CN115894525A - Synthesis method of lornoxicam intermediate - Google Patents
Synthesis method of lornoxicam intermediate Download PDFInfo
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- CN115894525A CN115894525A CN202310009719.0A CN202310009719A CN115894525A CN 115894525 A CN115894525 A CN 115894525A CN 202310009719 A CN202310009719 A CN 202310009719A CN 115894525 A CN115894525 A CN 115894525A
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- OXROWJKCGCOJDO-JLHYYAGUSA-N lornoxicam Chemical compound O=C1C=2SC(Cl)=CC=2S(=O)(=O)N(C)\C1=C(\O)NC1=CC=CC=N1 OXROWJKCGCOJDO-JLHYYAGUSA-N 0.000 title claims abstract description 51
- 229960002202 lornoxicam Drugs 0.000 title claims abstract description 51
- 238000001308 synthesis method Methods 0.000 title claims abstract description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 81
- 238000006243 chemical reaction Methods 0.000 claims abstract description 38
- 239000004280 Sodium formate Substances 0.000 claims abstract description 24
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims abstract description 24
- 235000019254 sodium formate Nutrition 0.000 claims abstract description 24
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 239000002994 raw material Substances 0.000 claims abstract description 14
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- 230000002194 synthesizing effect Effects 0.000 claims description 13
- 238000001035 drying Methods 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- 238000010791 quenching Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 16
- 238000007086 side reaction Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 3
- 239000007795 chemical reaction product Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000007664 blowing Methods 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- -1 5-chloro-3-sulfinylthiophene-2-carboxylic acid Chemical compound 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- LFVGISIMTYGQHF-UHFFFAOYSA-N ammonium dihydrogen phosphate Chemical compound [NH4+].OP(O)([O-])=O LFVGISIMTYGQHF-UHFFFAOYSA-N 0.000 description 1
- 229910000387 ammonium dihydrogen phosphate Inorganic materials 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000000692 cap cell Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 235000019837 monoammonium phosphate Nutrition 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the technical field of drug synthesis, in particular to a synthesis method of a lornoxicam intermediate. The lornoxicam intermediate is prepared by using methanol as a solvent, a compound I shown in a formula I as a raw material and magnesium methoxide and sodium formate as catalysts through cyclization reaction. The invention takes methanol as solvent and magnesium methoxide and sodium formate as catalyst, which can improve the cyclization reaction rate and the conversion rate of reaction raw material, and magnesium methoxide, sodium formate and raw material can not only ensure the reaction raw material to fully react, but also effectively reduce the occurrence of side reaction, the selectivity is good, the product yield and purity are improved, the reaction product can obtain the product with the purity more than 99.9% only by simple post-treatment, and the yield can reach more than 96%, and the invention is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a synthesis method of a lornoxicam intermediate.
Background
Lornoxicam, developed by nychomed corporation in norway, was first marketed in denmark in 10 months in 1997, belongs to a non-steroidal anti-inflammatory drug, and has the advantages of short biological half-life, light adverse reaction, strong analgesic and anti-inflammatory effects and the like, so that lornoxicam is widely used for relieving moderate and severe pain caused by osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, surgery and the like.
6-chloro-4-hydroxy-2-methyl-2H-thiophene [2,3-e ] -1,2-thiazine-3-methyl formate-1,1-dioxide is an important intermediate of lornoxicam, the structural formula is shown as formula II, and the main synthetic process route is as follows:
according to the route, 5-chloro-3- (N-methyl acetate-N-methyl aminosulfonyl) -thiophene-2-methyl formate (the structural formula is shown as a formula I) is used as a raw material, 6-chloro-4-hydroxy-2-methyl-2H-thiophene [2,3-e ] -1,2-thiazine-3-methyl formate-1,1-dioxide is prepared through cyclization reaction in a sodium methoxide solution, the yield is low, the raw material is easy to decompose to generate byproducts such as 5-chloro-3-sulfinylthiophene-2-carboxylic acid and the like, the purification is difficult, and the quality of the lornoxicam medicine is influenced finally. Therefore, the research and development of the synthesis method of the lornoxicam intermediate with higher yield and purity is of great significance.
