CN110041282A - Related substance of Parecoxib Sodium and its preparation method and application - Google Patents
Related substance of Parecoxib Sodium and its preparation method and application Download PDFInfo
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- CN110041282A CN110041282A CN201810035335.5A CN201810035335A CN110041282A CN 110041282 A CN110041282 A CN 110041282A CN 201810035335 A CN201810035335 A CN 201810035335A CN 110041282 A CN110041282 A CN 110041282A
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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Abstract
The present invention relates to related substances of a kind of Parecoxib Sodium and its preparation method and application, more particularly to 2- (5- methyl -3- phenyl isoxazole -4- base) benzsulfamide and its preparation method and application.The related substance of the Parecoxib Sodium of high-purity provided by the invention can effectively improve the science and accuracy of Parecoxib Sodium and its intermediate impurities detection, the impurity content of Parecoxib Sodium and its preparation can effectively and conveniently be monitored, the quality for being conducive to control Parecoxib Sodium and its preparation, to guarantee the safety and validity of the compound and its preparation.
Description
Technical field
The present invention relates to related substances of a kind of Parecoxib Sodium and its preparation method and application, more particularly to 2- (5- first
Base -3- phenyl isoxazole -4- base) benzsulfamide and its preparation method and application.
Background technique
SC 69124 (Parecoxib) and its sodium salt can be used for the treatment of moderate or severe postoperative acute pain, pa auspicious former times
The structural formula of cloth is as shown in formula I, and the structural formula of sodium salt is as shown in I a of formula.
Type I compound and its sodium salt are capable of the prodrug of alternatively property cox 2 inhibitor Valdecoxib (Valdecoxib),
The structural formula of Valdecoxib is as shown in I b of formula.
In order to safely and effectively use drug, the quality standard of drug is to the purity of effective ingredient and the limit of impurity
There is more stringent regulation.Chemical derivative, conjunction in medicine quality analysis technical field, in active pharmaceutical ingredient impurity
Spectrum, chromatography or the identification of other physical methods can be used at by-product and catabolite or quantify.To miscellaneous in compound
Before matter is analyzed, need it is higher using purity and with above-mentioned impurity phase with or close structural substance as reference marker,
And relative position of the reference marker in chromatogram is considered as relative position of the impurity in chromatogram, and with this to be checkedization
The defects inspecting for closing object is instructed.Obviously, impurity content in active pharmaceutical ingredient is examined in the selection and preparation of reference marker
The science and accuracy of survey have direct influence.
Summary of the invention
It is indicated the purpose of the present invention is to provide a kind of related substance of Parecoxib Sodium, preparation method and as reference
The purposes of object.
In order to achieve the above-mentioned object of the invention, the present invention provides following technical schemes:
On the one hand, the present invention provides following compound, its stereoisomer or salt:
Wherein R is selected from hydroxyl, halogen, amino, propionamido-.
Preferably, the present invention provides following compound, its stereoisomer or salt:
In some embodiments, the present invention provides a kind of II a of formula of purity >=90%, II b of formula, II c compounds of formula；
In some typical embodiments, the present invention provides a kind of II a of formula formula of purity >=95%, II b of formula, II c compounds of formula.
On the other hand, the present invention provides the preparation methods of a kind of II a of formula, II b of formula, II c compound of formula, comprising:
Step 1:(E) -1- (1- (2- bromophenyl) propyl- 1- alkene -2- base) pyrroles's (intermediate 1) preparation
1- (2- bromophenyl) propyl- 2- ketone dissolves in organic solvent, and heating reflux reaction after pyrrolidines is added, solvent is evaporated off
After obtain intermediate 1；
Preferably, being heated to reflux temperature is 60-100 DEG C, is reacted 6-10 hours, temperature≤60 DEG C when solvent is evaporated off；
Step 2:4- (2- bromophenyl) -5- methyl -3- phenyl -5- (pyrrolidin-1-yl) -4,5- dihydro-isoxazole is (intermediate
Body 2) preparation
Temperature control at 10 DEG C, dissolve in organic solvent by (E) -1- (1- (2- bromophenyl) propyl- 1- alkene -2- base) pyrroles, point
Not Jia Ru Chlorobenzaldehyde oxime and acid binding agent, be added after water to separate and organic phase and solvent be evaporated off, obtain intermediate 2.
