CN106008388B - A kind of preparation method for the SC 69124 for being used to treat postoperative pain - Google Patents
A kind of preparation method for the SC 69124 for being used to treat postoperative pain Download PDFInfo
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- CN106008388B CN106008388B CN201610353249.XA CN201610353249A CN106008388B CN 106008388 B CN106008388 B CN 106008388B CN 201610353249 A CN201610353249 A CN 201610353249A CN 106008388 B CN106008388 B CN 106008388B
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- phenyl
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- isoxazole
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
The invention discloses a kind of for treating the preparation method of the SC 69124 of postoperative pain, this method includes the following steps：1) 3 (4 sulfonic group phenyl) 4 phenyl 4 (1 pyrrolidinyl) 3 butylene, 2 ketone is subjected to haptoreaction with ammonium acetate in acetic acid at 90~100 DEG C, after reaction, dichloromethane dilutes, saturated sodium bicarbonate adjusts pH to 6~7, organic phase concentration, washing, then ethyl alcohol recrystallization, dry 5 methyl 3 phenyl 4 (4 sulfonic group phenyl) isoxazole；2) product for obtaining step 1) in the presence of anion exchange resin with ammonium chloride 35~45 DEG C 5 methyl 3 phenyl 4 (4 sulfoamido phenyl) isoxazole is obtained by the reaction；3) SC 69124 is obtained by the reaction with propionic andydride in the presence of triethylamine in the product that step 2) obtains.The present invention's prepares simple SC 69124 method and step, mild condition and high income.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular, to a kind of system for the SC 69124 for being used to treat postoperative pain
Preparation Method.
Background technology
Parecoxib Sodium (Parecoxib Sodium) be can intravenously administrable and intramuscular injection specific cyclooxygenase-2
Inhibitor, the inhibitor are researched and developed by Pharmacia companies, belong to the former times dry goods antalgesic in anti-arthritic.Parecoxib Sodium
Chemical name for N- [[4- (5- methyl -3- phenyl -4- isoxazolyls) phenyl] sulfonyl] propionamide sodium salt, concrete structure is such as
Under：
At present, the Study of synthesis method about SC 69124 (sodium) is more, but is substantially with 5- methyl -3,4- hexichol
Base isoxazole carries out preparing SC 69124 for key intermediate.Such as WO2005123701A1 discloses a kind of SC 69124
Preparation method, this method is first reacted using benzyl phenyl ketone as starting material with nafoxidine, then through acetylation, and hydrochloric acid hydroxyl
Amine ring-closure reaction, cancellation dehydration obtain intermediate 5- methyl -3,4- diphenyl isoxazoles, intermediate 5- methyl -3,4- diphenyl
Isoxazole semi-annular jade pendant is acylated, aminating reaction and amidation obtain Parecoxib Sodium.This method specific embodiment is as follows：
Above method step is longer, and overall yield is relatively low, traces it to its cause and is primarily due to prepare intermediate 5- methyl -3,4-
The cyclization step of diphenyl isoxazole, acetyl group oxygen can also participate in azanol reaction generation by-product；In addition, eliminating step uses three
Fluoroacetic acid system is dehydrated, and to equipment requirement height, fluoride will also result in environmental pollution.Although the method discloses have more than ten
Year, how to improve the yield of intermediate 5- methyl -3,4- diphenyl isoxazoles is still the key for preparing SC 69124 (sodium).Cause
This, there is an urgent need for a kind of method is simple, the method for preparing SC 69124 of mild condition and high income for this field.
Invention content
It is an object of the invention to overcome the defects of existing method for preparing SC 69124, a kind of condition temperature is provided
Simple and high income the method for preparing SC 69124 with step.
The present inventor has found under study for action, ammonium acetate as effective nitrogen source can in acetic acid quickly with 3- (4-
Sulfonic group phenyl) -4- phenyl -4- (1- pyrrolidinyls) -3- butene-2s -one reaction realize a step generation isozole ring, overcome
It is existing first to generate hydroxy group isoxazole, it is necessary to obtain the deficiency of isozole ring by eliminating dehydration, reduce reaction
Processing step improves reaction yield, and reacts mildly suitable industrialized production.
