CN113480561A - Synthesis method of high-purity lornoxicam - Google Patents

Synthesis method of high-purity lornoxicam Download PDF

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CN113480561A
CN113480561A CN202110760354.6A CN202110760354A CN113480561A CN 113480561 A CN113480561 A CN 113480561A CN 202110760354 A CN202110760354 A CN 202110760354A CN 113480561 A CN113480561 A CN 113480561A
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lornoxicam
methanol
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CN113480561B (en
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王琨
安勇
张治中
寇世超
范雨航
孙佳铭
王佳佳
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Beijing Jincheng Taier Pharmaceutical Co ltd
Cangzhou Branch Of Beijing Jincheng Taier Pharm Co ltd
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Cangzhou Branch Of Beijing Jincheng Taier Pharm Co ltd
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract

The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of high-purity lornoxicam. With 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ]]The method comprises the following steps of taking 1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide and 2-aminopyridine as raw materials, taking dimethylbenzene as a solvent, carrying out distillation reaction, condensing mixed gas obtained by the distillation reaction to obtain condensate, adsorbing methanol in the condensate by using a solid acid catalyst, and recycling the adsorbed condensate. The invention distills the methanol generated in the reaction, thereby promoting the forward reaction and then passing through H2SO4the/MxOy super acidic solid acid absorbs the methanol in a catalytic manner, so that the dimethylbenzene returned to the reaction system does not contain the methanol, the reaction coking and carbonization are reduced, and the product quality and the yield are improved. The prepared lornoxicam has high purity which can reach more than 99.9 percent, reduces the solvent amount and is suitable for industrial production.

