CN118184591A - Preparation method of 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline - Google Patents

Preparation method of 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline Download PDF

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CN118184591A
CN118184591A CN202410151075.3A CN202410151075A CN118184591A CN 118184591 A CN118184591 A CN 118184591A CN 202410151075 A CN202410151075 A CN 202410151075A CN 118184591 A CN118184591 A CN 118184591A
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nitrobenzonitrile
hydroxy
methyl
methoxy
aniline
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陈君豪
茆勇军
刘威
王晗
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Shanghai University of Engineering Science
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Abstract

The invention relates to the field of pharmaceutical chemicals, and provides a preparation method of a deuterium-celecoxib intermediate 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline, which comprises the following steps: 2-hydroxy-3-nitrobenzonitrile is subjected to methylolation and reduction to obtain 3-amino-2-methoxybenzonitrile; 3-amino-2-methoxybenzonitrile reacts with N-methylformylhydrazine under alkaline condition to obtain 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline. The invention has low cost of the initial raw materials and easily obtained raw materials; the process is simple, the reaction is mild, and the operation is convenient; the generated byproducts have use value, reduce the damage of the byproducts, and the post-treatment is simple and convenient, thereby being beneficial to mass production; the yield of the target product is high, and the purity of the product is high.

Description

Preparation method of 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline
Technical Field
The invention relates to the field of pharmaceutical chemical industry, in particular to a preparation method of a pharmaceutical intermediate 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline.
Background
Deuterium-celecoxib is currently the first oral TYK2 allosteric inhibitor approved by the U.S. food and drug administration for psoriasis treatment worldwide, 10 days of 2022, 9 months of the year, and the bai-time meishi-nobility (BMS) announces FDA approval of TYK2 inhibitor Sotyktu (Deucravacitinib, deuterium-celecoxib) to the market, and is an important targeted drug for the treatment of complicated diseases such as psoriasis, lupus erythematosus, multiple sclerosis, etc. that are co-participated in by the innate and adaptive immune systems. With the accumulation of practical clinical experimental experience, the real curative effect and the safety of the deuterium-celecoxib are fully evaluated, and the effect of the oral administration in the field of treatment of complicated immune diseases is proved. The final approval of deuterium-celecoxib may provide an alternative to currently available JAK inhibitors, possibly with greater safety and also greater economic value. Furthermore, deuterium-celecoxib may provide an effective treatment option for other potential dermatological indications, alopecia areata, psoriasis and lupus erythematosus. The chemical structure of the key intermediate is shown in a formula XI:
the current preparation of 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (XI), an organic intermediate for deuterium-celecoxib (Deucravacitinib), involves mainly two processes:
Method one (org. Process Res. Dev.2022,26,4,1202-1222) the synthetic route is shown in scheme I.
The first step of the method is to take 5-chloro-2-methoxybenzonitrile and N-methyl formylhydrazine as raw materials, react to obtain 3- (5-chloro-2-methoxyphenyl) -1-methyl-1H-1, 2, 4-triazole, and the yield is 94 percent (calculated by 5-chloro-2-methoxybenzonitrile), but the product is difficult to purify and has higher raw material cost, and the raw material 5-chloro-2-methoxybenzonitrile is not supplied in the market and still needs to be prepared; the second step of nitration reaction, the acid consumption is larger; and thirdly, catalytic hydrogenation reduction, reaction dechlorination can generate HCl, and the method has certain restriction on mass production.
Method II (J Med. Chem.2019,62, 8973-8995) and the synthetic route is shown in scheme II.
The method for synthesizing the 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline has high cost and low yield. Considering that the starting material methyl 2-methoxy-3-nitrobenzoate needs to go through the longest series of linear steps, it is prohibitively expensive. In addition, the overall yield of aniline fragment 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline is not high, only 26%; this is mainly due to the poor inherent regioselectivity of the triazole methylation reaction of the compound 3- (2-methoxy-3-nitrophenyl) -1H-1,2, 4-triazole.
Even with extensive optimization of bases, methylating agents, solvents and reaction temperatures, there are still a large number of isomers. Undesired isomers can be removed by crystallization but also result in a substantial loss of the desired isomer, so that the separation yield of the methylation step is only 40%.
The market price of raw materials of the two synthetic routes is high, and the market price is the key material cost of the routes. Accordingly, there is a need for an improvement over the prior art in view of the shortcomings of the prior art.
Disclosure of Invention
Aiming at the defects of the prior art, the preparation method and the application of the 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline in the technical scheme have the advantages of simple process route, low cost, convenient operation and high yield.
