Preparation method of N2-BOC-isonicotinic acid hydrazine-1-oxygen

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of N2-BOC-isonicotinic acid hydrazine-1-oxygen, which comprises the following steps: step 1, synthesizing isonicotinic acid nitric oxide: reacting methyl isonicotinic acid nitric oxide with hydrazine hydrate to obtain a reaction solution of isonicotinic acid nitric oxide; and 2, synthesizing N2-BOC-isonicotinic acid hydrazine-1-oxygen: directly reacting the reaction solution of the isonicotinic acid nitrogen oxide in the step 1 with sodium bicarbonate and BOC anhydride to obtain the final product N2-BOC-isonicotinic acid hydrazine-1-oxygen. The preparation method of the N2-BOC-isonicotinic acid hydrazine-1-oxygen has the beneficial effects that the total reaction yield is high, the purity of the prepared N2-BOC-isonicotinic acid hydrazine-1-oxygen is high, the safety of the raw materials is high, the reaction condition is mild, the reaction time is short, and the operation is simple.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxygen. Background Art

[0002] Gout is a crystal-related arthropathy caused by the deposition of monosodium urate, which is directly related to hyperuricemia caused by purine metabolism disorders or reduced uric acid excretion. Topinostat is an oral drug used to treat hyperuricemia and gout. It inhibits xanthine oxidase and reduces the production of uric acid, thereby effectively reducing the level of uric acid in the blood. Lowering uric acid levels helps reduce the frequency and severity of gout attacks. At the same time, topinostat also helps improve kidney problems related to hyperuricemia. The drug has performed well in clinical trials, has significant efficacy, and is highly safe. At present, the preparation method of topinostat usually uses 2-cyano-isonicotinic acid methyl ester as the starting material, which has a high cost. However, N2-BOC-isonicotinic acid hydrazine-1-oxy is used as the starting material of another route, and its synthesis method is rarely reported.

[0003] Patent EP1471065 discloses a method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxygen, using isonicotinic acid oxide as a starting material, first reacting with ethyl chloroformate to generate 4-pyridinecarbonyl chloride, and the acylate reacts with N-BOC hydrazine to generate N2-BOC-isonicotinic acid hydrazine-1-oxygen; the method has a long reaction time, a low reaction yield, and ethyl chloroformate has strong irritation and toxicity, so the method is not conducive to large-scale industrial production. Therefore, it is particularly important to develop a method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxygen with a short reaction time, high reaction yield and product purity, and without the participation of toxic ethyl chloroformate in the reaction. Summary of the invention

[0004] In view of the above problems, the present invention provides a method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxy.

[0005] The present invention relates to a method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxygen, comprising the following steps: Step 1: Synthesis of isoniazid nitrogen oxide: Add a reaction solvent to a reaction container, then add isonicotinoic acid methyl ester nitrogen oxide, start stirring, first cool down, then slowly drop hydrazine hydrate, after the dropwise addition is completed, carry out heat preservation reaction, TLC monitors the reaction, after the reaction is completed, obtains a reaction solution of isonicotinoic acid methyl ester nitrogen oxide; Step 2: Synthesis of N2-BOC-isonicotinic acid hydrazine-1-oxy: Sodium bicarbonate is added to the reaction solution of isoniazid nitrogen oxide in step 1, and then the temperature is raised, and BOC anhydride is slowly added dropwise. After the addition is complete, the reaction is kept warm and monitored by TLC. After the reaction is complete, water is added for crystallization and then filtered. The filter cake is a crude product of N2-BOC-isonicotinic acid hydrazine-1-oxygen. The crude product is recrystallized to obtain the final product N2-BOC-isonicotinic acid hydrazine-1-oxygen; The synthetic route is as follows: .

[0006] Preferably, in the step 1, the molar ratio of methyl isonicotinate nitrogen oxide to hydrazine hydrate is 1:1.0-3.0.

[0007] Preferably, in the step 1, the mass ratio of the methyl isonicotinate nitrogen oxide to the reaction solvent is 1:5-20, and the reaction solvent is N,N-dimethylformamide.

[0008] Preferably, in the step 1, the temperature is lowered to -10°C to -5°C; and the reaction is kept at -10°C to 0°C for 3 to 5 hours.

[0009] Preferably, in step 1 and step 2, the molar ratio of methyl isonicotinate nitrogen oxide, BOC anhydride and sodium bicarbonate is 1:1.0-3.0:1.0-3.0.

[0010] Preferably, in the step 2, the mass ratio of the methyl isonicotinate nitrogen oxide to water is 1:5-20.

[0011] Preferably, in the step 2, the temperature is raised to 20°C to 30°C; and the reaction is kept at 20°C to 30°C for 1 to 3 hours.

