Method for preparing mirogabalin besilate

Abstract

Provided in the present invention is a method for preparing mirogabalin besilate. The method comprises: reacting mirogabalin containing an epimer with benzenesulfonic acid in the presence of MTBE and an organic weak acid to precipitate a mirogabalin besilate solid. By means of performing salt formation in a specific reaction solvent, mirogabalin besilate with a high optical purity can be obtained, the separation of the epimer of the intermediate thereof by means of using a chiral organic amine or a chiral column is avoided, and the production cost is reduced. The method has the advantages of simple operation, a high yield and mild reaction conditions, is suitable for industrial production, and has good application prospects.

Description

A preparation method of mirogabalin besilate TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a preparation method of mirogabalin besilate. BACKGROUND

[0002] Mirogabalin besilate is a selective alpha2delta-1 ligand, which is highly efficient and selective to the alpha2delta-1 subunit of a voltage-sensitive calcium channel complex, and is used for treating peripheral neuropathic pain. It was first approved for marketing in Japan on January 8, 2019.

[0003] CN104755456B discloses a synthesis method of mirogabalin besilate, which separates the epimers by using a chiral amine, and the net yield of the resolution is 82%, and the actual resolution yield is only 68%, so the overall yield is not high.

[0004] The synthesis method of mirogabalin besilate disclosed in CN101878193B separates the epimers by using a chiral column before nitro reduction, and the resolution yield is only 50%, and it is difficult to realize industrialization.

[0005] In the existing synthesis route of mirogabalin besilate, the generated epimers need to be removed by resolution of a chiral organic amine or a chiral column, but the resolution cost is high, the operation is complicated, and the yield is not high, which is not suitable for industrial production. Therefore, it is urgent to provide a synthesis route of mirogabalin besilate with mild reaction conditions, simple operation, low production cost and high yield, so as to have a wide application prospect. SUMMARY

[0006] The present application provides a preparation method of mirogabalin besilate, comprising the following steps: reacting compound I or an acid salt thereof with benzenesulfonic acid in methyl tert-butyl ether, and precipitating mirogabalin besilate solid, wherein compound I is a mixture containing compound Ia and compound Ib, and the structures of the compound I, the compound Ia and the compound Ib are as follows:

[0007] Preferably, the present application further provides a preparation method of mirogabalin besilate, comprising the following steps:

[0008] (1) reducing compound II in the presence of Fe and HCOOH to generate compound III, and filtering to obtain a filtrate,

[0009] (2) adding the filtrate obtained in step (1) into methyl tert-butyl ether and benzenesulfonic acid to continue the reaction and precipitate mirogabalin besilate solid, and the reaction is as follows:

[0010] wherein compound II is a mixture of compound IIa and compound IIb, the content of compound IIa in compound II is greater than 50%, and the structures of compound IIa and compound IIb are as follows,

[0011] The preparation of meloxicam besylate of the present application further comprises the preparation of compound II, the steps of which are as follows:

[0012] (a) reacting compound IV with compound V to form compound VI,

[0013] (b) reacting compound VI with nitromethane to form compound VII,

[0014] (c) hydrolyzing compound VII to form compound II, the reaction being as follows:

[0015] wherein R is C1-C4 linear or branched alkyl. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1: H NMR spectrum of meloxicam besylate prepared in Example 2. 1 H NMR spectrum. DETAILED DESCRIPTION

[0017] The technical solutions of the present application will be further described and explained in combination with specific examples.

[0018] The present example is only a part of the examples of the present application, but not all the examples. Based on the examples of the present application, all other examples obtained by those skilled in the art without making creative efforts fall within the protection scope of the present application.

[0019] Terms:

[0020] The terms "comprising" and "including" should be interpreted as open-ended, indicating the presence of the listed elements but not excluding the presence of any other one or more elements, occurrences, or additions.

[0021] All ranges recited herein include those endpoints as well as the range between the two values. Unless otherwise indicated, all values recited herein include the expected error, technical error, and instrument error of the given technique used to measure the value.

[0022] A specific value given as used herein in reference to a number or interval can be understood as that specific value or about that specific value (e.g., the specific value plus or minus 10%).

[0023] The compound II of the present application can be obtained by the method disclosed in the prior art such as CN104755456B, CN101878193B, or the preparation method in the present application. The starting materials and reagents used in the reaction can be obtained by market.

