CN107365275B - High purity celecoxib - Google Patents

High purity celecoxib Download PDF

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CN107365275B
CN107365275B CN201710449906.5A CN201710449906A CN107365275B CN 107365275 B CN107365275 B CN 107365275B CN 201710449906 A CN201710449906 A CN 201710449906A CN 107365275 B CN107365275 B CN 107365275B
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celecoxib
purity
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compound
yield
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CN107365275A (en
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张倩倩
屈晓霞
吕裕斌
任月英
罗杨春
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Hangzhou Huadong Medicine Group Biopharmaceutical Co ltd
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Hangzhou Huadong Medicine Group Biopharmaceutical Co ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D241/00Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20Nitrogen atoms

Abstract

The invention discloses high-purity celecoxib. Prepared by reacting 2- (4- ((5, 6-diphenylpyrazin-2-yl) isopropylamino) butoxy) acetic acid, a key intermediate of celecoxib, with CDI and methanesulfonamide in an organic solvent under the condition of an organic base. The reaction has the advantages of simple operation, low cost, environmental protection, yield of more than 95 percent, suitability for industrial production, purity of the prepared celecoxib of more than or equal to 99.9 percent, and capability of well meeting the requirements of drug production. The celecoxib prepared by the method has high purity, so that the method is beneficial to obtaining higher-quality medicines in the subsequent process.

