CN115784896A - Preparation method of 2-bromo-6-fluoroaniline - Google Patents
Preparation method of 2-bromo-6-fluoroaniline Download PDFInfo
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- CN115784896A CN115784896A CN202211479105.0A CN202211479105A CN115784896A CN 115784896 A CN115784896 A CN 115784896A CN 202211479105 A CN202211479105 A CN 202211479105A CN 115784896 A CN115784896 A CN 115784896A
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- fluoroaniline
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- ALZFPYUPNVLVQM-UHFFFAOYSA-N 2-bromo-6-fluoroaniline Chemical compound NC1=C(F)C=CC=C1Br ALZFPYUPNVLVQM-UHFFFAOYSA-N 0.000 title claims abstract description 44
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 12
- 238000005893 bromination reaction Methods 0.000 claims abstract description 10
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 229940124530 sulfonamide Drugs 0.000 claims abstract description 6
- 150000003456 sulfonamides Chemical class 0.000 claims abstract description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims abstract description 6
- 238000007112 amidation reaction Methods 0.000 claims abstract description 5
- 230000009435 amidation Effects 0.000 claims abstract description 3
- 125000003277 amino group Chemical group 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- 230000006103 sulfonylation Effects 0.000 claims abstract description 3
- 238000005694 sulfonylation reaction Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 69
- 238000006243 chemical reaction Methods 0.000 claims description 34
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 22
- -1 t-butyloxycarbonyl (-Boc) Chemical class 0.000 claims description 22
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 19
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 11
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 10
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 claims description 6
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-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
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 238000006136 alcoholysis reaction Methods 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 4
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 238000007098 aminolysis reaction Methods 0.000 claims description 3
- 230000031709 bromination Effects 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 125000006242 amine protecting group Chemical group 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 229940043279 diisopropylamine Drugs 0.000 claims description 2
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 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 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 238000006277 sulfonation reaction Methods 0.000 claims 2
- 238000005915 ammonolysis reaction Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 34
- 239000012535 impurity Substances 0.000 abstract description 7
- 239000002360 explosive Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 231100000481 chemical toxicant Toxicity 0.000 abstract description 2
- 239000003440 toxic substance Substances 0.000 abstract description 2
- 238000004809 thin layer chromatography Methods 0.000 description 25
- 238000012544 monitoring process Methods 0.000 description 24
- 238000003756 stirring Methods 0.000 description 24
- 238000001816 cooling Methods 0.000 description 23
- 238000010438 heat treatment Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 17
- 238000001035 drying Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 6
- 235000011114 ammonium hydroxide Nutrition 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 5
- 239000012346 acetyl chloride Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000001569 carbon dioxide Substances 0.000 description 5
- 229910002092 carbon dioxide Inorganic materials 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 241000701022 Cytomegalovirus Species 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 230000001376 precipitating effect Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 3
- MDAZJVAIZVUWDE-UHFFFAOYSA-N 2-bromo-6-fluorobenzoic acid Chemical compound OC(=O)C1=C(F)C=CC=C1Br MDAZJVAIZVUWDE-UHFFFAOYSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 230000000735 allogeneic effect Effects 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
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229940125507 complex inhibitor Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000011134 hematopoietic stem cell transplantation Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of organic synthesis, and discloses a preparation method of 2-bromo-6-fluoroaniline, which comprises the following steps: s1, protecting the amino group of o-fluoroaniline to obtain an intermediate 1; s2, carrying out sulfonylation and amidation/esterification reactions on the intermediate 1 to obtain an intermediate 2; s3, performing bromination reaction on the intermediate 2 to obtain an intermediate 3; s4, removing sulfonamide/sulfonate from the intermediate 3 to obtain a target product 2-bromo-6-fluoroaniline, improving a synthesis route, using cheap and easily obtained o-fluoroaniline as a raw material, ingeniously utilizing the sulfonamide/sulfonate to replace amino para-position, and avoiding the generation of para-position impurities during bromination reaction, so that the 2-bromo-6-fluoroaniline is efficiently synthesized, improving the synthesis route, using cheap and easily obtained raw materials and solvents, avoiding the use of explosive and highly toxic chemical raw materials, and having the advantages of high product yield and purity, safe, simple and convenient operation, novel route and suitability for industrial production.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of 2-bromo-6-fluoroaniline.