[0024] The abbreviations used in the present application are explained as follows: 1 H NMR: hydrogen nuclear magnetic resonance S OH: benzenesulfonic acid MTBE: methyl tert-butyl ether DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DBN: 1,5-diazabicyclo[4.3.0]non-5-ene h: hour g: gram mL: milliliter

[0025] Main instrument: Bruker nuclear magnetic resonance spectrometer

[0026] Method for detecting and analyzing the content of epimer in benzenesulfonic acid migalbalin:

[0027] The present application provides a preparation method of benzenesulfonic acid migalbalin, comprising the following steps: reacting compound I or its acid salt with benzenesulfonic acid in methyl tert-butyl ether, and precipitating benzenesulfonic acid migalbalin solid, wherein the compound I is a mixture containing compound Ia and compound Ib, and the structures of the compound I, the compound Ia and the compound Ib are as follows:

[0028] In some embodiments, the acid salt of the compound I is a weak acid salt, preferably formate or acetate, more preferably formate. In some embodiments, the reaction is carried out in the presence of an organic weak acid.

[0029] In some embodiments, the organic weak acid is selected from formic acid or acetic acid, preferably formic acid.

[0030] In some embodiments, the mass-volume ratio of the mixture of the compound Ia and the compound Ib to the organic weak acid is 1:0.1-10 (g / mL). In some embodiments, the mass-volume ratio of the mixture of the compound Ia and the compound Ib to the organic weak acid is 1:1-5 (g / mL). In some embodiments, the mass-volume ratio of the mixture of the compound Ia and the compound Ib to the organic weak acid is 1:1-3 (g / mL).

[0031] In some embodiments, the molar ratio of the mixture of the compound Ia and the compound Ib to benzenesulfonic acid is 1:1-2. In some embodiments, the molar ratio of the mixture of the compound Ia and the compound Ib to benzenesulfonic acid is 1:1-1.3.

[0032] In some embodiments, the mass to volume ratio of the mixture of Compound la and Compound lb to methyl tert-butyl ether is 1 :2 to 20 (g / mL), in some embodiments, the mass to volume ratio of the mixture of Compound la and Compound lb to methyl tert-butyl ether is 1 :4 to 15 (g / mL). In some embodiments, the mass to volume ratio of the mixture of Compound la and Compound lb to methyl tert-butyl ether is 1 :4 to 12 (g / mL). In some embodiments, the mass to volume ratio of the mixture of Compound la and Compound lb to methyl tert-butyl ether is 1 :4 to 10 (g / mL). In some embodiments, the mass to volume ratio of the mixture of Compound la and Compound lb to methyl tert-butyl ether is 1 :6 to 12 (g / mL). In some embodiments, the mass to volume ratio of the mixture of Compound la and Compound lb to methyl tert-butyl ether is 1 :8 to 12 (g / mL). In some embodiments, the mass to volume ratio of the mixture of Compound la and Compound lb to methyl tert-butyl ether is 1 :8 to 10 (g / mL). In some embodiments, the mass to volume ratio of the mixture of Compound la and Compound lb to methyl tert-butyl ether is 1 :9 to 12 (g / mL).

[0033] In some embodiments, the reaction temperature is 0 to 50 °C. In some embodiments, the reaction temperature is 0 to 30 °C. In some embodiments, the reaction temperature is 0 to 5 °C. In some embodiments, the reaction temperature is 20 to 30 °C. In some embodiments, the reaction temperature is 25 to 30 °C. In some preferred embodiments, the reaction temperature is 20 to 25 °C.

[0034] In some embodiments, the content of compound Ia in the mixture containing compound Ia and compound Ib is > 50%. In some embodiments, the content of compound Ia in the mixture containing compound Ia and compound Ib is > 55%. In some embodiments, the content of compound Ia in the mixture containing compound Ia and compound Ib is > 60%. In some embodiments, the content of compound Ia in the mixture containing compound Ia and compound Ib is > 65%. In some embodiments, the content of compound Ia in the mixture containing compound Ia and compound Ib is > 70%. In some embodiments, the content of compound Ia in the mixture containing compound Ia and compound Ib is > 75%. In some embodiments, the content of compound Ia in the mixture containing compound Ia and compound Ib is > 80%. In some embodiments, the content of compound Ia in the mixture containing compound Ia and compound Ib is > 85%. In some embodiments, the content of compound Ia in the mixture containing compound Ia and compound Ib is 70% to 90%. In some embodiments, the content of compound Ia in the mixture containing compound Ia and compound Ib is 80% to 90%. In some embodiments, the content of compound Ia in the mixture containing compound Ia and compound Ib is 80 to 85%. In some embodiments, the content of compound Ia in the mixture containing compound Ia and compound Ib is 85 to 90%.

