IL139438A - Crystal form of n-(4-trifluoromethylphenyl)-4-methylisoxazole-4-carboxamide - Google Patents
Crystal form of n-(4-trifluoromethylphenyl)-4-methylisoxazole-4-carboxamideInfo
- Publication number
- IL139438A IL139438A IL13943898A IL13943898A IL139438A IL 139438 A IL139438 A IL 139438A IL 13943898 A IL13943898 A IL 13943898A IL 13943898 A IL13943898 A IL 13943898A IL 139438 A IL139438 A IL 139438A
- Authority
- IL
- Israel
- Prior art keywords
- modification
- compound
- formula
- organic solvent
- lines
- Prior art date
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 24
- 238000012986 modification Methods 0.000 claims abstract description 59
- 230000004048 modification Effects 0.000 claims abstract description 59
- 238000000034 method Methods 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 239000000203 mixture Substances 0.000 claims abstract description 18
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 238000005169 Debye-Scherrer Methods 0.000 claims abstract description 6
- 230000005540 biological transmission Effects 0.000 claims abstract description 6
- 239000007787 solid Substances 0.000 claims abstract description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000002425 crystallisation Methods 0.000 claims description 6
- 230000008025 crystallization Effects 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000011148 porous material Substances 0.000 claims 2
- 238000007865 diluting Methods 0.000 claims 1
- 239000000706 filtrate Substances 0.000 claims 1
- 238000010438 heat treatment Methods 0.000 claims 1
- 239000011874 heated mixture Substances 0.000 claims 1
- 239000002904 solvent Substances 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- VHOGYURTWQBHIL-UHFFFAOYSA-N leflunomide Chemical compound O1N=CC(C(=O)NC=2C=CC(=CC=2)C(F)(F)F)=C1C VHOGYURTWQBHIL-UHFFFAOYSA-N 0.000 description 6
- 238000010899 nucleation Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 4
- 229960000681 leflunomide Drugs 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000004566 IR spectroscopy Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- XTUSEBKMEQERQV-UHFFFAOYSA-N propan-2-ol;hydrate Chemical compound O.CC(C)O XTUSEBKMEQERQV-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- 239000000539 dimer Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002207 thermal evaporation Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
A process for the preparation of crystal Modification 1 of the compound of the formula which, in the transmission X-ray diffraction pattern obtained with a focusing Debye- Scherrer beam and Cu-Ka1-radiation, has lines at the following diffraction angles 2 theta (!): Lines of strong intensity: 16.70; 18.90; 23.00; 23.65; 29.05 Lines of medium intensity: 8.35; 12.65; 15.00; 15.30; 18.35; 21.25; 22.15; 24.10; 24.65; 25.45; 26.65; 27.40; 28.00; 28.30; wherein the compound of the formula I which is not present in Modification 1 or mixtures of Modification 1 and Modification 2 of the compound of the formula I which, in the transmission X-ray diffraction pattern obtained with a focusing Debye-Scherrer beam and Cu- Ka1-radiation, has lines at the following diffraction angles 2 theta (!): Lines of strong intensity: 10.65; 14.20; 14.80; 16.10; 21.70; 23.15; 24.40; 24.85; 25.50; 25.85; 26.90; 29.85 Lines of medium intensity: 7.40; 9.80; 13.10; 15.45; 16.80; 20.70; 21.45; 22.80; 23.85; 27.25; 28.95, is heated in solid form to a temperature of from 50!C to 130!C.
Description
CRYSTAL FORM OF N-(4-TRIFLUOROMETHYLPHENYL)-5-METHYLISOXAZOLE-4- CARBOXAMIDE Eitan, Pearl, Latzer & Cohen-Zedek P- 1832-IL1 Hoechst Marion Roussel Deutschland GmbH HMR 1997/L 208 Dr. TH/Ba The present patent application has been divided out from copending patent Application No. 125671 The invention relates to a process for the preparation of crystal Modification 1 the compound of the formula I which, in the transmission X-ray diffraction pattern obtained with a focusing Debye-Scherrer beam and Cu-Καΐ -radiation, has lines at the following diffraction angles 2 theta (°): Lines of strong intensity: 16.70; 18.90; 23.00; 23.65; 29.05 Lines of medium intensity: 8.35; 12.65; 15.00; 15.30; 18.35; 21.25; 22.15; 24.10; 24.65; 25.45; 26.65; 27.40; 28.00; 28.30; wherein the compound of the formula I which is not present in Modification 1 or mixtures of Modification 1 and Modification 2 of the compound of the formula I which, in the transmission X-ray diffraction pattern obtained with a focusing Debye-Scherrer beam and Cu-Κα,ι -radiation, has lines at the following diffraction angles 2 theta (°): Lines of strong intensity: 10.65; 14.20; 14.80; 16.10; 21.70; 23.15; 24.40; 24.85; 25.50; 25.85; 26.90; 29.85 Lines of medium intensity: 7.40; 9.80; 13.10; 15.45; 16.80; 20.70; 21.45; 22.80; 23.85; 27.25; 28.95. is heated in solid form to a temperature of from 50°C to 130°C.