Preferably, temperature control reacts 2-4h, temperature≤60 DEG C when solvent is evaporated off at 5 DEG C；
The preparation of step 3:4- (2- bromophenyl) -5- methyl -3- phenyl isoxazole (intermediate 3)
4- (2- bromophenyl) -5- methyl -3- phenyl -5- (pyrrolidin-1-yl) -4,5- dihydro-isoxazole and water mixing, are stirred
It mixes lower addition concentrated hydrochloric acid and heats, be cooled to room temperature, solvent is evaporated off after organic solvent extraction is added, obtains intermediate 3；
Preferably, heating temperature is 80-120 DEG C, reacts 1-3h, temperature≤60 DEG C when solvent is evaporated off.
The preparation of step 4:4- (2- (benzylthio) phenyl) -5- methyl -3- phenyl isoxazole (intermediate 4)
4- (2- bromophenyl) -5- methyl -3- phenyl isoxazole is dissolved in organic molten in the presence of organic base, multidentate ligand
Agent, is separately added into palladium catalyst and benzyl mercaptan, and heating reaction obtains intermediate 4；
Preferably, heating temperature is 90-140 DEG C, reacts 12-36h, and multidentate ligand is bidentate phosphine ligands, is reacted in inertia
It is carried out under gas shield.
The preparation of step 5:2- (5- methyl -3- phenyl isoxazole -4- base) benzene sulfonyl chloride (II a compound of formula)
Temperature control is to 10 DEG C hereinafter, being separately added into glacial acetic acid in 4- (2- (benzylthio) phenyl) -5- methyl -3- phenyl isoxazole
And concentrated hydrochloric acid, and N- chlorosuccinimide is added, rear heating reaction is cooled at 5 DEG C, adds organic solvent after water is added
Extraction, is evaporated off organic solvent, obtains intermediate 5.
Preferably, temperature control is to 5 DEG C hereinafter, being heated to 10-40 DEG C of reaction 1-3h, temperature≤40 DEG C when solvent is evaporated off.
The preparation of step 6:2- (5- methyl -3- phenyl isoxazole -4- base) benzsulfamide (II b compound of formula)
2- (5- methyl -3- phenyl isoxazole -4- base) benzene sulfonyl chloride dissolves in organic solvent, by dissolved solution plus
Enter in ammonium hydroxide, heating reaction.
Preferably, heating reaction temperature is 10-40 DEG C, reaction time 15min-1h, temperature≤40 DEG C when solvent is evaporated off.
Step 7:N- ((2- (5- methyl -3- phenyl isoxazole -4- base) phenyl) sulfonyl) propionamide (II c compound of formula)
Preparation
Propionic andydride and 2- (5- methyl -3- phenyl isoxazole -4- base) benzsulfamide are added into reaction kettle, is warming up to 40-
60 DEG C, sulfuric acid is added, is continuously heating to 70-90 DEG C, insulation reaction is cooled to 40-60 DEG C, and purified water is added, continues to be cooled to
Room temperature stirs, and filters, dry, obtains target compound.
Preferably, the insulation reaction time is 0.5-1.5h；
Preferably, filter cake is dissolved by heating with acetone after filtering, cools down and purified water is added, and continues to be cooled to 5 DEG C hereinafter, again
It is dry after filtering.
On the other hand, the present invention provides a kind of method for detecting purity of II b compound of formula:
(1) chromatographic condition: it is with the silica gel that surface is covalently bonded with cellulose-three (3,5- dichlorophenyl carbamate)
Filler [chromatographic column is CHIRALPAK IC (250mm × 4.6mm, 5 μm) or the suitable chromatographic column of performance]；With n-hexane-ethyl alcohol-
Trifluoroacetic acid (75:25:0.1) is mobile phase, flow velocity 1ml/min, Detection wavelength 215nm；Column temperature is 25 DEG C.
(2) measuring method: II b compound of modus ponens is appropriate, sets in 10ml measuring bottle, solubilizer [n-hexane-ethyl alcohol-trifluoro second
Sour (75:25:0.1)] solution being made in every 1ml containing about 0.5mg is dissolved and dilutes, as test solution, precision measures 10 μ
L injects liquid chromatograph, records chromatogram.(ignore not at peak of the peak area percent less than 0.02% by areas of peak normalization method
Meter) calculate test solution in main peak (II b compound of formula) purity.