To achieve these goals, the present invention provides a kind of method for preparing SC 69124, and this method includes the following steps：
1) by 3- (4- sulfonic groups phenyl)-4- phenyl-4- (1- pyrrolidinyls)-3- butene-2 -one in acetic acid with acetic acid
Ammonium carries out haptoreaction at 90~100 DEG C, and after reaction, dichloromethane dilution, saturated sodium bicarbonate adjusts pH to 6~7, has
Machine is mutually concentrated, is washed, then ethyl alcohol recrystallization, dry 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole；
2) 5- methyl -3- phenyl -4- (the 4- sulfonic groups phenyl) isoxazole for obtaining step 1) is in anion exchange resin
In the presence of with ammonium chloride 35~45 DEG C 5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazole is obtained by the reaction；
3) 5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazole that step 2) obtains in the presence of triethylamine with
SC 69124 is obtained by the reaction in propionic andydride.
For better cyclization, under preferable case, 3- (4- sulfonic groups phenyl) -4- phenyl -4- (1- pyrrolidinyls) -
3- butene-2s -one and the dosage molar ratio of ammonium acetate, acetic acid are 1：3~5：10~20.In the case of further preferably, 3- (4- sulphurs
Acidic group phenyl) -4- phenyl -4- (1- pyrrolidinyls) -3- butene-2s -one and ammonium acetate, acetic acid dosage molar ratio be 1：4~5：
12~15.
In the present invention, inventor also found, in cyclic amides generation step, using ammonium chloride as ammonia source, pass through addition
Anion exchange resin can promote the reaction to carry out, and improve the yield of the reaction.Under preferable case, 5- methyl -3- phenyl -4-
The molar ratio of the dosage of (4- sulfonic groups phenyl) isoxazole and ammonium chloride is 1：2~5, the dosage of the anion exchange resin is
The 15~35% of 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole weight；Under preferable case, 5- methyl -3- phenyl -
The molar ratio of the dosage of 4- (4- sulfonic groups phenyl) isoxazoles and ammonium chloride is 1：2~3, the dosage of the anion exchange resin
20~25% for 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole weight.
In the present invention, the ammonium chloride can add in as a solution, such as add in the saturated solution of ammonium chloride.
Preferably, the detailed process of step 3) includes：By 5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazole
It is blended in 20~25 DEG C of dichloromethane and reacts with triethylamine and propionic andydride, after reaction, be poured into water, dichloromethane extraction
It takes, concentrates, ethyl alcohol dissolving, 5~10 DEG C of crystallizations, dry SC 69124.
In the present invention, the method that this field routine may be used is monitored tracking to reacting, such as TLC, LCMS,
GCMS etc., reaction finish refer to TLC monitor not excess raw material disappeared or LCMS, GCMS in not excess raw material residue be less than
2%.
In the present invention, anion exchange resin is not particularly limited, such as the anion exchange resin
For strong base or weak base type anion exchange resin.As commercially available product, the strong basic type anion-exchange resin can be 201 ×
7 (717) strong-basicity styrene series anion exchange resins, 201 × 4 (711) strong-basicity styrene series I type anion exchange resin
Or D201 macroporous strong basic styrene series anion exchange resin etc.；The weak base type anion exchange resin can be 303 weak
Alkaline epoxy type anion exchange resin, D301 macroreticular weakly bases styrene series anion exchange resin or D311 macroporous acrylics
It is weak-base anion-exchange resin etc..The anion exchange resin that the present invention uses after use, can be by conventional method
It is regenerated, is further reduced costs.Regeneration method can refer to this field conventional method and carry out.
The specific route that the present invention prepares the method for SC 69124 is as follows：
Compared with prior art, using the method provided by the invention for preparing SC 69124, reaction step is simpler, instead
Yield is answered to effectively improve；Particularly, ring-closure reaction isoxazole yield greatly improves, and realizes one-step method and forms isozole ring；It adopts
With anion exchange resin catalyzed, ammonium chloride is simple as ammonia source sulfonamide reaction of formation processing, and yield is also improved.
Other features and advantages of the present invention will be described in detail in subsequent specific embodiment part.
