Preparation method of lornoxicam

Abstract

The invention provides a preparation method of lornoxicam, which comprises the following steps: (1) reacting 2-bromothiophene-3-sulfonyl chloride with glycine methyl ester hydrochloride to obtain a compound 4; (2) reacting the compound 4 with a chlorination reagent to obtain a compound 5; (3) mixing the compound 5 with phenyl formate, a catalyst and a phosphorus ligand, and carrying out carbonyl insertion reaction to obtain a compound 6; (4) mixing and reacting the compound 6 with alkali to obtain a compound 7; (5) mixing and reacting the compound 7 with a methylation reagent to obtain a compound 8; and (6) mixing and reacting the compound 8 with 2-aminopyridine to obtain a compound 1, namely lornoxicam. By adopting the specific starting raw materials, the impurity content can be effectively reduced, the reaction yield is improved, meanwhile, the reaction condition is mild, a high-toxicity reagent does not need to be adopted, and the method is green and environmentally friendly.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and specifically relates to a method for preparing lornoxicam, and in particular to a method for preparing lornoxicam with high yield. Background Art

[0002] Lornoxicam is a non-steroidal anti-inflammatory analgesic and a thiazide derivative with strong antipyretic, analgesic and anti-inflammatory effects. It was first launched in Denmark in October 1997. It was originally developed as Nycomed. Its chemical name is 6-chloro-4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-E]-1,2-thiazine-3-carboxamide 1,1-dioxide. Its structural formula is:

[0003]

[0004] At present, the preparation methods of lornoxicam disclosed in the literature are mainly limited to the following literature reports:

[0005] European patent EP4180662 uses 2,5-dichlorothiophene as the starting material, and obtains lornoxicam through sulfonation, aminolysis, carbonyl insertion, chlorination, esterification, intramolecular Claisen ester condensation, and 2-aminopyridine aminolysis. Although this process can synthesize lornoxicam, the total yield is less than 1% due to the long reaction steps, and the use of dangerous chemical reagents such as butyl lithium, PCl5, methyl iodochloroacetate, etc. makes the reaction extremely polluting, and also limits the industrialization of the process.

[0006]

[0007] Fan Weiming and others optimized the above route, mainly by replacing the highly toxic methyl iodoacetate and the easily hygroscopic sodium hydrogen sulfide with methyl chloroacetate and a phase transfer catalyst respectively in the preparation of compound 7, which greatly improved the yield and greatly reduced the operational safety risk; in the condensation reaction, dioxane was used instead of methanol as the solvent, which reduced the reaction temperature and also improved the yield.

[0008]

[0009] Chinese patent CN16999372A uses intermediate 9 (5-chloro-3-chlorosulfonylthiophene-2-carboxylic acid methyl ester) as the starting material, reacts with glycine methyl ester to obtain an ammonolysis product 10, 10 is subjected to Claisen ester condensation to obtain a thiazine derivative 11, and 11 is methylated with dimethyl sulfate to obtain lornoxicam. This route uses glycine methyl ester as an ammonolysis reagent, and since there is no interference from the methyl group, the subsequent intramolecular Claisen ester condensation reaction is relatively easy, and the yield is also improved. Its total yield is about 50%, but the highly toxic dimethyl sulfate needs to be used as a methylating reagent, which brings great pressure to large-scale production and environmental protection.

[0010]

[0011] Meng Wenxue et al. still used intermediate 9 (5-chloro-3-chlorosulfonylthiophene-2-carboxylic acid methyl ester) as the starting material, and obtained lornoxicam by aminolysis with sarcosine methyl ester, Claisen intramolecular condensation and then aminolysis with 2-aminopyridine. This route uses sarcosine methyl ester instead of glycine methyl ester for aminolysis, omitting the methylation step, making the process route simpler, but still does not solve the problem that Claisen intramolecular condensation is difficult to carry out and the yield is low.

[0012]

[0013] Chinese patent CN101314598A uses acrylonitrile as the starting material, and obtains the important intermediate 14 through chlorine addition, Fiesselmann thiophene synthesis, diazotization and sulfonylation. 14 reacts with chlorine using iron powder as a catalyst to obtain intermediate 5, and 5 is aminolyzed by methylamine to obtain intermediate 6. This route is a method for preparing intermediates, using cheap and easily available acrylonitrile as a raw material, and the material cost is low, but the yield of intermediate 5 is relatively low, less than 50%.