[0035] The meloxicam benzenesulfonate prepared by the above method can be well separated from its epimer, and high-optical-purity product is obtained.

[0036] Preferably, the present application further provides a preparation method of meloxicam benzenesulfonate, comprising the following steps:

[0037] (1) reducing compound II in the presence of Fe and HCOOH to generate compound III, and filtering to obtain a filtrate,

[0038] (2) adding the filtrate obtained in step (1) into methyl tert-butyl ether and benzenesulfonic acid to continue the reaction and precipitate meloxicam benzenesulfonate solid, and the reaction is as follows:

[0039] wherein, compound II is a mixture of compound IIa and compound IIb, the content of compound IIa in compound II is greater than 50%, and the structures of compound IIa and compound IIb are as follows,

[0040] In some embodiments, the molar ratio of compound II to Fe in step (1) is 1 :3-18. In some embodiments, the molar ratio of compound II to Fe in step (1) is 1 :8-12. In some embodiments, the molar ratio of compound II to Fe in step (1) is 1 :8-10.

[0041] In some embodiments, the mass to volume ratio of compound II to HCOOH in step (1) is 1 :3-25 (g / mL). In some embodiments, the mass to volume ratio of compound II to HCOOH in step (1) is 1 :3-22 (g / mL). In some embodiments, the mass to volume ratio of compound II to HCOOH in step (1) is 1 :10-22 (g / mL). In some embodiments, the mass to volume ratio of compound II to HCOOH in step (1) is 1 :15-20 (g / mL). In some embodiments, the mass to volume ratio of compound II to HCOOH in step (1) is 1 :20-22 (g / mL).

[0042] In some preferred embodiments, the filtrate in step (1) can be concentrated to remove part of the formic acid. In some preferred embodiments, the final volume to mass ratio of the filtrate in step (1) after concentration is 1-5: 1 (mL / g) to compound II. In some preferred embodiments, the final volume to mass ratio of the filtrate in step (1) after concentration is 1-3: 1 (mL / g) to compound II.

[0043] In some preferred embodiments, no other solvent is added in step (1).

[0044] In some embodiments, step (1) can also be carried out in the presence of an organic solvent.

[0045] In some embodiments, the reaction temperature of step (1) is 5-50 °C. In some embodiments, the reaction temperature of step (1) is 20-30 °C. In some embodiments, the reaction temperature of step (1) is 25-30 °C. In some preferred embodiments, the reaction temperature of step (1) is 20-25 °C.

[0046] In some embodiments, the reaction time of step (1) is 4-40 h. In some embodiments, the reaction time of step (1) is 10-20 h. In some embodiments, the reaction time of step (1) is 12-18 h. In some embodiments, the reaction time of step (1) is 13-16 h. In some embodiments, the reaction time of step (1) is 16-18 h.

[0047] In some embodiments, the mass to volume ratio of compound II in step (1) to methyl tert-butyl ether in step (2) is 1 :4-30 (g / mL). In some embodiments, the mass to volume ratio of compound II in step (1) to methyl tert-butyl ether in step (2) is 1 :4-20 (g / mL). In some preferred embodiments, the mass to volume ratio of compound II in step (1) to methyl tert-butyl ether in step (2) is 1 :4-12 (g / mL). In some preferred embodiments, the mass to volume ratio of compound II in step (1) to methyl tert-butyl ether in step (2) is 1 :4-10.5 (g / mL). In some preferred embodiments, the mass to volume ratio of compound II in step (1) to methyl tert-butyl ether in step (2) is 1 :8-11 (g / mL). In some preferred embodiments, the mass to volume ratio of compound II in step (1) to methyl tert-butyl ether in step (2) is 1 :8-10.5 (g / mL).