Background
The 2-bromo-6-fluoroaniline is an important medical synthetic intermediate, it is one of the important synthetic raw materials of Letelmovir, this kind of medicine is a CMV DNA terminating enzyme complex inhibitor, is suitable for preventing Cytomegalovirus (CMV) infection and adult CMV seropositive receptor [ R + ] allogeneic Hematopoietic Stem Cell Transplantation (HSCT).
The literature reports that there are two main methods for synthesizing 2-bromo-6-fluoroaniline:
route 1: taking 2-bromo-6-fluorobenzoic acid as an initial raw material, acidifying by concentrated sulfuric acid, reacting with sodium azide, and quenching by ammonia water to obtain the 2-bromo-6-fluoroaniline. The raw material of the route, namely the 2-bromo-6-fluorobenzoic acid, is not easy to obtain and has high price, and the sodium azide is an explosive product and is not beneficial to large-scale industrial production.
Route 1
Route 2: o-fluoroaniline is used as an initial raw material, and bromization reagents such as bromine, hydrobromic acid, sodium bromide and the like are used for bromination respectively, but the product yield is low, the purification is difficult and no actual production value exists due to the selectivity problem of ortho-position and para-position.
Route 2.
Disclosure of Invention
Technical problem to be solved
Aiming at the defects of the prior art, the invention provides a preparation method of 2-bromo-6-fluoroaniline, which solves the problems in the background technology.
(II) technical scheme
In order to achieve the purpose, the invention provides the following technical scheme: a preparation method of 2-bromo-6-fluoroaniline comprises the following steps:
s1, protecting the amino group of o-fluoroaniline to obtain an intermediate 1;
s2, carrying out sulfonylation and amidation/esterification reactions on the intermediate 1 to obtain an intermediate 2;
s3, carrying out bromination reaction on the intermediate 2 to obtain an intermediate 3;
s4, removing sulfonamide/sulfonate from the intermediate 3 to obtain the target product 2-bromo-6-fluoroaniline.
Preferably, the synthesis of intermediate 1 in S1: carrying out amidation reaction on o-fluoroaniline and different amino protecting groups to obtain an intermediate 1.
Wherein the structure of the intermediate 1 is as follows:
in the above formula, R1 is various types of amino protecting groups, such as acetyl (-Ac), t-butyloxycarbonyl (-Boc), benzyloxycarbonyl (-Cbz), p-toluenesulfonyl (-Tos), and the like.
Preferably, the synthesis of intermediate 2 in S2: the intermediate 1 obtained is reacted with a sulphonation reagent and then reacted with an amine/alcohol to obtain an intermediate 2.
Wherein the structural formula of the intermediate 2 is as follows:
in the above formula, R1 is different types of amino protecting groups, such as acetyl (-Ac), tert-butyloxycarbonyl (-Boc), benzyloxycarbonyl (-Cbz), p-toluenesulfonyl (-Tos), etc.; r2 is substituent of different types of amino or alcohol, such as-NH 2, -NMe2, -NEt2, -OH, -OMe, -OEt, etc.
Preferably, the synthesis of intermediate 3 in S3: and carrying out bromination reaction on the obtained intermediate 2 and a bromination reagent to obtain an intermediate 3.
Wherein the structural formula of the intermediate 3 is as follows:
in the above formula, R2 is different types of amino or alcohol substituent, such as-NH 2, -NMe2, -NEt2, -OH, -OMe, -OEt, etc.