The compound of the formula I is known per se and is also referred to as Leflunomide (HWA 486). It can be obtained in the manner described in US 4,284,786. However, the crystals prepared by recrystallization from, for example, toluene are obtained in crystal Modification 1. The X-ray diffraction pattern (Cu-K^ radiation) of Modification 1 is shown in Figure 2 and has characteristic lines at the following diffraction angles 2 theta (°): Lines of strong intensity: 16.70; 18.90; 23.00; 23.65; 29.05 Lines of medium intensity: 8.35; 12.65; 15.00; 15.30; 18.35; 21.25; 22.15; 24.10; 24.65; 25.45; 26.65; 27.40; 28.00; 28.30 The compound of the formula I crystallizes in Modification 1 in the space group P2-|/c with 4 molecules in the unit cell. The molecule is essentially planar. The angle between the planar groups of atoms is less than 2.4°. The molecules are arranged in stacks in the crystal. The molecules lie in stacks adjacent to one another and are arranged in an antiparallel manner. Very weak hydrogen bridge bonds link the dimers in the crystal (NH ... N: 3.1444 A). The C=0 group is not involved in any hydrogen bridge bonding.
The X-ray diffraction patterns furthermore permit the determination of the amount of Modification 2 in a mixture containing both modifications. The line at 2 theta = 8.35° of Modification 1 and the line at 2 theta = 16.1 ° of Modification 2 are suitable for the quantitative determination. If the ratio of the peak heights is calculated and is correlated with the content of the modification, a calibration line is obtained. The limit of detection of this method is about 0.3 % of Modification 2 in crystals containing Modification 1.
Modification 2 has better water solubility than Modification 1. At 37°C, 38 mg/l of Modification 2 can be dissolved whereas 25 mg/l of Modification 1 go into solution. Furthermore, Modification 2 is stable in the temperature range from -15°C to +40°C, preferably from 20°C to 40°C, and is not converted into Modification 1.
However, the invention also relates to novel processes for the preparation of the compound of the formula I in Modification 1. By means of the novel processes, it is also possible to convert mixtures containing Modifications 1 and 2 specifically into Modification 1. For this purpose, for example, crystals of Modification 2 or mixtures of Modifications 1 and 2 are dissolved in a solvent. Suitable solvents are, for example, water-miscible solvents, such as (C1-C4) alcohols, e.g. methanol, ethanol, propanol, isopropanol, butanol or isobutanol, as well as ketones, such as acetone or methyl ethyl ketone. Mixtures of organic solvents with water, for example of about 40 % to 90 % of isopropanol, have also proven useful. The dissolution process is preferably carried out at elevated temperature up to the boiling point of the respective solvent. The hot solution is kept at the boiling point for some time in order to ensure complete dissolution of the compound .of the formula I. The filtered solution is then cooled so slowly that only crystals of Modification 1 form. Cooling is preferably effected to final temperatures of 20°C to -10°C, in particular to temperatures of 10°C to -5°C, very particularly preferably to temperatures of from 10°C to 5°C. The crystals are separated off and washed with isopropanol and then with water. The substance is dried at elevated temperature, preferably at 60 °C under reduced pressure or at atmospheric pressure.
A preferred process comprises dissolving the compound I in an 80 % strength isopropanol at the boiling point of isopropanol and at atmospheric pressure or under reduced pressure and then cooling the hot solution so slowly that the crystallization takes place at temperatures of more than 40°C, preferably from 40°C to 85°C, particularly preferably from 45°C to 80°C, in particular from 50°C to 70°C. The precipitated crystals are then washed several times with isopropanol and are dried under reduced pressure. The crystallization can be carried out without seeding with crystals of Modification 1 or preferably in the presence of crystals of Modification 1 , which are introduced by seeding into the solution containing the compound of the formula I. Seeding may possibly be carried out several times at different temperatures. The amount of the seed material depends on the amount of the solution and can be readily determined by a person skilled in the art.
