A preparation method of topiroxostat

Abstract

The present invention provides a preparation method of tozasertib, which relates to the technical field of medicine. The preparation method provided by the present invention comprises the following steps: (1) reacting methyl 2-cyanoisonicotinate with hydrazine hydrate, and crystallizing to obtain intermediate TPS-1; (2) reacting 4-cyanopyridine with a base, and then reacting completely with TPS-1, followed by filtration, washing and drying to obtain TPS-2a; (3) subjecting TPS-2a to a cyclization reaction with a reaction solvent, and after the reaction is complete, mixing with a crystallization solvent to obtain the product TPS. The product obtained by this process has a relatively high yield, with the highest total yield being about 62%, high purity, with a purity greater than 99.9%; the preparation method is simple, under the conditions of this preparation method, the raw materials react quickly, and at the same time, time-consuming operations such as extraction and concentration are avoided, and the product can be directly obtained by filtration after the reaction, with a short production cycle; the reaction conditions are easy to realize industrial operation.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly relates to a preparation method of toperisone. Background Art

[0002] Gout is a crystal-related arthropathy caused by the deposition of monosodium urate (MSU), which is directly related to hyperuricemia caused by purine metabolism disorder or reduced uric acid excretion. It specifically refers to acute characteristic arthritis and chronic tophaceous disease, mainly including acute episodic arthritis, tophus formation, tophaceous chronic arthritis, urate nephropathy, and uric acid urinary calculi. In severe cases, joint disability and renal insufficiency may occur. Gout is often accompanied by manifestations such as abdominal obesity, hyperlipidemia, hypertension, type 2 diabetes, and cardiovascular diseases.

[0003] Toperisone tablets are a non-purine xanthine oxidase selective inhibitor, which can selectively and reversibly inhibit xanthine oxidoreductase and reduce serum uric acid levels. Toperisone is a mixed inhibitor, showing dual inhibitory effects based on structure and mechanism (it is a suicide substrate of XOR). What is the same as febuxostat in the binding mode is that it binds to the same hydrophobic cavity of the enzyme. The difference is that it can also form a Mo-O-C covalent bond with the molybdopterin center of the enzyme, inhibiting the binding of the enzyme to the substrate, thereby playing an anti-gout role. It is precisely because of the relatively long half-life of the decomposition of the toperisone-XOR complex that it shows a long-acting uric acid-lowering effect. The structural formula of toperisone is shown as follows:

[0004]

[0005] Patent CN106045979A discloses a method for synthesizing toperisone by a one-pot method. Methyl 2-cyanoisonicotinate is dissolved in a solvent and reacts with hydrazine hydrate to form an intermediate 2-cyanoisonicotinohydrazide. Then, a base is added to react in the same reactor, and 4-cyanopyridine is added to form a ring. Finally, purification is carried out to obtain toperisone. Although the one-pot method for synthesizing toperisone has a relatively simple process, the intermediates are not separated, impurities cannot be effectively removed, and the risk of high impurity content in the final product is relatively high.

[0006] Patent CN114315800A provides a preparation method of toperisone. In this invention, 2-cyanopyridine and hydrazine hydrate are mixed for a nucleophilic reaction to obtain a compound with the structure shown in formula II. Then, using the compound with the structure shown in formula I and the compound with the structure shown in formula II as raw materials, toperisone (formula III) is obtained through amidation reaction and cyclization reaction.

[0007]

[0008] The product obtained by this synthesis process has a relatively high purity, but the process is too complex and the production cost is relatively high, which is not conducive to large-scale promotion.

[0009] Patent CN1826335A discloses a synthesis route of topiroxetine, as shown below:

[0010]

[0011] This route has a long reaction time and uses expensive and highly toxic trimethylsilyl cyanide, which is highly dangerous to operate. In addition, in the salt formation step, p-toluenesulfonic acid is used to form the salt, which produces the genetic toxic impurity p-toluenesulfonate, which poses certain hazards to patients and is not conducive to industrial production.

