CN104592140B - A kind of synthetic method of SC 69124 sodium impurity - Google Patents
A kind of synthetic method of SC 69124 sodium impurity Download PDFInfo
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- CN104592140B CN104592140B CN201510002045.7A CN201510002045A CN104592140B CN 104592140 B CN104592140 B CN 104592140B CN 201510002045 A CN201510002045 A CN 201510002045A CN 104592140 B CN104592140 B CN 104592140B
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- 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
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Abstract
The invention discloses the synthetic method of a kind of SC 69124 sodium impurity N [3 (5 methyl 3 phenyl 4 isoxazolyl) phenyl] sulfonic acid, belong to technical field of pharmaceutical chemistry, with 5 methyl 3, 4 diphenyl isoxazoles are raw material, sulfonated reaction and hydrolysis obtain SC 69124 sodium impurity, the SC 69124 sodium impurity of synthesis of high purity can be as the contamination levels product in the analysis of Parecoxib Sodium finished product detection, thus promote Parecoxib Sodium finished product detection analysis to the being accurately positioned property of impurity and qualitative, be conducive to strengthening the control to this impurity, and then improve Parecoxib Sodium end product quality, the method raw material that the present invention provides is cheap and easily-available, simple to operate, products obtained therefrom yield 95% ± 5%, HPLC purity >=98%.
Description
Technical field
The invention belongs to technical field of pharmaceutical chemistry, be specifically related to a kind of Parecoxib Sodium impurity B N-[3-(5-methyl-3-phenyl
-4-isoxazolyl) phenyl] synthetic method of sulfonic acid.
Background technology
Inflammatory reaction after the noxious stimulations such as operation, wound may result in the release of inflammatory mediator and algogenic substance, and they are except directly
Outside induced pain, also can distend the blood vessels, tissue edema, make effector ceptor susceptibility increase, the threshold of pain reduces, thus cause around
Property hyperalgia.Selective COX-2 inhibitor can effectively suppress periphery COX-2 to express, and reduces periphery prostaglandin synthesis, from
And play analgesic and anti-inflammatory effects, and maincenter COX-2 can be suppressed to express simultaneously, suppression maincenter prostaglandin synthesizes and inhibition of pain is super quick,
Play periphery, maincenter dual analgesia advantage.
Parecoxib Sodium chemistry is entitled: N-[[4-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonyl] propionamide sodium salt,
Parecoxib Sodium is a kind of highly selective inhibition of COX-2, can be used for the short of postoperative pain, has preferably
Water-soluble physicochemical property.
Impurity B N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid is that in Parecoxib Sodium building-up process, sulfonation occurs
The isomers producing when meta hydrolyzes further, may remain in Parecoxib Sodium finished product, affect product quality,
Its structural formula is as shown in (I).It through retrieval, is not yet related to the document report of this impurity synthesis, therefore it provides a kind of handkerchief is auspicious
The synthetic method of former times cloth sodium impurity B has important practical significance for the preparation of contamination levels product.
Content of the invention
It is an object of the invention to overcome the shortcoming of prior art, a kind of Parecoxib Sodium impurity B N-[3-(5-methyl-3-is provided
Phenyl-4-isoxazolyl) phenyl] synthetic method of sulfonic acid, this synthetic method have simple to operate, raw material is cheap and easily-available, yield is high,
The high advantage of purity.
The purpose of the present invention is achieved through the following technical solutions: the synthetic method of a kind of Parecoxib Sodium impurity B, described impurity
B is N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid, and synthetic route is as follows:
Concrete preparation method comprises the following steps:
S1. sulfonating reaction: by 5-methyl-3,4-diphenyl isoxazole, zinc chloride, chlorosulfonic acid are added in reaction bulb, 50～70 DEG C
Reaction 1.5～2.5h, reactant liquor is post-treated obtains N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride；
S2. hydrolysis: above-mentioned gained N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride is added reaction bulb
In, adding water and acetonitrile, 85～95 DEG C of back flow reaction 12～20h, reduced pressure concentration obtains Parecoxib Sodium impurity B.
Further, 5-methyl-3 described in step S1, the weight ratio of 4-diphenyl isoxazole, zinc chloride and chlorosulfonic acid is
1:0.5～1:1～5.
Further, N-described in step S2 [3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride, water and acetonitrile
Weight than for 1:20～40:20～40.