[0048] In some embodiments, the molar ratio of compound II in step (1) to benzenesulfonic acid in step (2) is 1 : 1-2. In some embodiments, the molar ratio of compound II in step (1) to benzenesulfonic acid in step (2) is 1 : 1-1.5.

[0049] In some embodiments, the reaction temperature of step (2) is 0-50 °C. In some embodiments, the reaction temperature of step (2) is 0-30 °C. In some embodiments, the reaction temperature is 0-5 °C. In some embodiments, the reaction temperature is 5-10 °C. In some embodiments, the reaction temperature of step (2) is 10-20 °C. In some embodiments, the reaction temperature of step (2) is 20-30 °C. In some embodiments, the reaction temperature of step (2) is 25-30 °C. In some preferred embodiments, the reaction temperature of step (2) is 20-25 °C.

[0050] In some embodiments, the reaction time of step (2) is 0.5-20 h. In some embodiments, the reaction time of step (2) is 1-3 h.

[0051] In some embodiments, the content of compound Ha in compound II is ≥ 55%. In some embodiments, the content of compound Ha in compound II is ≥ 60%. In some embodiments, the content of compound Ha in compound II is ≥ 65%. In some embodiments, the content of compound Ha in compound II is ≥ 70%. In some embodiments, the content of compound Ha in compound II is ≥ 75%. In some embodiments, the content of compound Ha in compound II is ≥ 80%. In some embodiments, the content of compound Ha in compound II is ≥ 85%. In some embodiments, the content of compound Ha in compound II is 70% to 90%. In some embodiments, the content of compound Ha in compound II is 80% to 90%. In some embodiments, the content of compound Ha in compound II is 80 to 85%. In some embodiments, the content of compound Ha in compound II is 85 to 90%.

[0052] The above method can obtain optically pure benzenesulfonic acid meloxicam without separating compound II by using chiral organic amine or chiral column, and is simple, high in yield, mild in reaction condition, and suitable for industrial production.

[0053] The present application further provides a preparation method of compound II, comprising the following steps:

[0054] (a) reacting compound IV with compound V to obtain compound VI,

[0055] (b) reacting compound VI with nitromethane in the presence of an organic base to obtain compound VII,

[0056] (c) hydrolyzing compound VII to obtain compound II, and the reaction is as follows:

[0057] wherein R is C1-C4 linear or branched alkyl.

[0058] In some embodiments, R is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In some embodiments, R is ethyl or tert-butyl.

[0059] In some embodiments, the molar ratio of compound IV to compound V in step (a) is 1:1 to 3. In some embodiments, the molar ratio of compound IV to compound V in step (a) is 1:1 to 1.5. In some embodiments, the molar ratio of compound IV to compound V in step (a) is 1:1 to 1.3.

[0060] In some embodiments, the step (a) is carried out in sodium alcoholate, which is selected from sodium methoxide, sodium ethoxide or sodium tert-butoxide. In some embodiments, the sodium alcoholate is sodium ethoxide. In some embodiments, the molar ratio of the sodium alcoholate to the compound IV is 1:1-3. In some embodiments, the molar ratio of the sodium alcoholate to the compound IV is preferably 1:1-1.3.

[0061] In some embodiments, the step (a) is carried out in an organic solvent, which is selected from one or more of tetrahydrofuran, toluene, methyl tert-butyl ether, acetonitrile, ethanol, methanol and dichloromethane. In some embodiments, the organic solvent is selected from ethanol. In some embodiments, the volume to mass ratio of the organic solvent to compound IV is 3-12:1 (mL / g). In some embodiments, the volume to mass ratio of the organic solvent to compound IV is 5-10:1 (mL / g).

[0062] In some embodiments, the reaction temperature of the step (a) is 0-30 °C. In some embodiments, the reaction temperature is 0-5 °C. In some embodiments, the reaction temperature is 5-10 °C. In some embodiments, the reaction temperature is 10-20 °C. In some embodiments, the reaction temperature is 20-30 °C. In some embodiments, the reaction temperature is 20-25 °C. In some embodiments, the reaction temperature is 25-30 °C.

[0063] In some embodiments, the reaction time of the step (a) is 0.5-20 h. In some embodiments, the reaction time of the step (a) is 10-20 h. In some embodiments, the reaction time of the step (a) is 12-18 h. In some embodiments, the reaction time of the step (a) is 13-16 h. In some embodiments, the reaction time of the step (a) is 16-18 h.