Specific embodiment
With reference to specific embodiment, the present invention is further explained.But these embodiments be only limitted to illustrate the present invention without
It is the further restriction to protection scope of the present invention.
In the examples below, 3- (4- sulfonic groups phenyl) -4- phenyl -4- (1- pyrrolidinyls) -3- butene-2s -one refers to
Prepared by WO2005123701A1, purity 99.5%；D201 macroporous strong basic styrenes commercially available from anion exchange resin use
Series anion exchange resin.
Embodiment 1
The preparation of 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole
By 3- (4- sulfonic groups phenyl)-4- phenyl-4- (1- pyrrolidinyls)-3- butene-2 -one 37.1g (100mmol) with
Ammonium acetate 38g (500mmol) is added in the flask equipped with 65ml acetic acid, 95 DEG C of haptoreactions 0.5 hour, after reaction,
Dichloromethane dilutes, and saturated sodium bicarbonate adjusts pH to 7, organic phase concentration, washing, then ethyl alcohol recrystallization, dry 5- first
Base -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole 26.8g, yield 85.0%, purity 99.77%.
Embodiment 2
The preparation of 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole
By 3- (4- sulfonic groups phenyl)-4- phenyl-4- (1- pyrrolidinyls)-3- butene-2 -one 37.1g (100mmol) with
Ammonium acetate 30g (400mmol) is added in the flask equipped with 70ml acetic acid, 100 DEG C of haptoreactions 1 hour, after reaction, two
Chloromethanes dilutes, and saturated sodium bicarbonate adjusts pH to 7, organic phase concentration, washing, then ethyl alcohol recrystallization, and dry 5- methyl-
3- phenyl -4- (4- sulfonic groups phenyl) isoxazole 26.9g, yield 85.2%, purity 99.84%.
Embodiment 3
The preparation of 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole
By 3- (4- sulfonic groups phenyl)-4- phenyl-4- (1- pyrrolidinyls)-3- butene-2 -one 37.1g (100mmol) with
Ammonium acetate 30g (400mmol) is added in the flask equipped with 90ml acetic acid, 90 DEG C of haptoreactions 1.5 hours, after reaction,
Dichloromethane dilutes, and saturated sodium bicarbonate adjusts pH to 6, organic phase concentration, washing, then ethyl alcohol recrystallization, dry 5- first
Base -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole 26.8g, yield 84.9%, purity 99.72%.
Embodiment 4
The preparation of 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole
By 3- (4- sulfonic groups phenyl)-4- phenyl-4- (1- pyrrolidinyls)-3- butene-2 -one 37.1g (100mmol) with
Ammonium acetate 23g (300mmol) is added in the flask equipped with 100ml acetic acid, 90 DEG C of haptoreactions 2 hours, after reaction, two
Chloromethanes dilutes, and saturated sodium bicarbonate adjusts pH to 6, organic phase concentration, washing, then ethyl alcohol recrystallization, and dry 5- methyl-
3- phenyl -4- (4- sulfonic groups phenyl) isoxazole 26g, yield 82.5%, purity 99.65%.
Embodiment 5
The preparation of 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole
By 3- (4- sulfonic groups phenyl)-4- phenyl-4- (1- pyrrolidinyls)-3- butene-2 -one 37.1g (100mmol) with
Ammonium acetate 30.1g (400mmol) is added in the flask equipped with 60ml acetic acid, and 95 DEG C of haptoreactions 1.5 hours, reaction terminates
Afterwards, dichloromethane dilutes, and saturated sodium bicarbonate adjusts pH to 7, organic phase concentration, washing, then ethyl alcohol recrystallization, dry 5-
Methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole 25.6g, yield 81.3%, purity 99.60%.
Embodiment 6
The preparation of 5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazole
By 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) the isoxazole 3.2g's (10mmol) obtained equipped with embodiment 1
Anion exchange resin 0.6g (20%) is added in flask, temperature rises to 45 DEG C, and saturated ammonium chloride is added dropwise and (contains ammonium chloride
1.1g, 20mmol), after reaction, dichloromethane extraction is washed, and concentration, ethyl alcohol recrystallization obtains 5- methyl -3- phenyl -4-
(4- sulfoamidos phenyl) isoxazole 3g, yield 95.6%, purity 99.78%.