The invention aims to provide a preparation method of 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline, which comprises the following steps:
(1) Performing methylolation on the 2-hydroxy-3-nitrobenzonitrile to generate 2-hydroxy-3-nitrobenzonitrile;
(2) Reducing the 2-hydroxy-3-nitrobenzonitrile to obtain 3-amino-2-methoxybenzonitrile;
(3) 3-amino-2-methoxybenzonitrile reacts with N-methylformylhydrazine under alkaline condition to obtain 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline.
In the step (1), the preparation method of the 2-hydroxy-3-nitrobenzonitrile comprises the following steps: after the nitration of the o-hydroxybenzonitrile, separating 2-hydroxy-5-nitrobenzonitrile and 2-hydroxy-3-nitrobenzonitrile. Preferably, the nitration reaction is carried out with nitric acid as nitrating agent, preferably with a nitric acid concentration of 50% -75%, more preferably 65% -70%. The molar ratio of the o-hydroxybenzonitrile to the nitric acid is 1:0.5-2.0, preferably 1:1-2, more preferably 1:1.5-2.
The o-hydroxybenzonitrile, nitric acid and organic solvent are mixed for nitration reaction.
Further, the organic solvent is one or more of acetic acid, carbon tetrachloride, methylene dichloride or nitromethane.
The method for separating 2-hydroxy-5-nitrobenzonitrile and 2-hydroxy-3-nitrobenzonitrile is that the nitration reaction product is filtered, extracted by water and the organic phase is taken. The organic phase is concentrated and dried to obtain 2-hydroxy-3-nitrobenzonitrile. After drying, further purification with ethyl acetate and n-heptane was performed.
The reaction route is shown in a formula III:
Further, in the step (1), an electrophilic methylation reagent is selected for carrying out a methylolation reaction. 2-hydroxy-3-nitrobenzonitrile, electrophilic methylation reagent and alkali are mixed and reacted in organic solvent to obtain 2-methoxy-3-nitrobenzonitrile. The organic solvent is N, N-dimethylformamide, carbon tetrachloride, methylene dichloride, carbon tetrachloride or tetrahydrofuran.
Further, the electrophilic methylation reagent is a methyl ester electrophilic methylation reagent or a monohalomethane; the molar ratio of 2-hydroxy-3-nitrobenzonitrile to electrophilic methylating agent is 1:1-4; preferably 1:1-3.
The electrophilic methylation reagent is preferably dimethyl methyl sulfate or methyl iodide.
In a preferred mode of the invention, the molar ratio of the 2-hydroxy-3-nitrobenzonitrile to the electrophilic methylation reagent is 1:2.
The molar ratio of electrophilic methylating agent to base is 1:1-2, more preferably 1:1-1.5.
Preferably, the base is a carbonate.
Further, in the step (2), the nitro group of the 2-hydroxy-3-nitrobenzonitrile is reduced into an amino group by adopting a catalytic hydrogenation or Fe acid reduction method.
The hydrogenation process may employ a hydrogenation catalyst, such as a palladium catalyst or a nickel catalyst.
When adopting the Fe acid reduction method, the method comprises the following steps: dispersing Fe in an organic solvent, adding acid, and adding 2-methoxy-3-nitrobenzonitrile at 50-80 ℃ for reaction; and after the reaction is finished, regulating the pH to be alkaline, taking filtrate, adding water, and stirring to take precipitate. The molar ratio of 2-methoxy-3-nitrobenzonitrile to iron is 1:4-8, preferably 1:5.5-6.5. The acid is hydrochloric acid, and the molar ratio of the 2-methoxy-3-nitrobenzonitrile to the hydrochloric acid is 1:6-9.
Further, the alkaline condition of the step (3) is that the alkali is alkoxide and is selected from one of potassium tert-butoxide, sodium methoxide, sodium ethoxide, tert-butanol 2-methoxy-3-nitrobenzonitrile and sodium. The molar ratio of 3-amino-2-methoxybenzonitrile to alkoxide is 1:2-6, preferably 1:4. the molar ratio of 3-amino-2-methoxybenzonitrile to N-methylformylhydrazine is 1:2-5, preferably 1:3.4-3.5.
Further, the N-methylhydrazide is prepared by reacting methylhydrazine with methyl formate.
The 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline can be used as an intermediate for preparing the deuterium-celecoxib.
The invention has the advantages of easily obtained raw materials, low cost, mild reaction conditions, simple and convenient process and operation, simple and convenient post-treatment, suitability for amplified preparation, high yield of target products and high product purity.
