CN113563258A - Preparation method of 4-bromo-2- (difluoromethyl) -5-methylpyridine - Google Patents
Preparation method of 4-bromo-2- (difluoromethyl) -5-methylpyridine Download PDFInfo
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- IQTWSFUATZFIRE-UHFFFAOYSA-N Cc1cnc(cc1Br)C(F)F Chemical compound Cc1cnc(cc1Br)C(F)F IQTWSFUATZFIRE-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229940126062 Compound A Drugs 0.000 claims abstract description 16
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 238000006396 nitration reaction Methods 0.000 claims abstract description 6
- 238000006722 reduction reaction Methods 0.000 claims abstract description 6
- 238000006467 substitution reaction Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 63
- 238000006243 chemical reaction Methods 0.000 claims description 49
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- 238000003756 stirring Methods 0.000 claims description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- 238000010438 heat treatment Methods 0.000 claims description 17
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 17
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Substances CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 claims description 14
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims description 14
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 10
- 229910017604 nitric acid Inorganic materials 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- FXXACINHVKSMDR-UHFFFAOYSA-N acetyl bromide Chemical compound CC(Br)=O FXXACINHVKSMDR-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 2
- 239000012346 acetyl chloride Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000003682 fluorination reaction Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000005457 ice water Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000001035 drying Methods 0.000 description 8
- 238000001514 detection method Methods 0.000 description 7
- 239000000203 mixture Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 239000000126 substance Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000010791 quenching Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000575 pesticide Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of 4-bromo-2- (difluoromethyl) -5-methylpyridine. The preparation method takes the compound A as a raw material, and the 4-bromo-2- (difluoromethyl) -5-methylpyridine is prepared through oxidation reaction, nitration reaction, substitution reaction, reduction reaction, hydrolysis reaction, oxidation reaction and fluorination reaction in sequence.
Description
Technical Field
The invention belongs to the technical field of medical intermediates, and particularly relates to a preparation method of 4-bromo-2- (difluoromethyl) -5-methylpyridine.
Background
4-bromo-2- (difluoromethyl) -5-methylpyridine is a very important fluorine-containing pyridine intermediate, and is a common intermediate for synthesizing pharmaceutical compounds and pesticide compounds. Few methods for the synthesis of this compound have been reported in the prior art. Therefore, it is highly desirable to provide a method for synthesizing 4-bromo-2- (difluoromethyl) -5-methylpyridine.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: in view of the above problems, a process for producing 4-bromo-2- (difluoromethyl) -5-methylpyridine is provided.
In order to solve the technical problems, the invention adopts the following technical scheme:
a preparation method of 4-bromo-2- (difluoromethyl) -5-methylpyridine comprises the following steps:
(1) and (3) oxidation reaction: the compound A, m-CPBA is subjected to oxidation reaction in an organic solvent to obtain a compound B
(2) Nitration reaction: carrying out nitration reaction on the compound B and nitric acid in the environment of concentrated sulfuric acid to obtain a compound C
(3) And (3) substitution reaction: carrying out substitution reaction on the compound C, acetic acid and acetyl chloride to obtain a compound D
(4) Reduction reaction: carrying out reduction reaction on the compound D and acetic anhydride to obtain a compound E
(5) And (3) hydrolysis reaction: mixing the compound E and hydrochloric acid, and carrying out hydrolysis reaction to obtain a compound F
(6) And (3) oxidation reaction: carrying out oxidation reaction on the compound F and manganese dioxide in an organic solvent to obtain a compound G
(7) And (3) fluoro reaction: mixing the compound G, DAST and DCM for carrying out fluoro reaction to obtain 4-bromo-2- (difluoromethyl) -5-methylpyridine
Preferably, the specific operation of the step (1) is to take the compound A according to the mass ratio of the compound A, m-CPBA of 1: 2-4, firstly put the compound A into a reactor, add chloroform to completely dissolve the compound A, set the temperature to be 0-2 ℃, add m-CPBA, heat to room temperature, react overnight, and obtain the compound B.
Preferably, the specific operation of the step (2) is to take the compound B and a nitric acid solution according to the mass ratio of 1: 1-3, put the compound B in concentrated sulfuric acid, stir the mixture evenly, add the nitric acid solution at 0-2 ℃, heat the mixture to room temperature, perform heat preservation reaction, and heat the mixture again to obtain the compound C.
Preferably, the specific operation in the step (3) is to take the compound C and acetyl bromide according to the mass ratio of 1: 6-10, mix the compound C and acetic acid according to the solid-liquid g/mL ratio of 1:10, add acetyl bromide at 0 ℃, heat, stir and react to obtain the compound D.
Preferably, the specific operation of the step (4) is to mix the compound D and acetic anhydride according to the mass ratio of 1: 2-4, carry out nitrogen protection, heat up, and react to obtain the compound E.