Preferably, the synthesis of 2-bromo-6-fluoroaniline: the obtained intermediate 3 is subjected to sulfamide/sulfonic acid ester removal under acidic conditions to obtain a target product 2-bromo-6-fluoroaniline,
wherein the structural formula of the 2-bromo-6-fluoroaniline is:
the above reaction process is shown as the following formula:
preferably, the amine protecting group described in S1 may be selected from one of the following: acetyl (-Ac), tert-butoxycarbonyl (-Boc), benzyloxycarbonyl (-Cbz), p-toluenesulfonyl (-Tos), preferably acetyl (-Ac), and the acid-binding agent described in S1 may be selected from one of the following: triethylamine, diethylamine, diisopropylamine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc., preferably triethylamine, and the solvent described in S1 may be selected from one of the following: dichloromethane, dichloroethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, N-dimethylformamide and the like, preferably dichloromethane, wherein the molar ratio of the o-fluoroaniline, the amino protecting group and the acid-binding agent in S1 is 1.0:1.0 to 2.0:1.0 to 2.0, preferably: 1.0: 1.05-1.25, and the reaction temperature in S1 is 0-50 ℃, preferably 0-20 ℃.
Preferably, the sulfonating agent in S2 may be selected from one of the following: chlorosulfonic acid, sulfur dioxide plus chlorine, and the like, preferably chlorosulfonic acid, and the aminolysis/alcoholysis reagent in S2 may be selected from one of the following: ammonia, diethylamine, water, methanol, ethanol, etc., preferably ammonia, the solvent described in S2 may be selected from one of the following: dichloromethane, dichloroethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, N-dimethylformamide and the like, preferably dichloromethane, wherein the molar ratio of the intermediate 1, the sulfonating agent, the aminolysis/alcoholysis agent in S2 is 1.0: 1.0-5.0:1.0 to 10.0, preferably: 1.0: 3.0-3.5: 5.0-10.0, and the reaction temperature in S2 is 0-90 ℃, preferably 0-70 ℃.
Preferably, the brominating agent in S3 may be selected from one of the following: elemental bromine, a hydrogen bromide/hydrogen peroxide system, pyridinium tribromide (PBP), phosphorus tribromide, etc., preferably a hydrogen bromide/hydrogen peroxide system, and the molar ratio of the intermediate 2, the brominating agent, and hydrogen peroxide in S3 is 1.0: 1.0-8.0:1.0 to 1.5, preferably: 1.0: 5.0-6.0: 1.0-1.1, and the reaction temperature in S3 is 0-100 ℃, preferably 60-80 ℃.
Preferably, the acid in S4 is a mixed system of one or more of sulfuric acid, hydrochloric acid, methanesulfonic acid, trifluoroacetic acid and nitric acid, preferably sulfuric acid, the molar ratio of the intermediate 3 to the acid in S4 is 1.0 to 10.0, preferably 1.0 to 6.0, and the temperature in S4 is 0 to 200 ℃, preferably 150 to 180 ℃.
Compared with the prior art, the invention provides a preparation method of 2-bromo-6-fluoroaniline, which has the following beneficial effects:
1. by improving the synthesis route, cheap and easily-obtained o-fluoroaniline is used as a raw material, and the para-amino is ingeniously substituted by sulfonamide/sulfonate to avoid the generation of para-impurities during bromination reaction, so that the 2-bromo-6-fluoroaniline is efficiently synthesized;
2. by improving the synthesis route, the used raw materials and solvents are cheap and easy to obtain, the use of explosive dangerous and highly toxic chemical raw materials is avoided, the product yield and purity are high, the operation is safe and simple, the route is novel, and the method is suitable for industrial production.