The invention has low cost of the initial raw materials and easily obtained raw materials. 2-hydroxy-5-nitrobenzonitrile and 2-hydroxy-3-nitrobenzonitrile can be obtained through nitration of the o-hydroxybenzonitrile, and the two can be conveniently separated by utilizing the solubility difference of the two, wherein in the step, the yield of the target compound 2-hydroxy-3-nitrobenzonitrile can reach 32 percent, and the purity is more than 99 percent; the use of nitric acid close to the theoretical amount avoids the situation that a large amount of acid solvents are used to cause difficult environmental waste treatment; the nitrified byproduct 2-hydroxy-5-nitrobenzonitrile has use value, can be used for preparing various compounds and medical intermediates, has antitumor, anti-inflammatory activities (US20220305010;WO2020230136;ACS Chemical Biology(2018),13(9),2595-2602;European Journal of Medicinal Chemistry(2017),141,362-372;Bioorganic&Medicinal Chemistry Letters(2014),24(1),132-135; and the like, reduces the harm of byproducts, has simple post-treatment and has market application value;
2-hydroxy-3-nitrobenzonitrile is subjected to methylolation and reduction to obtain 3-amino-2-methoxyl benzonitrile, and the two steps of reaction are simple and convenient to operate and high in yield; the 3-amino-2-methoxybenzonitrile and N-methylformylhydrazine react under alkaline condition to obtain 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline, the yield is 80%, and the purity is more than 99%.
Detailed Description
The technical scheme of the invention is described below with reference to specific examples.
Example 1 2-hydroxy-3-nitrobenzonitrile (VI) (1)
O-hydroxybenzonitrile (V) (20 g,0.168 mol) was mixed with methylene chloride (170 mL), cooled to 3℃and 65% nitric acid (18 g,0.185 mol) was slowly added dropwise, the temperature was controlled at 5-10℃and after the addition was completed, the mixture was stirred at room temperature for 1h. After the reaction, 16.2g of yellow solid, mainly by-product 2-hydroxy-5-nitrobenzonitrile, was obtained by filtration. The nitration reaction conditions are relatively mild.
The filtrate was extracted twice with 100mL of ice water, and the organic phase was concentrated, dried and oven dried to give 14.62g of crude 2-hydroxy-3-nitrobenzonitrile. The crude product was dissolved in ethyl acetate (30 mL) at 70℃and after dissolution, n-heptane (30 mL) was added, stirred at room temperature, crystallized, filtered and dried to give 8.21g of 2-hydroxy-3-nitrobenzonitrile in a total yield of 29.8%.
1H NMR(400MHz,DMSO):δ8.47(dd,J＝8.4,1.6Hz,1H),8.15(dd,J＝7.6,1.6Hz,1H),7.31(dd,J＝8.4,7.6Hz,1H).ESI-MS(m/z)165.1[M+H]+.
HPLC: inertSustain C18 columns (250 mm. Times.4.6 mm. Times.5 μm); detecting 220nm; the flow rate is 0.8mL/min; the temperature is 30 ℃; injection amount is 1. Mu.L; a solvent, namely methanol; concentration is 0.2mg/mL; the running time is 25min; mobile phase A is water; mobile phase B, methanol; elution gradient mobile phase a/mobile phase b=10/90:t R =12.44 min, purity 99.2%.
Purification of 2-hydroxy-5-nitrobenzonitrile: 16g of crude product are added to dichloromethane (64 mL), heated to reflux and stirred for 2h; stirring for 2h at room temperature, crystallizing, filtering and drying to obtain 8.5g of 2-hydroxy-5-nitrobenzonitrile with the total yield of 30.9%.
HPLC: inertSustain C18 columns (250 mm. Times.4.6 mm. Times.5 μm); detecting 220nm; the flow rate is 0.8mL/min; the temperature is 30 ℃; injection amount is 1. Mu.L; a solvent, namely methanol; concentration: 0.2mg/mL; the running time is 25min; mobile phase A is water; mobile phase B, methanol; elution gradient: mobile phase a/mobile phase b=10/90:t R =13.91 min, purity 97.8%.
Example 2 2-hydroxy-3-nitrobenzonitrile (VI) (2)
O-hydroxybenzonitrile (20 g,0.168 mol) and acetic acid (100 mL) were mixed, warmed to 30℃and slowly added dropwise with 65% nitric acid (18 g,0.185 mol), the temperature was controlled to be less than 40℃and the mixture was allowed to react at room temperature for 2 hours after the completion of the addition. The reaction mixture was added to 400mL of ice water, stirred at room temperature for 1h, filtered, and the cake was heated with dichloromethane (300 mL), stirred at 45℃under reflux for about 1h, and then the heating was turned off and cooled to room temperature. The reaction solution was suction-filtered, and the filter cake was 9.4g of 2-hydroxy-5-nitrobenzonitrile as a by-product of the reaction. The nitration reaction conditions are relatively mild.
