CN115724791A - Preparation method of 2-methyl-3-nitro-5-aminopyridine - Google Patents
Preparation method of 2-methyl-3-nitro-5-aminopyridine Download PDFInfo
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- RZPSBEGGSZWYAN-UHFFFAOYSA-N 6-methyl-5-nitropyridin-3-amine Chemical compound CC1=NC=C(N)C=C1[N+]([O-])=O RZPSBEGGSZWYAN-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- -1 N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine Chemical compound 0.000 claims abstract description 24
- 238000000034 method Methods 0.000 claims abstract description 21
- 239000003054 catalyst Substances 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 14
- YEJGWUTXWBGOPG-UHFFFAOYSA-N 5-chloro-2-methyl-3-nitropyridine Chemical compound CC1=NC=C(Cl)C=C1[N+]([O-])=O YEJGWUTXWBGOPG-UHFFFAOYSA-N 0.000 claims abstract description 12
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003446 ligand Substances 0.000 claims abstract description 10
- 238000005859 coupling reaction Methods 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
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- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 4
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- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
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- 239000012312 sodium hydride Substances 0.000 claims description 4
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- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 claims description 4
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- 238000004519 manufacturing process Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- PPTXVXKCQZKFBN-UHFFFAOYSA-N (S)-(-)-1,1'-Bi-2-naphthol Chemical compound C1=CC=C2C(C3=C4C=CC=CC4=CC=C3O)=C(O)C=CC2=C1 PPTXVXKCQZKFBN-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 229910000881 Cu alloy Inorganic materials 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 2
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- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
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- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
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- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 2
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- 239000008096 xylene Substances 0.000 claims description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims 1
- 229910052802 copper Inorganic materials 0.000 claims 1
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- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000009776 industrial production Methods 0.000 abstract description 4
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- BJCJYEYYYGBROF-UHFFFAOYSA-N 4-[(4-methylpiperazin-1-yl)methyl]-n-[6-methyl-5-[(4-pyridin-3-ylpyrimidin-2-yl)amino]pyridin-3-yl]-3-(trifluoromethyl)benzamide Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=NC=2)C=C1C(F)(F)F BJCJYEYYYGBROF-UHFFFAOYSA-N 0.000 description 11
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Abstract
The invention discloses a preparation method of 2-methyl-3-nitro-5-aminopyridine, which comprises the steps of firstly carrying out coupling reaction on 2-methyl-3-nitro-5-chloropyridine and benzophenone imine under the action of a catalyst, a ligand and alkali to generate N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine, and then carrying out acid hydrolysis to obtain a target 2-methyl-3-nitro-5-aminopyridine. The method has the advantages of cheap and easily obtained raw materials, simple operation of the synthesis method, mild reaction conditions, low requirement on equipment, suitability for the requirement of industrial production, and high social use value and application prospect.
Description
Technical Field
The invention relates to the technical field of organic synthesis intermediates, in particular to a preparation method of 2-methyl-3-nitro-5-aminopyridine.
Background
The 2-methyl-3-nitro-5-aminopyridine is an important organic synthesis intermediate and can be used for synthesizing a chronic myelocytic leukemia treatment drug Flumatinib (Flumatinib). At present, the intermediate synthesis method has few reports and is difficult to purchase in the market, so that the development of an efficient and clean method for preparing the 2-methyl-3-nitro-5-aminopyridine is of great significance. The flumatinib is a new anti-tumor class 1 medicament independently developed by Jiangsu Haosen pharmaceutical industry group Limited company, is approved by NMPA (national drug supervision administration) in 11, 22 and 2019 in 11, and is mainly used for treating chronic myelocytic leukemia in clinic, and at present, the synthesis of the flumatinib mainly comprises the following methods:
WO2006069525 and the article "Synthetic Communications" An International Journal for Rapid Communication of Synthetic Organic Chemistry (Synthetic Communications,40 (17), 2564-2570) respectively disclose a method for preparing flumatinib by using 2-methyl-3-amino-5-nitropyridine as a starting material and sequentially carrying out substitution, reduction and condensation reactions. The intermediate 2-methyl-3-amino-5-nitropyridine used in the method is expensive, a sodium hydride hazardous reagent is required for the reaction, the requirement on equipment is high, a condensing agent or an acyl chloride intermediate is required for the condensation reaction, and the product purification is not facilitated, so that the method is not suitable for industrial production.