Detailed Description
The first embodiment is as follows:
a preparation method of 2-bromo-6-fluoroaniline comprises the following steps:
preparation of intermediate 1:
adding 100g of o-fluoroaniline and 100g of triethylamine into 300ml of dichloromethane for dissolving, cooling to 0-5 ℃, controlling the temperature (less than or equal to 20 ℃) and dropwise adding 77.6g of acetyl chloride, stirring for 3-5 hours at room temperature, monitoring by TLC (thin layer chromatography) for less than or equal to 1% of raw materials, adding 200ml of water into a system, stirring, separating, washing an organic phase by saturated saline, drying by anhydrous sodium sulfate, and directly putting the filtered organic phase into the next step;
preparation of intermediate 2:
cooling the reaction solution to 0-5 ℃, controlling the temperature (less than or equal to 20 ℃) and dropwise adding 524g of chlorosulfonic acid, heating the reaction system to 70 ℃ (carbon dioxide in the system is evaporated and recycled for reaction for 5-8 hours after dropwise adding is finished, monitoring the raw material by TLC (thin layer chromatography) to be less than or equal to 1%, carrying away the residual chlorosulfonic acid in the system by reduced pressure distillation, controlling the temperature (less than or equal to 20 ℃) and dropwise adding the obtained oily substance into 200ml of ammonia water solution (pH = 12-13), heating the reaction system to 70-75 ℃ after dropwise adding is finished, reacting for 3-5 hours, monitoring the raw material by TLC to be less than or equal to 1%, cooling to 0-5 ℃, dropwise adding 5% hydrochloric acid to adjust the pH =4-5, precipitating a large amount of solid in the system, filtering, drying to obtain 152g of solid, and purity: 98.3%, yield: 72.7 percent;
preparation of intermediate 3:
adding 150g of the intermediate 2 into 500ml of hydrobromic acid aqueous solution, heating to 70-75 ℃, stirring to be clear (1-3 hours), slowly dropwise adding 76g of 30% hydrogen peroxide, stirring at 70-75 ℃ for 5-8 hours, monitoring by TLC that the raw material is less than or equal to 1%, cooling the system to 10-20 ℃, filtering, and drying to obtain 137g of solid with purity: 99.1%, yield: 78.8 percent;
preparation of 2-bromo-6-fluoroaniline:
adding 100g of the intermediate 3 into 300ml of 80% sulfuric acid solution, heating to 160 ℃, stirring for 3-5 hours, monitoring by TLC that the raw material is less than or equal to 1%, cooling the system to 10-20 ℃, pouring the reaction system into 900g of crushed ice, adding 250ml of 2 dichloromethane into the water phase for extraction, combining organic phases, distilling under normal pressure to remove dichloromethane, and distilling under reduced pressure to obtain 56g of 2-bromo-6-fluoroaniline, wherein the yield is as follows: 79.3 percent; purity: 99.6 percent and less than 0.1 percent of single impurity.
Example two:
a preparation method of 2-bromo-6-fluoroaniline comprises the following steps:
preparation of intermediate 1:
250kg of o-fluoroaniline and 250kg of triethylamine are added into 900kg of dichloromethane to be dissolved, and the temperature is reduced to 0-5 ℃. 194kg of acetyl chloride is added dropwise at the controlled temperature (less than or equal to 20 ℃), the mixture is stirred for 5 to 8 hours at room temperature, and the raw materials are monitored by TLC to be less than or equal to 1 percent. Adding 500kg of water into the system, stirring, separating liquid, washing an organic phase by saturated saline, drying by anhydrous sodium sulfate, and directly putting the filtered organic phase into the next step;
preparation of intermediate 2:
cooling the reaction solution to 0-5 ℃, controlling the temperature (less than or equal to 20 ℃) and dropwise adding 1300kg of chlorosulfonic acid, heating the reaction system to 70 ℃ (carbon dioxide in the system is evaporated and recycled for use) after the dropwise adding is finished, reacting for 8-12 hours, and monitoring the raw materials by TLC (thin layer chromatography) to be less than or equal to 1%. Carrying out reduced pressure distillation to remove the residual chlorosulfonic acid in the system, controlling the temperature (less than or equal to 20 ℃) to dropwise add the obtained oily matter into 500kg of ammonia water solution (the pH of the system is = 12-13), heating the reaction system to 70-75 ℃ after the dropwise addition is finished, reacting for 3-5 hours, and monitoring by TLC (thin layer chromatography) to ensure that the raw material is less than or equal to 1%. Cooling to 0-5 ℃, dropwise adding 5% hydrochloric acid to adjust the pH of the system to be =4-5, separating out a large amount of solids in the system, and filtering. After drying, 381kg of solid is obtained, purity: 98.6%, yield: 73.4 percent;