Description

Synthesis method of high-purity lornoxicam
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method of high-purity lornoxicam.
Background
The anti-inflammatory analgesic lornoxicam was developed by nychomed, norway and is listed in the analgesic staging protocol established by the world health organization. The lornoxicam can be taken orally or injected, and is mainly used for treating mild and moderate pains caused by rheumatoid arthritis, rheumatoid arthritis or conventional operation, lumbago and the like.
At present, the synthesis method of lornoxicam is numerous, and the following two routes are mainly available:
route one: in 1997, 2, 5-dichlorothiophene was used as a starting material by norwegian nyomerd corporation, and lornoxicam was synthesized by 7-step reaction:
Figure BDA0003149455060000011
the synthetic route has multiple steps, lower total yield and serious pollution, adopts reagents such as n-butyllithium, chlorosulfonic acid, phosphorus pentachloride and the like, and is not suitable for industrial production; and in the last step, 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide is used as a raw material, and 2-aminopyridine is added to carry out ammonolysis reaction, wherein the solvent amount of xylene is huge, the volume number of xylene is 50-100V, side reactions are more, the reaction time is long, the yield is not ideal, and the total yield is about 0.45%.
And a second route: the Jiangsu engineering profession and technology institute applied for a Chinese patent CN106892932A for preparing lornoxicam in 2017, and the process route is as follows:
Figure BDA0003149455060000021
the second route is novel, simplifies the process route and shortens the synthesis steps. However, the last step of synthesis of lornoxicam has steric hindrance due to the 5-chloro-3- [ [ N-methyl-N- (acetamidopyridine) ] sulfonyl ] -2-thiophenecarboxylic acid methyl ester molecule, the yield of intramolecular cyclization is low, and the demand for corresponding metal alkali is too high. The reaction time is long, and the energy requirement is high.
In the prior art, the methanol generated by the reaction needs to be diluted by increasing the using amount of the solvent and is distilled, so that the reaction is carried out in the forward direction, the methanol generated by the reaction cannot be completely removed by solvent distillation, and the solvent returned to the reaction system in a recycling manner still contains part of methanol. Methanol will react with the product
Figure BDA0003149455060000022
The phenolic hydroxyl group on the benzene is methylated to generate impurities
Figure BDA0003149455060000023
The impurities are unstable at high temperature and are very easy to generate serious coking and carbonization. Therefore, the remaining methanol causes the reaction by-products to rise, causes severe coking, causes the yield to decrease, and affects the product quality.
The publications of ion exchange and adsorption 1992,8(1), 44-47 mention that HNA resin is used for adsorbing methanol, but the HNA resin cannot completely adsorb the methanol in a xylene system, and a small amount of methanol is refluxed to the reaction system, so that coking is generated during the reaction, and the purity of the product is still not high.
Disclosure of Invention
The invention aims to provide a synthesis method of high-purity lornoxicam, which is characterized in that the generated methanol is evaporated out through a distillation reaction, so that the reaction is carried out in a forward direction, the charring of the reaction is reduced, the product quality and yield are improved, and the product purity can reach more than 99.9%; the mixed gas obtained by the distillation reaction is condensed to obtain condensate, the solid acid catalyst is adopted to adsorb the methanol in the condensate, and the adsorbed condensate is recycled, so that the solvent amount is reduced, the cost is reduced, and the method is suitable for industrial production.
The technical scheme adopted by the invention for solving the technical problems is as follows:
the synthesis method of the high-purity lornoxicam takes 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide and 2-aminopyridine as raw materials, dimethylbenzene as a solvent, distillation reaction is carried out, mixed gas obtained by the distillation reaction is condensed to obtain condensate, a solid acid catalyst is adopted to adsorb methanol in the condensate, and the condensate after the adsorption is recycled.
Wherein:
the solid acid catalyst is H2SO4Solid superacid of the type/MxOy, preferably H2SO4/TiO2Solid superacid, H2SO4/ZrO2Solid superacids or H2SO4/Fe2O3Solid super acid.
The mass ratio of the solid acid catalyst to 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide is 0.3-2.0: 1.
The molar ratio of the 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide to the 2-aminopyridine is 1: 0.8-1.5.
The dosage ratio of the 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide to the dimethylbenzene is 1:10-20, wherein the 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide is calculated by g, and the dimethylbenzene is calculated by ml.
The distillation reaction temperature is 120-160 ℃.
The mixed gas is the mixed gas of methanol and dimethylbenzene.
And (3) concentrating the reaction liquid obtained by the distillation reaction under reduced pressure, filtering to obtain a lornoxicam crude product, and refining to obtain the lornoxicam.
The refining is carried out by adopting 1, 4-dioxane.
Specifically, the synthesis method of the high-purity lornoxicam comprises the following steps: under the protection of nitrogen, 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] is used]Heating and distilling to react (1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide and 2-aminopyridine) serving as raw materials and dimethylbenzene serving as a solvent, condensing a mixed gas obtained by the distillation reaction to obtain a condensate, and adopting H2SO4the/MxOy solid super acidic catalyst adsorbs the methanol in the condensate, and the adsorbed condensate is recycled. And (3) carrying out reduced pressure concentration on reaction liquid obtained by the distillation reaction, cooling to room temperature, filtering to obtain a lornoxicam crude product, and refining by adopting 1, 4-dioxane to obtain the lornoxicam.
The invention has the following beneficial effects:
(1) in a reaction system with dimethylbenzene as a solvent, 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e]The reaction of methyl-1, 1-thiazinoate-1, 1-dioxide with 2-aminopyridine produces lornoxicam with methanol. Methanol will be methylated with the phenolic hydroxyl group on the product lornoxicam to generate impurities
