CN108586371B - Preparation method of parecoxib sodium crystal form - Google Patents
Preparation method of parecoxib sodium crystal form Download PDFInfo
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- CN108586371B CN108586371B CN201810801663.1A CN201810801663A CN108586371B CN 108586371 B CN108586371 B CN 108586371B CN 201810801663 A CN201810801663 A CN 201810801663A CN 108586371 B CN108586371 B CN 108586371B
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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
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to the field of pharmaceutical chemistry, and particularly discloses a preparation method of parecoxib sodium crystal form B, which comprises the steps of dissolving a parecoxib sodium crude product in a ketone solvent, heating and stirring; cooling, stirring and crystallizing; drying to constant weight to obtain the parecoxib sodium B crystal form. The preparation method has the advantages of good reproducibility, simplicity, controllability, high yield, high purity and high crystallinity, and is suitable for industrial production.
Description
Technical Field
The invention relates to a novel preparation method of parecoxib sodium crystal form.
Background
Parecoxib sodium belongs to the class of cyclooxygenase-2 (COX-2) inhibitors, developed by the company Perey, USA, and approved in the European Union 3/22.2002 for the short-term treatment of postoperative pain, and is chemically designated as N- [ [4- (5-methyl-3-phenyl-4-isoxazolyl) phenyl ] sulfonyl ] propionamide sodium salt.
Parecoxib sodium was used as the first COX-2 inhibitor that was injected intravenously and intramuscularly. The product does not inhibit COX activity, enters the body and is rapidly hydrolyzed into valdecoxib by liver enzyme, and the valdecoxib is a high-selectivity COX-2 inhibitor and mainly blocks the synthesis and release of prostaglandin by inhibiting the COX activity, so that the effects of resisting inflammation, relieving pain and relieving fever are exerted. The inhibition effect of the valdecoxib on COX-2 is 2.8 ten thousand times of that of COX-1, so that when the therapeutic concentration is reached, the valdecoxib can selectively inhibit the COX-2, and the inhibition effect on the COX-1 is not obvious, so that the effects of analgesia and anti-inflammation are exerted, and meanwhile, the gastrointestinal mucosa, the blood platelet and the renal function are not influenced. Clinical studies have demonstrated that parecoxib sodium is safe and effective for the treatment of postoperative pain, and also reduces the need for opioid analgesics in patients undergoing surgery.
US 563272, US5859257 and US5932598 describe the preparation of substituted isoxazole compounds and substituted isoxazol-4-yl benzenesulfonamide compounds for the treatment of inflammation, but only disclose melting points of 271.5-272.7 ℃, without characterizing the crystalline form of parecoxib sodium.
WO2004/087682A1 describes six crystal forms I, II, III, IV, V and VI and discloses X-ray powder diffraction data and maps of the six crystal forms.
CN104418818A describes an anhydrous parecoxib sodium crystal form and discloses X-ray powder diffraction data and a spectrum.
CN104418819 describes a parecoxib sodium hemihydrate crystal form and discloses X-ray powder diffraction data and a spectrum thereof.
CN105616362B describes parecoxib sodium in parecoxib sodium composition as C crystal form, and the crystal form of parecoxib sodium used is Cu-KαX-ray powder diffraction measurement of the radiationThe firing angle 2 theta has obvious peaks at 6.1912, 8.3750, 10.9145, 12.1060, 14.5531, 17.0537, 18.0569, 20.5835, 22.7235, 23.9818, 25.5648 and 29.9764.
