethyl acetate, separating, washing with saturated saline solution, drying with anhydrous magnesium sulfate, concentrating, mixing with a sample, and performing column chromatography to obtain a compound 2;
(2) dissolving the compound 2 in a second solvent at 0 ℃, dropwise adding a borane compound at 2-3 ml/min, and stirring at room temperature at 300-400 rpm for 3 hours to obtain a mixed solution; cooling the mixed solution to 0 ℃, respectively dripping the aqueous solution of alkali 2 and hydrogen peroxide into the mixed solution at a rate of 4-5 ml/min, and stirring and reacting at a temperature of 20-25 ℃ at a speed of 300-400 rpm for 12 hours; adjusting the temperature to 0 ℃, adding saturated sodium thiosulfate aqueous solution with the mass 3 times that of the mixed solution for quenching, extracting with ethyl acetate, concentrating, mixing with a sample, and passing through a column to obtain a compound 3;
(3) adding the compound 3 into a third solvent at the temperature of 20-25 ℃, sequentially adding chromium trioxide and periodic acid to prepare a reaction mixed solution, and stirring and reacting at the temperature of 0-5 ℃ at 300-400 rpm for 3 hours; adding water with the same mass as the reaction mixed solution, extracting with ethyl acetate, drying, concentrating, mixing with a sample, and passing through a column to obtain a target compound 4.
4. The method for synthesizing 2, 3-difluoro-4-methoxyphenylacetic acid as claimed in claim 3, wherein in step (1): the alkali 1 is one or more of triethylamine, cesium carbonate, potassium carbonate, sodium carbonate, potassium acetate and n-butylamine; the first solvent is one or more of tetrahydrofuran, N-dimethylformamide, dimethyl sulfoxide, 1, 4-dioxane and toluene, and is mixed with water according to the mass ratio of 2: 1, mixing to obtain the product; the catalyst is one or more of [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, tetrakis (triphenylphosphine) palladium, 1-bis (diphenylphosphino) dicyclopentadieny iron palladium dichloride and bis (triphenylphosphine) palladium dichloride.
5. The method for synthesizing 2, 3-difluoro-4-methoxyphenylacetic acid as claimed in claim 3, wherein in step (1): the ratio of the compound 1 to the first solvent is 7-15 mL/g; the mol ratio of the compound 1 to the vinyl potassium trifluoroborate, the alkali 1 and the catalyst is 1: (1.0-1.5): (2.0-3.5): (0.003-0.01).
6. The method for synthesizing 2, 3-difluoro-4-methoxyphenylacetic acid as claimed in claim 3, wherein in step (2): the borane compound is one or a mixture of diborane, borane tetrahydrofuran and 9-boron bicyclo [3.3.1] nonane; the second solvent is one or a mixture of tetrahydrofuran, diethyl ether and ethylene glycol dimethyl ether; the alkali 2 is one or a mixture of sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium carbonate.
7. The method for synthesizing 2, 3-difluoro-4-methoxyphenylacetic acid as claimed in claim 3, wherein in step (2): the ratio of the compound 2 to the second solvent is 3.5-5.0 mL/g; the aqueous solution of the alkali 2 is alkali liquor with the mass fraction of 8-15%; the molar ratio of the compound 2 to borane, alkali 2 and hydrogen peroxide is 1: (1.5-3.0): (3.0-8.5): (3.0-10.5).
8. The method for synthesizing 2, 3-difluoro-4-methoxyphenylacetic acid as claimed in claim 3, wherein in step (3): the third solvent is one or more of acetone, acetonitrile, dichloromethane, ethyl acetate and water, and is mixed with the water according to a mass ratio of 2: 1, mixing to obtain the product.
9. The method for synthesizing 2, 3-difluoro-4-methoxyphenylacetic acid as claimed in claim 3, wherein in step (3): the ratio of the compound 3 to the third solvent is 7-15 mL/g;
the molar ratio of the compound 3 to the chromium trioxide and periodic acid is 1: (0.05-0.15): (2.0-3.0).
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