[0064] In some embodiments, the step (a) can be further purified by post-treatment after the reaction is completed. In some embodiments, the step (a) can be further purified by extraction after the reaction is completed.

[0065] In some embodiments, the molar ratio of compound VI to nitromethane in the step (b) is 1:2-10. In some embodiments, the molar ratio of compound VI to nitromethane in the step (b) is 1:2-4.

[0066] In some embodiments, the organic base in the step (b) is DBU or DBN, and the molar ratio of the organic base to compound VI is 1-3:1. In some embodiments, the molar ratio of the organic base to compound VI is 1-1.5:1.

[0067] In some preferred embodiments, the step (b) does not require reaction in a solvent.

[0068] In some embodiments, the step (b) is carried out in an organic solvent selected from one or more of tetrahydrofuran, toluene, methyl tert-butyl ether, acetonitrile, ethanol, methanol, dichloromethane, and ethyl acetate. In some embodiments, the organic solvent is selected from THF. In some embodiments, the volume to mass ratio of the organic solvent to compound VI is 1-10: 1 (mL / g).

[0069] In some embodiments, the reaction temperature of the step (b) is 0-80 °C. In some embodiments, the reaction temperature of the step (b) is 20-25 °C.

[0070] In some embodiments, the reaction time of the step (b) is 2-20 h. In some embodiments, the reaction time of the step (b) is 6-20 h. In some embodiments, the reaction time of the step (b) is 12-18 h. In some embodiments, the reaction time of the step (b) is 13-16 h. In some embodiments, the reaction time of the step (b) is 7-9 h.

[0071] In some embodiments, the step (b) can be further purified by post-treatment after the reaction is completed. In some embodiments, the step (b) can be further purified by extraction after the reaction is completed.

[0072] In some embodiments, the step (c) is hydrolyzed in the presence of a base selected from one or more of LiOH, KOH, NaOH, K2CO3, and Na2CO3. In some embodiments, the base is selected from NaOH. In some embodiments, the molar ratio of the base to compound VII is 1-5: 1. In some embodiments, the molar ratio of the base to compound VII is 1-3: 1.

[0073] In some embodiments, the step (c) is carried out in a solvent selected from one or more of THF, EtOH, MeOH, and water. In some embodiments, the solvent is selected from one or both of ethanol and water. In some embodiments, the volume to mass ratio of the organic solvent to compound VII is 1-5: 1 (mL / g). In some embodiments, the volume to mass ratio of the organic solvent to compound VII is 1-3: 1 (mL / g).

[0074] In some embodiments, the reaction temperature of step (c) is 0-50°C. In some embodiments, the reaction temperature of step (c) is 20-30°C. In some embodiments, the reaction temperature of step (c) is 20-25°C. In some embodiments, the reaction temperature of step (c) is 25-30°C.

[0075] In some embodiments, the reaction time of step (c) is 2-20h. In some embodiments, the reaction time of step (c) is 3-5h.

[0076] In some embodiments, after the reaction of step (c) is completed, the product can be further purified by post-treatment. In some embodiments, after the reaction of step (c) is completed, the product can be further purified by extraction.

[0077] In some embodiments, the meloxicam besylate prepared by the method of the present application can be further purified by recrystallization or other purification methods.

[0078] The method of the present application can obtain meloxicam besylate with high optical purity without separating compound II by chiral organic amine or chiral column, and is simple to operate, high in yield, and mild in reaction conditions, and is suitable for industrial production.

[0079] Example 1: Preparation of compound II

[0080] Step 1:

[0081] Add 90g of ethyl (diethoxyphosphoryl) acetate, 50g of compound IV, 137.5g of 20% (w / w) EtONa in ethanol solution into 363mL of ethanol, and incubate at 0-5°C for 16h, then add 250mL of water and 250mL of toluene, separate the layers, and concentrate the toluene phase to obtain 89.5g of yellowish oil compound Via (yield 92%, purity 99%).

[0082] Step 2:

[0083] Mix 75g of compound Via and 55g of nitromethane, add 72g of DBU, and incubate at 20-25°C for 16h, then add 375mL of water and 375mL of toluene, separate the layers, and concentrate the toluene phase to obtain 90g of compound VIIa (yield 91%).