[0012] Therefore, developing a method for preparing topicostat with a simple process, low impurities, and high purity has been a key research priority for researchers in this field. During the research process, it was discovered that preparing topicostat with high purity, especially purity exceeding 99.9%, requires overcoming multiple levels of difficulty: increasing the purity from 95% to 99%, from 99% to 99.5%, and then from 99.5% to 99.9%, with each step of increasing purity being challenging. Summary of the Invention

[0013] In response to the above problems, the present invention provides a method for preparing topicostat, specifically a method for industrializing the preparation of high-purity topicostat, which has a simple process, high yield and high purity of topicostat, and is suitable for large-scale promotion.

[0014] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0015] The present invention provides a method for preparing topinostat, and the synthetic route is as follows:

[0016]

[0017] Including steps:

[0018] (1) reacting methyl 2-cyanoisonicotinate with hydrazine hydrate and crystallizing to obtain intermediate TPS-1; the molar ratio of methyl 2-cyanoisonicotinate to hydrazine hydrate is 1:0.8-1.5;

[0019] (2) 4-cyanopyridine reacts with a base, and then reacts with TPS-1, and the reaction is filtered, washed, and dried to obtain TPS-2a; the molar ratio of TPS-1, base, and 4-cyanopyridine is 1:0.05-0..2:0.8-1.5;

[0020] (3) TPS-2a undergoes a ring-closure reaction with a reaction solvent. After the reaction is complete, it is mixed with a crystallization solvent for crystallization to obtain the product TPS.

[0021] Preferably, the molar ratio of methyl 2-cyanisonicotinate to hydrazine hydrate in step (1) is 1:0.8-1.2.

[0022] Preferably, the reaction of methyl 2-cyanisonicotinate with hydrazine hydrate in step (1) requires a reaction solvent, and the reaction solvent is selected from at least one of dichloromethane, isopropanol, N,N-dimethylformamide, and dimethyl sulfoxide; further preferably, the solvent is N,N-dimethylformamide.

[0023] Preferably, the crystallization in step (1) requires the addition of a crystallization solvent, and the crystallization solvent is selected from at least one of methanol, isopropanol, tert-butanol and sec-butanol; further preferably, the crystallization solvent is isopropanol.

[0024] Preferably, the methyl 2-cyanisonicotinate in step (1) is reacted with hydrazine hydrate under the following conditions: reaction at 20° C.-25° C. for 0.5-1 h; more preferably, reaction at 20° C. for 0.5 h.

[0025] Preferably, the crystallization in step (1) is carried out under the following conditions: mixing with a crystallization solvent after the reaction, cooling to -5°C-0°C, stirring for 5-15 minutes, filtering, washing, and drying at 50°C for 4-8 hours.

[0026] Further preferably, the crystallization is carried out under the following conditions: mixing with a crystallization solvent, cooling to 0°C, stirring for 10 minutes, filtering, washing, and drying at 50°C for 5-7 hours.

[0027] Preferably, the base in step (2) is selected from at least one of sodium tert-butoxide, sodium methoxide, potassium tert-butoxide, potassium methoxide and sodium hydride; further preferably, the base in step (2) is sodium methoxide.

[0028] Preferably, the molar ratio of TPS-1, base and 4-cyanopyridine in step (2) is 1:0.05-0.2:0.9-1.2.

[0029] More preferably, the molar ratio of TPS-1, base and 4-cyanopyridine is 1:0.1:1.

[0030] Preferably, the 4-cyanopyridine in step (2) is reacted with a base under the following conditions: reaction at 20° C.-25° C. for 1.5-3 h.

[0031] Preferably, the reaction with TPS-1 in step (2) is carried out under the following specific reaction conditions: reaction at 20° C.-25° C. for 1.5-3 h.

[0032] Preferably, the reaction solvent in step (3) is selected from at least one of dichloromethane, isopropanol, N,N-dimethylformamide, and dimethyl sulfoxide; further preferably, the reaction solvent is dimethyl sulfoxide.

[0033] Preferably, the amount of the reaction solvent added in step (3) is 2-3 vq.