preparation of intermediate 3:
adding 300kg of the intermediate 2 into 1000kg of hydrobromic acid aqueous solution, heating to 70-75 ℃, stirring until the solution is clear (1-3 hours), and slowly dropwise adding 152kg of 30% hydrogen peroxide. Stirring at 70-75 deg.C for 5-8 hr, and monitoring by TLC to obtain raw material less than or equal to 1%. The temperature of the system is reduced to 10-20 ℃, and after filtration and drying, 287kg of solid with the purity: 99.3%, yield: 82.5 percent;
preparation of 2-bromo-6-fluoroaniline:
adding 250kg of the intermediate 3 into 750kg of 80% sulfuric acid solution, heating to 160 ℃, stirring for 3-5 hours, and monitoring by TLC to enable the raw material to be less than or equal to 1%. Cooling the system to 10-20 ℃, pouring the reaction system into 2300kg of crushed ice, adding 700kg of methylene chloride to the water phase for extraction, combining the organic phases, distilling the organic phases at normal pressure to remove the methylene chloride, and then distilling the organic phases at reduced pressure to obtain 149kg of 2-bromo-6-fluoroaniline, wherein the yield is as follows: 84.4 percent; purity: 99.6 percent and less than 0.1 percent of single impurity.
Example three:
a preparation method of 2-bromo-6-fluoroaniline comprises the following steps:
preparation of intermediate 1:
adding 100g of o-fluoroaniline and 100g of triethylamine into 150ml of dichloromethane for dissolving, cooling to 0-5 ℃, controlling the temperature (less than or equal to 20 ℃) and dropwise adding 55.5g of acetyl chloride, stirring for 1-2 hours at room temperature, monitoring by TLC (thin layer chromatography) for less than or equal to 1%, adding 100ml of water into a system, stirring, separating, washing an organic phase by saturated saline, drying by anhydrous sodium sulfate, and directly putting the filtered organic phase into the next step;
preparation of intermediate 2:
cooling the reaction solution to 0-5 ℃, controlling the temperature (less than or equal to 20 ℃) to be dropwise added with 252g of chlorosulfonic acid, heating the reaction system to 70 ℃ (carbon dioxide in the system is evaporated and recycled for reaction for 1-4 hours after dropwise addition, monitoring the raw material by TLC (thin layer chromatography) to be less than or equal to 1%, carrying away the residual chlorosulfonic acid in the system by reduced pressure distillation, controlling the temperature (less than or equal to 20 ℃) to be dropwise added with the obtained oily substance into 100ml of ammonia water solution (pH = 12-13), heating the reaction system to 70-75 ℃ after dropwise addition, reacting for 3-5 hours, monitoring the raw material by TLC to be less than or equal to 1%, cooling to 0-5 ℃, dropwise adding 5% of hydrochloric acid to adjust the pH =4-5, precipitating a large amount of solid in the system, filtering, drying to obtain 80g of solid, and having the purity: 90.1%, yield: 65.5 percent;
preparation of intermediate 3:
adding 100g of the intermediate 2 into 250ml of hydrobromic acid aqueous solution, heating to 70-75 ℃, stirring to be clear (1-3 hours), slowly dropwise adding 50g of 20% hydrogen peroxide, stirring at 70-75 ℃ for 5-8 hours, monitoring by TLC that the raw material is less than or equal to 1%, cooling the system to 10-20 ℃, filtering, and drying to obtain 120g of solid with purity: 98%, yield: 70.7 percent;
preparation of 2-bromo-6-fluoroaniline:
adding 80g of the intermediate 3 into 150ml of 80% sulfuric acid solution, heating to 160 ℃, stirring for 3-5 hours, monitoring by TLC that the raw material is less than or equal to 1%, cooling the system to 10-20 ℃, pouring the reaction system into 600g of crushed ice, adding 150ml of 2 dichloromethane into the water phase for extraction, combining organic phases, distilling under normal pressure to remove dichloromethane, and then distilling under reduced pressure to obtain 56g of 2-bromo-6-fluoroaniline, wherein the yield is as follows: 60.2 percent; purity: 98.9 percent and less than 0.1 percent of single impurity.