On the other hand, the present invention also provides II b compound of formula in the determination of foreign matter of I b compound of formula as reference mark
Show the purposes of object.In some embodiments, the present invention provides a kind of II b compounds of the formula of purity >=90% in I b chemical combination of formula
As the purposes of reference marker when the determination of foreign matter of object；In some typical embodiments, the present invention provides a kind of pure
Purposes of the II b compound of formula of degree >=95% in the determination of foreign matter of I b compound of formula as reference marker.
In some specific embodiments, II b compound of formula is in the determination of foreign matter of I b compound of formula as reference mark
Show the purposes of object comprising following steps:
Test solution is prepared: II b compound of modus ponens is appropriate, sets in 10ml measuring bottle, solubilizer [n-hexane-ethyl alcohol-trifluoro
Acetic acid (75:25:0.1)] dissolve and dilute the solution being made in every 1ml containing about 0.5mg, shake up to get.
Contrast solution is prepared: precision measures test solution 1ml, sets in 100ml measuring bottle, solubilizer [n-hexane-ethyl alcohol-
Trifluoroacetic acid (75:25:0.1)] be diluted to scale, shake up to get.
System suitability solution is prepared: I b compound of modus ponens and II b compound of formula are each appropriate, solubilizer [n-hexane-second
Alcohol-trifluoroacetic acid (75:25:0.1)] it dissolves and quantifies dilution and be made in every 1ml containing about I b compound 0.5mg of formula, II bization containing formula
Close object be 5 μ g mixed solution to get.
Chromatographic condition: surface is covalently bonded with the silica gel of cellulose-three (3,5- dichlorophenyl carbamate) as filling
Agent (chromatographic column is CHIRALPAK IC (250mm × 4.6mm, 5 μm) or the suitable chromatographic column of performance)；With n-hexane-ethyl alcohol-trifluoro
Acetic acid (75:25:0.1) is mobile phase, flow velocity 1ml/min, Detection wavelength 215nm；Column temperature is 25 DEG C.
Measuring method: it is detected according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015).It is suitable in system
Under conditions of being required with property agreement with experimental, precision measures solvent, test solution and each 10 μ l of contrast solution, is injected separately into liquid phase
Chromatograph records chromatogram.It is calculated by the principal component Self-control method that correction factor is not added.
Calculation formula:
In formula:
AImpurity BThe peak area at impurity B peak in-test solution；
AControlThe peak area of-contrast solution main peak (i.e. the peak of Formulas I b compound).
Impurity B can be II b compound of formula: in the structure of the compound, 1,2 substituted benzene ring and isozole ring are due to sky
Between steric hindrance, it is not coplanar, resistance rotation isomerism is generated, there are a pair of of space multistory isomers, so there are two chromatographies
Peak.
Therefore when impurity B is II b compound of formula, the sum of two peak areas are calculated as.
The impurity B may be other and II b compound impurity with similar structure of formula, such as formula III, formula IV, formula V
With VI compound of formula:
In some embodiments of the present invention, the content of I b compound Chinese style of formula, II b compound must not exceed 0.5%,
In some preferred embodiments, the content of I b compound Chinese style of formula, II b compound must not exceed 0.15%, some more excellent
In the embodiment of choosing, the content of I b compound Chinese style of formula, II b compound must not exceed 0.1%.
Herein, unless otherwise indicated, the I b compound of formula to " test solution preparation " includes but not
It is limited to freshly prepared or I b raw materials of compound medicine of formula through storing, the pharmaceutical composition comprising I b compound of formula.
The present invention provides a kind of II b compound of formula of high-purity, the content of the compound directly affect type I compound and
The quality of its preparation.The II b compound of formula of high-purity provided by the invention can effectively improve type I compound and its preparation impurity
The science and accuracy of detection can effectively and conveniently monitor the impurity content of type I compound and its preparation, be conducive to control
The quality of type I compound processed and its preparation, to guarantee the safety and validity of type I compound and its preparation.
In addition, the present invention provides a kind of HPLC detection method of impurity in I b compound of formula, it is detectable using this method
II b of formula, formula III, VI compound of formula IV, formula V and formula out reach between the peak of I b compound of each impurity and formula and are kept completely separate,
When minor change occurs for chromatographic condition, do not have to the separating degree between the separating degree of I b compound of formula and each impurity, each impurity
Have an impact, durability is excellent.
Specific embodiment
The present invention is further described in detail With reference to embodiment.But this should not be interpreted as to the present invention
The range of above-mentioned theme is only limitted to following embodiment.