A particularly preferred process for the preparation of the compound of the formula I in Modification 1 comprises The complete conversion of Modification 1 to Modification 2 is dependent on the temperature and, as a rule, takes from 36 hours to 65 hours, preferably from 48 hours to 60 hours, at a temperature of 20°C. The reaction is monitored by X-ray diffraction of IR spectroscopy by means of samples taken during the treatment.
A further process for the preparation of Modification 2 of the compound of the formula I comprises dissolving Modification 1 or mixtures of Modifications 1 and 2 in a solvent and then cooling the solution abruptly to temperatures of from about -5°C to -25°C. Suitable solvents are, for example, water-miscible solvents such as (C1-C4) alcohols, as well as ketones, such as acetone or methyl ethyl ketone, or other solvents, such as ethyl acetate, toluene or dichloromethane. The dissolution process takes place at room temperature of from 20°C to 25°C or at elevated temperatures up to the boiling point of the solvent under atmospheric pressure or under superatmospheric or reduced pressure. The solution obtained is, if required, filtered in order to separate off undissolved components or crystals from Leflunomide. The filtered solution is then cooled so rapidly that only crystals of Modification 2 form. An adequate cooling process comprises, for example, introducing the filtered solution into a vessel which has been cooled to -15°C or spraying filtered solution into a space cooled to -10°C or cooling the solution under vacuum condensation conditions. The preferred process comprises introducing the compound of the formula I into methanol and carrying out the dissolution process at the boiling point of methanol at atmospheric pressure or reduced pressure, then filtering the hot solution and transferring the filtered solution to a vessel which has been cooled to -15°C, the transfer being effected so slowly that the temperature of the crystal suspension obtained does not increase to more than -10°C. The precipitated crystals are then washed several times with methanol and are dried under reduced pressure. The crystallization can be carried out without seeding with crystals of Modification 2 or preferably by seeding with crystals of Modification 2. The seeding is effected in the cooled vessel. The amount of seed material depends on the amount of the solution and can be easily determined by a person skilled in the art. The abovementioned processes are also suitable for converting mixtures containing Modifications 1 and 2 into an essentially pure Modification 2 of the compound of the formula I.
The complete conversion of Modification 2 into Modification 1 is dependent on the temperature and, as a rule, takes from 20 hours to 28 hours, preferably 24 hours, at a temperature of 50°C. The reaction is monitored by X-ray diffraction or IR spectroscopy by means of samples taken during the treatment.
Passages which are not in the ambit of the claims do not belong to the invention. The scope of protection is as defined in the claims, and as stipulated in the Patent Law (1967).
Example 1 Preparation of Modification 1 Water-moist crude Leflunomide is first dissolved in isopropanol/water (corresponding to 16 kg of crude, dry Leflunomide in 28 I of isopropanol plus the amount of water which, together with the water content of the moist product, gives a total amount of water of 9 I).
The mixture is then heated to 78°C to 82°C, stirred at this temperature for 25 minutes (min) and then filtered through a pressure funnel into a vessel also already heated to the same temperature. The pressure filter is rinsed with an amount of isopropanol which, together with isopropanol used (iPrOH), gives an iPrOH/water ratio of 4:1 (in this case 4 I). Thereafter, water also preheated to 78°C to 82°C is added (32 I, gives iPrOH/water = 0.8:1 ). The solution already becomes cloudy and is then cooled to about 65°C in 20 min, kept at this temperature for about 40 min, then cooled to about 40°C in 70 min and stirred for a further 20 min. The product is isolated by centrifuging.
Table 1 shows the results of 4 batches.
Table 1 : * The determination was carried out by X-ray powder diffractometry; the proportion of Modification 2 was always below the limit of detection, which was about;0.4 %. n.d. means not determined
Claims (11)
1. 1 A process for the preparation of crystal Modification 1 of the compound of the formula I which, in the transmission X-ray diffraction pattern obtained with a focusing Debye-Scherrer beam and Cu-Καΐ -radiation, has lines at the following diffraction angles 2 theta (°): Lines of strong intensity: 16.70; 8.90; 23.00; 23.65; 29.05 Lines of medium intensity: 8.35, 12.65; 15.00; 15.30; 18.35; 21.25; 22.15; 24.10; 24.65; 25.45; 26.65; 27.40; 28.00; 28.30; wherein the compound of the formula I which is not present in Modification 1 or mixtures of Modification 1 and Modification 2 of the compound of the formula I which, in the transmission X-ray diffraction pattern obtained with a focusing Debye-Scherrer beam and Cu-Καΐ -radiation, has lines at the following diffraction angles 2 theta (°): Lines of strong intensity: 10.65; 14.20; 14.80; 16.10; 21.70; 23.15; 24.40; 24.85; 25.50; 25.85; 26.90; 29.85 Lines of medium intensity: 7.40; 9.80; 13.10; 15.45; 16.80; 20.70; 21.45; 22.80; 23.85; 27.25; 28.95. is heated in solid form to a temperature of from 50°C to 130°C.