Example four:
a preparation method of 2-bromo-6-fluoroaniline comprises the following steps:
preparation of intermediate 1:
adding 100g of o-fluoroaniline and 100g of triethylamine into 100ml of dichloromethane for dissolving, cooling to 0-5 ℃, controlling the temperature (less than or equal to 20 ℃) and dropwise adding 77.6g of acetyl chloride, stirring for 0.5-1.5 hours at room temperature, monitoring by TLC (thin layer chromatography) until the raw material is less than or equal to 1%, adding 50ml of water into the system, stirring, separating, washing an organic phase by saturated saline, drying by anhydrous sodium sulfate, and directly putting the filtered organic phase into the next step;
preparation of intermediate 2:
cooling the reaction solution to 0-5 ℃, controlling the temperature (less than or equal to 20 ℃) and dropwise adding 300g of chlorosulfonic acid, heating the reaction system to 70 ℃ (carbon dioxide in the system is evaporated and recycled for use) for reaction for 1-2 hours after dropwise adding is finished, monitoring the raw material by TLC (thin layer chromatography) to be less than or equal to 1%, carrying away the residual chlorosulfonic acid in the system by reduced pressure distillation, controlling the temperature (less than or equal to 20 ℃) and dropwise adding the obtained oily substance into 50ml of ammonia water solution (pH = 12-13), heating the reaction system to 70-75 ℃ for reaction for 3-5 hours after dropwise adding is finished, monitoring the raw material by TLC to be less than or equal to 1%, cooling to 0-5 ℃, dropwise adding 5% hydrochloric acid to adjust the pH =4-5, precipitating a large amount of solid in the system, filtering, drying to obtain 91g of solid, and purity: 80.8%, yield: 50.5 percent;
preparation of intermediate 3:
adding 50g of the intermediate 2 into 150ml of hydrobromic acid aqueous solution, heating to 70-75 ℃, stirring until the solution is clear (1-3 hours), slowly dropwise adding 50g of 30% hydrogen peroxide, stirring at 70-75 ℃ for 5-8 hours, monitoring by TLC that the raw material is less than or equal to 1%, cooling the system to 10-20 ℃, filtering, and drying to obtain 40g of solid with purity: 90.1%, yield: 50.4 percent;
preparation of 2-bromo-6-fluoroaniline:
adding 40g of the intermediate 3 into 100ml of 80% sulfuric acid solution, heating to 160 ℃, stirring for 3-5 hours, monitoring by TLC that the raw material is less than or equal to 1%, cooling the system to 10-20 ℃, pouring the reaction system into 500g of crushed ice, adding 100ml of 2 dichloromethane into the water phase for extraction, combining organic phases, distilling under normal pressure to remove dichloromethane, and then distilling under reduced pressure to obtain 30g of 2-bromo-6-fluoroaniline, wherein the yield is as follows: 59.9 percent; purity: 89.9 percent and less than 0.1 percent of single impurity.