Further, described in step S1, post-processing approach is: drop in frozen water by reactant liquor after completion of the reaction, uses filter cake mistake
After filter, filter cake is dissolved in ethyl acetate, adds petroleum ether to carry out a crystallization, secondary crystallization after crystal reduced pressure concentration, gained two
Secondary crystal, at 50～60 DEG C of drying 6～10h, obtains N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride.
Further, the pressure of reduced pressure concentration described in step S2 is≤-0.07MPa.
The invention have the advantages that the present invention with 5-methyl-3,4-diphenyl isoxazole is raw material, and sulfonated reaction and hydrolysis are anti-
Should obtain Parecoxib Sodium impurity B, the Parecoxib Sodium impurity B of synthesis of high purity can be analyzed as Parecoxib Sodium finished product detection
In impurity B standard items, thus promote Parecoxib Sodium finished product detection analysis to the being accurately positioned property of impurity B and qualitative, favorably
In the control to this impurity for the reinforcement, and then improving Parecoxib Sodium end product quality, the method raw material that the present invention provides is cheap and easily-available,
Simple to operate, products obtained therefrom yield 95% ± 5%, HPLC purity >=98%.
Brief description
Fig. 1 is Parecoxib Sodium impurity B purity HPLC collection of illustrative plates；
Fig. 2 is Parecoxib Sodium impurity B mass spectrogram；
Fig. 3 is Parecoxib Sodium impurity B hydrogen nuclear magnetic resonance spectrogram.
Detailed description of the invention
Below in conjunction with the accompanying drawings and embodiment the present invention will be further described, protection scope of the present invention is not limited to the following stated.
Embodiment 1: the synthesis of Parecoxib Sodium impurity B N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid
By 10g 5-methyl-3,4-diphenyl isoxazole, 5g zinc chloride, 10g chlorosulfonic acid be added in reaction bulb, 50 DEG C of reaction 1.5h,
After completion of the reaction, dropping in 100g frozen water, filtering, filter cake is dissolved in 10g ethyl acetate, adds 50g petroleum ether crystallization body,
Filtering, filtrate reduced in volume is to doing, and concentration finishes, and adds 200g petroleum ether, filters, 50 DEG C of constant pressure and dry about 6h, obtains N-[3-(5-
Methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride 5.5g, yield 38.8%.
By above-mentioned for 5g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride, add in reaction bulb, add 100g
Water, 100g acetonitrile, 85 DEG C of back flow reaction 12h, it is decompressed to-0.08MPa and is concentrated to give white solid 4.5g, be N-[3-(5-
Methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid, yield 95.3%.
Parecoxib Sodium impurity B HPLC collection of illustrative plates is as it is shown in figure 1, purity is 98.5%.
Parecoxib Sodium impurity B mass spectrogram is as in figure 2 it is shown, MS:316 (M+1)；
Parecoxib Sodium impurity B proton nmr spectra as it is shown on figure 3, show in H spectrum chemical shift be 4.825 have one smooth
Peak, this peak is active hydrogen；Chemical shift (7.009-7.604) totally 9 hydrogen are benzene ring hydrogen, chemical shift (2.384-2.464)
Unimodal, totally three hydrogen, this hydrogen is methyl hydrogen.Testing result is consistent with Parecoxib Sodium impurity B structure.
Embodiment 2: the synthesis of Parecoxib Sodium impurity B N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid
By 10g 5-methyl-3,4-diphenyl isoxazole, 10g zinc chloride, 50g chlorosulfonic acid be added in reaction bulb, 70 DEG C of reactions
2.5h, after completion of the reaction, drops in 100g frozen water, filters, and filter cake is dissolved in 10g ethyl acetate, adds the analysis of 50g petroleum ether
Crystal, filters, and filtrate reduced in volume is to doing, and concentration finishes, and adds 200g petroleum ether, filters, 60 DEG C of constant pressure and dry about 10h,
Obtain N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride 5.2g, yield 36.7%.
By above-mentioned for 5g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride, add in reaction bulb, add 200g
Water, 200g acetonitrile, 95 DEG C of back flow reaction 20h, it is decompressed to-0.07MPa and is concentrated to give white solid 4.3g, be N-[3-(5-
Methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid.Yield 91.0%, purity is 99.1%.