Figure BDA0003149455060000031
The impurities are unstable at high temperature, and are easy to generate serious coking, so that the product yield is reduced, and the product quality is influenced. In order to avoid the phenomenon, the invention leads methanol to be distilled out of the reaction system in the form of gas through distillation reaction, thereby driving the reaction to be carried out in the forward direction. Distilling to obtain mixed gas of methanol and xylene, condensing to obtain condensate, and recovering hydrogen2SO4Solid superacid of the type/MxOy as adsorbent for methanol in the condensate, H2SO4The solid super acid of/MxOy and methanol can form a stable onium salt structure:
Figure BDA0003149455060000041
thereby realizing the adsorption of the methanol. In contrast to space adsorption, H of the present invention2SO4the/MxOy solid super acid can adsorb more methanol and has good effect on methanolThe adsorption quantity of the adsorbent can reach 205-314 mg/g; methanol is adsorbed by the super-strong acid solid acid catalyst, the methanol can be completely adsorbed in a xylene system, and only xylene in the condensate after adsorption can be recycled, so that the using amount of a solvent in the production process is reduced.
(2) The invention distills the methanol generated in the reaction, thereby promoting the forward reaction and then passing through H2SO4The generated methanol is absorbed by the/MxOy super acidic solid acid catalyst, so that the dimethylbenzene returned to the reaction system does not contain methanol, the reaction coking and carbonization are reduced, and the product quality and yield are improved. H2SO4the/MxOy super-strong solid acid catalyst has better regeneration capability and repeated practicability after being eluted by strong acid, and effectively reduces the cost.
(3) The purity of the lornoxicam prepared by the invention is high and can reach more than 99.9%. The invention also reduces the solvent amount and the cost, and is suitable for industrial production.
Drawings
FIG. 1 is a schematic view of the structure of a reaction apparatus according to the present invention;
FIG. 2 is a chromatogram of a reflux in example 1 of the present invention;
FIG. 3 is a chromatogram of a reflux in example 2 of the present invention;
FIG. 4 is a chromatogram of a reflux in example 3 of the present invention;
FIG. 5 is a chromatogram of a reflux in comparative example 1 of the present invention;
FIG. 6 is a chromatogram of a reflux in comparative example 2 of the present invention;
FIG. 7 is a chromatogram of a reflux liquid in comparative example 3 of the present invention;
FIG. 8 is a chromatogram of a reflux liquid in comparative example 4 of the present invention.
Detailed Description
The present invention is further described below with reference to examples.
Example 1
Under the protection of nitrogen, 200ml of dimethylbenzene, 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] is added into a 500ml four-mouth bottle]10g of methyl 1, 2-thiazinecarboxylate-1, 1-dioxide,3.65g of 2-aminopyridine, heating, distilling at 160 ℃, and boiling methanol and xylene generated by the reaction together by using the device. Condensing the mixed gas of methanol and xylene obtained by distillation reaction to obtain condensate, and introducing the condensate into a container filled with 5g H2SO4/Fe2O3In the device of the solid super acidic catalyst, methanol in the condensate is adsorbed, the adsorbed dimethylbenzene flows back to the reaction system through a U-shaped pipe for recycling, and the adsorption amount of the methanol is 205 mg/g. And (3) concentrating the reaction liquid obtained by the distillation reaction under reduced pressure, concentrating the reaction liquid to 100ml, cooling to room temperature, filtering to obtain a lornoxicam crude product, and refining by adopting 1, 4-dioxane to obtain 11.81g of lornoxicam. The yield was 98.4% and the purity was 99.93%. H2SO4/Fe2O3The solid super acidic catalyst can be repeatedly used after being eluted by strong acid.
After the reaction, the reflux was detected by GC, and the spectrum is shown in fig. 2: wherein rt 2.344 is the methanol peak and rt 13.971-14.807 is the xylene peak. The concentration of methanol in the reflux was 0.004%.
Example 2
Under the protection of nitrogen, 200ml of dimethylbenzene, 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] is added into a 500ml four-mouth bottle]20g of methyl 1, 2-thiazinecarboxylate-1, 1-dioxide and 7.3g of 2-aminopyridine, heating, distilling at 120 ℃, and boiling methanol generated by the reaction together with xylene by using the device. Condensing the mixed gas of methanol and xylene obtained by distillation reaction to obtain condensate, and introducing into a container containing 20g H2SO4/TiO2And in the solid super acidic catalyst device, adsorbing methanol in the condensate, and refluxing the adsorbed xylene to the reaction system through a U-shaped pipe for recycling, wherein the adsorption amount of the methanol is 314 mg/g. And (3) concentrating the reaction liquid obtained by the distillation reaction under reduced pressure, concentrating the reaction liquid to 100ml, cooling to room temperature, filtering to obtain a lornoxicam crude product, and refining by adopting 1, 4-dioxane to obtain 23.6g of lornoxicam. The yield was 98.3% and the purity was 99.91%. H2SO4/TiO2The solid super acidic catalyst can be repeatedly used after being eluted by strong acid.
After the reaction, the reflux was detected by GC, and the spectrum is shown in fig. 3: wherein rt 3.348 is the methanol peak and rt 14.062-14.933 is the xylene peak. The concentration of methanol in the reflux was 0.003%.
Example 3
Under the protection of nitrogen, 300ml of dimethylbenzene, 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] is added into a 500ml four-mouth bottle]20g of methyl 1, 2-thiazinecarboxylate-1, 1-dioxide and 7.3g of 2-aminopyridine, heating, distilling at 140 ℃, and boiling methanol generated by the reaction together with xylene by using the device. Condensing the mixed gas of methanol and xylene obtained by distillation reaction to obtain condensate, and introducing the condensate into a container filled with 40g H2SO4/ZrO2And in the solid super acidic catalyst device, adsorbing methanol in the condensate, and refluxing the adsorbed xylene to the reaction system through a U-shaped pipe for recycling, wherein the adsorption amount of the methanol is 300 mg/g. And (3) concentrating the reaction liquid obtained by the distillation reaction under reduced pressure, concentrating the reaction liquid to 150ml, cooling to room temperature, filtering to obtain a lornoxicam crude product, and refining by adopting 1, 4-dioxane to obtain 23.58g of lornoxicam. The yield was 98.2% and the purity was 99.92%. H2SO4/ZrO2The solid super acidic catalyst can be repeatedly used after being eluted by strong acid.