CN200710084348 describes a crystal form of parecoxib sodium, discloses detailed X-ray powder diffraction, DSC and TGA data and a spectrum of A, B, E three crystal forms, describes hygroscopicity conditions of the three crystal forms, and discloses stability and hygroscopicity data of the three crystal forms, wherein the crystal form B and the crystal form E have obvious advantages in the hygroscopicity aspect compared with the crystal form A, and are more beneficial to storage of bulk drugs. The patent also discloses a preparation method of three crystal forms, and for the crystal form B, the crystal form B can be prepared by two methods: firstly, after water is absorbed by the crystal form A to obtain hydrate, the crystal form A is dried by a drying agent to remove water to obtain the crystal form B, and the method has the defects of long time, high temperature for removing crystal water and no contribution to industrial production; and secondly, the parecoxib sodium forms an ethanolate firstly, then is added into a heptane suspension containing the crystal seeds of the B crystal form, and then is refluxed for 4 hours to obtain the parecoxib sodium crystal suspension.
Therefore, the development of the preparation process of the parecoxib sodium B crystal form with high crystallinity, which has good reproducibility, simple operation, high product yield and high purity and is suitable for industrial production, has important significance.
Disclosure of Invention
The invention develops a preparation method of the parecoxib sodium B crystal form with high crystallinity, and the method has the advantages of good reproducibility, simple and convenient operation, high product yield and high purity, and is suitable for industrial production. The invention aims to provide a preparation method of a parecoxib sodium B crystal form with high crystallinity, which is suitable for industrial production.
In an embodiment of the present invention, the present invention provides a process for preparing parecoxib sodium form B comprising the steps of:
a) dissolving the parecoxib sodium crude product in a ketone solvent, heating to a certain temperature, and stirring;
b) cooling to a certain temperature, stirring and crystallizing;
c) drying at 10-75 ℃ to constant weight to obtain the parecoxib sodium B crystal form.
Among them, the crude parecoxib sodium can be prepared according to methods known in the art, such as CN 1308315C.
In a preferred embodiment of the present invention, the present invention provides a method for preparing parecoxib sodium crystal form B, wherein, in step (a), parecoxib sodium is dissolved in a ketone solvent. Wherein, the ketone solvent is acetone, methyl butanone, methyl isobutyl ketone or cyclohexanone, and acetone is preferred.
In a preferred embodiment of the present invention, the present invention provides a preparation method of parecoxib sodium crystal form B, wherein, in step (a), the certain temperature is 5 ℃ to 65 ℃, preferably 55 ℃.
In a preferred embodiment of the present invention, the preparation method of parecoxib sodium crystal form B is provided, wherein, in the step (B), the certain temperature is 5 ℃ to 35 ℃, preferably room temperature.
In a preferred embodiment of the present invention, the process for preparing parecoxib sodium crystal form B is provided, wherein, in the step (c), the drying temperature is 10 ℃ to 75 ℃, preferably 60 ℃.
The technical scheme of the invention is further explained and illustrated by researching the parecoxib sodium B crystal form provided by the invention as follows:
1. powder X-ray diffraction
Taking the parecoxib sodium B crystal form prepared by the invention, and using Cu-KαX-ray powder diffraction measured by ray is characterized by having obvious peaks at 4.0, 8.1, 12.1, 12.6, 14.7, 16.7, 17.4, 20.0, 20.7, 22.8, 23.8, 24.7, 25.6, 26.8, 27.9, 29.0, 29.9, 31.8, 32.4, 33.2, 34.4, 35.1, 36.2, 36.7, 37.6 and 38.9 in terms of 2 theta +/-0.2 degrees. See the attached figure 1 of the specification.
2. Differential thermal analysis (DSC) and thermogravimetric analysis (TGA)
The parecoxib sodium B crystal form prepared by the method is respectively measured on a Mettler DSC1 differential scanner and a TGA2 thermogravimetric analyzer, and the result shows that the weight loss of a sample is 0.1% in a region of 23.7-100 ℃; from DSC curve analysis, an endothermic peak at 202.06 ℃ should be a crystal transformation peak of the B crystal form, and an exothermic peak at 276.83 ℃ should be a melting peak thereof. See the description attached to fig. 2 and 3.
3. Determination of purity
Through HPLC purity determination, the purity of the parecoxib sodium B crystal form prepared by the invention is 100%.