[0034] Further preferably, the addition amount of the reaction solvent is 2.5 vq.

[0035] In the present invention, "vq" refers to the volume-mass ratio, that is, when 1 kg of raw materials are fed, the solvent dosage is 2.5 L.

[0036] Preferably, the crystallization solvent in step (3) is selected from at least one of methanol, isopropanol, tert-butanol and sec-butanol; further preferably, the crystallization solvent is methanol.

[0037] Preferably, for the ring-closing reaction in step (3), the specific conditions are: heating to 105°C - 115°C and stirring the reaction until the HPLC shows that the raw material residue is less than 0.50%.

[0038] Preferably, for the crystallization in step (3), the specific operation is: adding 8 - 12 vq of crystallization solvent, cooling to 5°C - 10°C, filtering, washing, and drying at 50°C for 5 - 7 h.

[0039] Further preferably, for the crystallization, the specific operation is: adding 10 vq of crystallization solvent, cooling to 5°C - 10°C, filtering, washing, and drying at 50°C for 5 - 7 h.

[0040] Compared with the prior art, the present invention has the following beneficial effects:

[0041] (1) The product obtained by this process has a relatively high yield of about 62% and high purity, with a purity greater than 99.9%;

[0042] (2) The process is simple. Under the conditions of this preparation method, the raw materials react quickly, and at the same time, time-consuming operations such as extraction and concentration are avoided. After the reaction, the product is directly obtained by filtration, and the production cycle is short;

[0043] (3) The reaction conditions are easy to realize industrial operation. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1 It is the HPLC purity spectrum of intermediate TPS-1;

[0045] Figure 2 It is the HPLC purity spectrum of intermediate TPS-2a;

[0046] Figure 3 It is the HPLC purity spectrum of tozasertib prepared in Example 1;

[0047] Figure 4 It is the HNMR spectrum of tozasertib prepared in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0048] In order to make the technical means, creative features, achieved purposes and effects of the present invention easy to understand, the present invention will be further illustrated below in conjunction with specific embodiments. However, the following embodiments are only the preferred embodiments of the present invention, not all of them. Based on the embodiments in the implementation manners, other embodiments obtained by those skilled in the art without creative efforts all fall within the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all ordinary commercially available products, and no specific limitation is made on their sources. The technical and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the technical field to which the present invention belongs.

[0049] In the present invention, the calculation of the final yield of TPS (topiroxostat) is: the yield of TPS-1 × the yield of TPS-2a × the yield of TPS.

[0050] In the present invention, the detection method for the purity of the product is: HPLC method;

[0051] Method for detecting related substances of topiroxostat: Determined with reference to the high performance liquid chromatography method (Appendix VD, Part II of the Chinese Pharmacopoeia 2010 Edition); Chromatographic conditions and system suitability test for purity detection: Using octadecylsilane chemically bonded silica gel (C18-AQ 250 mm × 4.6 mm, 5 μm) as the filler; Using 0.05 mol / L potassium dihydrogen phosphate (adjust the pH value to 5.0 with phosphoric acid) as mobile phase A and acetonitrile as mobile phase B; Perform gradient elution according to the following table program; The detection wavelength is 220 nm (274 nm), the flow rate is 1.0 ml / min, and the column temperature is 30 °C. The number of theoretical plates calculated based on the topiroxostat peak should not be less than 30,000. Take this product, dissolve and dilute it with a diluent (0.05 mol / L potassium dihydrogen phosphate solution (adjust the pH value to 3.0 with phosphoric acid)-acetonitrile (50:50)) to prepare a solution containing 0.15 mg per 1 ml as the test solution. Separately, accurately measure 1 ml of the test solution, place it in a 200 ml volumetric flask, dilute it to the mark with a diluent (0.05 mol / L potassium dihydrogen phosphate solution (adjust the pH value to 3.0 with phosphoric acid)-acetonitrile (50:50)), and shake well to obtain the control solution. Inject 10 μl of the control solution into the liquid chromatograph, adjust the detection sensitivity to make the peak height of the main component peak approximately 20% of the full scale. Accurately measure 10 μl each of the test solution and the control solution, inject them into the liquid chromatograph respectively, and record the chromatogram. If there are impurity peaks in the chromatogram of the test solution, after removing the solvent peak, the area of a single impurity peak shall not be greater than 0.3 times (0.15%) of the area of the main peak of the control solution, and the sum of the areas of each impurity peak shall not be greater than 2 times (1.0%) of the area of the main peak of the control solution. The specific HPLC gradient detection is as follows:

[0052] Time (min) Mobile phase A (%) Mobile phase B (%) 0 95 5 3 95 5 15 70 30 20 50 50 35 50 50 45 95 5 50 95 5

[0053] Example 1

[0054] (1) Synthesis of TPS-1

[0055] Weigh 1.18 kg of methyl 2-cyanoisonicotinate (1.0 eq) into a 50 L reaction kettle, add 2.36 L of DMF (2.0 vq), cool down to 20 °C, and slowly add 546.0 g of hydrazine hydrate (1.0 eq) dropwise through a constant-pressure dropping funnel. After reacting at 20 °C for 0.5 h, a large amount of solid precipitates. Monitor the reaction by TLC plate spotting. When the raw material spot disappears, the reaction is complete. Add 10 vq of isopropanol, cool down to 0 °C, stir for 10 min, filter, wash with 900 ml of isopropanol, and dry at 50 °C for 6 h to obtain TPS-1 with a yield of 76% and a purity of 89.63%.

[0056] (2) Synthesis of TPS-2a

[0057] Weigh 577.80 g of 4-cyanopyridine (1.0 eq) into a 50 L reaction kettle, add 7.2 L of methanol (8 vq) and 30.00 g of sodium methoxide (0.1 eq), and stir at room temperature (24 °C) for 2 h. After monitoring by TLC that most of the 4-cyanopyridine has reacted (about 90% conversion), add 900.00 g of TPS-1 (1.0 eq) at 20 °C and stir at 20 °C for 2 h. After monitoring by TLC that TPS-1 has reacted completely, cool down to 0 °C, filter, wash with 1 L of isopropanol, and dry at 50 °C for 6 h to obtain TPS-2a with a yield of 87% and a purity of 95.07%.

[0058] (3) Synthesis of TPS

[0059] Weigh 1.00 kg of TPS-2a (1.0 eq) into a 20 L reaction kettle, add 2.5 L of DMSO (2.5 vq), start stirring and heat up to 110 °C for reaction until HPLC shows that the raw material residue is less than 0.50%. Cool down to 70 °C, add 10 L of methanol (10 vq), and then cool down to 10 °C. Filter, wash with 0.7 L of methanol, and dry at 50 °C for 6 h to obtain TPS with a yield of 94% and a purity of 99.93%.

[0060] The final yield of TPS is 62%.

[0061] Example 2

[0062] (1) Synthesis of TPS-1

[0063] Weigh 1.18 kg of methyl 2-cyanoisonicotinate (1.0 eq) into a 50 L reactor, add 2.36 L of dimethyl sulfoxide (2.0 vq), cool down to 20 °C, and slowly add 600.6 g of hydrazine hydrate (1.1 eq) dropwise through a constant-pressure dropping funnel. After reacting at 20 °C for 0.5 h, a large amount of solid precipitates. Monitor the reaction by TLC plate. When the raw material spot disappears, the reaction is complete. Add 10 vq of methanol, cool down to 0 °C, stir for 15 min, filter, wash with 900 ml of methanol, and dry at 50 °C for 7 h to obtain TPS-1 with a yield of 80% and a purity of 82.50%.