Chinese patent CN102796079 discloses a method for synthesizing flumatinib by using carboxylic acid and amino compound as raw materials under the action of a condensing agent EDCI. The method needs a condensing agent EDCI, is not beneficial to the purification of products, and is not suitable for industrial production.
Chinese patent CN105884746 reports a method for synthesizing flumatinib by using 2-methyl-3-nitro-5-aminopyridine as a starting material and sequentially performing condensation, reduction and substitution reactions, although the method also requires hazardous reagents such as sodium hydride, the method does not need to use a condensing agent, and avoids the complicated product post-treatment problem.
Since the preparation of flumatinib by using a condensing agent causes complicated post-treatment and product quality problems, it is particularly important to develop a new method for preparing flumatinib without using a condensing agent. The 2-methyl-3-nitro-5-aminopyridine is used as a key intermediate for synthesizing the flumatinib, has wide sources of synthetic raw materials, is easy for large-scale production and is applied to the production of the flumatinib. Therefore, the development of an efficient synthesis method for preparing the 2-methyl-3-nitro-5-aminopyridine is of great significance.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide the preparation method of the 2-methyl-3-nitro-5-aminopyridine, which has the advantages of cheap and easily obtained raw materials, simple operation of the synthesis method, mild reaction conditions, lower equipment requirement, feasibility in technology, reasonableness in economy and higher cost performance and is suitable for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of 2-methyl-3-nitro-5-aminopyridine comprises the following steps:
step 1: taking 2-methyl-3-nitro-5-chloropyridine as a raw material, and carrying out a coupling reaction with benzophenone imine under the action of a catalyst, a ligand and alkali to generate N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine;
step 2: and (2) carrying out hydrolysis reaction on the N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine intermediate obtained in the step (1) under an acidic condition to obtain the 2-methyl-3-nitro-5-aminopyridine.
The reaction equation is as follows:
in step 1, the catalyst is selected from copperAny one or combination of more than two of a catalyst, a palladium-copper alloy catalyst, a nickel catalyst and a platinum catalyst. Further, pd is preferable 2 (dba) 3 、Pd(PPh 3 ) 4 、PdCl 2 (Ph 3 P) 2 Or Pd (OAc) 3 Pd is particularly preferable 2 (dba) 3 . In step 1, the ligand is selected from XantPhos, PPh 3 、P t Bu、PCy 3 Any one of dppf, XPhos, SPhos, BINOL or (S) - (-) -BINAP, preferably (S) - (-) -BINAP.
In the step 1, the base is an organic base and/or an inorganic base, the organic base is selected from one or a combination of more than two of triethylamine, N-diisopropylethylamine, N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, and the inorganic base is selected from one or a combination of more than two of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate or sodium hydride. Preference is given to the inorganic bases sodium carbonate, potassium carbonate or cesium carbonate.
In step 1, the molar ratio of 2-methyl-3-nitro-5-chloropyridine to benzophenone imine to catalyst to ligand to base is 1.0-1.5. For example 1.0.01, 1.0.
In step 1, the coupling reaction is carried out in the presence of a solvent, wherein the solvent is any one or a combination of more than two of toluene, xylene, trimethylbenzene, chlorobenzene, benzene, acetonitrile, tetrahydrofuran, 1,4-dioxane, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and hexamethylphosphoric triamide. Toluene, a non-polar aprotic solvent, is preferred.
In step 1, the reaction is carried out at a suitable temperature, which may range from room temperature to the boiling point of the solvent used. For example, 25 ℃, 30 ℃, 35 ℃,40 ℃, 45 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃, 130 ℃, or the like, or the reaction is carried out under the condition of the boiling point of the solvent, i.e., the reflux state.