[0014]

[0015] Chinese patent CN106892932A first condenses tert-butyloxycarbonyl sarcosine with 2-aminopyridine, and then removes the amino protection with hydrogen chloride to obtain an amine derivative intermediate 15, which is then reacted with 5-chloro-3-chlorosulfonylthiophene-2-carboxylic acid methyl ester under the action of an acid binding agent to obtain an aminolysis product intermediate 16, and finally condenses intramolecularly under the action of potassium tert-butoxide to obtain lornoxicam. This route requires the use of Boc to protect glycine, and then the protective group needs to be removed, which actually prolongs the reaction route, greatly reduces the overall yield, and greatly increases the cost.

[0016]

[0017] There are a series of problems in the above method, such as low intramolecular condensation yield, less than 70%; low chlorination reaction yield, less than 50%; using 2,5-dichlorothiophene as the starting material, the carbonylation reaction conditions are harsh, and the 5-position chlorination is also easily carbonylated to produce impurities; using highly toxic dimethyl sulfate as a methylation agent, it brings great pressure to environmental protection and production. Therefore, how to provide a preparation method of lornoxicam with high yield, mild reaction conditions, low impurity content, and green environmental protection has become an urgent problem to be solved. Summary of the invention

[0018] In view of the shortcomings of the prior art, the purpose of the present invention is to provide a method for preparing lornoxicam, in particular to provide a method for preparing lornoxicam with high yield. The present invention adopts specific starting materials, can effectively reduce the impurity content, improve the reaction yield, and at the same time, the reaction conditions are mild, no highly toxic reagents are required, and it is green and environmentally friendly.

[0019] In order to achieve the purpose of the invention, the present invention adopts the following technical solutions:

[0020] The present invention provides a method for preparing lornoxicam, which comprises the following steps:

[0021] (1) reacting 2-bromothiophene-3-sulfonyl chloride with glycine methyl hydrochloride to obtain compound 4;

[0022] (2) reacting compound 4 with a chlorinating agent to obtain compound 5;

[0023] (3) Compound 5 is mixed with phenyl formate, a catalyst, and a phosphorus ligand to undergo carbonyl insertion reaction to obtain compound 6;

[0024] (4) Compound 6 is mixed with a base to react to obtain compound 7;

[0025] (5) Compound 7 is mixed with a methylating agent to react to obtain compound 8;

[0026] (6) Compound 8 is mixed with 2-aminopyridine to react to obtain compound 1, i.e., lornoxicam.

[0027] The reaction process is as follows:

[0028]

[0029] The above reaction uses 2-bromothiophene-3-sulfonyl chloride as a starting material, condenses with glycine methyl ester hydrochloride, and obtains an important intermediate compound 6 through chlorination and carbonyl insertion reaction, and then undergoes Claisen ester condensation to form an intramolecular ring, methylation, and finally obtains lornoxicam through 2-aminopyridine aminolysis. The overall process has mild reaction conditions, does not require the use of highly toxic reagents, and is green and environmentally friendly. By using 2-bromothiophene-3-sulfonyl chloride as a starting material, the impurity content can be effectively reduced, and the situation of reducing chlorination at the 5th position during the carbonyl insertion reaction can be reduced. Combined with the method of first performing ring closure and then performing methylation, the reaction yield can be effectively improved.

[0030] Preferably, the reaction in step (1) is carried out in an aprotic solvent.

[0031] Preferably, the molar ratio of 2-bromothiophene-3-sulfonyl chloride to glycine methyl hydrochloride in step (1) is 1:(1.1-1.5), for example 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, but is not limited to the above values, and other values ​​not listed within the above numerical range are also applicable.

[0032] Preferably, the reaction temperature in step (1) is 10-30°C, and the reaction time is 0.3-1h, for example, 10°C, 15°C, 20°C, 25°C or 30°C, and the reaction time can be 0.3h, 0.4h, 0.5h, 0.6h, 0.7h, 0.8h, 0.9h or 1h, but is not limited to the above-listed values. Other values ​​not listed within the above numerical range are also applicable.