Disclosure of Invention
In view of the above, the invention provides a synthesis method of a lornoxicam intermediate, and the prepared intermediate has high yield and purity, and reaction conditions are easy to control, so that the method is suitable for large-scale industrial safe production.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a synthesis method of a lornoxicam intermediate, wherein the structure of the lornoxicam intermediate is shown as a formula II, and the synthesis method comprises the following steps:
the compound I is prepared by taking methanol as a solvent, taking a compound I shown in a formula I as a raw material, and taking magnesium methoxide and sodium formate as catalysts through cyclization reaction;
wherein the molar ratio of the magnesium methoxide to the sodium formate to the compound I is 1.4-1.6: 0.4-0.6: 1;
the structural formulas of the compounds shown in the formula I and the formula II are as follows:
compared with the prior art, the synthesis method of the lornoxicam intermediate provided by the invention takes methanol as a solvent and takes magnesium methoxide and sodium formate as catalysts, so that the cyclization reaction rate and the conversion rate of reaction raw materials can be improved; meanwhile, the magnesium methoxide and the sodium formate in a specific ratio are mixed with the raw materials, so that the reaction raw materials are ensured to fully react, side reactions can be avoided, the generation of byproducts such as 5-chloro-3-sulfinylthiophene-2-carboxylic acid and the like is effectively reduced, the yield and the purity of the lornoxicam intermediate are greatly improved, the yield can reach more than 96 percent, and the purity can reach more than 99.9 percent; and the reaction condition is mild, the catalyst is convenient and thorough to recover, impurities cannot be brought to the subsequent preparation of the lornoxicam, and the method is suitable for large-scale industrial safe production.
In some other embodiments, the method of synthesizing the lornoxicam intermediate specifically includes the steps of:
step a, adding magnesium methoxide, sodium formate and a compound I into methanol in sequence, and carrying out cyclization reaction at 60-65 ℃; after the reaction is finished, cooling to 0-10 ℃, adding hydrochloric acid to quench the reaction to obtain reaction liquid containing the lornoxicam intermediate;
and b, removing methanol from the reaction solution containing the lornoxicam intermediate, extracting with dichloromethane, concentrating, recrystallizing, filtering and drying to obtain the lornoxicam intermediate.
According to the synthesis method of the lornoxicam intermediate, magnesium methoxide and sodium formate are used as catalysts for cyclization reaction, cyclization reaction is carried out at 60-65 ℃, the conversion rate of reaction raw materials is high, the raw materials are not easy to decompose under the reaction condition to generate byproducts, and the target product can be separated and purified by extraction and recrystallization, so that the purity of the lornoxicam intermediate is greatly improved, the post-treatment process is simple, the condition is mild, the reaction cost and energy consumption are reduced, the industrial feasibility is improved, and the method has a wide application prospect; meanwhile, after the cyclization reaction is finished, hydrochloric acid is added at 0-10 ℃ for quenching, so that the occurrence of side reactions is effectively reduced, the selectivity is good, and the yield and the purity of the product are improved.
Optionally, in the step a, the mass volume ratio of the compound I to the methanol is 1; wherein the unit of mass is g, and the unit of volume is mL;
optionally, in the step a, the temperature is controlled to be 60-65 ℃ in the feeding process of the magnesium methoxide, the sodium formate and the compound I.
Optionally, in the step a, the cyclization reaction time is 6 to 7 hours.
The optimal reaction time is combined with the specific reaction temperature, so that the reaction efficiency can be improved and the yield and the quality of the target product can be ensured on the premise of reducing side reactions to the maximum extent.
