A pharmaceutical composition comprising favipiravir prepared from a specific intermediate

Abstract

This invention provides a pharmaceutical composition containing favipiravir, belonging to the pharmaceutical field. The favipiravir is prepared through a specific intermediate, which is prepared from 1-fluoroethane-1,2-diol and 1,2-diaminoethanol as raw materials. By adding a catalyst, the reaction time is shortened, the yield and purity of the final favipiravir product are improved, and it is beneficial for the batch-by-batch industrial production of favipiravir under mild conditions.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to a pharmaceutical composition containing favipiravir prepared from a specific intermediate. BACKGROUND

[0002] The favipiravir is developed by Japan's Toyama Chemical Co., Ltd. In 2011, the III phase clinical trial was completed in Japan, and in 2014, it was approved for marketing. It is mainly used for influenza treatment in clinical practice. It is a broad-spectrum antiviral drug of the RNA-dependent RNA polymerase inhibitor class. Studies have shown that favipiravir forms favipiravir-ribofuranosyl-5-triphosphate (T-705 RTP) under the action of intracellular enzymes, competitively inhibits viral RNA-dependent RNA polymerase, thereby inhibiting viral genome replication and transcription; it can also penetrate into the viral gene and induce mutation to play an antiviral role.

[0003] The favipiravir, also known as favilavir, haifukang, etc., has a chemical name of 5-Fluoro-2-hydroxypyrazine-3-carboxamide, and an alias of T-705; Avigan; favilavir; CAS: 259793-96-9. It is a pyrazine amide derivative.

[0004] The approval and use of favipiravir in different countries and regions are different. It is first used for the treatment of influenza, especially for patients with influenza virus resistance. The compound 6-fluoro-3-hydroxypyrazine-2-carboxylic acid (CAS: 1079990-21-8) is an important intermediate for the synthesis of favipiravir.

[0005] The existing literature reports that the intermediate 6-fluoro-3-hydroxypyrazine-2-carboxylic acid is synthesized from 3-aminopyrazine-2-carboxylic acid methyl ester as a raw material, through substitution, nitrosation, hydrolysis, displacement and other 5-step reactions.

[0006] The patent WO2010 / 087117 also reports that the favipiravir is obtained from ethylamino malonic acid hydrochloride as a starting material through 7-step reactions, and the key intermediate 3,6-dichloro-2-cyanopyrazine is obtained in 4 steps, and the total yield is about 19.5%.

[0007] The existing technology has a long synthesis route, high cost of steps, complex requirements for equipment, and in addition, the synthesis process of the key intermediate in the preparation method requires harsh conditions and does not have the characteristics of mild and controllable, and the product purity is low, so it is necessary to find a synthesis method with short route, low cost and simple operation. SUMMARY

[0008] In view of the problems of long reaction steps, low reaction yield and low separation purity of compounds in each step in the prior art, the present application improves the existing process and provides a new route for synthesizing intermediates. The route has the characteristics of few reaction steps, low cost, simple operation and mild controllability.

[0009] The intermediate is a compound of formula 4,

[0010]

[0011] The synthesis route comprises the following steps:

[0012]

[0013] In the step 1), the compound 1 and the compound 2 are reacted in a solvent to obtain the compound 3; in the step 2), the compound 3 is subjected to a pressurized reaction to obtain the compound 4.

[0014] Preferably, the solvent of the step 1 is one or more of water, isopropyl ether and ethanol, and more preferably isopropyl ether; a catalyst can be used in the step 1, and the catalyst is one or more of platinum chloride, nickel chloride and manganese oxide, and more preferably platinum chloride.

[0015] Preferably, the mass ratio of the compound 1 to the compound 2 is 1-5:1-5, the reaction system is heated to ≥50℃ and subjected to a reflux reaction, and after the reaction is completed, the temperature is lowered to room temperature. Further, the reflux reaction time is ≥2h, preferably ≥5h, and more preferably ≥8h.

[0016] In another technical solution, the HPLC monitoring is performed through the water in the separation system until the compound 2 is completely reacted, and then the temperature is lowered. Preferably, the temperature is lowered to ≤30℃. Further, the obtained crude product is further washed, filtered and dried, and preferably, the washing is performed through ethanol.

[0017] In another technical solution, the step 1 can be assisted by adding a triacetylacetone ferric(III) (co-catalyst), and the reaction temperature of the step 1 is ≤50℃.

[0018] Further, the reaction pressure of the step 2 is 1-5MPa; a catalyst can be used in the step 2, and the catalyst is one or more of potassium carbonate, cesium carbonate and triethylamine; preferably, the solvent of the step 2 is one or more of isopropyl alcohol, dichloromethane and tetrahydrofuran, and preferably tetrahydrofuran;

[0019] Preferably, the reaction pressure of the step 2 is 2-3MPa, and further, the vacuum is drawn after the nitrogen is replaced, and the carbon dioxide is introduced.