[0033] Preferably, the chlorination reagent in step (2) comprises NCS (N-chlorosuccinimide) and / or chlorine gas, preferably NCS.

[0034] Preferably, the molar ratio of compound 4 to the chlorination agent in step (2) is 1:(1.1-1.5), for example 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, but is not limited to the above-listed values, and other values ​​not listed within the above numerical range are also applicable.

[0035] Preferably, the reaction temperature in step (2) is -10 to 10°C, and the reaction time is 6 to 10 h, wherein the temperature may be -10°C, -5°C, 0°C, 5°C or 10°C, etc., and the reaction time may be 6 h, 7 h, 8 h, 9 h or 10 h, etc., but are not limited to the values ​​listed above, and other values ​​not listed within the above numerical range are also applicable.

[0036] Preferably, in step (3), the molar ratio of compound 5 to phenyl formate is 1:(1.5-3), the molar amount of the catalyst is 1-5% of the molar amount of compound 5, and the molar amount of the phosphorus ligand is 5-15% of the molar amount of compound 5, wherein the molar ratio of compound 5 to phenyl formate can be 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9 or 1:3, etc., the molar amount of the catalyst can be 1%, 2%, 3%, 4% or 5% of the molar amount of compound 5, and the molar amount of the phosphorus ligand can be 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% of the molar amount of compound 5, but are not limited to the values ​​listed above, and other values ​​not listed within the above numerical range are equally applicable.

[0037] Preferably, the catalyst comprises palladium acetate and / or bis(benzonitrile)palladium chloride.

[0038] Preferably, the phosphorus ligand comprises tri-tert-butylphosphine tetrafluoroborate and / or 4,5-bisdiphenylphosphine-9,9-dimethylxanthene.

[0039] Preferably, the temperature of the carbonylation reaction in step (3) is 60-100° C. and the time is 10-20 h.

[0040] Preferably, the base in step (4) comprises any one of sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride, or a combination of at least two thereof.

[0041] Preferably, the molar ratio of compound 6 to the base in step (4) is 1:(1.5-3), for example 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9 or 1:3, but is not limited to the above-listed values, and other values ​​not listed within the above numerical range are also applicable.

[0042] Preferably, the reaction temperature in step (4) is 60-80°C, such as 60°C, 65°C, 70°C, 75°C or 80°C, but is not limited to the above-listed values. Other values ​​not listed within the above range are also applicable.

[0043] Preferably, the methylating agent in step (5) comprises any one of iodomethane, tetramethylammonium fluoride, methyl p-toluenesulfonate or methyl trifluoromethanesulfonate, or a combination of at least two thereof.

[0044] Preferably, the molar ratio of compound 7 to the methylating agent in step (5) is 1:(1.5-5), for example 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5 or 1:5, etc., but is not limited to the above-listed values, and other values ​​not listed within the above numerical range are also applicable.

[0045] Preferably, the reaction temperature in step (5) is 80-110°C and the reaction time is 8-10h, wherein the temperature can be 80°C, 85°C, 90°C, 95°C, 100°C, 105°C or 110°C, etc., and the reaction time can be 8h, 8.5h, 9h, 9.5h or 10h, etc., but are not limited to the values ​​listed above. Other values ​​not listed within the above numerical range are also applicable.

[0046] Compared with the prior art, the present invention has the following beneficial effects:

[0047] The invention provides a preparation method of lornoxicam. 2-bromothiophene-3-sulfonyl chloride is used as a starting material, and condensed with glycine methyl ester hydrochloride, and an important intermediate compound 6 is obtained through chlorination and carbonyl insertion reaction, and then Claisen ester condensation is performed to form an intramolecular ring, methylation, and finally 2-aminopyridine aminolysis is performed to obtain lornoxicam. The overall process has mild reaction conditions, does not need to use highly toxic reagents, and is green and environmentally friendly. By using 2-bromothiophene-3-sulfonyl chloride as a starting material, the impurity content can be effectively reduced, the situation of reducing chlorination at position 5 during carbonyl insertion reaction can be reduced, and the reaction yield can be improved. DETAILED DESCRIPTION

[0048] In order to further explain the technical means and effects adopted by the present invention, the technical solution of the present invention is further described below in conjunction with the preferred embodiments of the present invention, but the present invention is not limited to the scope of the embodiments.