Optionally, in the step a, the concentration of the hydrochloric acid is 2mol/L, and the mass ratio of the hydrochloric acid to the compound I is 700-750: 1.
optionally, in step b, the specific process for removing methanol is as follows: and (3) carrying out reduced pressure concentration on the reaction solution containing the lornoxicam intermediate at the temperature of 40-45 ℃ and the vacuum degree of less than or equal to-0.09 MPa, and stopping concentration when no liquid drops are dripped.
Optionally, in the step b, the concentration is carried out at the temperature of 30-35 ℃ and the vacuum degree of less than or equal to-0.07 MPa, and the concentration is stopped when no liquid drops are dripped.
Optionally, in step b, the recrystallization specifically comprises: dissolving the concentrated product in methanol, heating to 60-65 ℃, stirring for 0.5-1 h, cooling to 0-10 ℃, stirring for 1-2 h, and separating out crystals.
Optionally, in the step b, the stirring frequency is 20Hz to 30Hz.
The preferable temperature rise, temperature drop, stirring time and stirring frequency are beneficial to fully separating out the lornoxicam intermediate, reducing the separation of impurities and improving the yield and purity of the target product.
Optionally, in the step b, the drying temperature is 40-45 ℃, and the drying time is 5-7 h.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings required to be used in the embodiments will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and it is obvious for those skilled in the art that other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a liquid chromatogram of a lornoxicam intermediate obtained in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and do not limit the invention.
In the following examples, various procedures and methods not described in detail are conventional methods well known in the art.
Example 1
The embodiment provides a synthesis method of a lornoxicam intermediate, which comprises the following steps:
1L of methanol was added to a 2L reaction flask, and then 37.91g of magnesium methoxide, 9.95g of sodium formate and 100g of compound I were sequentially added at 60 ℃ and the reaction was incubated for 7h, monitored by TLC (developing reagent: EA =1:1, 254nm color development). After the reaction is finished, the temperature is reduced to 10 ℃, 720ml of HCl solution with the concentration of 2mol/L is dripped into the reaction solution for quenching reaction, then methanol is concentrated and removed under the conditions of 45 ℃ and the vacuum degree of less than or equal to minus 0.09MPa, and when no liquid drips, the concentration is stopped. Extracting the concentrate with 1L dichloromethane, stirring for 20min, standing, separating phases, drying the organic phase, concentrating at 35 deg.C under vacuum degree of-0.07 MPa, and stopping concentration when no liquid drops are dropped. Dissolving the organic phase concentrate in 200ml of methanol, heating to 65 ℃, stirring for 1h at the frequency of 30Hz, cooling to 10 ℃ for crystallization, keeping the frequency for stirring for 2h, filtering, and drying the filter cake by blowing at 45 ℃ for 7h to obtain pale yellow solid powder 87.82g, the yield is 96.9%, and the purity is 99.94%.
The lornoxicam intermediate prepared above is analyzed by liquid chromatography, the detection spectrum is shown as figure 1, and the data is shown as table 1:
TABLE 1 liquid chromatography data
Wherein, the peak 1 and the peak 2 are impurity peaks, and the peak 3 is 6-chloro-4-hydroxy-2-methyl-2H-thiophene [2,3-e ] -1,2-thiazine-3-methyl formate-1,1-dioxide.
As can be seen from the data in table 1, peak 3 appeared at the retention time of 12.285min, and the peak area ratio was 99.94%, from which the purity of the prepared lornoxicam intermediate impurity was 99.94%.
The specific test conditions were:
a chromatographic column: CAPCELL PAK MGII C18 (4.6 x 250mm,5 μm); detection wavelength: 290nm; mobile phase: 0.025mol/L ammonium dihydrogen phosphate solution (ph 7.3 adjusted with triethylamine)/methanol =58:42; sample injection amount: 20 μ L.