The reaction time of step 1 is 0.5 to 48 hours, for example, 0.5 hour, 1 hour, 3 hours, 5 hours, 8 hours, 10 hours, 12 hours, 15 hours, 18 hours, 20 hours, 23 hours, 25 hours, 28 hours, 30 hours, 33 hours, 35 hours, 38 hours, 40 hours, 44 hours or 48 hours.
In step 2, the acid is any one or a combination of two or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, glacial acetic acid or hydrobromic acid. Hydrochloric acid is further preferred.
In step 2, the amount of the acidic substance is 1 to 5 times, for example, 1 time, 1.3 times, 1.5 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 4.5 times, or 5 times the molar amount of N- (diphenylmethylene) -6-methyl-5-nitropyridin-3-amine.
In the step 2, the reaction is carried out in the presence of a solvent, wherein the solvent is any one or the combination of more than two of water, tetrahydrofuran, 1,4-dioxane or N, N-dimethylformamide. Further preferred is water, a polar protic solvent.
In step 2, the reaction is carried out at an appropriate temperature, which may range from room temperature to the boiling point of the solvent used, for example, 25 ℃, 30 ℃, 35 ℃,40 ℃, 45 ℃, 50 ℃, 60 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃ or the like, or under the boiling point of the solvent, i.e., under reflux.
Further, the reaction of the 2-methyl-3-nitro-5-chloropyridine and benzophenone imine in the step 1 to generate the N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine through the coupling reaction under the action of a catalyst, a ligand and alkali comprises the following steps:
dissolving 2-methyl-3-nitro-5-chloropyridine in toluene, and sequentially adding benzophenone imine, alkali and tris (dibenzylideneacetone) dipalladium (Pd) under stirring at room temperature 2 (dba) 3 ) And S- (-) -1,1 '-binaphthyl-2,2' -bis-diphenylphosphine ((S) - (-) -BINAP). N for complete feed system 2 The reaction was terminated by 3 times of replacement, heating to reflux (110 ℃ C.), and TLC monitoring until the reaction did not proceed any more. Cooling the reaction liquid to room temperature, performing suction filtration, washing the filter cake with toluene for 3 times, combining the filtrates, and concentrating the filtrate under reduced pressure to obtain an oily liquid, i.e. a crude product N- (diphenyl)Methylene) -6-methyl-5-nitropyridin-3-amine, the crude product was not purified and was directly subjected to the next reaction.
Further, the reaction of hydrolyzing N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine under acidic condition to obtain 2-methyl-3-nitro-5-aminopyridine in the step 2 comprises the following steps:
adding a proper amount of hydrochloric acid aqueous solution into N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine, adjusting the pH of the system to be = 3-4, stirring for 4h at room temperature, and finishing the reaction after the raw material reaction is monitored by TLC. Extracting the system with petroleum ether, discarding an organic phase, adjusting the pH of a water phase to be 8-9 with 1M sodium hydroxide aqueous solution, extracting with ethyl acetate, concentrating under reduced pressure, recrystallizing a crude product with ethyl acetate, and performing suction filtration to obtain a light yellow solid, namely the product 2-methyl-3-nitro-5-aminopyridine.
Compared with the prior art, the invention has the beneficial effects that:
the method for preparing the 2-methyl-3-nitro-5-aminopyridine has the advantages of simple reaction operation, mild reaction conditions, cheap and easily obtained raw materials, low requirement on equipment, capability of meeting the requirement of industrial mass production, and higher social use value and application prospect.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a 1H NMR nuclear magnetic spectrum of 2-methyl-3-nitro-5-aminopyridine.