Description

High purity celecoxib
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to an efficient preparation method of a prostacyclin receptor agonist selecetrapa, wherein the purity of the seleceta is more than or equal to 99.9%, and the yield is more than 95%.
Background
Celecoxib (Selexipag ) is a novel oral long-acting PGI2 receptor agonist, developed by acteolion biopharmaceutical corporation, switzerland, approved by the U.S. FDA in 2015 for the treatment of adult pulmonary hypertension. The chemical name of celecoxib is: 2- {4- [ N- (5, 6-diphenylpyrazin-2-yl) -N-isopropylamino ] butoxy } -N- (methylsulfonyl) acetamide having the following structural formula:
the compound of the formula (S-I) is an important intermediate of celecoxib, and a plurality of documents report the process for preparing the celecoxib by reacting the compound with methanesulfonamide.
WO2002088084(Heterocyclic compounds and derivatives and mediators) first reported the reaction of (S-I) with methanesulfonamide to form celecoxib. The reaction operation steps are as follows: (S-I) and Carbonyldiimidazole (CDI) react in anhydrous tetrahydrofuran for 1 hour (room temperature and heating reflux are respectively half an hour), then the mixture reacts with methane sulfonamide for overnight under the condition that 1, 8-diazabicyclo [5.4.0] -undec-7-ene (DBU) is used as alkali, and the product is obtained by ether extraction and column chromatography separation and purification after the reaction is completed. The yield of the reaction was 76.6% and the purity of the product celecoxib was not disclosed.
WO2011017612 (deuterated naphthyridine derivatives) uses the same method to prepare the corresponding deuterated celecoxib from deuterium-Substituted (S-I) derivatives in 52% -58% yield.
WO2017060827(An advanced process for the preparation of selexitag orientations pharmaceutical acceptable salts) discloses the steps of preparing selexipag: (S-I) heating and refluxing the mixture and CDI in a tetrahydrofuran solution for 2 hours, reacting the mixture with methanesulfonamide for half an hour at room temperature, finally adding DBU, stirring for 40 minutes, adding 1N hydrochloric acid to adjust the pH of the system after the reaction is finished, extracting the mixture with ethyl acetate, washing the mixture with water and brine, and finally recrystallizing the mixture with heptane to obtain the celecoxib, wherein the yield is 84.5%.
The above preparation method uses DBU as a base to participate in the reaction. The reaction using DBU as a base has the defect of low yield. Not only the impurity represented by the formula (Z-II) introduced from DBU is produced by the reaction, but also the content of the impurity represented by the formula (Z-I) is high. The inventor researches and discovers that even if the reaction conditions and the post-treatment process of the reaction are optimized, the yield is improved to be more than 90 percent, but the purity of the obtained celecoxib cannot reach 99.9 percent because the contents of the impurities (Z-I) and (Z-II) cannot be reduced to be less than 0.1 percent in the product refining process, and the requirement of pharmaceutical preparations cannot be met.
CN106279047 (a preparation method of prostacyclin receptor agonist) discloses that acetonitrile or chloroform solution of acyl chloride obtained by reacting (S-I) with chlorinating agents such as phosphorus oxychloride, oxalyl chloride, solid phosgene and the like is dripped into acetonitrile solution of acid-binding agents such as methanesulfonyl chloride, triethylamine and the like, the mixture is subjected to heat preservation reaction for 5 hours at 10 ℃, and then ethanol is used for recrystallization after extraction, so that the purity of the celecoxib is 99.1-99.5%, and the reaction yield is 80-88%. The reaction uses acyl chloride as an intermediate, and the reaction process needs to keep the temperature at 10 ℃ for a long time, so that the method is not suitable for industrial production.
WO2017042828(Process for the preparation of selexipag and intermediates therof) discloses two methods for preparing selexipag. One method is to react (S-I) with methanesulfonamide under the conditions of CDI, DBU and tetrahydrofuran, and the obtained crude celecoxib product is recrystallized for three times through ethanol-isopropanol-ethanol to obtain celecoxib with the purity of 99.75 percent, and the yield is 74 percent. The other method comprises the following operation steps: (S-I) and thionyl chloride are reacted in dichloromethane for 4 hours (two hours at 25-30 ℃ and 35-40 ℃), methanesulfonamide is added at 25-30 ℃, then the reaction is carried out for 2 hours at 40 ℃, water is added into the reaction liquid for layering during post-treatment, an organic layer is washed by water and 2% sodium bicarbonate, and after concentration, the organic layer is recrystallized by ethanol to obtain the celecoxib with the purity of 99.6%, and the yield is 67.6%.
In addition, other intermediates are used in the preparation of celecoxib:
CN102459198 (crystal) discloses a method for preparing celecoxib by reacting intermediate (S-II) with 2-chloro-N- (methylsulfonyl) acetamide, but no specific examples are given in the literature.
CN106008364 (a preparation method of selexipag) discloses a method for preparing selexipag by reacting (S-II) with 2-chloro-N- (methylsulfonyl) acetamide under the conditions of base and 1, 4-dioxane. Wherein the alkali can be potassium tert-butoxide, sodium tert-butoxide or a mixture of the potassium tert-butoxide and the sodium tert-butoxide, and the crude product obtained after the reaction is recrystallized by a tetrahydrofuran/n-hexane mixed solvent to obtain the celecoxib with the purity of 99.97 percent and the yield of 76 to 83.8 percent.
CN106316967 (intermediate of cilipague and process for preparation of cilipague) discloses a process for the preparation of celecoxib by reaction of (S-II), 2-chloro-N- (methylsulfonyl) acetamide and potassium tert-butoxide in N-methylpyrrolidone for 12 hours. The crude product obtained by the reaction is recrystallized by using an ethyl acetate/petroleum ether mixed solvent to obtain the celecoxib with the purity of 99.2-99.5 percent, and the yield is 81-83 percent.