[0064] (2) Synthesis of TPS-2a

[0065] Weigh 866.70 g of 4-cyanopyridine (1.2 eq) into a 50 L reactor, add 7.2 L of methanol (8 vq) and 106.78 g of sodium tert-butoxide (0.2 eq), and stir at 20 °C for 3 h. After monitoring by TLC and finding that most of the 4-cyanopyridine has reacted (about 90% conversion), add 900.00 g of TPS-1 (1.0 eq) at 20 °C and stir for 2 h. After monitoring by TLC and finding that TPS-1 has reacted completely, cool down to 0 °C, filter, wash with 1 L of isopropanol, and dry at 50 °C for 6 h to obtain TPS-2a with a yield of 82% and a purity of 92.35%.

[0066] (3) Synthesis of TPS

[0067] Weigh 1.00 kg of TPS-2a (1.0 eq) into a 20 L reactor, add 2.5 L of N,N-dimethylformamide (2.5 vq), start stirring and heat up to 105 °C. React until HPLC shows that the residual raw material is less than 0.50%. Cool down to 70 °C, add 10 L of isopropanol (10 vq), and then cool down to 5 °C. Filter, wash with 0.7 L of isopropanol, and dry at 50 °C for 7 h to obtain TPS with a yield of 90% and a purity of 99.75%. The final yield of TPS is 59%.

[0068] Example 3

[0069] (1) Synthesis of TPS-1

[0070] Weigh 1.18 kg of methyl 2-cyanoisonicotinate (1.0 eq) into a 50 L reactor, add 2.36 L of DMF (2.0 vq), cool down to 25 °C, and slowly add 436.8 g of hydrazine hydrate (0.9 eq) dropwise through a constant-pressure dropping funnel. After reacting at 25 °C for 1 h, a large amount of solid precipitates. Monitor the reaction by TLC plate. Only a small amount of raw material remains. After 1 h, monitor by TLC again. When the raw material no longer converts, the reaction is complete. Add 10 vq of tert-butanol, cool down to 0 °C, stir for 5 min, filter, wash with 900 ml of tert-butanol, and dry at 50 °C for 5 h to obtain TPS-1 with a yield of 69% and a purity of 92.50%.

[0071] (2) Synthesis of TPS-2a

[0072] Weigh 520.02 g of 4-cyanopyridine (0.9 q) into a 50 L reactor, add 7.2 L of methanol (8 vq) and 19.44 g of potassium methoxide (0.05 eq), and stir at 25 °C for 1.5 h. After monitoring by TLC that most of the 4-cyanopyridine has reacted (about 90% conversion), add 900.00 g of TPS-1 (1.0 eq) at 25 °C and stir at 25 °C for 2 h. After monitoring by TLC that the reaction of TPS-1 is complete, cool down to 0 °C, filter, wash with 1 L of isopropanol, and dry at 50 °C for 6 h to obtain TPS-2a with a yield of 78% and a purity of 95.76%.

[0073] (3) Synthesis of TPS

[0074] Weigh 1.00 kg of TPS-2a (1.0 eq) into a 20 L reactor, add 2.5 L of dimethyl sulfoxide (2.5 vq), start stirring and heat up to 115 °C for reaction until HPLC shows that the raw material residue is less than 0.50%. Cool down to 70 °C, add 10 L of tert-butanol (10 vq), and then cool down to 5 °C. Filter, wash with 0.7 L of tert-butanol, and dry at 50 °C for 6 h to obtain TPS with a yield of 92% and a purity of 99.85%.

[0075] The final yield of TPS is 50%.

[0076] Comparative Example 1

[0077] (1) Synthesis of TPS-1

[0078] Weigh 1.18 kg of methyl 2-cyanoisonicotinate (1.0 eq) into a 50 L reactor, add 2.36 L of DMF (2.0 vq), cool down to 20 °C, and dropwise add 982.8 g of hydrazine hydrate (1.8 eq) using a constant pressure dropping funnel. After reacting at 20 °C for 0.5 h, a large amount of solid precipitates. Monitor the reaction by TLC on a TLC plate, and the reaction is complete when the raw material spot disappears. Add 10 vq of isopropanol, cool down to 0 °C, stir for 10 min, filter, wash with 900 ml of isopropanol, and dry at 50 °C for 6 h to obtain TPS-1 with a yield of 92% and a purity of 75.80%.