[0084] Step 3:

[0085] To 77 g of compound VIIa and 230 mL of ethanol, 173 g of 20% aqueous sodium hydroxide solution was added and the reaction was carried out at 20-25°C for 4 h. Then 385 mL of water was added and the pH was adjusted to 2-3. The reaction mixture was extracted with 385 mL of toluene and the toluene layer was separated and concentrated to obtain 62 g of compound II as a light yellow oily substance (yield 90%, purity 97%, ratio of IIa to IIb 5.76).

[0086] Example 2: Preparation of meloxicam benzene sulfonic acid

[0087] To 16 g of compound II (purity 97%, ratio of IIa to IIb 5.76) and 33.6 g of iron powder, 320 mL of formic acid was added and the reaction was carried out at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated to obtain a brown liquid having a volume in the range of 15-50 mL. Then, 168 mL of MTBE was added and 13.7 g of benzene sulfonic acid was added and the reaction was carried out at 20-25°C for 2 h. The reaction mixture was filtered to obtain 19.6 g of meloxicam benzene sulfonic acid (yield 79.7%, purity 99.66%, epimer <LOD).

[0088] Example 3: Preparation of meloxicam benzene sulfonic acid

[0089] To 10 g of compound II (purity 97%, ratio of IIa to IIb 5.76) and 21 g of iron powder, 200 mL of formic acid was added and the reaction was carried out at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated to obtain a brown liquid having a volume in the range of 10-30 mL. Then, 40 mL of MTBE was added and 8.6 g of benzene sulfonic acid was added and the reaction was carried out at 0-5°C for 2 h. The reaction mixture was filtered to obtain 11.9 g of meloxicam benzene sulfonic acid (yield 77.7%, purity 98.07%, epimer 1.67%).

[0090] Example 4: Preparation of meloxicam benzene sulfonic acid

[0091] To 10 g of compound II (purity 97%, ratio of IIa to IIb 5.76) and 21 g of iron powder, 200 mL of formic acid was added and the reaction was carried out at room temperature for 16 h. The reaction mixture was filtered and the filtrate was concentrated to obtain a brown liquid having a volume in the range of 10-30 mL. Then, 80 mL of MTBE was added and 8.6 g of benzene sulfonic acid was added and the reaction was carried out at 0-5°C for 2 h. The reaction mixture was filtered to obtain 12.3 g of meloxicam benzene sulfonic acid (yield 79.8%, purity 97.83%, epimer 1.70%).

[0092] Example 5: Preparation of meloxicam benzene sulfonic acid

[0093] To 10 g of compound II (purity 97%, ratio of Ha to lib 5.76), 21 g of iron powder was added in 200 mL of formic acid and reacted at room temperature for 16 h. The filtrate was concentrated to obtain a brown liquid, the volume of which was in the range of 10-30 mL. Then, 80 mL of MTBE was added, 8.6 g of benzenesulfonic acid was added, and stirring was performed at 20-25 °C for 2 h. Filtration resulted in 11.3 g of meloxicam benzenesulfonic acid (yield 73.4%, purity 99.71%, epimer <LOD).

[0094] Example 6: Preparation of meloxicam benzenesulfonic acid

[0095] To 10 g of compound II (purity 97%, ratio of Ha to lib 5.76), 21 g of iron powder was added in 200 mL of formic acid and reacted at room temperature for 16 h. The filtrate was concentrated to obtain a brown liquid, the volume of which was in the range of 10-30 mL. Then, 80 mL of MTBE was added, 8.6 g of benzenesulfonic acid was added, and stirring was performed at 20-25 °C for 2 h. Filtration resulted in 11.3 g of meloxicam benzenesulfonic acid (yield 73.4%, purity 99.71%, epimer <LOD).

[0096] Example 7: Preparation of meloxicam

[0097] To 10 g of compound II (purity 97%, ratio of Ha to lib 5.76), 21 g of iron powder was added in 200 mL of formic acid and reacted at room temperature for 16 h. The filtrate was concentrated to obtain a brown liquid, the volume of which was in the range of 10-30 mL. Then, 80 mL of MTBE was added, 8.6 g of benzenesulfonic acid was added, and stirring was performed at 20-25 °C for 2 h. Filtration resulted in 11.3 g of meloxicam benzenesulfonic acid (yield 73.4%, purity 99.71%, epimer <LOD).