Preferably, the specific operation of the step (5) is to mix the compound E and hydrochloric acid according to a solid-liquid g/mL ratio of 1:10, and react to obtain the compound F.
Preferably, the specific operation of the step (6) is to mix the compound F and manganese dioxide according to the mass ratio of 1: 4-6, place the mixture in dichloromethane, and stir for reaction to obtain the compound G.
Preferably, the specific operation of the step (7) is to put the compound G in DCM, add DAST 2-3 times the mass of the compound G, and stir to react to obtain 4-bromo-2- (difluoromethyl) -5-methylpyridine.
Compared with other methods, the method has the beneficial technical effects that:
the preparation method takes the compound A as a raw material, and the 4-bromo-2- (difluoromethyl) -5-methylpyridine is prepared through oxidation reaction, nitration reaction, substitution reaction, reduction reaction, hydrolysis reaction, oxidation reaction and fluorination reaction in sequence.
Detailed Description
A method for preparing 4-bromo-2- (difluoromethyl) -5-methylpyridine, which comprises
(1) Taking materials according to the mass ratio of the compound A, m-CPBA of 1: 2-4, firstly putting the compound A into a reactor, adding chloroform to completely dissolve the compound A, setting the temperature to be 0-2 ℃, adding m-CPBA, heating to room temperature, and reacting overnight to obtain a compound B;
(2) taking a compound B and a nitric acid solution according to the mass ratio of 1: 1-3, putting the compound B into concentrated sulfuric acid, uniformly stirring, adding the nitric acid solution at 0-2 ℃, heating to room temperature, carrying out heat preservation reaction, and heating again for reaction to obtain a compound C;
(3) taking the compound C and acetyl bromide according to the mass ratio of 1: 6-10, mixing the compound C and acetic acid according to the solid-liquid g/mL ratio of 1:10, adding the acetyl bromide at 0 ℃, heating, and stirring for reaction to obtain a compound D.
(4) And mixing the compound D and acetic anhydride according to the mass ratio of 1: 2-4, carrying out nitrogen protection, heating, and reacting to obtain a compound E.
(5) And mixing the compound E and hydrochloric acid according to the solid-liquid g/mL ratio of 1:10, and reacting to obtain a compound F.
(6) Mixing the compound F and manganese dioxide according to the mass ratio of 1: 4-6, placing the mixture into dichloromethane, and stirring to react to obtain a compound G;
(7) and (3) placing the compound G into DCM, adding DAST with the mass of 2-3 times of that of the compound G, and stirring for reaction to obtain the 4-bromo-2- (difluoromethyl) -5-methylpyridine.
In the preparation process: DCM is dichloromethane; DAST is diethylaminosulfur trifluoride; m-CPBA is m-chloroperoxybenzoic acid.
In order to make the objects, technical solutions and advantages of the present invention more clear, the present invention is further described with reference to the following embodiments:
example 1
A method for preparing 4-bromo-2- (difluoromethyl) -5-methylpyridine, which comprises
(1) Adding 20g of compound A and 400mL of chloroform into a reaction bottle, stirring for dissolving, cooling to 0 ℃ in an ice water bath, adding 40gm-CPBA (at least 30 min), slowly heating to normal temperature for reacting overnight, detecting by TLC, reacting the raw materials, and adding saturated Na2SO3The solution was stirred for 1h to quench m-CPBA and saturated NaHCO was added3The organic layer was washed 3 times with the solution, and after washing, the sample was stirred and passed through a column, about n-hexane: the product yield is 18.8g of colorless transparent oily matter when the ethyl acetate is =1:1, namely the compound B with the purity of 97.8 percent;
(2) adding 200mL of concentrated sulfuric acid into a reaction bottle, slowly adding 18g of compound B in an ice-water bath, slowly adding 18g of nitric acid solution (mass fraction of 65%) at 0 ℃ after dripping, heating to room temperature for reaction for 1h after dripping, heating to 110 ℃ for reaction for 72h, detecting by TLC, slowly pouring the reaction solution into ice water, extracting by using dichloromethane 300mL X5, mixing the sample and passing through a column, and adding n-hexane: the product is obtained when ethyl acetate =3:1, 17.9g of yellow solid is obtained, namely the compound C, and the purity is 98.3%;
(3) adding 180mL of acetic acid and 18g of the compound C into a reaction bottle, slowly dropwise adding 108g of acetyl bromide under stirring at 0 ℃, heating to 80 ℃ for reaction for 4 hours after dropwise addition, pouring the reaction solution into ice water after TLC detection reaction, extracting dichloromethane with 200mL of X5, concentrating the organic layer under reduced pressure, and spin-drying to obtain a yellow brown solid, namely compound D with the purity of 98.2%;
(4) adding 18g of the compound D and 36g of acetic anhydride into a reaction bottle, performing nitrogen replacement for 3 times, heating to 110 ℃ under the protection of nitrogen, reacting for 2 hours, pouring the reaction liquid into ice water after TLC detection reaction is finished, extracting with ethyl acetate, and spin-drying to obtain 15.3g of colorless transparent oily substance, namely the compound E, wherein the purity is 98.1%;