The preparation of 1 2- of embodiment (5- methyl -3- phenyl isoxazole -4- base) benzsulfamide (II b compound of formula)
Step 1:(E) -1- (1- (2- bromophenyl) propyl- 1- alkene -2- base) pyrroles's (intermediate 1) preparation
At room temperature, 1- (2- bromophenyl) propyl- 2- ketone and hexamethylene stirring and dissolving are added into 100mL single port bottle, pyrrole is added
Alkane is coughed up, increases temperature to 80 DEG C of reflux 8h.In the case where revolving temperature is no more than 50 DEG C, reaction solution decompression is boiled off into hexamethylene and excess
Pyrrolidines, obtain pale tan oil 2.5g.MS(m/z):266.0[M+H]+。
Step 2:4- (2- bromophenyl) -5- methyl -3- phenyl -5- (pyrrolidin-1-yl) -4,5- dihydro-isoxazole is (intermediate
Body 2) preparation
At 5 DEG C, (E) -1- (1- (2- bromophenyl) propyl- 1- alkene -2- base) pyrroles and dichloromethane are added into 100mL single port bottle
Alkane stirring and dissolving is separately added into Chlorobenzaldehyde oxime and triethylamine, reacts 3h.20mL water is added, stirs 30min at room temperature, it is quiet
Layering is set, liquid separation obtains organic phase, and water phase successively uses 10mL methylene chloride to extract twice, merges organic phase, does not surpass in revolving temperature
It crosses at 50 DEG C, decompression boils off solvent and obtains pale tan oil 3g, and crude product is directly used in next step.MS(m/z):385.1
[M+H]+。
The preparation of step 3:4- (2- bromophenyl) -5- methyl -3- phenyl isoxazole (intermediate 3)
At room temperature, 4- (2- bromophenyl) -5- methyl -3- phenyl -5- (pyrrolidin-1-yl)-is added into 100mL single port bottle
4,5- dihydro-isoxazoles and water are added with stirring concentrated hydrochloric acid, increase temperature to 100 DEG C of reaction 2h.Reaction solution is cooled to room temperature,
It is successively extracted three times with methylene chloride (10mL), merges organic phase, in the case where revolving temperature is no more than 50 DEG C, decompression boils off solvent and obtains
Pale tan oil, column chromatograph to obtain faint yellow solid 2.1g, three step total recoverys 54%；MS(m/z):314.0[M+H]+。
The preparation of step 4:4- (2- (benzylthio) phenyl) -5- methyl -3- phenyl isoxazole (intermediate 4)
At room temperature, it is bis- that 4- (2- bromophenyl) -5- methyl -3- phenyl isoxazole, 4,5- are separately added into 100mL single port bottle
(diphenylphosphine) -9,9- xanthphos (Xantphos), DIPEA and dioxane (dioxane), are separately added under stirring
Palladium catalyst Pd2(dba)3And benzyl mercaptan, the lower raising temperature of argon gas protection to 120 DEG C of reactions is for 24 hours.Filtering, filtrate decompression are concentrated to give
Dark brown oil, column chromatograph to obtain 0.7g yellow oil, yield 41%；MS(m/z):358.1[M+H]+。
The preparation of step 5:2- (5- methyl -3- phenyl isoxazole -4- base) benzene sulfonyl chloride (intermediate 5)
At 0 DEG C, 4- (2- (benzylthio) phenyl) -5- methyl -3- phenyl isoxazole, ice are separately added into 50mL single port bottle
Acetic acid and concentrated hydrochloric acid are slowly added to N- chlorosuccinimide under stirring, increase temperature to 25 DEG C of reaction 1h.Reaction solution is cooling
It to 0 DEG C, is added water (10mL), and is successively extracted three times with methylene chloride (10mL), merge organic phase, be no more than in revolving temperature
At 35 DEG C, decompression boils off solvent and obtains pale tan oil 0.6g.MS(m/z):334.0[M+H]+。
The preparation of step 6:2- (5- methyl -3- phenyl isoxazole -4- base) benzsulfamide (II b compound of formula)
At room temperature, 2- (5- methyl -3- phenyl isoxazole -4- base) benzene sulfonyl chloride and two is separately added into 50mL single port bottle
Chloromethanes stirring and dissolving, and dissolved solution is added into ammonium hydroxide and reacts 30min.Reaction solution is stood, liquid separation obtains organic