Example five:
a preparation method of 2-bromo-6-fluoroaniline comprises the following steps:
preparation of intermediate 1:
adding 100g of o-fluoroaniline and 100g of triethylamine into 80ml of dichloromethane for dissolving, cooling to 0-5 ℃, controlling the temperature (less than or equal to 20 ℃) and dropwise adding 45.5g of acetyl chloride, stirring for 3-5 hours at room temperature, monitoring by TLC (thin layer chromatography) that the raw material is less than or equal to 1%, adding 90ml of water into the system, stirring, separating liquid, washing an organic phase by saturated saline water, drying by anhydrous sodium sulfate, and directly putting the filtered organic phase into the next step;
preparation of intermediate 2:
cooling the reaction liquid to 0-5 ℃, controlling the temperature (less than or equal to 20 ℃) to be dropped with 300g of chlorosulfonic acid, heating the reaction system to 70 ℃ (carbon dioxide in the system is evaporated and recycled for reaction for 0.5-1 hour after dropping is finished, monitoring raw materials by TLC (thin layer chromatography) to be less than or equal to 1%, carrying away the residual chlorosulfonic acid in the system by reduced pressure distillation, controlling the temperature (less than or equal to 20 ℃) to be dropped with the obtained oily matter into 90ml of ammonia water solution (system pH = 12-13), heating the reaction system to 70-75 ℃ after dropping is finished for reaction for 3-5 hours, monitoring the raw materials by TLC to be less than or equal to 1%, cooling to 0-5 ℃, dropping 5% of hydrochloric acid to adjust the system pH =4-5, precipitating a large amount of solid in the system, filtering, and drying to obtain 90g of solid with purity: 79.3%, yield: 49.5 percent;
preparation of intermediate 3:
adding 60g of the intermediate 2 into 50ml of hydrobromic acid aqueous solution, heating to 70-75 ℃, stirring until the solution is clear (1-3 hours), slowly dropwise adding 40g of 30% hydrogen peroxide, stirring at 70-75 ℃ for 5-8 hours, monitoring by TLC (thin layer chromatography) until the raw material content is less than or equal to 1%, cooling the system to 10-20 ℃, filtering, and drying to obtain 80g of solid with purity: 80.8%, yield: 49.6 percent;
preparation of 2-bromo-6-fluoroaniline:
adding 60g of the intermediate 3 into 90ml of 80% sulfuric acid solution, heating to 160 ℃, stirring for 3-5 hours, monitoring by TLC that the raw material is less than or equal to 1%, cooling the system to 10-20 ℃, pouring the reaction system into 300g of crushed ice, adding 90ml of 2 dichloromethane into the water phase for extraction, combining organic phases, distilling under normal pressure to remove dichloromethane, and then distilling under reduced pressure to obtain 56g of 2-bromo-6-fluoroaniline, wherein the yield is as follows: 40.4 percent; purity: 85.4 percent and less than 0.1 percent of single impurity.
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 considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (9)
1. A preparation method of 2-bromo-6-fluoroaniline comprises the following steps:
s1, protecting the amino group of o-fluoroaniline to obtain an intermediate 1;
s2, carrying out sulfonylation and amidation/esterification reactions on the intermediate 1 to obtain an intermediate 2;
s3, carrying out bromination reaction on the intermediate 2 to obtain an intermediate 3;
s4, removing sulfonamide/sulfonate from the intermediate 3 to obtain the target product 2-bromo-6-fluoroaniline.
2. The process for the preparation of 2-bromo-6-fluoroaniline according to claim 1, wherein: synthesis of intermediate 1 in S1: carrying out amidation reaction on o-fluoroaniline and different amino protecting groups to obtain an intermediate 1, wherein the structure of the intermediate 1 is as follows:
in the above formula, R1 is various types of amino protecting groups, such as acetyl (-Ac), t-butyloxycarbonyl (-Boc), benzyloxycarbonyl (-Cbz), p-toluenesulfonyl (-Tos), and the like.
3. The process according to claim 2, wherein the process comprises the steps of: synthesis of intermediate 2 in S2: reacting the obtained intermediate 1 with a sulfonation reagent, and then reacting with amine/alcohol to obtain an intermediate 2, wherein the intermediate 2 has a structural formula as follows:
in the above formula, R1 is different types of amino protecting groups, such as acetyl (-Ac), tert-butyloxycarbonyl (-Boc), benzyloxycarbonyl (-Cbz), p-toluenesulfonyl (-Tos), etc.; r2 is substituent of different types of amino or alcohol, such as-NH 2, -NMe2, -NEt2, -OH, -OMe, -OEt, etc.
4. The process according to claim 1, wherein the reaction is carried out in the presence of a 2-bromo-6-fluoroaniline: synthesis of intermediate 3 in S3: carrying out bromination reaction on the obtained intermediate 2 and a bromination reagent to obtain an intermediate 3, wherein the structural formula of the intermediate 3 is as follows:
in the above formula, R2 is different types of amino or alcohol substituent, such as-NH 2, -NMe2, -NEt2, -OH, -OMe, -OEt, etc.