CN105949135 (a synthesis method of celecoxib) discloses a synthesis method shown in the following formula, the yield of the method is 90.5% -92.3%, and the purity of the obtained celecoxib is not disclosed.
In summary, the currently disclosed technical scheme does not meet the requirements of high preparation yield and high purity of the prepared celecoxib at the same time, and particularly for the most disclosed reactions using (S-I) as an intermediate, a new method needs to be developed to prepare the high-purity celecoxib at high yield.
Disclosure of Invention
The invention aims to provide a method for preparing celecoxib, which comprises the steps of reacting a key intermediate 2- {4- [ N- (5, 6-diphenylpyrazin-2-yl) -N-isopropylamino ] butoxy } acetic acid of the celecoxib with methanesulfonamide, and selecting proper reaction conditions and post-treatment processes to ensure that the reaction yield is more than 95%, and the purity of the prepared celecoxib is more than or equal to 99.9%, wherein the purpose of the invention can be realized by the following technical scheme:
the invention provides a method for efficiently preparing high-purity celecoxib, which comprises the following operation steps:
a. adding a compound shown as a formula (S-I) and 1, 1' -carbonyldiimidazole into an organic solvent, and heating and refluxing for 1-2 hours;
b. adding methanesulfonamide at room temperature, stirring for 10-20 minutes, adding organic base, and purifying to obtain celecoxib;
wherein, the organic base in the step b is triethylamine, diisopropylethylamine or a mixture of the triethylamine and the diisopropylethylamine.
In a preferred embodiment, the compound (S-I) and 1, 1' -carbonyldiimidazole are fed in a molar ratio of 1:1.0 to 1:3.0, preferably 1:1.5, in step a.
In a preferred embodiment, the compound (S-I) in step a and the methanesulfonamide in step b are dosed in a molar ratio of 1:1.0 to 1:5.0, preferably 1: 2.0.
In a preferred embodiment, the compound (S-I) in step a and the organic base in step b are dosed in a molar ratio of 1:0 to 1:8.0, preferably 1: 2.0.
In a preferred embodiment, the organic solvent in step a is tetrahydrofuran or dichloromethane, preferably dichloromethane.
In a preferred embodiment, the volume-to-mass ratio of the organic solvent to the compound (S-I) is 5:1 to 20:1, preferably 8:1 to 15:1, more preferably 10:1 to 15: 1.
In a preferred embodiment, the purification described in step b uses recrystallization purification.
In a preferred embodiment, compound (S-I) is prepared by the following method:
the first step is as follows: heating 5-bromo-2, 3-diphenylpyrazine and 4- (isopropyl) amino-1-butanol in the presence of KI to 150 ℃ for reaction to obtain 4- ((5, 6-diphenylpyrazin-2-yl) - (isopropyl) amino) -1-butanol;
the second step is that: reacting 4- ((5, 6-diphenylpyrazin-2-yl) - (isopropyl) amino ] -1-butanol, tert-butyl bromoacetate, tetrabutylammonium hydrogen sulfate and an aqueous solution of potassium hydroxide in toluene to generate tert-butyl 2- (4- ((5, 6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetate;
the third step: tert-butyl 2- (4- ((5, 6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetate was reacted with an aqueous sodium hydroxide solution in a methanol solution to give a compound (S-I).
The invention effectively avoids the generation of difficult-to-remove impurities in the prior art, the product obtained after the reaction is recrystallized and purified after simple conventional treatment to prepare the celecoxib with the purity of more than or equal to 99.9 percent, the reaction yield is more than 95 percent, and the defects that the prior art can not meet the requirements of high yield and high product purity at the same time are overcome. The method has the advantages of simple operation, low cost, strong controllability, safety and environmental protection, and can simultaneously meet the requirements of medicine production and industrial production. The celecoxib prepared by the method has high purity, so that the method is beneficial to obtaining higher-quality medicines in the subsequent process.
Drawings
FIG. 1 is an HPLC chromatogram of crude celecoxib obtained in example 4, with a purity of 99.16%.
FIG. 2 is an HPLC chromatogram of a purified product of celecoxib obtained in example 4, the purity being 99.93%.
FIG. 3 is an HPLC chromatogram of crude celecoxib obtained in example 5, with a purity of 99.20%.
FIG. 4 is an HPLC chromatogram of a purified product of celecoxib obtained in example 5, the purity being 99.93%.
FIG. 5 is an HPLC chromatogram of crude celecoxib obtained in example 6, with a purity of 99.04%.
FIG. 6 is an HPLC chromatogram of the celecoxib fine product obtained in example 6, with a purity of 99.94%.
FIG. 7 is an HPLC chromatogram of crude celecoxib obtained in comparative example, with a purity of 97.29%.
FIG. 8 is an HPLC chromatogram of a celecoxib purified product obtained in comparative example, the purity being 99.27%.
Detailed Description
For better understanding of the contents of the present invention, the technical solutions of the present invention are further described below with reference to specific examples, but the specific embodiments are not meant to limit the present invention in any way.
The structure of the compound is determined by Nuclear Magnetic Resonance (NMR). The solvent was determined to be deuterated chloroform (CDCl) using (Bruker Avance III 400 and Bruker Avance 600) nuclear magnetic instrument3) Internal standard Tetramethylsilane (TMS);
HPLC was carried out by using Shimadzu high pressure liquid chromatograph (Zorbax SB-C18250 × 4.6.6 mm, 5. mu.M);
the starting materials and reagents not described in the present invention are all purchased by conventional methods.
Example 1
5-bromo-2, 3-diphenylpyrazine (100g, 0.32mol), 4-isopropylamino-1-butanol (127g, 0.96mol) and potassium iodide (15.9g, 0.096mol) were charged into a reaction flask, heated to 150 ℃ and reacted for 16 hours, after the system was cooled to room temperature, ethyl acetate (800mL) was added, washed with water (800mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from dichloromethane/heptane (1.2L, v/v ═ 1:5) to give 4- ((5, 6-diphenylpyrazin-2-yl) - (isopropyl) amino) -1-butanol (75.5g, yield: 65.3%).