Phase, water phase successively use methylene chloride (10mL) to extract twice, merge organic phase, and in the case where revolving temperature is no more than 35 DEG C, decompression is steamed
It goes solvent to obtain pale tan oil 0.3g, obtains target compound.MS(m/z):315.1[M+H]+；1H-NMR(500MHz,
DMSO-d6):δ2.21(s,3H),7.25-7.28(m,3H),7.31-7.34(m,1H),7.36-7.38(m,2H),7.44(br,
2H),7.57-7.65(m,2H),8.04-8.06(dd,1H)；
Embodiment 2N- ((2- (5- methyl -3- phenyl isoxazole -4- base) phenyl) sulfonyl) propionamide (II c chemical combination of formula
Object) preparation
Propionic andydride and intermediate 2 are added into reaction kettle, is warming up to 50 DEG C, sulfuric acid is added, is continuously heating to 80 DEG C, heat preservation
Be stirred to react 1h, be cooled to 50 DEG C, be slowly added to 9kg water, continue to be cooled to room temperature, add 9kg water, be cooled to 5 DEG C hereinafter,
1h is stirred, rejection filter dries after filter cake washing, and filter cake is slightly dissolved by heating with 13.5L acetone, is cooled to 25 DEG C, and 27kg water is added dropwise
White solid is precipitated, cool down 5 DEG C of 1h stirred below, and rejection filter obtains off-white powder, 70 DEG C forced air drying 8 hours, every 2h stirring one
It is secondary, survey loss on drying to 0.5% hereinafter, target product,1H-NMR(500MHz,DMSO-d6):δ0.68-0.71(t,3H),
1.61-1.68(m,1H),1.94-2.02(m,1H),2.21(s,3H),7.26-7.29(m,2H),7.33-7.36(m,3H),
7.44-7.46(m,1H),7.72-7.79(m,2H),8.19-8.21(dd,1H)。
The impurity of 3 formula of embodiment, II b, formula III and IV compound of formula as reference marker detection I b compound of formula
Test solution is prepared: II b of modus ponens, formula III and IV compound of formula are appropriate respectively, set in 10ml measuring bottle, solubilizer
[n-hexane-ethyl alcohol-trifluoroacetic acid (75:25:0.1)], which is dissolved and diluted, to be made in every 1ml containing about II b of 0.5mg formula, formula III or formula
The solution of IV compound, shake up to get.
Contrast solution is prepared: precision measures test solution 1ml, sets in 100ml measuring bottle, solubilizer [n-hexane-ethyl alcohol-
Trifluoroacetic acid (75:25:0.1)] be diluted to scale, shake up to get.
System suitability solution: I b compound of modus ponens and II b of formula, formula III and IV compound of formula are appropriate respectively, and solubilizer is [just
Hexane-EtOAc-trifluoroacetic acid (75:25:0.1)] it dissolves and quantifies dilution and be made in every 1ml containing about I b compound 0.5mg of formula, contain
I b of formula, II b of formula, formula III or IV compound of formula be 5 μ g mixed solution to get.
Chromatographic condition: surface is covalently bonded with the silica gel of cellulose-three (3,5- dichlorophenyl carbamate) as filling
Agent (chromatographic column is CHIRALPAK IC (250mm × 4.6mm, 5 μm) or the suitable chromatographic column of performance)；With n-hexane-ethyl alcohol-trifluoro
Acetic acid (75:25:0.1) is mobile phase, flow velocity 1ml/min, Detection wavelength 215nm；Column temperature is 25 DEG C.
Measuring method: it is detected according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015).System is applicable in
Property agreement with experimental requirement, peak sequence is followed successively by II b compound peaks 1 of formula, formula III, IV compound of formula, II b compound peaks of formula, 2 and
I b compound of formula reaches between each ingredient and is kept completely separate, and main peak peak purity meets the requirements.
After determining that system suitability meets the requirements, precision measures solvent, test solution and each 10 μ l of contrast solution,
It is injected separately into liquid chromatograph, records chromatogram.It is calculated by the principal component Self-control method that correction factor is not added.
Calculation formula:
In formula:
AImpurity BThe peak area at impurity B peak in-test solution；
AControlThe peak area of-contrast solution main peak (i.e. the peak of Formulas I b compound).
