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CN-117886760-B - Synthesis method of 3- (5-fluoropyrimidine-2-yl) -2-methoxy aniline

CN117886760BCN 117886760 BCN117886760 BCN 117886760BCN-117886760-B

Abstract

The invention provides a method for synthesizing 3- (5-fluoropyrimidine-2-yl) -2-methoxy aniline, and belongs to the technical field of chemical synthesis. The invention firstly provides an intermediate for synthesizing 3- (5-fluoropyrimidin-2-yl) -2-methoxyaniline shown in a formula I and a formula II. The intermediate can be used for successfully preparing the 3- (5-fluoropyrimidin-2-yl) -2-methoxyaniline. The synthesis method of the invention has simple operation and high product yield and purity. Meanwhile, in the key C-C bond coupling, a low-cost metal Ni catalyzed reduction coupling strategy is adopted to replace the traditional two-step Pd catalytic coupling reaction, so that the material cost of the reaction is greatly reduced, meanwhile, the problem of regioselectivity is avoided in the step of introducing nitro, and further purification is avoided. The synthesis method is simple and efficient, has low cost and has good industrialized prospect.

Inventors

  • Kuang Yulong
  • ZHANG BIN
  • QIN TIANHONG
  • WANG XUECHAO
  • GUO PENG

Assignees

  • 爱斯特（成都）生物制药股份有限公司
  • 甘肃道璞爱斯特生物科技有限公司

Dates

Publication Date
20260508
Application Date
20231218

Claims (15)