[0012] Preferably, in the step 2, the crude product of N2-BOC-isonicotinic acid hydrazine-1-oxy is recrystallized with methanol.

[0013] Preferably, the mass ratio of the crude N2-BOC-isonicotinic acid hydrazine-1-oxide to methanol is 1:1-5.

[0014] Preferably, in the step 2, the recrystallization temperature is -5°C to 10°C, and the time is 0.5h to 3h.

[0015] Compared with the prior art, the advantages and positive effects of the present invention are: (1) The method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxygen has a high total reaction yield, improves the utilization efficiency of raw materials, reduces the generation of by-products, thereby reducing production costs and reducing the burden on the environment; at the same time, the prepared N2-BOC-isonicotinic acid hydrazine-1-oxygen has high purity, better chemical stability, and improved market competitiveness; (2) The preparation method of N2-BOC-isonicotinic acid hydrazine-1-oxy has mild reaction conditions and does not require toxic ethyl chloroformate to participate in the reaction, so the reaction process is easier to control, reducing the impact of scaling up to industrial production scale on reaction performance, and the production process is safer, reducing harm to the environment; (3) The preparation method of N2-BOC-isonicotinic acid hydrazine-1-oxy has a short reaction time and is simple to operate, thereby reducing time and labor costs and improving the stability of large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] In order to more clearly illustrate the technical solution of the embodiment of the present invention, the following briefly introduces the drawings required for describing the embodiment. Figure 1 The HPLC spectrum of the final product obtained in Example 1. DETAILED DESCRIPTION

[0017] In order to more clearly understand the above-mentioned objects, features and advantages of the present invention, the present invention is further described below in conjunction with embodiments.

[0018] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways than those described herein. Therefore, the present invention is not limited to the specific embodiments of the following disclosure.

[0019] Example 1 A method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxygen comprises the following steps: Step 1: Synthesis of isoniazid nitrogen oxide: Add 500 g of N,N-dimethylformamide to a 1L reaction bottle, then add 50 g of methyl isonicotinate N-oxide, start stirring, first cool to -10°C, then slowly add 16.52 g of hydrazine hydrate, after the addition is complete, keep the reaction at 0°C for 4 hours, monitor the reaction by TLC, and after the reaction is complete, obtain a reaction solution of isonicotinoic acid hydrazine N-oxide.

[0020] Step 2: Synthesis of N2-BOC-isonicotinic acid hydrazine-1-oxy: 54.8 g of sodium bicarbonate was added to the reaction solution of isoniazid nitrogen oxide in step 1, and then the temperature was raised to 25° C., and then 85 g of BOC anhydride was slowly added dropwise. After the addition was completed, the reaction was kept at 25° C. for 2 h, and the reaction was monitored by TLC. After the reaction was completed, 500 g of water was added for crystallization and then filtered to obtain 82 g of a crude product of N2-BOC-isonicotinic acid hydrazine-1-oxygen. The crude product was recrystallized with 100 g of methanol at -5° C. for 2 h to obtain 79 g of the final product N2-BOC-isonicotinic acid hydrazine-1-oxygen, with a yield of 95.5%, an HPLC purity (area normalization method) of 99.76%, and a single impurity of less than 0.2%. The melting point was 171.3° C.

[0021] Example 2 A method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxygen comprises the following steps: Step 1: Synthesis of isoniazid nitrogen oxide: Add 2.5 kg of N,N-dimethylformamide to a 5L reaction bottle, then add 250 g of methyl isonicotinate N-oxide, start stirring, first cool to -5°C, then slowly add 150.2 g of hydrazine hydrate, after the addition is complete, keep warm at -5°C for 3 hours, monitor the reaction by TLC, after the reaction is complete, obtain a reaction solution of isoniazid N-oxide.

[0022] Step 2: Synthesis of N2-BOC-isonicotinic acid hydrazine-1-oxy: 274 g of sodium bicarbonate was added to the reaction solution of isoniazid nitrogen oxide in step 1, and then the temperature was raised to 25° C., and 698.4 g of BOC anhydride was slowly added dropwise. After the addition was completed, the reaction was kept warm at 30° C. for 1.5 h, and the reaction was monitored by TLC. After the reaction was completed, 12.5 kg of water was added for crystallization and then filtered to obtain 401 g of a crude product of N2-BOC-isonicotinic acid hydrazine-1-oxygen. The crude product was recrystallized with 1.2 kg of methanol at 8° C. for 3 h to obtain 395 g of the final product N2-BOC-isonicotinic acid hydrazine-1-oxygen, with a yield of 95.7%, an HPLC purity (area normalization method) of 99.28%, a single impurity of less than 0.15%, and a melting point of 172.0° C.