[0049] Example 1

[0050] This embodiment provides a method for preparing lornoxicam, and the specific steps are as follows:

[0051] (1) Preparation of (2-bromothiophen-3-yl)sulfonylglycine methyl ester (Compound 4)

[0052]

[0053] To a four-necked flask, 400 mL of dichloromethane, glycine methyl hydrochloride (30.3 g, 240 mmol), and triethylamine (46 g, 460 mmol) were added, and the temperature was lowered to 0-5 ° C. 2-bromothiophene-3-sulfonyl chloride (51.96 g, 200 mmol) was added in batches. After the addition was completed, the reaction was stirred at 25 ° C for 0.5 h. After the reaction was completed, 200 mL of purified water was added, stirred for 10 min, and the layers were allowed to stand for 10 min. The aqueous phase was separated, the organic phase was collected, and the solvent was evaporated under reduced pressure to obtain an oily substance. 110 mL of ethanol was added and stirred to dissolve. n-heptane was added and stirred for 30 min. The temperature was lowered to 0 ° C., stirred for 2 h, and filtered to obtain 55.9 g of a solid with a yield of 92%.

[0054] (2) Preparation of (2-bromo-5-chlorothiophen-3-yl)sulfonylglycine methyl ester (Compound 5)

[0055]

[0056] To a dry reactor, add 780 mL of dry chloroform, 12 g of glacial acetic acid, and intermediate 4 (62.58 g, 200 mmol), cool to 5 ° C, add NCS (32.05 g, 0.24 mol) and stir for 8 h. After the reaction is completed, add 800 mL of water and stir for 0.5 h. Separate the organic phase, wash once with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter, and evaporate the solvent under reduced pressure. Add 180 mL of isopropyl ether and heat to dissolve the solid. Cool to 0-5 ° C and stir for 2 h. Filter, wash with 50 mL of isopropyl ether, and dry in vacuo at 50 ° C for 8 h to obtain 60.35 g of a milky white solid with a yield of 87.10%.

[0057] (3) Preparation of 5-chloro-3-(N-(2-methoxy-2-oxoethyl)sulfamoyl)thiophene-2-carboxylic acid phenyl ester (Compound 5)

[0058]

[0059] Compound 5 (34.7 g, 0.1 mol), phenyl formate (21.8 g, 0.2 mol), 0.67 g (3 mol%) of palladium acetate, 3.48 g (12 mol%) of tri-tert-butylphosphine tetrafluoroborate, 12.14 g of triethylamine and 240 mL of acetonitrile were added to a four-necked flask in sequence at 20°C. After the addition was completed, the temperature was raised to 80°C and the reaction was carried out for 15 h. After the reaction was completed, the temperature was lowered to 20°C and the solid was filtered out. 200 mL of dichloromethane and 200 mL of purified water were added to the organic phase and stirred for 10 min. The organic phase was allowed to stand and the layers were separated. The organic phase was collected and the dichloromethane was evaporated under reduced pressure at 50°C. The remaining organic phase was added and transferred to another four-necked flask. Concentrated hydrochloric acid was added dropwise at 20°C to pH = 3-3.5. The temperature was lowered to 0-5°C and stirred for 2 h. The solid was filtered out and dried in vacuo at 50°C for 12 h to obtain 37.39 g of solid with a yield of 88.13%.

[0060] (4) Preparation of 6-chloro-4-hydroxy-2H-thieno[2,3-e][1,2]thiazine-3-carboxylic acid methyl ester 1,1-dioxide (7)

[0061]

[0062] At 20°C, add intermediate 6 (17 g, 40 mmol) and 400 mL of methanol into a four-necked bottle, slowly add sodium methoxide (4.3 g, 80 mmol) in batches while stirring, and after the addition is completed, heat to 70°C under nitrogen protection until TLC shows that the raw material disappears completely. Stop heating, cool to 20°C, add 200 mL of purified water and 300 mL of dichloromethane to extract once, collect the organic phase, evaporate the dichloromethane under reduced pressure at 20°C, cool the remaining methanol to 0-5°C, stir for 2 hours, and filter to obtain 10.74 g of light yellow solid with a yield of 91.10%.