The preparation method of parecoxib sodium B crystal form provided by the invention has obvious advantages, pure B crystal form can be obtained by refining parecoxib sodium crude product in one step, the operability is strong, the operation is simple, the yield and purity are high, kilogram-level batch verification shows that the parecoxib sodium B crystal form can be produced in a technological mode, and the major defects of crystal transformation, seed crystal induction, complex operation and the like in the prior art are overcome.
Drawings
FIG. 1 is an X-ray powder diffraction diagram of parecoxib sodium B crystal form prepared by the invention;
FIG. 2 is a DSC of parecoxib sodium B crystal form prepared by the invention;
fig. 3 is a TGA diagram of parecoxib sodium B crystal form prepared by the invention.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following examples. It should be properly understood that: the methods of the embodiments of the present invention are given by way of illustration only and not by way of limitation, and therefore, simple modifications of the present invention in the light of the methods of the present invention are within the scope of the invention as claimed.
When the parecoxib sodium B crystal form is prepared, the parecoxib sodium crude product used can be prepared by referring to a method in a patent CN 1308315C.
The room temperature mentioned in the embodiment of the invention is 10-25 ℃.
In the invention, the related powder X-ray diffraction test instrument is as follows: DX-2700 powder diffractometer (DANDONGHAO source); and (3) testing conditions are as follows: cu KαThe radiation, 40kV, 30mA,
3°-40°。
in the present invention, the thermal differential analysis (DSC) and thermogravimetric analysis (TGA) test instruments involved are: a mettler DSC1 differential scanner and TGA2 thermogravimetric analyzer; the test conditions were:
| TGA | DSC | |
| sample plate | Aluminum oxide crucible | Aluminum plate and gland |
| Temperature range/. degree.C | 35-250℃ | 35-250℃ |
| Scanning Rate/(. degree. C./min) | 10 | 10 |
| Protective gas | Nitrogen gas | Nitrogen gas |
Example 1
Adding 4kg of parecoxib sodium crude product and 19kg of acetone into a 50L glass reaction kettle, stirring, heating to 55 ℃, keeping the temperature and stirring for 3 hours, cooling to room temperature, carrying out suction filtration, leaching a filter cake with 1.6kg of acetone, carrying out suction drying, carrying out reduced pressure drying at room temperature for 8 hours, and carrying out reduced pressure drying at 60 ℃ for 8 hours to obtain 3.75kg of parecoxib sodium as white powder with the yield of 93.8%. The purity of the relevant substances is 100%.
XRD and DSC/TGA showed form B. As shown in the drawings of the specification.
1H-NMR(D2O，δTMS0)：7.64ppm(2H，tt，JH-H＝8.4，2.0)，7.29 ppm(1H，ttt，JH-H＝7.6，1.6)，7.17ppm(2H，tsd，JH-H＝8.0，7.6)， 7.10ppm(2H，tt，JH-H＝8.0，1.6)，7.02ppm(2H，tt，JH-H＝8.4，2.0)， 2.23ppm(3H，s)，2.07ppm(2H，q，JH-H＝7.6)，0.89ppm(3H，t， JH-H＝7.6)；
13C-NMR(D2O，δTMS0)：184.8，168.4，161.2，141.1，133.2， 130.0，129.7，128.7，128.2，127.5，126.7，114.5，32.0，10.7，9.7。 IR(cm-1)：3119，2978，2875，2931，1618，1499，1463，1388， 1139，1243，1089，1034，846，619。ESI：[M-Na]-369.12. The Na content was 5.88% (theoretical 5.86%). XRD and DSC/TGA showed form B.