Example 2
The present embodiment provides a method for synthesizing lornoxicam intermediate:
1L of methanol was added to a 2L reaction flask, and then 35.22g of magnesium methoxide, 9.95g of sodium formate and 100g of compound I were added in this order at 60 ℃ and the reaction was incubated for 6h and monitored by TLC (developer: PE: EA =1:1, 254nm color development). After the reaction is finished, the temperature is reduced to 0 ℃, 720ml of HCl solution with the concentration of 2mol/L is dripped into the reaction solution for quenching reaction, then methanol is concentrated and removed under the conditions of 40 ℃ and the vacuum degree of less than or equal to minus 0.09MPa, and when no liquid drips, the concentration is stopped. Extracting the concentrate with 1L of dichloromethane, stirring for 20min, standing for phase separation, drying the organic phase, concentrating at 30 deg.C under vacuum degree of-0.07 MPa, and stopping concentration when no drop is dropped. Dissolving the organic phase concentrate in 200ml of methanol, heating to 60 ℃, stirring for 1h at the frequency of 20Hz, cooling to 0 ℃ for crystallization, keeping the frequency, stirring for 1h, filtering, and drying the filter cake for 5h at the temperature of 40 ℃ by air blowing to obtain light yellow solid powder 87.63g, wherein the yield is 96.7%, and the purity is 99.91%.
Example 3
The embodiment provides a synthesis method of a lornoxicam intermediate, which comprises the following steps:
1L of methanol was added to a 2L reaction flask, followed by sequentially adding 40.24g of magnesium methoxide, 9.95g of sodium formate and 100g of Compound I at 60 ℃ and incubating for 6.5h, and monitoring the reaction by TLC (developing reagent: PE: EA =1:1, 254nm color development). After the reaction is finished, the temperature is reduced to 5 ℃, 720ml of HCl solution with the concentration of 2mol/L is dripped into the reaction solution for quenching reaction, then methanol is removed under the conditions of 43 ℃ and the vacuum degree of less than or equal to minus 0.09MPa, and when no liquid drips, the concentration is stopped. Extracting the concentrate with 1L of dichloromethane, stirring for 20min, standing for phase separation, drying the organic phase, concentrating at 33 deg.C under vacuum degree of-0.07 MPa, and stopping concentration when no drop is dropped. Dissolving the organic phase concentrate in 200ml of methanol, heating to 62 ℃, stirring for 1h at the frequency of 25Hz, cooling to 5 ℃ for crystallization, keeping the frequency, stirring for 1h, filtering, and drying a filter cake for 6h at the temperature of 42 ℃ by air blowing to obtain light yellow solid powder 87.91g, wherein the yield is 97.0 percent, and the purity is 99.92 percent.
Example 4
This example provides a synthesis method of lornoxicam intermediate, which is different from example 1 in that the amount of sodium formate added is 7.96g, the yield of the product is 96.7% and the purity is 99.93%.
Example 5
This example provides a method for synthesizing lornoxicam intermediate, which is different from example 1 in that 1.1L of methanol was added into a 2L reaction flask, and the yield of the product was 96.5% and the purity was 99.91%.
Example 6
This example provides a synthesis of lornoxicam intermediate, which differs from example 1 in that 11.94g of sodium formate is added, the yield of the product is 97.8% and the purity is 99.94%.
While carrying out the embodiments of the present invention, the inventors have also studied other different synthetic methods, specifically as follows:
comparative example 1
This comparative example provides a synthesis of lornoxicam intermediate, which differs from example 1 in that the amount of sodium formate added is 13.93g, the yield of the product is 90.6% and the purity is 97.2%.
Comparative example 2
This comparative example provides a synthesis method of lornoxicam intermediate, which is different from example 1 in that sodium methoxide is used as catalyst instead of magnesium methoxide and sodium formate, the addition amount is 23.72g, the yield of product is 89.7%, and the purity is 97.1%.
Comparative example 3
This comparative example provides a method for synthesizing a lornoxicam intermediate, which differs from example 1 in that only magnesium methoxide is added as a catalyst, no sodium formate is added, the yield of the product is 92.6%, and the purity is 97.8%.