Embodiment 7
The preparation of 5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazole
By 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) the isoxazole 3.2g's (10mmol) obtained equipped with embodiment 1
Anion exchange resin 0.6g (20%) is added in flask, temperature rises to 40 DEG C, and saturated ammonium chloride 15.6g is added dropwise and (contains chlorination
Ammonium 1.6g, 30mmol), after reaction, dichloromethane extraction, wash, concentration, ethyl alcohol recrystallization obtain 5- methyl -3- phenyl -
4- (4- sulfoamidos phenyl) isoxazole 2.96g, yield 94.3%, purity 99.79%.
Embodiment 8
The preparation of 5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazole
By 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) the isoxazole 3.2g's (10mmol) obtained equipped with embodiment 1
Anion exchange resin 0.8g (25%) is added in flask, temperature rises to 35 DEG C, and saturated ammonium chloride 15.6g is added dropwise and (contains chlorination
Ammonium 1.1g, 20mmol), after reaction, dichloromethane extraction, wash, concentration, ethyl alcohol recrystallization obtain 5- methyl -3- phenyl -
4- (4- sulfoamidos phenyl) isoxazole 2.95g, yield 93.7%, purity 99.90%.
Embodiment 9
The preparation of 5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazole
By 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) the isoxazole 3.2g's (10mmol) obtained equipped with embodiment 1
Anion exchange resin 1.1g (35%) is added in flask, temperature rises to 45 DEG C, and saturated ammonium chloride 15.6g is added dropwise and (contains chlorination
Ammonium 2.7g, 50mmol), after reaction, dichloromethane extraction, wash, concentration, ethyl alcohol recrystallization obtain 5- methyl -3- phenyl -
4- (4- sulfoamidos phenyl) isoxazole 2.92g, yield 93.0%, purity 99.69%.
Embodiment 10
The preparation of 5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazole
By 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) the isoxazole 3.2g's (10mmol) obtained equipped with embodiment 1
Anion exchange resin 0.5g (15%) is added in flask, temperature rises to 40 DEG C, and saturated ammonium chloride 15.6g is added dropwise and (contains chlorination
Ammonium 2.1g, 40mmol), after reaction, dichloromethane extraction, wash, concentration, ethyl alcohol recrystallization obtain 5- methyl -3- phenyl -
4- (4- sulfoamidos phenyl) isoxazole 2.92g, yield 92.8%, purity 99.70%.
Embodiment 11
The preparation of SC 69124
By 5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazole 3.1g (10mmol) and triethylamine 3g
(30mmol) and propionic andydride 3.9g (30mmol), which are blended in 20 DEG C of dichloromethane, to react, and after reaction, is poured into water, dichloro
Methane extracts, concentration, ethyl alcohol dissolving, 5~10 DEG C of crystallizations, filtering, dry SC 69124 3.43g, yield 92.5%, purity
99.77%.
Comparative example 1
Method in WO2005123701A1 embodiments 1 prepares SC 69124, is as follows：
The addition of 22.3g 3- (4- sulfonic groups phenyl) -4- phenyl -4- (1- pyrrolidinyls) -3- butene-2s -one is contained
In the reaction bulb of 41.6g sodium acetate trihydrates, 43.5g water and 21.3g hydroxylamine hydrochlorides, 40 DEG C are heated to, is stirred 1 hour, concentration,
Hydroxy group isoxazole intermediate is obtained by filtration, is then added in 21.4g ethyl acetate, is heated to 70 DEG C, is slowly added into
11.3g trifluoroacetic acids, the reaction was continued 20 minutes, adds in 16.1g isopropanols to reaction solution and is cooled to 5 DEG C, crystallization filters, 80
DEG C it is dried to obtain 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole 12.7g, yield 70.6%, purity 99.10%.
Comparative example 2
Such as the method for preparing 5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazole in embodiment 6, institute's difference
, anion exchange resin is added without, obtains 5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazole 1.97g, yield
It is 62.8%, purity 99.02%.