  1. 1. A method for preparing an intermediate of 3- (5-fluoropyrimidin-2-yl) -2-methoxyaniline shown in a formula I is characterized by comprising the following steps: (1) In a solvent, mixing a compound 1, a compound 2, a nickel salt catalyst, 2' -bipyridine, zinc powder, magnesium chloride and sodium iodide, and reacting to obtain a reaction solution; (2) Filtering the reaction liquid, leaching, collecting filtrate, concentrating to dryness, and purifying by a column to obtain the compound shown in the formula I.
  2. 2. The method according to claim 1, characterized in that: In the step (1), the equivalent ratio of the compound 1 to the compound 2 to the nickel salt catalyst to the 2,2' -bipyridine to the zinc powder to the magnesium chloride to the sodium iodide is 1 (1-3): (0.1-0.5): (2-4): (0.1-0.5); in the step (1), the volume-mass ratio of the solvent to the compound 1 is (5-100) mL 1g; In the step (1), the reaction temperature is 100-120 ℃ and the reaction time is 10-20 hours; In the step (1), the nickel salt catalyst is nickel chloride hexahydrate, nickel bromide, nickel iodide, ethylene glycol dimethyl ether nickel bromide or ethylene glycol dimethyl ether nickel chloride; in the step (1), the solvent is N-methylpyrrolidone, N '-dimethylformamide or N, N' -dimethylacetamide.
  3. 3. The method according to claim 2, characterized in that: in the step (1), the equivalent ratio of the compound 1, the compound 2, the nickel salt catalyst, the 2,2' -bipyridine, the zinc powder, the magnesium chloride and the sodium iodide is 1:1:0.1:0.15:2:2:0.1; In the step (1), the volume-mass ratio of the solvent to the compound 1 is 10 mL/1 g; In the step (1), the nickel salt catalyst is nickel chloride hexahydrate and nickel iodide; In the step (1), the solvent is N-methyl pyrrolidone; In the step (2), the reaction solution is cooled before being filtered; in the step (2), the reaction solution is filtered by using diatomite; in step (2), the leaching is performed by using ethyl acetate; in the step (2), the concentration is carried out until the concentration is carried out at 60-70 ℃ in vacuum until the concentration is carried out; in the step (2), the column purification is performed by adopting 100-200 meshes of silica gel, and the eluent is a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 3:1.
  4. 4. A method according to claim 3, characterized in that: in step (1), the reaction is sealed under nitrogen atmosphere.
  5. 5. The method according to any one of claims 1 to 4, wherein the preparation method of the compound 1 comprises the following steps: Step a, adding N-bromosuccinimide to react after the compound 1-1 reacts with concentrated sulfuric acid in a solvent, and purifying the reaction solution to obtain a compound 1-2; and b, in a solvent, reacting the compound 1-2, potassium carbonate and dimethyl sulfate, and purifying the reaction liquid to obtain the compound 1.
  6. 6. The method according to claim 5, wherein: In the step a, the equivalent ratio of the compound 1-1 to the concentrated sulfuric acid to the N-bromosuccinimide is 1 (1-3) (0.8-1); in the step a, the volume-mass ratio of the solvent to the compound 1-1 is (5-10) mL 1g; in the step a, the reaction temperature of the compound 1-1 and the concentrated sulfuric acid is 20-30 ℃, and the reaction time is 10-30 min; In the step a, the reaction temperature of adding N-bromosuccinimide is 25-30 ℃, and the reaction time is 5-10 h; in the step b, the equivalent ratio of the compound 1-2 to the potassium carbonate to the dimethyl sulfate is 1 (1-3); in the step b, the volume-mass ratio of the solvent to the compound 1-2 is (5-10) mL 1g; in the step b, the reaction temperature is 50-70 ℃ and the reaction time is 10-20 h.
  7. 7. The method according to claim 6, wherein: in the step a, the equivalent ratio of the compound 1-1, the concentrated sulfuric acid and the N-bromosuccinimide is 1:1.05:0.95; in the step a, the volume-mass ratio of the solvent to the compound 1-1 is 6mL to 1g; In the step a, the solvent is acetonitrile; In the step a, the reaction time of adding the N-bromosuccinimide is 6 hours; the purification in step a comprises the steps of concentrating the reaction solution to remove the solvent, adding saturated sodium carbonate solution, adjusting pH to be more than 7, adding ethyl acetate for extraction, taking an organic phase, washing the organic phase with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate to be dry; In the step b, the equivalent ratio of the compound 1-2 to the potassium carbonate to the dimethyl sulfate is 1:1.5:1.5; in the step b, the volume-mass ratio of the solvent to the compound 1-2 is 6mL to 1g; In the step b, the solvent is acetone; In the step b, the purification comprises the steps of cooling the reaction liquid, filtering and leaching, concentrating the filtrate to be dry, adding water and ethyl acetate, stirring uniformly, standing for separating liquid, collecting an organic phase, washing the organic phase with saturated saline water, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate to be dry.