[0063] (5) Preparation of 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e][1,2]thiazine-3-carboxylic acid methyl ester 1,1-dioxide (8)

[0064]

[0065] At 20°C, add intermediate 7 (29.6 g, 100 mmol), 240 mL toluene, and tetramethylammonium fluoride (23.3 g, 250 mmol) into a four-necked bottle, stir and heat to 100°C, and react for 10 h. Stop heating, cool to 20°C, add 200 mL of purified water, stir for 10 min, let stand and separate, collect the organic phase, evaporate toluene under reduced pressure to obtain an oily substance, add 380 mL of ethanol, cool to 0-5°C, stir for 2 h, filter, and vacuum dry at 50°C for 8 h to obtain 27.05 g of solid, with a yield of 87.58%.

[0066] (6) Preparation of Lornoxicam

[0067]

[0068] At 20°C, intermediate 8 (10 g, 32 mmol), 2-aminopyridine (3.6 g, 38 mmol), p-toluenesulfonic acid (0.6 g, 3.2 mmol) and 160 mL of toluene were added to a four-necked bottle and heated to 110°C for reflux. The reaction was monitored by TLC until the raw material completely disappeared and the reaction was stopped. After two-thirds of the solvent was evaporated under reduced pressure, activated carbon was added and boiled for 10 minutes. The filtrate was filtered while hot, and the filtrate was transferred to another four-necked bottle, stirred for 30 min, cooled to 0-5°C, stirred for 2 h, filtered, and dried in vacuo at 50°C to obtain 10.14 g of solid with a yield of 85.45% and a HPLC purity of 99.85%.

[0069] The characterization data are as follows:

[0070] 1 HNMR (DMSO), δ: 2.90 (3H, s), 7.32 (1H, t, J = 6.4Hz), 7.58 (1H, s), 7.72 (1H, d, J = 8. 8Hz), 8.22 (1H, t, J = 7.6Hz), 8.31 (1H, t, J = 6.0Hz), 14.11 (1H, brs), 15.82 (1H, s).

[0071] Example 2

[0072] This embodiment provides a method for preparing lornoxicam, which is consistent with Example 1 except that tri-tert-butylphosphine tetrafluoroborate is replaced by an equimolar amount of 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene in step (3).

[0073] The final step (3) yielded 35.27 g of solid with a yield of 83%.

[0074] Example 3

[0075] This embodiment provides a method for preparing lornoxicam, which is consistent with Example 1 except that sodium methoxide is replaced by an equimolar amount of sodium hydride in step (4).

[0076] The final step (4) yielded 10.38 g of a light yellow solid with a yield of 88.10%.

[0077] Example 4

[0078] This embodiment provides a method for preparing lornoxicam, which is consistent with Example 1 except that step (2) is as follows.

[0079] (2) In a dry four-necked flask, 80 mL of chloroform was added, followed by rapid addition of anhydrous ferric chloride (0.32 g, 2 mmol), and chlorine gas dried over concentrated sulfuric acid was introduced into the reaction solution, and the temperature was maintained at 30°C. After one hour, the introduction of chlorine gas was stopped, and intermediate 4 (6.28 g, 20 mmol) was rapidly added, and the mixture was stirred for 45 minutes at this temperature. After the reaction was completed, the temperature was lowered to 10°C, 80 mL of water was added, and the mixture was stirred vigorously for half an hour. When the yellow-green color of the solution faded, the mixture was allowed to stand for stratification, and the organic phase was separated and washed once with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was recrystallized from isopropyl ether to obtain 4.03 g of a milky white solid with a yield of 58%.

[0080] Comparative Example 1

[0081] This comparative example provides a method for preparing lornoxicam, which is consistent with Example 1 except that step (3) is as follows.