The filtrate was distilled off in a rotary manner to obtain about 23.4g of a crude product of 2-hydroxy-3-nitrobenzonitrile as a yellow solid. The crude product was dissolved in ethyl acetate (35 mL) at 70℃and then n-heptane (35 mL) was added thereto, followed by stirring at room temperature, crystallization, filtration and drying to give 8.83g of 2-hydroxy-3-nitrobenzonitrile in a total yield of 32.0%.
The result of the spectrogram was the same as in example 1.
Example 3 2-methoxy-3-nitrobenzonitrile (VII) (1)
2-Hydroxy-3-nitrobenzonitrile (13 g,0.08 mol), dimethyl sulfate (20.2 g,0.16 mol), anhydrous potassium carbonate (22.1 g,0.16 mol), N, N-dimethylformamide (65 mL) were mixed, heated to 60℃for 2 hours, and then heated to 80℃for 2 hours, and the center control reaction was completed. The anhydrous potassium carbonate serves to neutralize the byproduct sulfate after the dimethyl sulfate reaction. The reaction solution was added to 365mL of ice water, stirred for 1h, and filtered to give 12.7g of a yellow solid with a total yield of 89.5%.
1H NMR(400MHz,DMSO):δ8.29(dd,J＝8.2,1.7Hz,1H),8.19
(dd,J＝7.8,1.7Hz,1H),7.51(t,J＝8.0Hz,1H),4.09(s,3H)。
Example 4 2-methoxy-3-nitrobenzonitrile (VII) (2)
2-Hydroxy-3-nitrobenzonitrile (5 g,0.0305 mol), methyl iodide (3.81 mL,0.0609 mol), anhydrous potassium carbonate (12.63 g,0.0914 mol), N, N-dimethylformamide (25 mL) were mixed, stirred at room temperature for 16h, and the reaction was completed under control. The reaction solution was added to 150mL of ice water, stirred for 1h, and filtered to give 5.19g of a yellow solid with a total yield of 95.6%.
The result of the spectrogram was the same as in example 3.
Example 5 3-amino-2-methoxybenzonitrile (VIII) (1)
2-Methoxy-3-nitrobenzonitrile (5.0 g,0.028 mol) is dissolved in methanol (40 mL), 5% wet Pd-C1.0 g is added, hydrogen is replaced for 3 times, under the condition of introducing hydrogen, the temperature is raised to 40 ℃ for heating reaction for 4 hours, the reaction is finished, and the catalyst is filtered; the filtrate was distilled off in a rotary manner, and the obtained liquid was crystallized at room temperature to obtain 4.0g of dark green crystals, with a total yield of 98%.
1H NMR(400MHz,DMSO):δ6.97-6.96(s,2H),6.85-6.82(m,1H),5.45(s,2H),3.80(s,3H).
Example 6 3-amino-2-methoxybenzonitrile (VIII) (2)
Fe powder (13.52 g,0.242 mol) was added to ethanol (72 mL) and stirred. Dilute hydrochloric acid (21.74 g,0.322 mol) was added dropwise and the temperature was raised to 60 ℃. 2-methoxy-3-nitrobenzonitrile (7.18 g,0.04 mol) was added to the reaction solution in three portions at 10min intervals, and after the addition was completed, the temperature was raised to 80 ℃. After the reaction, 30% NaOH solution was added dropwise to adjust the pH to 9, then 40mL of ethanol was added, the mixture was filtered, the filtrate was distilled off by spinning, water was added, stirring was carried out, and 4.9g of yellow solid was obtained by filtration, and the total yield was 83%.
The result of the spectrogram was the same as in example 5.
EXAMPLE 7N-methylformylhydrazine (X)
Methyl hydrazine sulfate (40 g,0.278 mol) was dissolved in methanol (200 mL) in an ice bath under nitrogen, and 30% sodium methoxide methanol solution (105 g,0.583 mol) was added dropwise, keeping the temperature below 10 ℃. After the reaction, methyl hydrazine is obtained. The filtrate was filtered, cooled to-5℃and a solution of methyl formate (18.3 g,0.306 mol) in methanol (20 mL) was added to the filtrate, and the mixture was stirred at room temperature after the completion of the dropwise addition. The mixture was distilled to obtain 24.4g of crude liquid. The crude product was distilled under reduced pressure with an oil pump at an external temperature of 110℃to give 13.8g of N-methylformylhydrazine in a total yield of 67.2%.