5. The process for the preparation of 2-bromo-6-fluoroaniline according to claim 1, wherein: synthesis of 2-bromo-6-fluoroaniline: removing sulfonamide/sulfonate from the obtained intermediate 3 under an acidic condition to obtain a target product 2-bromo-6-fluoroaniline, wherein the structural formula of the 2-bromo-6-fluoroaniline is as follows:
the above reaction process is shown as the following formula:
6. the process for the preparation of 2-bromo-6-fluoroaniline according to claim 1, wherein: the amine protecting group described in S1 may be selected from one of the following: acetyl (-Ac), tert-butoxycarbonyl (-Boc), benzyloxycarbonyl (-Cbz), p-toluenesulfonyl (-Tos), preferably acetyl (-Ac), and the acid-binding agent described in S1 may be selected from one of the following: triethylamine, diethylamine, diisopropylamine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, etc., preferably triethylamine, and the solvent described in S1 may be selected from one of the following: dichloromethane, dichloroethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, N-dimethylformamide and the like, preferably dichloromethane, wherein the molar ratio of the o-fluoroaniline, the amino protecting group and the acid-binding agent in S1 is 1.0:1.0 to 2.0:1.0 to 2.0, preferably: 1.0: 1.05-1.25, and 1.1-1.3, wherein the reaction temperature in S1 is 0-50 ℃, and preferably 0-20 ℃.
7. The process for the preparation of 2-bromo-6-fluoroaniline according to claim 1, wherein: the sulfonating agent in S2 may be selected from one of the following: chlorosulfonic acid, sulfur dioxide plus chlorine, and the like, preferably chlorosulfonic acid, and the aminolysis/alcoholysis reagent in S2 may be selected from one of the following: ammonia, diethylamine, water, methanol, ethanol, etc., preferably ammonia, the solvent described in S2 may be selected from one of the following: dichloromethane, dichloroethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, N-dimethylformamide and the like, preferably dichloromethane, wherein the molar ratio of the intermediate 1, the sulfonation reagent and the ammonolysis/alcoholysis reagent in S2 is 1.0: 1.0-5.0:1.0 to 10.0, preferably: 1.0: 3.0-3.5: 5.0-10.0, and the reaction temperature in S2 is 0-90 ℃, preferably 0-70 ℃.
8. The process for the preparation of 2-bromo-6-fluoroaniline according to claim 1, wherein: the brominating agent in S3 can be selected from one of the following: elemental bromine, hydrogen bromide/hydrogen peroxide systems, pyridinium tribromide (PBP), phosphorus tribromide and the like, preferably hydrogen bromide/hydrogen peroxide systems, the molar ratio of the intermediate 2, the brominating agent, and hydrogen peroxide in S3 is 1.0: 1.0-8.0:1.0 to 1.5, preferably: 1.0: 5.0-6.0: 1.0-1.1, and the reaction temperature in S3 is 0-100 ℃, preferably 60-80 ℃.
9. The process for the preparation of 2-bromo-6-fluoroaniline according to claim 1, wherein: the acid in S4 is a mixed system consisting of one or more of sulfuric acid, hydrochloric acid, methanesulfonic acid, trifluoroacetic acid and nitric acid, preferably sulfuric acid, the molar ratio of the intermediate 3 to the acid in S4 is 1.0 to 10.0, preferably 1.0 to 3.0, and the temperature in S4 is 0 to 200 ℃, preferably 150 to 180 ℃.
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| CN118084678A (en) * | 2024-03-01 | 2024-05-28 | 长沙唯楚医药科技有限公司 | Preparation method of 2-bromo-6-fluoroaniline |
| CN118084678B (en) * | 2024-03-01 | 2024-09-06 | 长沙唯楚医药科技有限公司 | Preparation method of 2-bromo-6-fluoroaniline |
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