2. The process for the preparation of crystal Modification 1 of the compound of the formula I as claimed in claim 1 , wherein the compound of the formula I which is not present in Modification 1 or mixtures of Modifications 1 and 2 is heated in suspension to a temperature of more than 40°C, in particular from 41 °C to 100°C, preferably from 50°C to 70°C.
3. The process for the preparation of crystal Modification 1 of the compound of the formula I as claimed in claim 1 , wherein the compound of the formula I which is not present in Modification 1 or mixtures containing Modifications 1 and 2 is dissolved in an organic solvent or mixtures of organic solvents and is crystallized at temperatures of more than 40°C, preferably from 41 °C to 80°C, in particular from 50°C to 70°C.
4. The process as claimed in claim 3, comprising transferring the compound of the formula I which is not present in Modification 1 or mixtures of Modification 1 and other crystal forms of the compound of the formula I into an organic solvent or into mixtures of organic solvents and water, heating the mixture obtained to a temperature of from 1 °C to the boiling point of the organic solvent, diluting the resulting solution with water or distilling off the organic solvent so that the organic solvent and the water are present in a ratio of from 4:1 to 0.3:1 and carrying out the crystallization at temperatures above 40°C.
5. The process as claimed in claim 4, wherein the solution obtained is filtered after processing step b).
6. The process as claimed in one or more of claims 3 to 5, wherein the organic solvent used is methanol, ethanol, propanol, isopropanol, butanol, isobutanol, acetone, methyl ethyl ketone or a mixture thereof.
7. The process as claimed in one or more of claims 4 to 6, wherein the mixture of organic solvent and water according to process step b) is heated to a temperature of from 40°C to 85°C.
8. The process as claimed in one or more of claims 4 to 6, wherein the ratio of organic solvent to water in process step a) is from 1 :1 to 8:1 , preferably from 2:1 to 6:1 , in particular from 3:1 to 5:1.
9. The process as claimed in one or more of claims 5 to 8, wherein the heated mixture is filtered through a filter of from 0.1 pm to 200 μπη pore diameter.
10. The process as claimed in one or more of claims 4 to 9, wherein the ratio of organic solvent to water in process step c) is from 2:1 to 0.6:1 , preferably from 1.6:1 to 0.8:1.
11. The process as claimed in one or more of claims 3 to 11 , wherein the temperature is reduced from 83°C to 85°C to slightly above 40°C in the crystallization. The process as claimed in claim 4, wherein the organic solvent is isopropanol, the temperature during dissolution of the compound of the formula I is 85°C, a filter of 1 μηη pore diameter is used, the ratio of isopropanol to water in the filtrate is from 1.6:1 to 0.8:1 and the crystallization takes place on cooling from 83°C to about 41 °C. A process according to any of claims 1 to 12 substantially as described hereinabove. For the Applicant,
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19734438A DE19734438A1 (en) | 1997-08-08 | 1997-08-08 | New crystal modification 2 of leflunomid has better water solubility than modification 1 and is stable over wide temperature range |
| DE1997156093 DE19756093A1 (en) | 1997-12-17 | 1997-12-17 | New crystal modification 2 of leflunomid |
| IL12567198A IL125671A (en) | 1997-08-08 | 1998-08-05 | Crystal form of n-(4-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IL139438A true IL139438A (en) | 2001-12-23 |
Family
ID=27217628
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL13943898A IL139438A (en) | 1997-08-08 | 1998-08-05 | Crystal form of n-(4-trifluoromethylphenyl)-4-methylisoxazole-4-carboxamide |
| IL13943800A IL139438A0 (en) | 1997-08-08 | 2000-11-02 | Crystal form of n- (4-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL13943800A IL139438A0 (en) | 1997-08-08 | 2000-11-02 | Crystal form of n- (4-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide |
Country Status (1)
| Country | Link |
|---|---|
| IL (2) | IL139438A (en) |
-
1998
- 1998-08-05 IL IL13943898A patent/IL139438A/en not_active IP Right Cessation
-
2000
- 2000-11-02 IL IL13943800A patent/IL139438A0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL139438A0 (en) | 2001-11-25 |
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