1H NMR(400MHz,DMSO):δ8.04(s,1H),4.81(s,2H),2.99(s,3H)
Example 8 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline (XI)
3-Amino-2-methoxybenzonitrile (10 g,0.067 mol) and N-methylhydrazide (17.4 g,0.234 mol) were added to anhydrous THF (500 mL), mixed, and warmed to 60 ℃. An anhydrous solution of potassium t-butoxide in THF (268 mL,0.268 mol) was slowly added dropwise. The reaction was completed. To the reaction solution was added 100mL of water, heated to 40℃and stirred for 2h. The reaction was completed. The heating was turned off, cooled to room temperature, the aqueous layer was discarded, and 100mL of saturated brine was added. Concentrating under reduced pressure to 1/2 of the volume of the solution.
60ML of ethyl acetate was added and the mixture was distilled off with rotation, and the procedure was repeated three times.
To the reaction solution was added 100mL of ethyl acetate. Under the ice bath condition, 19.7g of concentrated sulfuric acid is slowly dripped to remove water, and the temperature is controlled to be lower than 10 ℃. Filtration gave 10.9g of solid, overall yield 80.2%.
1H NMR(400MHz,DMSO):δ8.47(s,1H),6.96(dd,J＝7.6,1.8Hz,1H),6.86(t,J＝7.7Hz,1H),6.75(dd,J＝7.8,1.8Hz,1H),4.98(s,2H),3.92(s,3H),3.67(s,3H).ESI-MS(m/z)205.1[M+H]+.
HPLC: inertSustain C18 columns (250 mm. Times.4.6 mm. Times.5 μm); detecting 220nm; the flow rate is 0.8mL/min; the temperature is 30 ℃; injection amount is 1. Mu.L; a solvent, namely methanol; concentration is 0.2mg/mL; the running time is 15min; mobile phase A is water; mobile phase B methanol/triethylamine = 100:0.1; elution gradient mobile phase a/mobile phase b=10/90:t R =6.38 min, purity 99.0%.
It should be noted that the foregoing embodiments are merely illustrative of the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the present invention and implement the same according to the present invention without limiting the scope of the present invention. All equivalent changes or modifications made in accordance with the spirit of the present invention should be construed to be included in the scope of the present invention.

Claims (10)

  1. A process for the preparation of 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazol-3-yl) aniline, characterized in that the steps comprise:
    (1) Performing methylolation on the 2-hydroxy-3-nitrobenzonitrile to generate 2-hydroxy-3-nitrobenzonitrile;
    (2) Reducing the 2-hydroxy-3-nitrobenzonitrile to obtain 3-amino-2-methoxybenzonitrile;
    (3) 3-amino-2-methoxybenzonitrile reacts with N-methylformylhydrazine under alkaline condition to obtain 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline.
  2. 2. The method according to claim 1, wherein in the step (1), the methylolation is performed with an electrophilic methylating agent.
  3. 3. The method of claim 2, wherein the electrophilic methylation reagent is a methyl ester electrophilic methylation reagent or a monohalomethane; the molar ratio of 2-hydroxy-3-nitrobenzonitrile to electrophilic methylating agent is 1:1-3.
  4. 4. The method of claim 2, wherein the electrophilic methylation reagent is dimethyl sulfate or methyl iodide.
  5. 5. The method according to claim 1, wherein in the step (2), the nitro group of 2-hydroxy-3-nitrobenzonitrile is reduced to an amino group by catalytic hydrogenation or Fe acid reduction.
  6. 6. The process according to claim 1, wherein in the step (1), the process for producing 2-hydroxy-3-nitrobenzonitrile comprises: after the nitration of the o-hydroxybenzonitrile, separating 2-hydroxy-5-nitrobenzonitrile and 2-hydroxy-3-nitrobenzonitrile.
  7. 7. The process according to claim 6, wherein the nitration reaction is carried out with nitric acid as a nitrating agent.
  8. 8. The method of claim 6, wherein the molar ratio of o-hydroxybenzonitrile to nitric acid is 1:0.5-2.0.
  9. 9. The method according to claim 1, wherein the N-methylhydrazide is prepared by reacting methylhydrazine with methyl formate.
  10. 10. The process of claim 1, wherein in step (3), the base is an alkoxide.
CN202410151075.3A 2024-02-02 2024-02-02 Preparation method of 2-methoxy-3- (1-methyl-1H-1, 2, 4-triazole-3-yl) aniline Pending CN118184591A (en)

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