[0079] (2) Synthesis of TPS-2a

[0080] Weigh 577.80 g of 4-cyanopyridine (1.0 eq) into a 50 L reactor, add 7.2 L of methanol (8 vq) and 90.00 g of sodium methoxide (0.3 eq), and stir at room temperature (24 °C) for 2 h. After monitoring by TLC that most of the 4-cyanopyridine has reacted (about 90% conversion), add 450.00 g of TPS-1 (0.5 eq) at 20 °C and stir at 20 °C for 2 h. After monitoring by TLC that TPS-1 has reacted completely, cool down to 0 °C, filter, wash with 1 L of isopropanol, and dry at 50 °C for 6 h to obtain TPS-2a with a yield of 74% and a purity of 55.32%.

[0081] (3) Synthesis of TPS

[0082] Weigh 1.00 kg of TPS-2a (1.0 eq) into a 20 L reactor, add 3.5 L of DMSO (3.5 vq), start stirring and heat up to 110 °C for reaction until HPLC shows that the raw material residue is less than 0.50%. Cool down to 70 °C, add 10 L of methanol (10 vq), and then cool down to 10 °C. Filter, wash with 0.7 L of methanol, and dry at 50 °C for 6 h to obtain TPS with a yield of 82% and a purity of 99.90%.

[0083] The total yield of TPS is 34%.

[0084] Comparative Example 2

[0085] Steps (1)-(2) are the same as those in Example 1. In step (3), ethanol is used as the reaction solvent, with a yield of 78% and a purity of 95.60%. The total yield of TPS is 52%.

[0086] Comparative Example 3

[0087] Steps (1)-(2) are the same as those in Example 1. In step (3), n-butanol is used as the reaction solvent, with a yield of 93% and a purity of 95.08%. The total yield of TPS is 57%.

[0088] Comparative Example 4

[0089] Different from Example 1, in step (2), the dosage of 4-cyanopyridine is 1.8 eq, and TPS-2a is obtained, with a yield of 55% and a purity of 87.50% in step (2). The total yield of TPS is 39%.

[0090] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than limiting the protection scope of the present invention. Any simple modification or equivalent replacement of the technical solution of the present invention by those of ordinary skill in the art shall not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A preparation method of toperisone, characterized in that, The synthetic route is as follows: It includes the steps: (1) Synthesis of TPS-1: Weigh 1.18 kg of methyl 2-cyanoisonicotinate into a 50 L reaction kettle, add 2.36 L of DMF, cool down to 20 °C, and dropwise add 546.0 g of hydrazine hydrate through a constant-pressure dropping funnel; after reacting at 20 °C for 0.5 h, a large amount of solid precipitates. Monitor the reaction by TLC plate spotting. When the raw material spot disappears, the reaction is complete; add 10 vq of isopropanol, cool down to 0 °C, stir for 10 min, filter, wash with 900 ml of isopropanol, and dry at 50 °C for 6 h to obtain TPS-1; (2) Synthesis of TPS-2a: Weigh 577.80 g of 4-cyanopyridine into a 50 L reaction kettle, add 7.2 L of methanol and 30.00 g of sodium methoxide, and stir at room temperature for 2 h; after monitoring by TLC that most of the 4-cyanopyridine has reacted, add 900.00 g of TPS-1 at 20 °C and stir at 20 °C for 2 h; after monitoring by TLC that TPS-1 has reacted completely, cool down to 0 °C, filter, wash with 1 L of isopropanol, and dry at 50 °C for 6 h to obtain TPS-2a; (3) Synthesis of TPS: Weigh 1.00 kg of TPS-2a into a 20 L reaction kettle, add 2.5 L of DMSO, start stirring and heat up to 110 °C for reaction until HPLC shows that the raw material residue is less than 0.50%; cool down to 70 °C, add 10 L of methanol, and then cool down to 10 °C; filter, wash with 0.7 L of methanol, and dry at 50 °C for 6 h to obtain TPS.

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