  8. 8. The method according to any one of claims 1 to 4, wherein the preparation method of the compound 2 comprises the following steps: Step A, uniformly mixing a compound 2-1, N-dimethylaniline and phosphorus oxychloride, reacting, and purifying to obtain a compound 2-2; And B, uniformly mixing the compound 2-2, sodium bicarbonate and 5% palladium-carbon in a solvent, reacting in a hydrogen environment, and purifying to obtain the compound 2.
  9. 9. The method according to claim 8, wherein: in the step A, the equivalent ratio of the compound 2-1 to N, N-dimethylaniline to phosphorus oxychloride is 1 (0.1-1): 2-5; In the step A, the reaction temperature is 100-120 ℃ and the reaction time is 10-20 hours; in the step B, the equivalent ratio of the compound 2-2 to the sodium bicarbonate is 1 (1-3); in the step B, the volume-mass ratio of the solvent to the compound 2-2 is (5-10) mL 1g; In the step B, the mass ratio of the compound 2-2 to 5% of palladium-carbon is 1 (0.1-0.5); In the step B, the reaction pressure is 1-3 MPa, the reaction temperature is 30-40 ℃, and the reaction time is 10-20 h.
  10. 10. The method according to claim 9, wherein: in the step A, the equivalent ratio of the compound 2-1, N-dimethylaniline to phosphorus oxychloride is 1:0.5:2.3; The purification method comprises cooling the reaction solution, adding into ice, quenching, extracting with ethyl acetate, washing the organic phase with water, washing the organic phase with saturated saline solution, drying the organic phase with anhydrous sodium sulfate, filtering, and concentrating the filtrate to dryness; In the step B, the equivalent ratio of the compound 2-2 to the sodium bicarbonate is 1:1.2; in the step B, the volume-mass ratio of the solvent to the compound 2-2 is 8mL to 1g; In the step B, the mass ratio of the compound 2-2 to 5% of palladium carbon is 1:0.1; in the step B, the solvent is ethanol; In the step B, the purification method comprises the following steps of decompressing after the reaction, filtering the reaction liquid by diatomite, leaching by ethanol, collecting filtrate, and concentrating to dryness.
  11. 11. A method for synthesizing 3- (5-fluoropyrimidin-2-yl) -2-methoxyaniline is characterized by comprising the following steps: step 1) synthesizing a compound shown in a formula I by adopting the method of any one of claims 2-5; Step 2), dissolving the compound shown in the formula I in a solvent, dropwise adding concentrated sulfuric acid and fuming nitric acid for reaction, and purifying the reaction solution to synthesize the compound shown in the formula II; Step 3), in a solvent, reacting a compound shown in a formula II with a catalyst and acid in a hydrogen environment, and purifying to obtain 3- (5-fluoropyrimidine-2-yl) -2-methoxyaniline; in the step 3), the catalyst is Raney Ni, pd/C or Pt/C; in step 3), the acid is concentrated hydrochloric acid.
  12. 12. The method according to claim 11, wherein: In the step 3), the equivalent ratio of the compound shown in the formula II to the acid is 1 (2-5); In the step 3), the mass ratio of the compound shown in the formula II to the catalyst is 1 (1-5); In the step 3), the mass volume ratio of the compound shown in the formula II to the solvent is 1g (8-10) mL; In the step 3), the pressure of the reaction is 3-5 MPa, the temperature of the reaction is 80-100 ℃, and the reaction time is 10-20 hours; In step 3), the solvent is methanol.
  13. 13. The method according to claim 12, wherein: In the step 3), the equivalent ratio of the compound shown in the formula II to the acid is 1:2; In the step 3), the mass ratio of the compound shown in the formula II to the catalyst is 1:1; In the step 3), the mass-volume ratio of the compound shown in the formula II to the solvent is 1g to 8mL; in the step 3), the catalyst is Raney Ni; In the step 3), the purification method comprises the following steps of decompressing after reaction, filtering a reaction liquid pad diatomite, eluting with methanol, collecting filtrate, concentrating to dryness, and purifying by a column, wherein the column purification is performed by adopting 100-200 meshes of silica gel, and the eluent is a petroleum ether and ethyl acetate mixed solution with the volume ratio of 2:1.
  14. 14. The method according to claim 11, wherein: In the step 2), the equivalent ratio of the compound shown in the formula I, the concentrated sulfuric acid and the fuming nitric acid is 1 (1-3); the mass volume ratio of the compound shown in the formula I to the solvent is 1g (8-10) mL; the reaction temperature is 20-30 ℃, and the reaction time is 10-20 h.
  15. 15. The method according to claim 14, wherein: In the step 2), the equivalent ratio of the compound shown in the formula I to the concentrated sulfuric acid to the fuming nitric acid is 1:1.6:2; the mass volume ratio of the compound shown in the formula I to the solvent is 1g to 8mL; The solvent is concentrated sulfuric acid; The temperature is less than 20 ℃ when the concentrated sulfuric acid and fuming nitric acid are added dropwise; The purification comprises the steps of adding the reaction solution into ice to quench the reaction, adding dichloromethane to extract, washing an organic phase by using saturated sodium bicarbonate, washing the organic phase by using saturated saline water, drying the organic phase by using anhydrous sodium sulfate, filtering, and concentrating the filtrate to be dry.