FIG. 2 is a 13C NMR nuclear magnetic spectrum of 2-methyl-3-nitro-5-aminopyridine.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all embodiments of the present invention. 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
(1) The preparation method of the N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine comprises the following steps:
2-methyl-3-nitro-5-chloropyridine (1.0kg, 5.79mol, 1.0eq) was dissolved in 8L of toluene, and benzophenone imine (1.1kg, 6.08mol, 1.05eq), potassium carbonate (1.6kg, 11.59mol, 2.0eq), tris (dibenzylideneacetone) dipalladium (52.99g, 57.90mmol, 0.01eq) and S- (-) -1,1 '-binaphthyl-2,2' -bis-diphenylphosphine (72.111g, 115.80mmol, 0.02eq) were added in this order with stirring at room temperature. After the addition of the raw material system, the reaction was terminated by replacing the system with N2 3 times, heating to reflux (110 ℃), and monitoring by TLC until the reaction did not proceed any more. The reaction solution was cooled to room temperature, filtered, the filter cake was washed 3 times with toluene (500ml. Times.3), the filtrates were combined and concentrated under reduced pressure to give an oily liquid product N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine (1.8 kg, yield: about 95%), and the crude product was directly subjected to the next reaction without purification.
(2) The preparation method of the 2-methyl-3-nitro-5-aminopyridine comprises the following steps:
an appropriate amount of aqueous hydrochloric acid was added to N- (diphenylmethylene) -6-methyl-5-nitropyridin-3-amine (1.7kg, 5.36mol, 1.0eq), the system PH was adjusted to 3 to 4, stirring was carried out at room temperature for 4 hours, and the reaction was terminated after completion of the raw material reaction by tlc monitoring. The system was extracted with petroleum ether (1l × 2), the organic phase was discarded, the aqueous phase was adjusted to PH = 8-9 with 1M aqueous sodium hydroxide solution, extracted with ethyl acetate (1l × 3), the organic phase was concentrated under reduced pressure, and the crude product was recrystallized with ethyl acetate (1L), and suction filtered to give a pale yellow solid, i.e., the product 2-methyl-3-nitro-5-aminopyridine ((787.56 g, yield: 96%). 1H NMR (400mhz, dmso-d 6) δ 8.12 (d, J =2.6hz, 1h), 7.49 (d, J =2.6hz, 1h), 5.79 (s, 2H), 2.53 (s, 3H).
13C NMR(101MHz,DMSO-d6)δ145.92,144.61,140.26,138.63,115.12,22.67.HRMS(ESI)calcd for C6H7N3O2[M+H+]:154.0611,found:154.0376.
Example 2
(1) The preparation method of the N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine comprises the following steps:
2-methyl-3-nitro-5-chloropyridine (1.0kg, 5.79mol, 1.0eq) was dissolved in 8L of toluene, and benzophenone imine (1.1kg, 6.08mol, 1.05eq), cesium carbonate (3.78kg, 11.59mol, 2.0eq), tris (dibenzylideneacetone) dipalladium (52.99g, 57.90mmol, 0.01eq) and S- (-) -1,1 '-binaphthyl-2,2' -bis-diphenylphosphine (72.111g, 115.80mmol, 0.02eq) were added in this order with stirring at room temperature. After the addition of the raw material system, the reaction was terminated by replacing the system with N2 3 times, heating to reflux (110 ℃ C.), and monitoring by TLC until the reaction did not proceed any more. The reaction solution was cooled to room temperature, filtered, the filter cake was washed 3 times with toluene (500ml. Times.3), the filtrates were combined and concentrated under reduced pressure to give an oily liquid product N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine (1.75 kg, yield: about 94%), and the crude product was directly subjected to the next reaction without purification.
(2) The preparation method of the 2-methyl-3-nitro-5-aminopyridine comprises the following steps:
an appropriate amount of aqueous hydrochloric acid was added to N- (diphenylmethylene) -6-methyl-5-nitropyridin-3-amine (1.6 kg,5.04mol, 1.0eq), the system PH was adjusted to 3 to 4, the mixture was stirred at room temperature for 4 hours, and the reaction was terminated after completion of the reaction of the starting materials monitored by tlc. The system was extracted with petroleum ether (1l × 2), the organic phase was discarded, the aqueous phase was adjusted PH = 8-9 with 1M aqueous sodium hydroxide solution, extracted with ethyl acetate (1l × 3), the organic phase was concentrated under reduced pressure, and the crude product was recrystallized with ethyl acetate (1L), and suction filtered to give the product 2-methyl-3-nitro-5-aminopyridine ((741.23 g, yield: 96%). 1H NMR (400mhz, dmso-d 6) δ 8.12 (d, J =2.6hz, 1h), 7.49 (d, J =2.6hz, 1h), 5.79 (s, 2H), 2.53 (s, 3H), as a pale yellow solid.