Comparative example 4
This comparative example provides a method for synthesizing lornoxicam intermediate, which is different from example 1 in that only sodium formate is added as catalyst, no magnesium methoxide is added, the yield of the product is 72.6%, and the purity is 89.5%.
As can be seen from the examples 1-6 and the comparative examples 1-4, the invention takes methanol as a solvent, and magnesium methoxide and sodium formate as catalysts, under a specific dosage, the invention can ensure that the reaction raw materials fully react, can effectively reduce the occurrence of side reactions, has good selectivity, improves the yield and purity of the product, can obtain the product with the purity of more than 99.9 percent only by simple post-treatment of the reaction product, and the yield can reach more than 96 percent, thus being suitable for large-scale industrial production.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (10)
1. A synthesis method of a lornoxicam intermediate is disclosed, the structure of the lornoxicam intermediate is shown in formula II, and the synthesis method is characterized in that:
the compound I is prepared by taking methanol as a solvent, taking a compound I shown in a formula I as a raw material, and taking magnesium methoxide and sodium formate as catalysts through cyclization reaction;
wherein the molar ratio of the magnesium methoxide to the sodium formate to the compound I is 1.4-1.6: 0.4 to 0.6:1;
the structural formulas of the compounds shown in the formula I and the formula II are as follows:
2. the method of synthesizing a lornoxicam intermediate according to claim 1, comprising the following steps:
step a, adding magnesium methoxide, sodium formate and a compound I into methanol in sequence, and carrying out cyclization reaction at 60-65 ℃; after the reaction is finished, cooling to 0-10 ℃, adding hydrochloric acid to quench the reaction to obtain reaction liquid containing the lornoxicam intermediate;
and b, removing methanol from the reaction liquid containing the lornoxicam intermediate, extracting with dichloromethane, concentrating, recrystallizing, filtering and drying to obtain the lornoxicam intermediate.
3. The method for synthesizing a lornoxicam intermediate as claimed in claim 2, wherein, in step a, the mass-to-volume ratio of the compound I and methanol is 1.
4. The method for synthesizing lornoxicam intermediate of claim 2, wherein in step a, the temperature of the charging process of the magnesium methoxide, sodium formate and compound I is controlled to be 60-65 ℃, and the time of the cyclization reaction is 6-7 h.
5. The method for synthesizing a lornoxicam intermediate according to claim 2, wherein in step a, the concentration of hydrochloric acid is 2mol/L, the mass ratio of hydrochloric acid to compound I is 700-750: 1.
6. the method for synthesizing lornoxicam intermediate of claim 2, wherein in step b, the specific process of removing methanol is as follows: and (3) carrying out reduced pressure concentration on the reaction solution containing the lornoxicam intermediate at the temperature of 40-45 ℃ and the vacuum degree of less than or equal to-0.09 MPa, and stopping concentration when no liquid drops are dripped.
7. The method of claim 2, wherein in step b, the concentration is performed at a temperature of 30 ℃ to 35 ℃ and a vacuum of ≤ 0.07MPa, and the concentration is stopped when no droplet is added.
8. The method for synthesizing lornoxicam intermediate of claim 2, wherein in step b, the specific process of recrystallization is: dissolving the concentrated product in methanol, heating to 60-65 ℃, stirring for 0.5-1 h, cooling to 0-10 ℃, stirring for 1-2 h, and separating out crystals.
9. The method of synthesizing a lornoxicam intermediate of claim 8, wherein in step b, the frequency of stirring is 20Hz to 30Hz.
10. The method for synthesizing a lornoxicam intermediate as claimed in claim 2, wherein in step b, the drying temperature is 40-45 ℃ and the drying time is 5-7 h.
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| 孟文学 等: "氯诺昔康的合成工艺改进", 《精细化工中间体》, vol. 44, no. 5, 31 October 2014 (2014-10-31), pages 38 - 40 * |
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