1H NMR(400MHz,CDCl3)δ8.01(s,1H),7.45(d,J=5.8Hz,2H),7.35(d,J=6.8Hz,2H),7.28–7.21(m,6H),4.79(hept,J=6.6Hz,1H),3.68(t,J=6.3Hz,2H),3.47–3.38(m,2H),1.86(s,1H),1.80–1.72(m,2H),1.69–1.58(m,2H),1.27(d,J=6.7Hz,6H).
13C NMR(100MHz,CDCl3)δ151.6,149.0,139.6,139.5,139.0,129.8,129.3,128.1,128.0,127.9,127.1,126.9,62.4,46.2,42.2,30.0,25.7,20.4.
Example 2
A reaction flask was charged with 4- ((5, 6-diphenylpyrazin-2-yl) -isopropylamino) -1-butanol (72.3g, 0.20mol), toluene (200mL), tetrabutylammonium hydrogen sulfate (33.9g, 0.10mol) and 40% potassium hydroxide solution (150mL, w%), tert-butyl bromoacetate (78.0g, 0.40mol) was added dropwise in an ice-water bath, and the reaction was allowed to continue for 20 hours after dropwise addition, concentrated hydrochloric acid was added dropwise to adjust the system pH to 5-6, extracted with ethyl acetate (500mL), washed with water (500mL × 2), and concentrated under reduced pressure to give crude tert-butyl 2- (4- ((5, 6-diphenylpyrazinyl) (isopropyl) amino) butoxy) acetate, which was directly subjected to the next reaction.
Example 3
To the crude product obtained in the above example 2 were added tetrahydrofuran (300mL) and 10% sodium hydroxide solution (300mL, w%), heated under reflux, TLC was checked to completion, the tetrahydrofuran was removed by concentration under reduced pressure, the aqueous phase was extracted with methyl tert-butyl ether (300mL × 2), then the pH was adjusted to 2-3 with 1N hydrochloric acid, ethyl acetate (800mL) was extracted, concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate (500mL) to give 2- (4- ((5, 6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetic acid (S-I) (55.8g, two-step yield: 66.5%).
1H NMR(400MHz,CDCl3)δ8.10(s,1H),7.42(dd,J=7.6,1.8Hz,2H),7.32(dd,J=7.4,2.1Hz,2H),7.27–7.21(m,6H),4.85(hept,J=6.6Hz,1H),4.07(s,2H),3.61(t,J=6.0Hz,2H),3.48–3.39(m,2H),1.81–1.70(m,4H),1.26(d,J=6.7Hz,6H).
13C NMR(400MHz,CDCl3)δ173.3,152.0,149.6,139.4,138.8,138.4,129.9,129.5,128.1,128.0,127.9,127.1,126.7,71.4,68.0,46.2,42.3,27.0,26.0,20.3.
Example 4
2- (4- ((5, 6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetic acid (S-I) (21.0g, 0.05mol), carbonyldiimidazole (12.2g, 0.075mol) and dichloromethane (210mL) were added to a reaction flask, and the mixture was heated under reflux for 1 hour, cooled to 20 to 30 ℃, methanesulfonamide (9.5g, 0.10mol) was added, stirred for 10 minutes, triethylamine (10.1g, 0.10mol) was added, and the reaction was continued for 5 hours, water (50mL) was added, 1N hydrochloric acid was added dropwise to adjust the system pH to 5 to 6, liquid separation was performed, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude celecoxib (purity 99.16%, HPLC chromatogram was shown in FIG. 1), and crude celecoxib (270mL) was recrystallized with anhydrous ethanol to obtain a white-like solid celecoxib (24.0g, yield: 96.8%, purity: 99.93%, HPLC is shown in FIG. 2).
1H NMR(600MHz,CDCl3)δ8.00(s,1H),7.43(d,J=6.9Hz,2H),7.34(d,J=7.4Hz,2H),7.29–7.16(m,6H),4.73(hept,J=6.6Hz,1H),3.92(s,2H),3.55(t,J=5.6Hz,2H),3.45–3.40(m,2H),3.25(s,3H),1.78–1.64(m,4H),1.27(d,J=6.6Hz,6H).
13C NMR(150MHz,CDCl3)δ169.0,151.6,149.0,139.6,139.4,139.2,129.8,129.3,128.1,128.0,127.9,127.1,127.0,77.3,77.1 76.9,71.8,69.7 46.4,42.0,41.5,26.9,25.9,20.4.
Example 5
2- (4- ((5, 6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetic acid (S-I) (21.0g, 0.05mol), carbonyldiimidazole (12.2g, 0.075mol) and dichloromethane (210mL) were added to a reaction flask, and the mixture was heated under reflux for 1 hour, cooled to 20 to 30 ℃, methanesulfonamide (9.5g, 0.10mol) was added, and stirred for 10 minutes, diisopropylethylamine (12.9g, 0.10mol) was added, and the reaction was continued for 5 hours.water (50mL) was added, 1N hydrochloric acid was added dropwise to adjust the system pH to 5 to 6, followed by liquid separation, washing of the organic phase with water (50mL × 2), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure to obtain crude Seleticarpa (purity: 99.20%, HPLC chromatogram was shown in FIG. 3), and recrystallization was carried out with anhydrous ethanol (270mL) to obtain Seleticarpa white-like solid.
Example 6
2- (4- ((5, 6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetic acid (S-I) (21.0g, 0.05mol), carbonyldiimidazole (12.2g, 0.075mol) and tetrahydrofuran (210mL) were added to a reaction flask, and the mixture was heated under reflux for 1 hour, cooled to 20 to 30 ℃, added with methanesulfonamide (9.5g, 0.10mol), stirred for 10 minutes, added with triethylamine (10.1g, 0.10mol), and further stirred for 5 hours, the solvent was removed by concentration under reduced pressure, dichloromethane (200mL) and water (150mL) were added, 1N hydrochloric acid was added dropwise to adjust the system pH to 5 to 6, the mixture was separated, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude Cyopaca (purity: 99.04%, HPLC as shown in FIG. 5). the crude product was recrystallized with anhydrous ethanol (270mL) to give Cyopaca (23.7g, yield: 95.94%, HPLC as a chromatogram shown in FIG. 5).
Comparative examples
2- (4- ((5, 6-diphenylpyrazin-2-yl) (isopropyl) amino) butoxy) acetic acid (S-I) (21.0g, 0.05mol), carbonyldiimidazole (12.2g, 0.075mol) and tetrahydrofuran (210mL) were added to a reaction flask, and the mixture was heated under reflux for 1 hour, cooled to 20-30 ℃, added with methanesulfonamide (9.5g, 0.10mol), stirred for 10 minutes, then added with DBU (15.2g, 0.10mol), and stirred for 5 hours, then the solvent was removed by concentration under reduced pressure, dichloromethane (200mL) and water (150mL) were added, 1N hydrochloric acid was added dropwise to adjust the system pH to 5-6, the mixture was separated, the organic phase was washed with water (50mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to give Sessipa (purity: 97.29%, the chromatogram was shown in FIG. 7), and the crude product was recrystallized with anhydrous ethanol (270mL) to give Sessipa-like white solid Sessica (22.9g, yield, purity: 92.3%, purity: 99.27%, HPLC is shown in FIG. 7).
The analytical data for celecoxib obtained in the above examples are shown in table 1.
TABLE 1 Selexipa product parameters obtained in the examples
Note: ND means no relevant impurity was detected.