13C NMR(101MHz,DMSO-d6)δ145.92,144.61,140.26,138.63,115.12,22.67.HRMS(ESI)calcd for C6H7N3O2[M+H+]:154.0611,found:154.0376.
Example 3
(1) The preparation method of the N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine comprises the following steps:
2-methyl-3-nitro-5-chloropyridine (1.0kg, 5.79mol, 1.0eq) was dissolved in 8.5L of toluene, and benzophenone imine (1.1kg, 6.08mol, 1.05eq), sodium carbonate (1.23kg, 11.59mol, 2.0eq), tris (dibenzylideneacetone) dipalladium (52.99g, 57.90mmol, 0.01eq) and S- (-) -1,1 '-binaphthyl-2,2' -bis-diphenylphosphine (72.111g, 115.80mmol, 0.02eq) were added in this order with stirring at room temperature. After the addition of the raw material system, the reaction was terminated by replacing the system with N2 3 times, heating to reflux (110 ℃ C.), and monitoring by TLC until the reaction did not proceed any more. The reaction solution was cooled to room temperature, filtered, the filter cake was washed 3 times with toluene (600ml x 3), the filtrates were combined and concentrated under reduced pressure to give an oily liquid product N- (diphenylmethylene) -6-methyl-5-nitropyridin-3-amine (1.82 kg, yield: about 97%), and the crude product was directly subjected to the next reaction without purification.
(2) The preparation method of the 2-methyl-3-nitro-5-aminopyridine comprises the following steps:
n- (diphenylmethylene) -6-methyl-5-nitropyridin-3-amine (1.65kg, 5.20mol, 1.0eq) was added with an appropriate amount of aqueous hydrochloric acid solution, the system pH = 3-4 was adjusted, stirred at room temperature for 4 hours, and the reaction was terminated after TLC monitoring of completion of the reaction of the raw materials. Extracting the system with petroleum ether (1L × 2), discarding the organic phase, adjusting the pH of the aqueous phase with 1M aqueous solution of sodium hydroxide to be 8-9, extracting with ethyl acetate (1L × 3), concentrating the organic phase under reduced pressure, recrystallizing the crude product with ethyl acetate (1L), and performing suction filtration to obtain a light yellow solid, namely the product of 2-methyl-3-nitro-5-aminopyridine (756.43 g, yield: 95%). 1H NMR (400MHz, DMSO-d 6) delta 8.12 (d, J =2.6Hz, 1H), 7.49 (d, J =2.6Hz, 1H), 5.79 (s, 2H), 2.53 (s, 3H).
13C NMR(101MHz,DMSO-d6)δ145.92,144.61,140.26,138.63,115.12,22.67.HRMS(ESI)calcd for C6H7N3O2[M+H+]:154.0611,found:154.0376。
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 (10)
1. A preparation method of 2-methyl-3-nitro-5-aminopyridine is characterized by comprising the following steps:
step 1: taking 2-methyl-3-nitro-5-chloropyridine as a raw material, and carrying out a coupling reaction with benzophenone imine under the action of a catalyst, a ligand and alkali to generate N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine;
step 2: carrying out hydrolysis reaction on the N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine intermediate obtained in the step 1 under an acidic condition to obtain 2-methyl-3-nitro-5-aminopyridine;
the reaction equation is as follows:
2. the process according to claim 1, wherein the reaction is carried out in the presence of a 2-methyl-3-nitro-5-aminopyridine: in step 1, the catalyst is selected from one or a combination of more than two of a copper catalyst, a palladium-copper alloy catalyst, a nickel catalyst and a platinum catalyst.
3. The process according to claim 1, wherein the reaction is carried out in the presence of a 2-methyl-3-nitro-5-aminopyridine: in step 1, the ligand is selected from XantPhos and PPh 3 、P t Bu、PCy 3 Any one of dppf, XPhos, SPhos, BINOL or (S) - (-) -BINAP.