[0098] Example 8: Preparation of meloxicam benzenesulfonic acid

[0099] To 100 mg of meloxicam prepared in Example 7, 0.4 mL of formic acid was added in 0.4 mL of MTBE, and then 98.3 mg of benzenesulfonic acid was added. Stirring was performed at 20-25 °C for 4 h. Filtration resulted in 112 mg of meloxicam benzenesulfonic acid (yield 63.8%, purity 99.93%, epimer:

Claims

1. A process for the preparation of meloxicam benzene sulfonic acid characterized in that, comprising the steps of: reacting compound I or an acid salt thereof in methyl tert-butyl ether with benzenesulfonic acid and isolating a solid of benzenesulfonic acid milnacipran, wherein compound I is a mixture comprising compound la and compound lb, the structures of said compound I, compound la and compound lb are as follows, respectively:

2. The method of claim 1, wherein, The acid salt of the compound I is a weak acid salt, preferably formate or acetate.

3. The preparation method according to claim 1, characterized in that, The content of the compound Ia in the mixture containing the compound Ia and the compound Ib is > 50%.

4. The preparation method according to claim 1, characterized in that, The reaction is carried out in the presence of an organic weak acid.

5. The preparation method according to claim 4, characterized in that, The organic weak acid is selected from formic acid or acetic acid, preferably formic acid.

6. The preparation method according to claim 4 or 5, characterized in that, The mass-volume ratio of the mixture of the compound Ia and the compound Ib to the organic weak acid is 1:0.1-10 (g / mL), preferably 1:1-5 (g / mL), more preferably 1:1-3 (g / mL).

7. The method of any one of claims 1 to 5, wherein the method is carried out at a temperature of from 20 to 40 °C. The mass-volume ratio of the mixture of the compound Ia and the compound Ib to methyl tert-butyl ether is 1:2-20 (g / mL), preferably 1:4-15 (g / mL), more preferably 1:4-12 (g / mL).

8. The method of any one of claims 1 to 5, wherein the method is carried out at a temperature of from 20 °C to 30 °C. The reaction temperature is 0-50°C, preferably 0-30°C, more preferably 20-30°C.

9. A process for the preparation of meloxicam benzene sulfonic acid characterized in that, Comprising the following steps: (1) reducing the compound II in the presence of Fe and HCOOH to generate the compound III, and filtering to obtain a filtrate, (2) The filtrate obtained in step (1) is added to methyl tert-butyl ether, the reaction with benzenesulfonic acid is continued and the benzenesulfonic acid meloxicam solid is precipitated, the reaction being as follows: wherein the compound II is a mixture of compound Ha and compound lib, the content of compound Ha in the compound II is greater than 50%, and the structures of the compound Ha and the compound lib are as follows, 10. The preparation method according to claim 9, characterized in that, The molar ratio of the compound II to Fe in the step (1) is 1:3-18, preferably 1:8-12, more preferably 1:8-10.

11. The preparation method according to claim 9, characterized in that, The mass-volume ratio of the compound II to HCOOH in the step (1) is 1:3-25 (g / mL), preferably 1:10-22 (g / mL), more preferably 1:15-20 (g / mL).

12. The preparation method according to claim 9, characterized in that, The filtrate in the step (1) can remove part of formic acid by concentration, and the mass ratio of the final volume of the filtrate after concentration in the step (1) to the compound II is 1-5:1 (mL / g); preferably 1-3:1 (mL / g).

13. The preparation method according to claim 9, characterized in that, The mass-volume ratio of the compound II in the step (1) to methyl tert-butyl ether in the step (2) is 1:4-30 (g / mL), preferably 1:4-20 (g / mL), more preferably 1:4-12 (g / mL), most preferably 1:8-11 (g / mL).

14. The preparation method according to claim 9, characterized in that, The reaction temperature of the step (2) is 0-50°C, preferably 0-30°C, more preferably 20-30°C.

15. The method of any one of claims 9 to 14, wherein the method is carried out at a temperature of from 20 °C to 30 °C. Further comprising the preparation of the compound II, the steps of which are as follows: (a) reacting the compound IV with the compound V to generate the compound VI, (b) reacting the compound VI with nitromethane to generate the compound VII, (c) hydrolysis of compound VII to form compound II, as follows: wherein R is C1-C4 linear or branched alkyl.

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