[0082] (3) Compound 5 (34.7 g, 0.1 mol), diethyl oxalate (32 g, 0.2 mol), 3 mol% of bis(triphenylphosphine)palladium dichloride, 6 mol% of bis(diphenylphosphine)propane, 1.2 equivalents of 4-dimethylaminopyridine (based on compound 5), 240 mL of N-methylpyrrolidone, and 9.6 g of methanol were added to a four-necked flask at 20°C in sequence. After the addition was completed, the temperature was raised to 120°C and the reaction was carried out for 1 h. After the reaction was completed, the temperature was lowered to 20°C and the solid was filtered out. 200 mL of dichloromethane and 200 mL of purified water were added to the organic phase and stirred for 10 min. The organic phase was allowed to stand and the layers were separated. The organic phase was collected and the dichloromethane and methanol were evaporated under reduced pressure at 50°C. The remaining organic phase was transferred to another four-necked flask. Concentrated hydrochloric acid was added dropwise to pH = 3-3.5 at room temperature. The temperature was lowered by 0-5°C and stirred for 2 h. The solid was filtered out and dried in vacuo at 50°C for 12 h to obtain 29.5 g of solid with a yield of 84%.

[0083] Comparative Example 2

[0084] This comparative example provides a method for preparing lornoxicam, which is consistent with Example 1 except that steps (4) and (5) are as follows.

[0085] (4) Preparation of 5-chloro-3-(N-methoxycarbonylmethylene-N-methyl)-aminosulfonylthiophene-2-carboxylic acid methyl ester

[0086] Compound 6 (120 g, 0.44 mol), CICH2COOCH3 (48 mL, 0.53 mol), Na2CO3 (68 g, 0.64 mol) and acetone (700 mL) were put into a 1L three-necked flask at once, and tetrabutylammonium bromide (2 g) was added. The mixture was stirred at 40°C for 10 h. The mixture was transferred to a mixture of water (1.5 L) and chloroform (1 L), and the organic phase was separated. The aqueous phase was extracted with chloroform (100 mL × 2), and the organic phases were combined. The mixture was washed with water until neutral, dried with anhydrous Na2SO4, concentrated to dryness, and then recrystallized with ethanol. The mixture was dried to obtain a white needle-shaped solid (132 g, 867%).

[0087] (5) Preparation of 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1-thiazine-3-carboxylic acid methyl ester-1,1-dioxide

[0088] Add dioxane (700ml) and powdered sodium methoxide solid (24g) to a 1L three-necked flask, stir and disperse, then add the white needle-shaped solid (160g) obtained in step (4) at once, heat to 50°C and react for 5h. After cooling, pour into a mixture of 2mol / L HCl (1500ml) and dichloromethane (800mL), and separate the organic phase. Take the aqueous phase and combine the organic phase with dichloromethane (100mL×2). Wash the organic phase with 10% sodium acetate aqueous solution (500mL×2) and 10% Na2CO3 solution (400mL×2), and a large amount of yellow solid precipitates. Filter, transfer the filter cake into a mixture of water (500ml) and dichloromethane (800ml), stir vigorously and disperse, then acidify with concentrated hydrochloric acid to pH=2, separate the layers, take the organic phase, and dry it with anhydrous Na2SO4. After concentrating to dryness, the residue was soaked in methanol (300 mL), filtered, and dried to obtain light yellow crystals 8 (112 g, 77.2%).

[0089] Comparative Example 3

[0090] This comparative example provides a method for preparing lornoxicam, and the specific steps are as follows:

[0091] Preparation of 5-chloro-3-(chlorosulfonyl)thiophene-2-carboxylic acid methyl ester

[0092]

[0093] Into a three-necked round-bottom flask, add 80mL of dry chloroform and then quickly add anhydrous ferric chloride (0.32g, 2mmol), pass chlorine gas dried by concentrated sulfuric acid into the above reaction solution, and maintain the temperature at 30°C, and alkaline water receives tail chlorine; after about one hour, the mass of the reaction system increases by 1g, at this time, stop passing chlorine gas, quickly add intermediate 9 (4.8g, 20mmol), and stir for 45 minutes at this temperature, transfer the mixed solution to a 500mL beaker, add 80mL of water, stir vigorously for half an hour, wait for the yellow-green color of the solution to fade, separate the organic phase, wash once with saturated brine, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate to obtain a crude product, which is recrystallized from isopropyl ether to obtain 3.5g of a milky white solid with a yield of 60%.