4. The process according to claim 1, wherein the reaction is carried out in the presence of a 2-methyl-3-nitro-5-aminopyridine: in the step 1, the base is an organic base and/or an inorganic base, the organic base is one or a combination of more than two of triethylamine, N-diisopropylethylamine, N-dimethylaniline, pyridine, sodium methoxide, sodium ethoxide, sodium tert-butoxide or potassium tert-butoxide, and the inorganic base is one or a combination of more than two of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate or sodium hydride.
5. The process according to claim 1, wherein the reaction is carried out in the presence of a 2-methyl-3-nitro-5-aminopyridine: in step 1, the molar ratio of 2-methyl-3-nitro-5-chloropyridine to benzophenone imine to catalyst to ligand to base is 1.0-1.5.
6. The process according to claim 1, wherein the reaction is carried out in the presence of a 2-methyl-3-nitro-5-aminopyridine: in the step 1, the coupling reaction is carried out in the presence of a solvent, wherein the solvent is any one or a combination of more than two of toluene, xylene, trimethylbenzene, chlorobenzene, benzene, acetonitrile, tetrahydrofuran, 1,4-dioxane, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone and hexamethylphosphoric triamide.
7. The process according to claim 1, wherein the reaction is carried out in the presence of a 2-methyl-3-nitro-5-aminopyridine: in step 2, the acid is any one or a combination of two or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, glacial acetic acid or hydrobromic acid.
8. The process according to claim 1, wherein the reaction is carried out in the presence of a 2-methyl-3-nitro-5-aminopyridine: in the step 2, the dosage of the acidic substance is 1 to 5 times of the molar weight of the N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine.
9. The process of any one of claims 1 to 6, wherein the step 1 of coupling 2-methyl-3-nitro-5-chloropyridine with benzophenone imine in the presence of a catalyst, a ligand and a base to produce N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine comprises the steps of:
dissolving 2-methyl-3-nitro-5-chloropyridine in toluene, and sequentially adding benzophenone imine, alkali, ligand and catalyst under stirring at room temperature; n for complete feed system 2 Replacing for 3 times, heating up and refluxing, and finishing the reaction when TLC monitors that the reaction is not carried out any more; and (2) cooling the reaction liquid to room temperature, performing suction filtration, washing a filter cake for 3 times by using toluene, combining filtrate, and performing reduced pressure concentration on the filtrate to obtain oily liquid, namely a crude product N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine, wherein the crude product is not purified and is directly subjected to the next reaction.
10. The process for preparing 2-methyl-3-nitro-5-aminopyridine according to claim 1, 7 or 8, wherein the step 2 of hydrolyzing N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine under acidic condition to obtain 2-methyl-3-nitro-5-aminopyridine comprises the following steps:
slowly adding a hydrochloric acid aqueous solution into the oily matter N- (diphenylmethylene) -6-methyl-5-nitropyridine-3-amine obtained in the step 1, adjusting the pH of the system to be = 3-4, stirring at room temperature, and finishing the reaction after TLC monitors that the raw materials are reacted; extracting the system with petroleum ether, adjusting the pH value of a water phase to 8-9 with 1M sodium hydroxide aqueous solution, extracting with ethyl acetate, concentrating an organic phase under reduced pressure, and recrystallizing a crude product with ethyl acetate to obtain the 2-methyl-3-nitro-5-aminopyridine.
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| WO2006067445A2 (en) * | 2004-12-22 | 2006-06-29 | Astrazeneca Ab | Csf-1r kinase inhibitors |
| CN111072636A (en) * | 2019-12-16 | 2020-04-28 | 江苏豪森药业集团有限公司 | Synthesis method of flumatinib |
| CN111763170A (en) * | 2020-07-10 | 2020-10-13 | 江苏豪森药业集团有限公司 | Preparation method of flumatinib intermediate |
| WO2022136509A1 (en) * | 2020-12-23 | 2022-06-30 | Actelion Pharmaceuticals Ltd | Pyrazolothiazole carboxamides and their uses as pdgfr inhibitors |
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