Claims (5)

1. A method for efficiently preparing high-purity celecoxib comprises the following operation steps:
a. adding a compound shown as a formula (S-I) and 1, 1' -carbonyldiimidazole into an organic solvent, and heating and refluxing for 1-2 hours;
b. adding methanesulfonamide at room temperature, stirring for 10-20 minutes, adding organic base, and purifying to obtain celecoxib;
wherein, the organic base in the step b is triethylamine, diisopropylethylamine or a mixture of the triethylamine and the diisopropylethylamine; the feeding molar ratio of the compound (S-I) in the step a to the organic base in the step b is 1:1.0-1: 8.0; the purification described in step b uses recrystallization purification.
2. The method for efficiently preparing high purity celecoxib according to claim 1 wherein: the feeding molar ratio of the compound (S-I) and the 1, 1' -carbonyl diimidazole in the step a is 1:1.0-1: 3.0.
3. The method for efficiently preparing high purity celecoxib according to claim 1 wherein: the feeding molar ratio of the compound (S-I) in the step a to the methanesulfonamide in the step b is 1:1.0-1: 5.0.
4. The method for efficiently preparing high purity celecoxib according to claim 1 wherein: the organic solvent in the step a is tetrahydrofuran or dichloromethane.
5. The method for efficiently preparing high-purity celecoxib according to claim 1 or 4, wherein: the volume-mass ratio of the dosage of the organic solvent to the compound (S-I) is 5:1-20: 1.
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CN110128358A (en) * 2019-04-08 2019-08-16 河北科技大学 4 [(5,6 diphenyl pyrazine, 2 base) (isopropyl) amino] butyl 2 (sulfonyloxy methyl amino) acetic acid esters preparation methods
CN112939877A (en) * 2019-12-11 2021-06-11 南京理工大学 Synthesis method of diphenylpyrazine derivative
CN112500358B (en) * 2020-11-18 2022-03-15 江苏豪森药业集团有限公司 Celecoxib crystal form and preparation method thereof
CN113480484A (en) * 2021-06-30 2021-10-08 湖南方盛制药股份有限公司 Preparation method of medical intermediate

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WO2017042828A2 (en) * 2015-09-10 2017-03-16 Megafine Pharma (P) Ltd. Process for the preparation of selexipag and intermediates thereof

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