Peak sequence is followed successively by II b compound peaks 1 of formula, formula III, I b chemical combination of IV compound of formula, II b compound peaks 2 of formula and formula
Object, separating degree should meet the requirements.
The experiment of 3 durability of embodiment
The experimental program in embodiment 2 is repeated according to above-mentioned 1-7 chromatographic condition, it is right when comparison chromatographic condition changes
The influence of measurement result: 1) in mixed solution, the separating degree between I b compound of formula and each impurity, other each impurity does not have shadow
It rings, can be kept completely separate；2) measurement result on test liquid in relation to substance does not influence, and impurity number is measured under the conditions of each and is contained
It measures almost the same.
Claims (14)
1. a kind of II compound of formula, stereoisomer or salt, structure are as follows:
Wherein R is selected from hydroxyl, halogen, amino, propionamido-.
2. compound according to claim 1, specific structure is as shown in II a of formula, II b of formula and formula II:
3. compound according to claim 1, it is characterised in that purity >=90%；It is preferred that purity >=95%.
4. a kind of preparation method of the preparation method of II a compound of formula, it is characterised in that include the following steps:
(1) 1- (2- bromophenyl) propyl- 2- ketone dissolves in hexamethylene, and heating reflux reaction after pyrrolidines is added, solvent is evaporated off, obtains
To (E) -1- (1- (2- bromophenyl) propyl- 1- alkene -2- base) pyrroles；
(2) temperature control at 10 DEG C, dissolve in methylene chloride by (E) -1- (1- (2- bromophenyl) propyl- 1- alkene -2- base) pyrroles, respectively
Chlorobenzaldehyde oxime and acid binding agent is added, separate organic phase after water is added and solvent is evaporated off, obtains 4- (2- bromophenyl) -5- first
Base -3- phenyl -5- (pyrrolidin-1-yl) -4,5- dihydro-isoxazole；
(3) 4- (2- bromophenyl) -5- methyl -3- phenyl -5- (pyrrolidin-1-yl) -4,5- dihydro-isoxazole and water mixing, stirring
Lower addition concentrated hydrochloric acid simultaneously heats, and is cooled to room temperature, and solvent is evaporated off after methylene chloride extraction is added, obtains 4- (2- bromophenyl) -5-
Methyl -3- phenyl isoxazole；
(4) 4- (2- bromophenyl) -5- methyl -3- phenyl isoxazole is dissolved in dioxy six in the presence of DIPEA, multidentate ligand
Ring, is separately added into palladium catalyst and benzyl mercaptan, and heating reaction obtains the different evil of 4- (2- (benzylthio) phenyl) -5- methyl -3- phenyl
Azoles；
(5) temperature control is to 10 DEG C hereinafter, being separately added into glacial acetic acid in 4- (2- (benzylthio) phenyl) -5- methyl -3- phenyl isoxazole
And concentrated hydrochloric acid, and N- chlorosuccinimide is added, rear heating reaction is cooled at 5 DEG C, adds methylene chloride after water is added
Extraction, is evaporated off organic solvent, obtains 2- (5- methyl -3- phenyl isoxazole -4- base) benzene sulfonyl chloride.
5. a kind of preparation method of the preparation method of II b compound of formula, it is characterised in that include the following steps:
(1) 1- (2- bromophenyl) propyl- 2- ketone dissolves in hexamethylene, and heating reflux reaction after pyrrolidines is added, solvent is evaporated off, obtains
To (E) -1- (1- (2- bromophenyl) propyl- 1- alkene -2- base) pyrroles；
(2) temperature control at 10 DEG C, dissolve in methylene chloride by (E) -1- (1- (2- bromophenyl) propyl- 1- alkene -2- base) pyrroles, respectively
Chlorobenzaldehyde oxime and acid binding agent is added, separate organic phase after water is added and solvent is evaporated off, obtains 4- (2- bromophenyl) -5- first
Base -3- phenyl -5- (pyrrolidin-1-yl) -4,5- dihydro-isoxazole；
(3) 4- (2- bromophenyl) -5- methyl -3- phenyl -5- (pyrrolidin-1-yl) -4,5- dihydro-isoxazole and water mixing, stirring
Lower addition concentrated hydrochloric acid simultaneously heats, and is cooled to room temperature, and solvent is evaporated off after methylene chloride extraction is added, obtains 4- (2- bromophenyl) -5-
Methyl -3- phenyl isoxazole；
(4) 4- (2- bromophenyl) -5- methyl -3- phenyl isoxazole is dissolved in dioxy six in the presence of DIPEA, multidentate ligand
Ring, is separately added into palladium catalyst and benzyl mercaptan, and heating reaction obtains the different evil of 4- (2- (benzylthio) phenyl) -5- methyl -3- phenyl
Azoles；
(5) temperature control is to 10 DEG C hereinafter, being separately added into glacial acetic acid in 4- (2- (benzylthio) phenyl) -5- methyl -3- phenyl isoxazole
And concentrated hydrochloric acid, and N- chlorosuccinimide is added, rear heating reaction is cooled at 5 DEG C, adds methylene chloride after water is added
Extraction, is evaporated off organic solvent, obtains 2- (5- methyl -3- phenyl isoxazole -4- base) benzene sulfonyl chloride；
(6) 2- (5- methyl -3- phenyl isoxazole -4- base) benzene sulfonyl chloride dissolves in methylene chloride, by dissolved solution plus
Enter in ammonium hydroxide and react, obtains 2- (5- methyl -3- phenyl isoxazole -4- base) benzsulfamide.