[0023] Example 3 A method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxygen comprises the following steps: Step 1: Synthesis of isoniazid nitrogen oxide: Add 50 kg of N,N-dimethylformamide to a 100 L reaction bottle, then add 5 kg of methyl isonicotinate nitrogen oxide, start stirring, first cool to 0°C, then slowly add 3 kg of hydrazine hydrate, after the addition is complete, keep warm at 0°C for 5 hours, monitor the reaction by TLC, and after the reaction is completed, obtain a reaction solution of isoniazid nitrogen oxide.

[0024] Step 2: Synthesis of N2-BOC-isonicotinic acid hydrazine-1-oxy: 5.5 kg of sodium bicarbonate was added to the reaction solution of isoniazid nitrogen oxide in step 1, and then the temperature was raised to 20° C., and then 8.5 kg of BOC anhydride was slowly added dropwise. After the addition was completed, the reaction was kept at 25° C. for 2 h, and the reaction was monitored by TLC. After the reaction was completed, 12.5 kg of water was added for crystallization and then filtered to obtain 8.1 kg of crude N2-BOC-isonicotinic acid hydrazine-1-oxygen. The crude product was recrystallized with 40 kg of methanol at 0° C. for 1 h to obtain 8 kg of the final product N2-BOC-isonicotinic acid hydrazine-1-oxygen, with a yield of 96.9%, an HPLC purity (area normalization method) of 99.5%, and a single impurity of less than 0.2%. The melting point was 171.6° C.

[0025] The above description is only a preferred embodiment of the present invention and does not limit the present invention in other forms. Any technician familiar with the profession may use the technical content disclosed above to change or modify it into an equivalent embodiment with equivalent changes for application in other fields. However, any simple modification or equivalent change made to the above embodiment based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxygen, characterized in that: The following steps are involved: Step 1: Synthesis of isoniazid nitrogen oxide: Add a reaction solvent to a reaction container, then add isonicotinoic acid methyl ester nitrogen oxide, start stirring, first cool down, then slowly drop hydrazine hydrate, after the dropwise addition is completed, carry out heat preservation reaction, TLC monitors the reaction, after the reaction is completed, obtains a reaction solution of isonicotinoic acid methyl ester nitrogen oxide; Step 2: Synthesis of N2-BOC-isonicotinic acid hydrazine-1-oxy: Sodium bicarbonate is added to the reaction solution of isoniazid nitrogen oxide in step 1, and then the temperature is raised, and BOC anhydride is slowly added dropwise. After the addition is complete, the reaction is kept warm and monitored by TLC. After the reaction is complete, water is added for crystallization and then filtered. The filter cake is a crude product of N2-BOC-isonicotinic acid hydrazine-1-oxygen. The crude product is recrystallized to obtain the final product N2-BOC-isonicotinic acid hydrazine-1-oxygen; The synthetic route is as follows: 。 2. The method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxygen according to claim 1, characterized in that: In the step 1, the molar ratio of the methyl isonicotinate nitrogen oxide to the hydrazine hydrate is 1:1.0-3.

0.

3. The method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxy according to claim 1, characterized in that: In the step 1, the mass ratio of the methyl isonicotinate nitrogen oxide to the reaction solvent is 1:5-20, and the reaction solvent is N,N-dimethylformamide.

4. The method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxy according to claim 1, characterized in that: In the step 1, the temperature is lowered to -10°C to -5°C; and the reaction is kept at -10°C to 0°C for 3 to 5 hours.

5. The method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxy according to claim 1, characterized in that: In the step 1 and the step 2, the molar ratio of the methyl isonicotinate nitrogen oxide, BOC anhydride and sodium bicarbonate is 1:1.0-3.0:1.0-3.

0.

6. The method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxy according to claim 1, characterized in that: The mass ratio of isonicotinate methyl ester nitrogen oxide in step 1 to the water used for crystallization in step 2 is 1:5-20.

7. The method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxy according to claim 1, characterized in that: In the step 2, the temperature is raised to 20°C to 30°C; and the reaction is kept at 20°C to 30°C for 1 to 3 hours.

8. The method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxy according to claim 1, characterized in that: In the step 2, the crude product of N2-BOC-isonicotinic acid hydrazine-1-oxy is recrystallized with methanol.

9. The method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxy according to claim 8, characterized in that: The mass ratio of the crude N2-BOC-isonicotinic acid hydrazine-1-oxygen to methanol is 1:1-5.

10. The method for preparing N2-BOC-isonicotinic acid hydrazine-1-oxy according to claim 1, characterized in that: In the step 2, the recrystallization temperature is -5°C to 10°C, and the time is 0.5h to 3h.

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