(5) adding 14g of compound E and 140mL of hydrochloric acid (3M) into a reaction flask, stirring for reaction for 2h, and detecting by TLC, wherein NaHCO is used for detection after the reaction is finished3Adjusting the pH value of the solid to be alkalescent, extracting by ethyl acetate, and spin-drying the organic phase to obtain 12.2g of solid with the purity of 98.9 percent;
(6) adding 12G of compound F, 48G of manganese dioxide and 250mL of dichloromethane into a reaction bottle, stirring at room temperature overnight, detecting by TLC, filtering, spin-drying filtrate to obtain a dark gray solid, and purifying by a column to obtain 9.3G of yellow solid, namely compound G with the purity of 97.6%;
(7) adding 5G of compound G and 50mL of DCCM into a reaction flask, reducing the temperature to-78 ℃ under the protection of nitrogen, keeping the temperature, slowly adding 10G of DAST dropwise after finishing dropping, slowly increasing the temperature to room temperature, reacting overnight, detecting the reaction by TLC, pouring the reaction solution into ice water (150 mL), extracting 3 times with ethyl acetate (100 mL x 2), mixing the sample with silica gel, passing through a column, and obtaining n-hexane: ethyl acetate =5:1 to give the product, which was spin-dried to give 4.1g of a colorless transparent oil with a purity of 98.8%.
Nuclear magnetic data: 1H NMR (d 6-DMSO) 8.62(s, 1H), 7.95(s, 1H), 6.96(t, J =54.4Hz, 1H),2.40(s, 3H).
Example 2
A method for preparing 4-bromo-2- (difluoromethyl) -5-methylpyridine, which comprises
(1) Adding 20g of compound A and 400mL of chloroform into a reaction bottle, stirring for dissolving, cooling to 0 ℃ in an ice water bath, adding 80gm-CPBA (at least 30 min), slowly heating to normal temperature for reacting overnight, detecting by TLC, reacting the raw materials, and adding saturated Na2SO3The solution was stirred for 1h to quench m-CPBA and saturated NaHCO was added3The organic layer was washed 3 times with the solution, and after washing, the sample was stirred and passed through a column, about n-hexane: when the ethyl acetate =1:1, 19.2g of colorless transparent oily substance is obtained, namely the compound B with the purity of 98.2 percent;
(2) adding 200mL of concentrated sulfuric acid into a reaction bottle, slowly adding 18g of compound B in an ice-water bath, slowly adding 54g of nitric acid solution (mass fraction of 65%) at 0 ℃ after dripping, heating to room temperature for reaction for 1h after dripping, heating to 110 ℃ for reaction for 72h, detecting by TLC, slowly pouring the reaction solution into ice water, extracting by using dichloromethane 300mL X5, mixing the sample with a sample, passing through a column, and adding n-hexane: the product is obtained when ethyl acetate =3:1, 18.1g of yellow solid is obtained, namely the compound C, and the purity is 99.2%;
(3) adding 180mL of acetic acid and 18g of the compound C into a reaction bottle, slowly dropwise adding 180g of acetyl bromide under stirring at 0 ℃, heating to 80 ℃ for reaction for 4 hours after dropwise addition, pouring the reaction solution into ice water after TLC detection reaction, extracting dichloromethane with 200mL of X5, concentrating the organic layer under reduced pressure, and spin-drying to obtain a yellow brown solid, namely compound D with the purity of 98.1%;
(4) adding 18g of the compound D and 76g of acetic anhydride into a reaction bottle, performing nitrogen replacement for 3 times, heating to 110 ℃ under the protection of nitrogen, reacting for 2 hours, pouring the reaction liquid into ice water after TLC detection reaction is finished, extracting with ethyl acetate, and spin-drying to obtain 16.0g of colorless transparent oily substance, namely the compound E, wherein the purity is 98.2%;
(5) adding 14g of compound E and 140mL of hydrochloric acid (3M) into a reaction flask, stirring for reaction for 2h, and detecting by TLC, wherein NaHCO is used for detection after the reaction is finished3Adjusting the pH value of the solid to be alkalescent, extracting by ethyl acetate, and spin-drying the organic phase to obtain 12.2g of solid with the purity of 98.9 percent;
(6) adding 12G of compound F, 72G of manganese dioxide and 250mL of dichloromethane into a reaction bottle, stirring overnight at room temperature, performing TLC detection reaction, filtering, spin-drying filtrate to obtain a dark gray solid, and performing column purification to obtain 10.1G of yellow solid, namely compound G with the purity of 98.2%;
(7) adding 5G of compound G and 50mL of DCCM into a reaction flask, reducing the temperature to-78 ℃ under the protection of nitrogen, keeping the temperature, slowly adding 15G of DAST dropwise after finishing dropping, slowly increasing the temperature to room temperature, reacting overnight, detecting the reaction by TLC, pouring the reaction solution into ice water (150 mL), extracting 3 times with ethyl acetate (100 mL x 2), mixing the sample with silica gel, passing through a column, and obtaining n-hexane: ethyl acetate =5:1 to give the product, which was spin-dried to give 5.3g of a colorless transparent oil with a purity of 99.1%.