[0020] In another technical solution, the reaction time in step 2 is ≥10h, preferably ≥15h, more preferably ≥20h; the reaction temperature is ≥30℃; and more preferably, the pressure is released after monitoring the raw material concentration by HPLC as <0.5% (g / 100ml). Furthermore, the pressure is released while simultaneously cooling to room temperature and then filtration is performed; even further, the filtrate is further washed with water and then dried.

[0021] The present invention also includes a method for preparing favipiravir, the method comprising the preparation steps described above.

[0022] All raw materials and reagents used in this invention were commercially available or prepared experimentally. Compound 1 (1-fluoroethane-1,2-diol) and Compound 2 (1,2-diaminoethanol) were purchased from Leyong Biotechnology, and the remaining reagents and equipment were purchased from Sigma.

[0023] The beneficial effects of this invention are:

[0024] 1) Compounds 3 and 4 obtained by this invention have high purity as intermediates, which is beneficial for storage and batch modular production.

[0025] 2) The two-step addition process optimizes the steps, shortens the reaction route, uses readily available and recyclable catalysts, and has low raw material costs. Under certain conditions, it also avoids the use of by-products and harmful reagents.

[0026] 3) High yield and high purity, mild preparation conditions, easy to repeat, especially when using additives, avoids high temperature reaction, suitable for large-scale CNC production. Attached Figure Description

[0027] Appendix Figure 1 The 1H NMR spectra of compound 3 in Examples 1 and 2 of this invention are shown.

[0028] Appendix Figure 2 The 1H NMR spectrum of compound 4 in Examples 1 and 2 of this invention;

[0029] Appendix Figure 3 The liquid phase spectra of compound 3 in Examples 1 and 2 of this invention are shown.

[0030] Appendix Figure 4 The liquid phase spectrum of compound 4 in Examples 1 and 2 of this invention is shown. Detailed Implementation

[0031] Example 1:

[0032] 1. Preparation of compound 3

[0033]

[0034] At room temperature, 50g of starting compound 1, 47.5g of starting compound 2, 300mL of isopropyl ether, and 0.5g of platinum chloride were added to a 500mL reaction flask. The mixture was heated to 68℃ and refluxed for 10 hours, during which water was continuously separated from the system. HPLC monitoring showed that starting compound 2 had reacted completely. The mixture was then cooled to 25℃, filtered, and the filtrate was concentrated to obtain the crude product. 100mL of ethanol was added to the crude product, and the mixture was stirred at room temperature, filtered, and the filter cake was dried at 50℃ to obtain compound 3 (see Appendix). Figure 1 , attached Figure 3 The total yield was 61.3g, with a yield of 86% and a purity of 98%.

[0035] 2. Synthesis of intermediate compound 4

[0036]

[0037] At room temperature, 30 g (0.263 mol, 1 equivalent) of compound 3, 300 mL of tetrahydrofuran, and 30 g (0.217 mol, 0.83 equivalent) of potassium carbonate were added to a 500 mL pressure vessel. After purging with nitrogen, the pressure was evacuated and carbon dioxide was introduced to 2.5 MPa. The reaction was carried out at 50 °C for 24 h. HPLC monitoring showed that the reactant concentration was less than 0.5%. The pressure was released, the temperature was lowered to 25 °C, and the mixture was filtered. The filtrate was washed once with 100 mL of water, dried, and then concentrated to obtain all the tetrahydrofuran in the system, yielding a yellow solid, which is compound 4 (see Appendix). Figure 2 , attached Figure 4 The total yield was 38.3g, with a yield of 92% and a purity of 99.15%.

[0038] Example 2:

[0039] 1. Preparation of compound 3

[0040] At room temperature, 40g of raw material 1, 42.5g of raw material 2, 300mL of isopropyl ether, 0.5g of platinum chloride, and 0.5g of triacetylacetone with ferric iron were added to a 500ml reaction flask. The mixture was heated to 50℃ and reacted for 8 hours, during which water was continuously separated from the system. HPLC monitoring showed that the reaction of raw material 2 was complete. The mixture was cooled to 25℃, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was added to ethanol and stirred at room temperature, filtered, and the filter cake was dried at 50℃ to obtain compound 3 (see Appendix). Figure 1 , attached Figure 3 The total yield was 65.8g, with a yield of 91.6% and a purity of 99.05%.

[0041]

[0042] 2. Synthesis of intermediate compound 4

[0043]

[0044] At room temperature, 30 g (0.263 mol, 1 equivalent) of compound 3, 300 mL of tetrahydrofuran, and 30 g (0.217 mol, 0.83 equivalent) of potassium carbonate were added to a 500 mL pressure vessel. After purging with nitrogen, the pressure was evacuated and carbon dioxide was introduced to 2.5 MPa. The reaction was carried out at 50 °C for 24 h. HPLC monitoring showed that the reactant concentration was less than 0.5%. The pressure was released, the temperature was lowered to 25 °C, and the mixture was filtered. The filtrate was washed once with 100 mL of water, dried, and then concentrated to obtain all the tetrahydrofuran in the system, yielding a yellow solid, which is compound 4 (see Appendix). Figure 2 , attached Figure 4 The total yield was 38.4g, with a yield of 92.3% and a purity of 99.2%.