[0094] Preparation of 5-chloro-3-(N-(2-methoxy-2-oxoethyl)sulfamoyl)thiophene-2-carboxylic acid methyl ester

[0095]

[0096] The intermediate 10 (5.48 g, 20 mmol) prepared in the previous step and 100 mL of dichloromethane were added to a three-necked flask. Glycine methyl ester hydrochloride (3.03 g, 24 mmol) was added in batches under an ice bath, and triethylamine (4.6 g, 46 mmol) was slowly added dropwise. After the addition was completed, ethyl acetate was added to the reaction mixture to precipitate solids. The solids were filtered out, and the filter cake was washed with ethyl acetate (30 mL × 3). The filtrate was collected, washed with water and saturated brine in turn, dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated; the obtained oily liquid was placed in a refrigerator to freeze to obtain a light yellow solid, and the light yellow solid was then placed in anhydrous ethanol and petroleum ether for recrystallization to obtain 6.0 g of light yellow needle-shaped crystals, with a yield of 92%.

[0097] Preparation of 6-chloro-4-hydroxy-2H-thieno[2,3-e][1,2]thiazine-3-carboxylic acid methyl ester 1,1-dioxide

[0098]

[0099] At room temperature, add intermediate 11 (1.2 g, 4 mmol) and 40 mL of methanol into a 100 mL dry flask, and slowly add sodium methoxide (0.43 g, 8 mmol) in batches while stirring. After the addition is completed, heat to 70 ° C with nitrogen protection until TLC shows that the raw material disappears completely. Stop heating, cool to room temperature, and evaporate the solvent under reduced pressure to obtain a light yellow solid. In an ice bath, disperse the light yellow solid into water and completely dissolve it. First adjust the pH of the solution to about neutral with glacial acetic acid, and then adjust the solution to pH 3 with 2M hydrochloric acid; extract with dichloromethane (20 mL × 3) and extract once with saturated brine, collect the organic phase, dry it with anhydrous sodium sulfate, filter it, and concentrate the mother liquor; recrystallize the concentrate with cold anhydrous ethanol to obtain 0.89 g of a light yellow solid with a yield of 75%.

[0100] Preparation of 6-chloro-4-hydroxy-2-methyl-2H-pheno[2,3-e][1,2]thiazine-3-carboxylic acid 1,1-dioxide

[0101]

[0102] Under ice bath, add intermediate 12 (1.18g, 4mmol) and 4mL methanol into a 50mL dry round-bottom flask, and add 2mL methanol solution of dimethyl sulfate (1.31g, 10.4mmol) and 15mL methanol solution of sodium hydroxide (0.32g, 8mmol) dropwise respectively. After the reaction at room temperature, TLC shows that the raw material disappears completely, and the reaction is over. Under ice bath, add 10mL water to dilute, acidify the solution with 1M hydrochloric acid to pH 3, and a large amount of solid precipitates. Filter by suction, wash the filter cake with water and dry it to obtain a crude product. The crude product is recrystallized in cold anhydrous methanol, and dried under reduced pressure at 60℃ to obtain 0.93g of off-white fine needle-shaped solid, with a yield of 75%.

[0103] Preparation of Lornoxicam

[0104]

[0105] At 20°C, intermediate 13 (1.0 g, 3.2 mmol), 2-aminopyridine (0.36 g, 3.8 mmol), p-toluenesulfonic acid (0.06 g, 0.32 mmol) and 16 mL of dry toluene were added to a 25 mL dry round-bottom flask, heated to 100°C, and a short air condenser was installed at the mouth of the flask. The reaction was monitored by TLC until the raw material completely disappeared. The reaction was stopped, and two-thirds of the solvent was evaporated under reduced pressure. Activated carbon was added and boiled for 10 minutes, filtered while hot, cooled to precipitate a yellow solid, placed in a refrigerator to freeze, and the solid was completely precipitated. Filter to obtain a crude product, which can be recrystallized from 14-dioxane to obtain a refined product of 0.95 g, with a purity of 99.1% and a yield of 80%.