Description

Synthesis method of 3- (5-fluoropyrimidine-2-yl) -2-methoxy aniline Technical Field The invention belongs to the technical field of chemical synthesis, and particularly relates to a synthesis method of 3- (5-fluoropyrimidine-2-yl) -2-methoxyaniline. Background The kinase family (JAK) is a class of non-receptor tyrosine kinases, four members of JAK1, JAK2, JAK3 and TYK2 have been found. Signal Transduction and Activator of Transcription (STAT) are direct substrates of JAKs. Many cytokines and growth factors signal (J.Med.Chem.2021,64,677-694,Discovery of BMS-986202:A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2).BMS-986202 through the JAK-STAT signaling pathway are potent, selective, orally active inhibitors of Tyk2, binding to Tyk2 JH2, with IC 50 of 0.19nM and ki of 0.02nM. BMS-986202 is highly selective for other kinases including members of the JAK family. BMS-986202 is also a weak inhibitor of CYP2C19, IC 50 is 14. Mu.M. BMS-986202 can be used in the study of IL-23 driven acanthosis, anti-CD 40 induced colitis and idiopathic lupus. 3- (5-Fluoropyrimidin-2-yl) -2-methoxyaniline is an important intermediate for the synthesis of BMS-986202. Using 3- (5-fluoropyrimidin-2-yl) -2-methoxyaniline, the following route can be used to synthesize the target product BMS-986202(J.Med.Chem.2021,64,677-694,Discovery of BMS-986202:A Clinical Tyk2 Inhibitor that Binds to Tyk2 JH2)： For 3- (5-fluoropyrimidin-2-yl) -2-methoxyaniline, the synthetic route which has been reported is as follows: route one (described in patent application publication No. WO2021222153 A1): The synthetic route needs Pd/C+H 2 to synthesize 2-chloro-5-fluoropyrimidine, and needs to directly purchase or synthesize 5-bromo-6-methoxyaniline and use two-Step Pd catalysis (Step 3 and Step 4), the total yield of the two steps is 53%, the yield is lower, and the Pd catalyst is expensive, so that the material cost of the synthetic route is relatively higher. Route two (described in patent application publication No. WO2022117016 A1): The synthetic route reduces nitro to amino in the last step, but two-step Pd catalysis is still needed to complete C-C bond coupling to construct the compound, the total three-step yield is 31%, and the cost of the route is high because of using Pd catalyst. Disclosure of Invention In order to solve the problems, the invention provides a synthesis method of 3- (5-fluoropyrimidin-2-yl) -2-methoxyaniline. The invention provides an intermediate for synthesizing 3- (5-fluoropyrimidin-2-yl) -2-methoxyaniline, wherein the structure of the intermediate is shown in the following formula I: the invention also provides a method for preparing the intermediate, which comprises the following steps: (1) In a solvent, mixing a compound 1, a compound 2, a nickel salt catalyst, 2' -bipyridine, zinc powder, magnesium chloride and sodium iodide, and reacting to obtain a reaction solution; (2) Filtering the reaction liquid, leaching, collecting filtrate, concentrating to dryness, and purifying by a column to obtain the compound shown in the formula I. Further, the method comprises the steps of, In the step (1), the equivalent ratio of the compound 1 to the compound 2 to the nickel salt catalyst to the 2,2' -bipyridine to the zinc powder to the magnesium chloride to the sodium iodide is 1 (1-3): (0.1-0.5): (2-4): (0.1-0.5); and/or in the step (1), the volume-mass ratio of the solvent to the compound 1 is (5-100) mL 1g; And/or in the step (1), the reaction temperature is 100-120 ℃ and the reaction time is 10-20 hours; And/or in the step (1), the nickel salt catalyst is nickel chloride hexahydrate, nickel bromide, nickel iodide, ethylene glycol dimethyl ether nickel bromide or ethylene glycol dimethyl ether nickel chloride; and/or, in step (1), the solvent is N-methylpyrrolidone, N '-dimethylformamide or N, N' -dimethylacetamide; Preferably, the method comprises the steps of, In the step (1), the equivalent ratio of the compound 1, the compound 2, the nickel salt catalyst, the 2,2' -bipyridine, the zinc powder, the magnesium chloride and the sodium iodide is 1:1:0.1:0.15:2:2:0.1; And/or, in the step (1), the volume to mass ratio of the solvent to the compound 1 is 10 ml/1 g; And/or in the step (1), the nickel salt catalyst is nickel chloride hexahydrate or nickel iodide; And/or, in the step (1), the solvent is N-methyl pyrrolidone; And/or, in the step (2), cooling the reaction solution before filtering the reaction solution; And/or, in the step (2), the reaction liquid is filtered by using diatomite; and/or, in step (2), the rinsing is performed using ethyl acetate; And/or in the step (2), concentrating to dryness at 60-70 ℃ in vacuum; and/or in the step (2), the column purification is performed by adopting 100-200 mesh silica gel, and the eluent is petroleum ether and ethyl acetate mixed solution with the volume ratio of 3:1; More preferably, the process is carried out, And/or, in the step (1), the reaction is sealed under nitrogen atmosphere. Fu