After the reaction, the reflux was detected by GC, and the spectrum is shown in fig. 4: wherein rt-2.342 is the methanol peak and rt-13.967-14.808 is the xylene peak. The concentration of methanol in the reflux liquid was 0.005%.
Comparative example 1
Methanol is adsorbed without any catalyst, and the method comprises the following specific steps:
under the protection of nitrogen, 500ml of dimethylbenzene, 10g of 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide and 3.65g of 2-aminopyridine are added into a 1000ml four-mouth bottle, heating reflux is carried out, after the reaction is finished, reaction liquid is concentrated to 250ml, the temperature is reduced to the room temperature, filtering is carried out, dichloromethane is added into a filter cake, the heating reflux is carried out, the temperature is reduced to the room temperature, a lornoxicam crude product is obtained by filtering, and 6.82g of lornoxicam is obtained by refining with 1, 4-dioxane. The yield was 56.8% and the purity was 96.93%.
After the reaction, the reflux was detected by GC, and the spectrum is shown in fig. 5: wherein rt-2.428 is the methanol peak and rt-14.051-14.920 is the xylene peak. The methanol concentration in the reflux was 2.892%.
Comparative example 2
The method adopts calcium chloride to adsorb methanol, and comprises the following steps:
under the protection of nitrogen, 200ml of dimethylbenzene, 20g of 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide and 7.3g of 2-aminopyridine are added into a 500ml four-mouth bottle, the mixture is heated and distilled at 140 ℃ for reaction, and methanol generated by the reaction and the dimethylbenzene are boiled together by using the device. Condensing the mixed gas of methanol and xylene obtained by the distillation reaction to obtain condensate, feeding the condensate into a device filled with 20g of calcium chloride to adsorb the methanol in the condensate, and refluxing the adsorbed xylene into the reaction system through a U-shaped pipe for recycling, wherein the adsorption amount of the methanol is 10 mg/g. And (3) concentrating the reaction liquid obtained by the distillation reaction under reduced pressure, concentrating the reaction liquid to 100ml, cooling to room temperature, filtering to obtain a lornoxicam crude product, and refining by adopting 1, 4-dioxane to obtain 14.77g of lornoxicam. The yield was 61.5% and the purity was 97.13%.
After the reaction, the reflux was detected by GC, and the spectrum is shown in fig. 6: wherein rt 2.425 is the methanol peak and rt 14.053-14.923 is the xylene peak. The concentration of methanol in the reflux was 0.494%.
Comparative example 3
The method adopts a 3A molecular sieve to adsorb methanol, and comprises the following specific steps:
under the protection of nitrogen, 200ml of dimethylbenzene, 20g of 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide and 7.3g of 2-aminopyridine are added into a 500ml four-mouth bottle, the mixture is heated and distilled at 140 ℃ for reaction, and methanol generated by the reaction and the dimethylbenzene are boiled together by using the device. Condensing the mixed gas of methanol and xylene obtained by the distillation reaction to obtain condensate, introducing the condensate into a device filled with 20g of 3A molecular sieve to adsorb the methanol in the condensate, refluxing the adsorbed xylene into the reaction system through a U-shaped pipe for recycling, wherein the adsorption amount of the methanol is 48 mg/g. And (3) concentrating the reaction liquid obtained by the distillation reaction under reduced pressure, concentrating the reaction liquid to 100ml, cooling to room temperature, filtering to obtain a lornoxicam crude product, and refining by adopting 1, 4-dioxane to obtain 21.2g of lornoxicam. The yield was 88.3% and the purity was 97.14%.
After the reaction, the reflux was detected by GC and the spectrum is shown in fig. 7: wherein rt-2.426 is the methanol peak and rt-14.053-14.922 is the xylene peak. The concentration of methanol in the reflux was 0.077%.
Comparative example 4
The method adopts HNA resin to adsorb methanol, and comprises the following specific steps:
under the protection of nitrogen, 200ml of dimethylbenzene, 20g of 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide and 7.3g of 2-aminopyridine are added into a 500ml four-mouth bottle, the mixture is heated and distilled at 140 ℃ for reaction, and methanol generated by the reaction and the dimethylbenzene are boiled together by using the device. Condensing the mixed gas of methanol and xylene obtained by the distillation reaction to obtain condensate, introducing the condensate into a device filled with 20g of HNA resin to adsorb the methanol in the condensate, and refluxing the adsorbed xylene into the reaction system through a U-shaped pipe for recycling, wherein the adsorption amount of the methanol is 110 mg/g. And (3) concentrating the reaction liquid obtained by the distillation reaction under reduced pressure, concentrating the reaction liquid to 100ml, cooling to room temperature, filtering to obtain a lornoxicam crude product, and refining by adopting 1, 4-dioxane to obtain 22.4g of lornoxicam. The yield was 93.3% and the purity 98.94%.
After the reaction, the reflux was detected by GC, and the spectrum is shown in fig. 8: wherein rt-2.346 is the methanol peak and rt-13.994-14.840 is the xylene peak. The concentration of methanol in the reflux liquid was 0.069%.
According to research, when the calcium chloride is used for adsorbing the methanol, the adsorption quantity of the calcium chloride to the methanol is very small, and is about 8-15 mg/g; when the 3A molecular sieve is used for adsorbing the methanol, the adsorption quantity of the methanol is 47-49 mg/g; when HNA resin is used for adsorbing methanol, the resin is weak-acid cation exchange resin, the adsorption effect is mainly space adsorption, the adsorption quantity of the resin to the methanol is 105-154mg/g, the adsorption quantity is still not high, the methanol cannot be completely adsorbed in a xylene system, a small amount of methanol still flows back to the reaction system, and coking is generated during the reactionThe product purity is not high. H of the invention2SO4the/MxOy solid super acid can adsorb more methanol, and the adsorption capacity to the methanol can reach 205-; methanol is adsorbed by using a super-strong acid solid acid catalyst, the methanol can be completely adsorbed in a xylene system, and only xylene in the condensate after adsorption can be recycled.