6. a kind of preparation method of the preparation method of II c compound of formula, it is characterised in that include the following steps:
(1) 1- (2- bromophenyl) propyl- 2- ketone dissolves in hexamethylene, and heating reflux reaction after pyrrolidines is added, solvent is evaporated off, obtains
To (E) -1- (1- (2- bromophenyl) propyl- 1- alkene -2- base) pyrroles；
(2) temperature control at 10 DEG C, dissolve in methylene chloride by (E) -1- (1- (2- bromophenyl) propyl- 1- alkene -2- base) pyrroles, respectively
Chlorobenzaldehyde oxime and acid binding agent is added, separate organic phase after water is added and solvent is evaporated off, obtains 4- (2- bromophenyl) -5- first
Base -3- phenyl -5- (pyrrolidin-1-yl) -4,5- dihydro-isoxazole；
(3) 4- (2- bromophenyl) -5- methyl -3- phenyl -5- (pyrrolidin-1-yl) -4,5- dihydro-isoxazole and water mixing, stirring
Lower addition concentrated hydrochloric acid simultaneously heats, and is cooled to room temperature, and solvent is evaporated off after methylene chloride extraction is added, obtains 4- (2- bromophenyl) -5-
Methyl -3- phenyl isoxazole；
(4) 4- (2- bromophenyl) -5- methyl -3- phenyl isoxazole is dissolved in dioxy six in the presence of DIPEA, multidentate ligand
Ring, is separately added into palladium catalyst and benzyl mercaptan, and heating reaction obtains the different evil of 4- (2- (benzylthio) phenyl) -5- methyl -3- phenyl
Azoles；
(5) temperature control is to 10 DEG C hereinafter, being separately added into glacial acetic acid in 4- (2- (benzylthio) phenyl) -5- methyl -3- phenyl isoxazole
And concentrated hydrochloric acid, and N- chlorosuccinimide is added, rear heating reaction is cooled at 5 DEG C, adds methylene chloride after water is added
Extraction, is evaporated off organic solvent, obtains 2- (5- methyl -3- phenyl isoxazole -4- base) benzene sulfonyl chloride；
(6) 2- (5- methyl -3- phenyl isoxazole -4- base) benzene sulfonyl chloride dissolves in methylene chloride, by dissolved solution plus
Enter in ammonium hydroxide and react, obtains 2- (5- methyl -3- phenyl isoxazole -4- base) benzsulfamide；
(7) propionic andydride and 2- (5- methyl -3- phenyl isoxazole -4- base) benzsulfamide are added into reaction kettle, is warming up to 40-60
DEG C, sulfuric acid is added, is continuously heating to 70-90 DEG C, insulation reaction is cooled to 40-60 DEG C, and purified water is added, continues to be cooled to room
Temperature stirs, and filters, dry, obtains target compound.