Example 2
5g of parecoxib sodium crude product and 23.7ml of 2-butanone are added into a 100ml three-necked bottle, mechanically stirred and heated to 55 ℃. The system is fully dissolved, and is stirred for 3 hours under the condition of heat preservation. Cooling to room temperature, stirring for 4 hours, carrying out suction filtration, leaching a filter cake by using 2ml of 2-butanone, carrying out suction drying, carrying out reduced pressure drying for 10 hours at room temperature, then heating to 60 ℃, carrying out reduced pressure drying for 48 hours, and obtaining 2.48g of parecoxib sodium as white powder with the yield of 49.6%. The purity of related substances is 98.33%, the maximum single impurity is 0.52%, and the total impurity is 1.67%.
The results of nuclear magnetic and mass spectrometric identification were consistent with example 1 except for a small amount of 2-butanone in the nuclear magnetic spectrum, with XRD and DSC/TGA showing form B.
Example 3
50g of the crude parecoxib sodium and 237ml of acetone are added into a 1L three-necked flask and mechanically stirred for 3 hours at 25 ℃. And (3) carrying out suction filtration, leaching a filter cake by using 20ml of acetone, carrying out suction drying, drying for 8 hours at room temperature, heating to 60 ℃, and drying for 24 hours under reduced pressure to obtain white powder 46.3 g of parecoxib sodium with the yield of 92.6%. The purity of related substances is 99.33%, the maximum single impurity is 0.25%, and the total impurity is 0.67%.
The results of nuclear magnetic and mass spectrometric identification are consistent with example 1, with XRD and DSC/TGA showing form B.
Example 4
50g of the crude parecoxib sodium and 237ml of acetone are added into a 1L three-necked flask and mechanically stirred for 3 hours at 5 ℃. And (3) carrying out suction filtration, leaching a filter cake by using 20ml of acetone, carrying out suction drying, drying at room temperature for 8 hours, heating to 60 ℃, and drying under reduced pressure for 18 hours to obtain white powder 46.55g of parecoxib sodium with the yield of 93.1%. The purity of related substances is 99.33%, the maximum single impurity is 0.25%, and the total impurity is 0.67%.
The results of nuclear magnetic and mass spectrometric identification are consistent with example 1, with XRD and DSC/TGA showing form B.
Example 5
5g of the crude parecoxib sodium and 23.7ml of acetone are added into a 100ml three-necked flask and mechanically stirred for 3 hours at 65 ℃. Cooling to room temperature, carrying out suction filtration, leaching a filter cake by using 2ml of acetone, carrying out suction drying, carrying out vacuum drying at room temperature for 8 hours, and carrying out vacuum drying at 60 ℃ for 18 hours to obtain white powder 4.51g of parecoxib sodium, wherein the yield is 90.1%. The purity of related substances is 99.61%, the maximum single impurity is 0.11%, and the total impurity is 0.39%.
The results of nuclear magnetic and mass spectrometric identification are consistent with example 1, with XRD and DSC/TGA showing form B.
Example 6
5g of the crude parecoxib sodium and 23.7ml of methyl isobutyl ketone are added into a 100ml three-necked flask and mechanically stirred for 3 hours at 55 ℃. Cooling to 5 ℃, carrying out suction filtration, leaching a filter cake by using 2ml of methyl isobutyl ketone, carrying out suction drying, carrying out reduced pressure drying at room temperature for 12 hours, and carrying out reduced pressure drying at 60 ℃ for 36 hours to obtain white powder 4.73g of parecoxib sodium, wherein the yield is 94.6%. The purity of related substances is 99.77%, the maximum single impurity is 0.09%, and the total impurity is 0.23%.
The results of nuclear magnetic and mass spectrometric identification are consistent with example 1, with XRD and DSC/TGA showing form B.
Example 7
5g of the crude parecoxib sodium product and 23.7ml of cyclohexanone are added into a 100ml three-necked flask and mechanically stirred for 3 hours at 55 ℃. Cooling to 35 ℃, carrying out suction filtration, leaching a filter cake by using 2ml of cyclohexanone, carrying out suction drying, carrying out vacuum drying at room temperature for 12 hours, and carrying out vacuum drying at 60 ℃ for 56 hours to obtain white powder of 4.61g of parecoxib sodium, wherein the yield is 92.2%. The purity of related substances is 99.91 percent, the maximum single impurity is 0.05 percent, and the total impurity is 0.09 percent.