[0045] Example 3:

[0046] In step 1, the catalyst was replaced with nickel chloride instead of platinum chloride, and the remaining conditions were the same as in Example 1, yielding compound 3 (identification spectrum same as in Example 1), with a yield of 84.6%, purity of 98.3%, and single impurity content >0.5%. Compound 4 (identification spectrum same as in Example 1) had a yield of 89% and a purity of 98.1%.

[0047] Example 4:

[0048] In step 1, the catalyst was replaced with nickel chloride instead of platinum chloride, and triacetylacetone ferric iron was not used. The other conditions were exactly the same as in Example 2, and compound 3 was obtained (identification spectrum same as in Example 2), with a yield of 61%, impurity content >8%, and purity of 91%. Because of the low purity, step 2 was not carried out.

[0049] Example 5;

[0050] In step 2, the solvent was changed from tetrahydrofuran to dichloromethane, and the other conditions were exactly the same as in Example 1, yielding compound 3 (identification spectrum same as in Example 1), with a yield of 89%, purity of 98.8%, and single impurity content <0.25%; and compound 4 (identification spectrum same as in Example 1), with a yield of 92.1% and purity of 99.3%.

[0051] Example 6

[0052] In step 2, the solvent was changed from tetrahydrofuran to dichloromethane, and the other conditions were exactly the same as in Example 2, yielding compound 3 (identification spectrum same as in Example 2), with a yield of 87%, purity of 97.8%, and single impurity content <0.5%; and compound 4 (identification spectrum same as in Example 2), with a yield of 90.1% and purity of 98.5%.

[0053] Example 7

[0054] Favipiravir prepared from the above-mentioned specific intermediates

[0055] Example 8

[0056] Pharmaceutical composition containing favipiravir from Example 7

[0057] The above experimental results show that by optimizing the preparation process, a product with higher purity was obtained. Under certain conditions (with the addition of special additives), the reaction conditions are milder, the temperature can be controlled within 50°C, and the yield and purity are higher. However, the synergistic effect of the additives and catalysts is somewhat accidental and may be related to electrical properties. The change of solvent does not significantly affect the reaction, but it has a slight impact on the catalyst-additive combination effect in Example 2.

[0058] The specific embodiments described above do not constitute a limitation on the scope of protection of the present invention. Those skilled in the art can make various changes and applications to the present invention based on the above description.

Claims

1. A process for the preparation of a specific intermediate of favipiravir characterized in that: The intermediate is compound 4, The intermediate is synthesized by the following synthetic route: The preparation method of the specific intermediate of favipiravir specifically comprises the following steps: Step 1: preparation of compound 3; In the preparation, compound 3 is obtained by reacting compound 1 and compound 2 in a solvent: The specific preparation process is as follows: At room temperature, 50 g of raw material compound 1, 47.5 g of raw material compound 2, 300 mL of isopropyl ether, and 0.5 g of catalyst are added into a 500 mL reaction bottle, and the reaction is carried out at 68°C under reflux for 10 h, during which water in the system is continuously separated, and HPLC is used to monitor the complete reaction of raw material 2; cooling to 25°C, filtration, and the filtrate is concentrated to obtain a crude product, which is added into 100 mL of ethanol and stirred at room temperature, then filtered, and the filter cake is dried at 50°C to obtain compound 3; The catalyst is platinum chloride or nickel chloride; Step 2: synthesis of intermediate compound 4; In the preparation, compound 4 is obtained by pressure reaction of compound 3: The specific preparation process is as follows: At room temperature, 30 g of compound 3, 300 mL of tetrahydrofuran, and 30 g of potassium carbonate are added into a 500 mL pressure kettle, then nitrogen is replaced, vacuum is applied, carbon dioxide is introduced to 2.5 MPa, and the reaction is carried out at 50°C for 24 h, HPLC is used to monitor that the content of raw material is less than 0.5%, the pressure is released, the temperature is lowered to 25°C, and filtration is carried out, then the filtrate is washed with 100 mL of water once, and the system is concentrated to dryness to obtain a yellow solid, which is compound 4.

2. The process for the preparation of a particular intermediate of favipiravir as claimed in claim 1 wherein, The reaction pressure of step 2 is 2-3 MPa.

3. The process for the preparation of a particular intermediate of favipiravir as claimed in claim 1 wherein, In step 1, the mass ratio of compound 1 to compound 2 is 1-5:1-5, the reaction system is heated to ≥50°C, and the reflux reaction is carried out, and after the reaction is completed, the temperature is lowered to room temperature.

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