Embodiment 3: the synthesis of Parecoxib Sodium impurity B N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid
By 10g 5-methyl-3,4-diphenyl isoxazole, 7g zinc chloride, 30g chlorosulfonic acid be added in reaction bulb, 60 DEG C of reaction 1.8h,
After completion of the reaction, dropping in 100g frozen water, filtering, filter cake is dissolved in 10g ethyl acetate, adds 50g petroleum ether crystallization body,
Filtering, filtrate reduced in volume is to doing, and concentration finishes, and adds 200g petroleum ether, filters, 52 DEG C of constant pressure and dry about 7h, obtains N-[3-(5-
Methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride 6.1g, yield 43.0%.
By above-mentioned for 5.5g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride, add in reaction bulb, add 160g
Water, 160g acetonitrile, 90 DEG C of back flow reaction 16h, it is decompressed to-0.09MPa and is concentrated to give white solid 4.8g, be N-[3-(5-
Methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid.Yield 92.4%, purity is 98.3%.
Embodiment 4: the synthesis of Parecoxib Sodium impurity B N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid
By 10g 5-methyl-3,4-diphenyl isoxazole, 9g zinc chloride, 42g chlorosulfonic acid be added in reaction bulb, 65 DEG C of reaction 2h,
After completion of the reaction, dropping in 100g frozen water, filtering, filter cake is dissolved in 10g ethyl acetate, adds 50g petroleum ether crystallization body,
Filtering, filtrate reduced in volume is to doing, and concentration finishes, and adds 200g petroleum ether, filters, 58 DEG C of constant pressure and dry about 9h, obtains N-[3-(5-
Methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride 5.4g, yield 38.1%.
By above-mentioned for 5g N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride, add in reaction bulb, add 180g
Water, 160g acetonitrile, 92 DEG C of back flow reaction 18h, it is decompressed to-0.10MPa and is concentrated to give white solid 4.6g, be N-[3-(5-
Methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid.Yield 97.4%, purity is 98.9%.
Claims (1)
1. a synthetic method for SC 69124 sodium impurity, described impurity is N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl]
Sulfonic acid, it is characterised in that synthetic route is as follows:
Concrete preparation method comprises the following steps:
S1. sulfonating reaction: by 5-methyl-3,4-diphenyl isoxazole, zinc chloride, chlorosulfonic acid are added in reaction bulb, 50～70 DEG C
Reaction 1.5～2.5h, reactant liquor is post-treated obtains N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride；
S2. hydrolysis: above-mentioned gained N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride is added reaction bulb
In, adding water and acetonitrile, 85～95 DEG C of back flow reaction 12～20h, reduced pressure concentration obtains SC 69124 sodium impurity；
Wherein, 5-methyl-3 described in step S1, the weight of 4-diphenyl isoxazole, zinc chloride and chlorosulfonic acid than for 1:0.5～1:1～
5；
The weight of N-described in step S2 [3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride, water and acetonitrile than for 1:20～
40:20～40；
Described in step S1, post-processing approach is: drop to reactant liquor in frozen water after completion of the reaction, is dissolved in filter cake with after cake filtration
In ethyl acetate, adding petroleum ether to carry out a crystallization, secondary crystallization after crystal reduced pressure concentration, gained secondary crystal is at 50～60 DEG C
It is dried 6～10h, obtain N-[3-(5-methyl-3-phenyl-4-isoxazolyl) phenyl] sulfonic acid chloride；
Pressure≤-the 0.07MPa of reduced pressure concentration described in step S2.
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| CN104965041B (en) * | 2015-06-11 | 2016-06-29 | 成都克莱蒙医药科技有限公司 | A kind of high-efficiency liquid chromatography method for detecting of Parecoxib Sodium isomer |
| CN112028849A (en) * | 2019-06-03 | 2020-12-04 | 鲁南制药集团股份有限公司 | Preparation method of parecoxib sodium impurity compound |
| CN112390764A (en) * | 2019-08-19 | 2021-02-23 | 鲁南制药集团股份有限公司 | Parecoxib sodium impurity compound |
| 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 |
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Denomination of invention: A synthetic method of parecoxib sodium impurity Effective date of registration: 20201029 Granted publication date: 20161005 Pledgee: Zhejiang Mintai commercial bank Limited by Share Ltd. Chengdu Gaoxin Branch Pledgor: CHENGDU CLIMB PHARMACEUTICAL TECHNOLOGY Co.,Ltd. Registration number: Y2020510000099 |