The preferred embodiment of the present invention has been described above in detail, still, during present invention is not limited to the embodiments described above
Detail, within the scope of the technical concept of the present invention, a variety of simple variants can be carried out to technical scheme of the present invention, this
A little simple variants all belong to the scope of protection of the present invention.
It is further to note that specific technical features described in the above specific embodiments, in not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to it is various can
The combination of energy no longer separately illustrates.In addition, arbitrary group can also be carried out between a variety of different embodiments of the present invention
It closes, as long as its thought without prejudice to the present invention, it should also be regarded as the disclosure of the present invention.
Claims (4)
1. a kind of preparation method for the SC 69124 for being used to treat postoperative pain, which is characterized in that this method includes the following steps：
1）By 3- (4- sulfonic groups phenyl) -4- phenyl -4-（1- pyrrolidinyls）- 3- butene-2 -one exists in acetic acid with ammonium acetate
90 ~ 100 DEG C of progress haptoreactions, after reaction, dichloromethane dilution, saturated sodium bicarbonate adjusts pH to 6~7, organic phase
Concentration, washing, then ethyl alcohol recrystallization, dry 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole；
2）By step 1）Obtained 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazoles exist in anion exchange resin
5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazole is obtained by the reaction in lower and 35 ~ 45 DEG C of ammonium chloride；
3）Step 2）Obtained 5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazole in the presence of triethylamine with propionic acid
Anhydride reactant obtains SC 69124；
3- (4- sulfonic groups phenyl) -4- phenyl -4- (1- pyrrolidinyls) -3- butene-2s -one and the dosage mole of ammonium acetate, acetic acid
Than being 1：3~5：10~20；The molar ratio of the dosage of 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazoles and ammonium chloride is
1：2 ~ 5, the dosage of the anion exchange resin for 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) isoxazole weight 15 ~
35%。
2. preparation method according to claim 1, which is characterized in that 3- (4- sulfonic groups phenyl) -4- phenyl -4- (1- pyrroles
Cough up alkyl) -3- butene-2s -one and ammonium acetate, acetic acid dosage molar ratio be 1：4~5：12~15.
3. preparation method according to claim 1, which is characterized in that 5- methyl -3- phenyl -4- (4- sulfonic groups phenyl) is different
The molar ratio of the dosage of oxazole and ammonium chloride is 1：2 ~ 3, the dosage of the anion exchange resin is 5- methyl -3- phenyl -4-
The 20 ~ 25% of (4- sulfonic groups phenyl) isoxazole weight.
4. according to the preparation method described in any one in claim 1-3, which is characterized in that step 3）Detailed process packet
It includes：5- methyl -3- phenyl -4- (4- sulfoamidos phenyl) isoxazoles and triethylamine and propionic andydride are blended in 20 ~ 25 DEG C of dichloros
It reacts in methane, after reaction, is poured into water, dichloromethane extraction, concentration, ethyl alcohol dissolving, 5 ~ 10 DEG C of crystallizations, dry pa
Auspicious former times cloth.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005123701A1 (en) * | 2004-06-14 | 2005-12-29 | Pharmacia Corporation | Method for the preparation of diarylisoxazole sulfonamide compounds and intermediates |
| CN104447600A (en) * | 2013-09-22 | 2015-03-25 | 江苏奥赛康药业股份有限公司 | Preparation method of parecoxib sodium compound as well as intermediate impurity and application of parecoxib sodium compound |
-
2016
- 2016-05-25 CN CN201610353249.XA patent/CN106008388B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005123701A1 (en) * | 2004-06-14 | 2005-12-29 | Pharmacia Corporation | Method for the preparation of diarylisoxazole sulfonamide compounds and intermediates |
| CN104447600A (en) * | 2013-09-22 | 2015-03-25 | 江苏奥赛康药业股份有限公司 | Preparation method of parecoxib sodium compound as well as intermediate impurity and application of parecoxib sodium compound |
Non-Patent Citations (1)
| Title |
|---|
| 帕瑞昔布钠合成路线图解;王凯 等;《中国医药工业杂志》;20130831;第44卷(第8期);第836-838页 * |
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