7. according to any method of claim 4-6, it is characterised in that when the method involves the steps of:
It is 60-100 DEG C that temperature is heated to reflux in step (1), is reacted 6-10 hours, temperature≤60 DEG C when solvent is evaporated off, preferably
Hot reflux temperature is 80 DEG C, is reacted 8 hours, temperature≤50 DEG C when solvent is evaporated off；
Temperature control is at 5 DEG C, reacting 2-4h in step (2), and temperature≤60 DEG C when solvent is evaporated off, preferably temperature control are at 0 DEG C, reaction
3h, temperature≤50 DEG C when solvent is evaporated off；
Heating temperature is 80-120 DEG C in step (3), reacts 1-3h, temperature≤60 DEG C when solvent is evaporated off, preferably heating temperature
It is 100 DEG C, reacts 2h, temperature≤50 DEG C when solvent is evaporated off；
Heating temperature is 90-140 DEG C in step (4), reacts 12-36h, and multidentate ligand is bidentate phosphine ligands, is reacted in indifferent gas
Body protection is lower to be carried out, and preferably heating temperature is 120 DEG C, is reacted for 24 hours, multidentate ligand Xantphos；
Temperature control is to 5 DEG C hereinafter, be heated to 10-40 DEG C of reaction 1-3h in step (5), temperature≤40 DEG C when solvent is evaporated off, preferably
Temperature control is to 0 DEG C hereinafter, being heated to 25 DEG C of reaction 2h, temperature≤35 DEG C when solvent is evaporated off；
Step (6) reaction time is 0.5h, temperature≤35 DEG C when solvent is evaporated off；
Step (7) the insulation reaction time is 0.5-1.5h；Filter cake is dissolved by heating with acetone after filtering, is cooled down and is added purified water,
Continue to be cooled to 5 DEG C hereinafter, dry after refiltering.
8. purposes of II compound of formula in type I compound determination of foreign matter as reference marker,
Wherein R is selected from hydroxyl, halogen, amino, propionamido-.
9. a kind of I b compound Chinese style of formula, II b, formula III, the HPLC detection method of VI compound of formula IV, formula V and/or formula, condition
Are as follows: use surface to be covalently bonded with the silica gel of polysaccharide derivates for the chromatographic column of filler, with n-hexane-ethyl alcohol-trifluoroacetic acid
For mobile phase, proportion of mobile phase 65-85:15-35:0.05-0.2,
10. detection method according to claim 6, it is characterised in that the polysaccharide derivates are cellulose-three (3,5- bis-
Meta-chlorocarbanilate).
11. detection method according to claim 6, it is characterised in that flow rate of mobile phase 0.5-1.5ml/min.
12. detection method according to claim 6, it is characterised in that column temperature is 15-35 DEG C.
13. detection method according to claim 6, it is characterised in that sample volume is 5-20 μ l.
14. detection method according to claim 6, it is characterised in that Detection wavelength 200-230nm.
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| CN111153865A (en) * | 2020-01-19 | 2020-05-15 | 上海臣邦医药科技股份有限公司 | Parecoxib sodium substituted impurity and preparation method thereof |
| CN114200034A (en) * | 2021-10-28 | 2022-03-18 | 上海旭东海普药业有限公司 | Analysis method of vernakalant related substances |
| CN114441666A (en) * | 2020-11-05 | 2022-05-06 | 成都百裕制药股份有限公司 | Method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride |
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| CN104557756A (en) * | 2015-01-04 | 2015-04-29 | 成都克莱蒙医药科技有限公司 | Synthetic method of parecoxib sodium impurity |
| CN104557754A (en) * | 2015-01-04 | 2015-04-29 | 成都克莱蒙医药科技有限公司 | Synthesis method for parecoxib sodium impurity |
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| CN104557756A (en) * | 2015-01-04 | 2015-04-29 | 成都克莱蒙医药科技有限公司 | Synthetic method of parecoxib sodium impurity |
| CN104557754A (en) * | 2015-01-04 | 2015-04-29 | 成都克莱蒙医药科技有限公司 | Synthesis method for parecoxib sodium impurity |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111153865A (en) * | 2020-01-19 | 2020-05-15 | 上海臣邦医药科技股份有限公司 | Parecoxib sodium substituted impurity and preparation method thereof |
| CN114441666A (en) * | 2020-11-05 | 2022-05-06 | 成都百裕制药股份有限公司 | Method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride |
| CN114441666B (en) * | 2020-11-05 | 2024-02-27 | 成都百裕制药股份有限公司 | Method for detecting impurities in 4- (5-methyl-3-phenyl-4-isoxazole) benzenesulfonyl chloride |
| CN114200034A (en) * | 2021-10-28 | 2022-03-18 | 上海旭东海普药业有限公司 | Analysis method of vernakalant related substances |
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