Claims (10)

1. A synthetic method of high-purity lornoxicam takes 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide and 2-aminopyridine as raw materials, xylene as solvent, and distillation reaction is carried out, and the method is characterized in that: condensing the mixed gas obtained by the distillation reaction to obtain condensate, and adsorbing the methanol in the condensate by using a solid acid catalyst.
2. The method of synthesizing lornoxicam of high purity according to claim 1, wherein: the solid acid catalyst is H2SO4Solid super acid of/MxOy type.
3. The method of synthesizing lornoxicam of high purity according to claim 2, wherein: said H2SO4the/MxOy solid super acid is H2SO4/TiO2Solid superacid, H2SO4/ZrO2Solid superacids or H2SO4/Fe2O3Solid super acid.
4. The method of synthesizing lornoxicam of high purity according to claim 1, wherein: the mass ratio of the solid acid catalyst to 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide is 0.3-2.0: 1.
5. The method of synthesizing lornoxicam of high purity according to claim 1, wherein: the molar ratio of the 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide to the 2-aminopyridine is 1: 0.8-1.5.
6. The method of synthesizing lornoxicam of high purity according to claim 1, wherein: the dosage ratio of the 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide to the dimethylbenzene is 1:10-20, wherein the 6-chloro-4-hydroxy-2-methyl-2-H-thieno [2,3-e ] -1, 2-thiazine carboxylic acid methyl ester-1, 1-dioxide is calculated by g, and the dimethylbenzene is calculated by ml.
7. The method of synthesizing lornoxicam of high purity according to claim 1, wherein: the distillation reaction temperature is 120-160 ℃.
8. The method of synthesizing lornoxicam of high purity according to claim 1, wherein: the mixed gas is the mixed gas of methanol and dimethylbenzene.
9. The method of synthesizing lornoxicam of high purity according to claim 1, wherein: and (3) concentrating the reaction liquid obtained by the distillation reaction under reduced pressure, filtering to obtain a lornoxicam crude product, and refining to obtain the lornoxicam.
10. The method of synthesizing lornoxicam of high purity according to claim 9, wherein: the refining is carried out by adopting 1, 4-dioxane.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114213434A (en) * 2021-12-29 2022-03-22 北京金城泰尔制药有限公司 Lornoxicam crystal form and preparation method thereof
CN115227655A (en) * 2022-08-17 2022-10-25 海南锦瑞制药有限公司 Preparation method of lornoxicam for injection

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114213434A (en) * 2021-12-29 2022-03-22 北京金城泰尔制药有限公司 Lornoxicam crystal form and preparation method thereof
CN115227655A (en) * 2022-08-17 2022-10-25 海南锦瑞制药有限公司 Preparation method of lornoxicam for injection

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