The results of nuclear magnetic and mass spectrometric identification are consistent with example 1, with XRD and DSC/TGA showing form B.
Example 8
5g of the crude parecoxib sodium and 23.7ml of acetone are added into a 100ml three-necked flask and mechanically stirred for 3 hours at 55 ℃. Cooling to room temperature, carrying out suction filtration, leaching a filter cake by using 2ml of acetone, carrying out suction drying, carrying out vacuum drying at room temperature for 8 hours, and carrying out vacuum drying at 75 ℃ for 18 hours to obtain white powder 4.69g of parecoxib sodium, wherein the yield is 93.8%. The purity of related substances is 99.95%, the maximum single impurity is 0.03%, and the total impurity is 0.05%.
The results of nuclear magnetic and mass spectrometric identification are consistent with example 1, with XRD and DSC/TGA showing form B.
Comparative example
The parecoxib sodium B crystal form is prepared by referring to a preparation method of patent CN200710084348 in example 2.
Adding 5g of parecoxib sodium into 50mL of ethanol, heating and refluxing, cooling to room temperature, adding into 225mL of heptane containing 0.5g of crystal seeds of crystal form B, stirring for 1 hour, filtering, transferring into heptane suspension containing 0.5g of crystal seeds of crystal form B, heating and refluxing for 4 hours under vigorous stirring, filtering, and vacuum-drying filter cake at 40 ℃ for 12 hours to obtain 3.18g of white solid (minus the quantity of the crystal seeds), wherein the yield is 63.6%. The chromatogram is consistent with the B crystal form chromatogram disclosed in CN200710084348 by XRD and DSC detection.
The purity, yield and related substances of the parecoxib sodium B crystal form prepared in the embodiment 1 of the invention and the parecoxib sodium B crystal form prepared according to the preparation method disclosed in the CN200710084348 patent (embodiment 9) are compared, and the results are as follows:
| index (I) | CN200710084348 patent method (comparative sample) | Example 1 sample |
| Purity of | 98.2％ | 100％ |
| Yield of | 63.6％ | 93.8％ |
| Related substances | Maximum single hetero 1.05%. | Not detected out |
Comparative test of influence factors
The influence factor test is carried out on the sample prepared in the embodiment 1 of the invention and the sample prepared in the comparative example, and the result shows that the product of the invention has no obvious change in the data of various aspects such as related substances, moisture, content and the like, while the change of the comparative example is very obvious, which shows that the product prepared by the invention has better quality than the prior art.
Therefore, as can be seen from the above table, compared with the existing preparation process for preparing parecoxib sodium B crystal, the preparation reaction condition is mild, the operation is simple, the process reproducibility is good, the obtained product has high yield and purity, the product quality is superior to that of the prior art, the seed crystal is not required to be added, the whole operation time is shortened, and the preparation method is more suitable for industrial mass production.
It will be apparent to those skilled in the art that various modifications and variations can be made in the compounds, compositions, and methods of making the same of the present application without departing from the spirit or scope of the application, and it is intended that the scope of the present application cover all modifications and variations of this application provided they come within the scope of the appended claims and their equivalents.
Claims (1)
1. A preparation method of parecoxib sodium B crystal form is characterized by comprising the following steps:
adding 4kg of parecoxib sodium crude product and 19kg of acetone into a 50L glass reaction kettle, stirring, heating to 55 ℃, keeping the temperature and stirring for 3 hours, cooling to room temperature, carrying out suction filtration, leaching a filter cake with 1.6kg of acetone, carrying out suction drying, carrying out reduced pressure drying at room temperature for 8 hours, and carrying out reduced pressure drying at 60 ℃ for 8 hours to obtain white powder 3.75kg of parecoxib sodium, wherein the yield is 93.8%, and the purity of related substances is 100%.
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