[0106] Test Case

[0107] Total yield test:

[0108] The total yields of the final products of the preparation methods of the embodiments and comparative examples were calculated and statistically analyzed, and the results are as follows:

[0109] Group Example 1 Example 2 Example 3 Example 4 Comparative Example 1 Comparative Example 2 Comparative Example 3 Total yield 48.1％ 45.83％ 43.3％ 41.2％ 39.5％ 35.8％ 31％

[0110] From the above data, it can be found that the preparation method provided by the present invention has the advantages of high yield, mild reaction conditions, and green environmental protection; by comparing Example 1 and Example 4, it can be found that the present invention can effectively improve the yield of chlorination reaction and the total yield by adopting a specific chlorination reagent (NCS); by comparing Example 1 and Comparative Example 1, it can be found that the present invention adopts phenyl formate to carry out carbonyl insertion reaction, and the reaction effect is better, and the leaving effect is also improved, thereby improving the total yield of the reaction; by comparing Example 1 and Comparative Example 2, it can be found that the present invention adopts a method of first performing ring closing and then performing methylation, which can effectively improve the ring closing yield and thereby improve the total yield; by comparing Example 1 and Comparative Example 3, it can be found that the present invention selects a specific starting raw material 2-bromothiophene-3-sulfonyl chloride, and compared with conventional starting raw materials, the carbonyl insertion reaction is easier to carry out, the reaction conditions are effectively reduced, and the carbonyl impurities generated by 5-position chlorination are greatly reduced, the product purity is higher, and the total yield is higher.

[0111] The applicant declares that the present invention illustrates the preparation method of lornoxicam of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0112] The preferred embodiments of the present invention are described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the technical concept of the present invention, a variety of simple modifications can be made to the technical solution of the present invention, and these simple modifications all belong to the protection scope of the present invention.

[0113] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not further describe various possible combinations.

Claims

1. A method for preparing lornoxicam, characterized in that, The preparation method comprises the following steps: (1) reacting 2-bromothiophene-3-sulfonyl chloride with glycine methyl hydrochloride to obtain compound 4; (2) reacting compound 4 with a chlorinating agent to obtain compound 5; (3) Compound 5 is mixed with phenyl formate, a catalyst, and a phosphorus ligand to undergo carbonyl insertion reaction to obtain compound 6; (4) Compound 6 is mixed with a base to react to obtain compound 7; (5) Compound 7 is mixed with a methylating agent to react to obtain compound 8; (6) Compound 8 is mixed with 2-aminopyridine to react to obtain compound 1, i.e., lornoxicam; The reaction process is as follows:

2. The preparation method according to claim 1, characterized in that: The reaction in step (1) is carried out in an aprotic solvent; Preferably, the molar ratio of 2-bromothiophene-3-sulfonyl chloride to glycine methyl hydrochloride in step (1) is 1:(1.1-1.5); Preferably, the reaction temperature in step (1) is 10-30°C and the reaction time is 0.3-1h.

3. The preparation method according to claim 1 or 2, characterized in that: The chlorination reagent in step (2) comprises NCS and / or chlorine, preferably NCS.

4. The preparation method according to any one of claims 1 to 3, characterized in that The molar ratio of the compound 4 in step (2) to the chlorination reagent is 1:(1.1-1.5); Preferably, the reaction temperature in step (2) is -10 to 10°C and the reaction time is 6 to 10 hours.

5. The preparation method according to any one of claims 1 to 4, characterized in that: In step (3), the molar ratio of compound 5 to phenyl formate is 1:(1.5-3), the molar amount of the catalyst is 1-5% of the molar amount of compound 5, and the molar amount of the phosphorus ligand is 5-15% of the molar amount of compound 5; Preferably, the catalyst comprises palladium acetate and / or bis(benzonitrile)palladium chloride; Preferably, the phosphorus ligand comprises tri-tert-butylphosphine tetrafluoroborate and / or 4,5-bisdiphenylphosphine-9,9-dimethylxanthene.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The temperature of the carbonylation reaction in step (3) is 60-100° C. and the time is 10-20 h.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The base in step (4) includes any one of sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride, or a combination of at least two thereof.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The molar ratio of compound 6 to base in step (4) is 1:(1.5-3); Preferably, the reaction temperature in step (4) is 60-80°C.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The methylating agent in step (5) comprises any one of iodomethane, tetramethylammonium fluoride, methyl p-toluenesulfonate or methyl trifluoromethanesulfonate, or a combination of at least two thereof; Preferably, the molar ratio of compound 7 to the methylating agent in step (5) is 1:(1.5-5).

10. The preparation method according to any one of claims 1 to 9, characterized in that: The reaction temperature in step (5) is 80-110° C. and the reaction time is 8-10 h.

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