Nuclear magnetic data: 1H NMR (d 6-DMSO) 8.62(s, 1H), 7.95(s, 1H), 6.96(t, J =54.4Hz, 1H),2.40(s, 3H).
Claims (8)
1. A preparation method of 4-bromo-2- (difluoromethyl) -5-methylpyridine is characterized by comprising the following steps:
(1) and (3) oxidation reaction: the compound A, m-CPBA is subjected to oxidation reaction in an organic solvent to obtain a compound B
(2) Nitration reaction: carrying out nitration reaction on the compound B and nitric acid in the environment of concentrated sulfuric acid to obtain a compound C
(3) And (3) substitution reaction: carrying out substitution reaction on the compound C, acetic acid and acetyl chloride to obtain a compound D
(4) Reduction reaction: carrying out reduction reaction on the compound D and acetic anhydride to obtain a compound E
(5) And (3) hydrolysis reaction: mixing the compound E and hydrochloric acid, and carrying out hydrolysis reaction to obtain a compound F
(6) And (3) oxidation reaction: carrying out oxidation reaction on the compound F and manganese dioxide in an organic solvent to obtain a compound G
(7) And (3) fluoro reaction: mixing the compound G, DAST and DCM for carrying out fluoro reaction to obtain 4-bromo-2- (difluoromethyl) -5-methylpyridine
2. The preparation method of 4-bromo-2- (difluoromethyl) -5-methylpyridine according to claim 1, wherein the step (1) is specifically carried out by taking a compound A, m-CPBA in a mass ratio of 1: 2-4, first putting the compound A into a reactor, adding chloroform to completely dissolve the compound A, setting the temperature at 0-2 ℃, adding m-CPBA, heating to room temperature, and reacting overnight to obtain the compound B.
3. The preparation method of 4-bromo-2- (difluoromethyl) -5-methylpyridine according to claim 1, wherein the specific operation of step (2) is to take compound B and nitric acid solution according to a mass ratio of 1: 1-3, put compound B in concentrated sulfuric acid, stir uniformly, then add nitric acid solution at 0-2 ℃, heat up to room temperature, keep warm and react, and then heat up to react, thereby obtaining compound C.
4. The preparation method of 4-bromo-2- (difluoromethyl) -5-methylpyridine according to claim 1, wherein the specific operation in step (3) is to take the compound C and acetyl bromide in a mass ratio of 1: 6-10, mix the compound C and acetic acid in a solid-liquid g/mL ratio of 1:10, add acetyl bromide at 0 ℃, heat, stir and react to obtain the compound D.
5. The preparation method of 4-bromo-2- (difluoromethyl) -5-methylpyridine according to claim 1, wherein the step (4) comprises the specific steps of mixing the compound D and acetic anhydride in a mass ratio of 1: 2-4, carrying out nitrogen protection, heating, and reacting to obtain the compound E.
6. The method for producing 4-bromo-2- (difluoromethyl) -5-methylpyridine according to claim 1, wherein the step (5) is specifically performed by mixing compound E and hydrochloric acid at a solid-liquid g/mL ratio of 1:10, and reacting to obtain compound F.
7. The preparation method of 4-bromo-2- (difluoromethyl) -5-methylpyridine according to claim 1, wherein step (6) comprises mixing compound F and manganese dioxide at a mass ratio of 1: 4-6, placing in dichloromethane, and stirring for reaction to obtain compound G.
8. The method for preparing 4-bromo-2- (difluoromethyl) -5-methylpyridine according to claim 1, wherein the step (7) comprises the specific steps of placing the compound G in DCM, adding DAST 2-3 times the mass of the compound G, and stirring for reaction to obtain 4-bromo-2- (difluoromethyl) -5-methylpyridine.
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| CN115340492A (en) * | 2022-09-26 | 2022-11-15 | 武汉海特生物创新医药研究有限公司 | Preparation method of 2-hydroxy-4-amino-5-methylpyridine |
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