Method for preparing 2-chloro-n-(1-cyanocyclopropyl)-5-[2'-methyl-5'-(pentafluoroethyl)-4'-(trifluoromethyl)-2'h-1,3'-bipyrazol-4-yl]benzamide

Abstract

The present invention relates to a method for preparing 2-chloro-N-(1-cyanocyclopropyl)-5-[2′-methyl-5′-(pentafluoroethyl)-4′-(trifluoromethyl)-2′H-1,3′-bipyrazol-4-yl]benzamide, i.e. the compound of the formula (I) and to a method for purifying the compound of the formula I. The present invention additionally relates to new crystal forms of the compound of the formula I.

##STR00001##

Claims

1. Method for preparing the compound of the formula (I) ##STR00018## by reacting compounds of the formula (VI) ##STR00019## where A is a boron-containing substituent selected from: a boronic acid radical of the formula ##STR00020## a trifluoroborate of the formula
—BF.sub.3M, where M is an alkali metal salt, preferably sodium or potassium, and a boronic ester of the formula ##STR00021## where R.sup.1 and R.sup.2 are independently C.sub.1-C.sub.6 alkyl or C.sub.3-C.sub.6 cycloalkyl, or R.sup.1 and R.sup.2 together form a C.sub.1-C.sub.6 alkylene group optionally substituted by one or more C.sub.1-C.sub.4 alkyl groups, with compounds of the formula (VII) ##STR00022## where X is a reactive group selected from: bromine, iodine and the radical —O—SO.sub.2—Y, where Y is C.sub.1-C.sub.8 perfluoroalkyl, in the presence of a base and a catalyst.

2. Method according to claim 1, wherein R.sup.1 and R.sup.2 together form a C.sub.1-C.sub.6 alkylene group preferably substituted by one or more C.sub.1-C.sub.2 alkyl groups.

3. Method according to claim 1, wherein X is bromine or iodine.

4. Method according to claim 1, wherein compound VI is used in amounts of 0.7 to 1.3 equivalents based on the structural unit of the formula VII.

5. Method according to claim 1, wherein the solvent used is dimethylformamide, dimethylacetamide, N-methylpyrrolidone, open-chain or cyclic ethers, or a C.sub.1-C.sub.6 alkyl-derived alcohol, preferably a C.sub.1-C.sub.4 alkyl-derived alcohol.

6. Method according to claim 1, wherein the catalyst comprises a palladium-containing component.

7. Method according to claim 6, wherein the catalyst additionally comprises a phosphorus-containing component.

8. Method according to claim 1, wherein the bases used are alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydrogen carbonates, alkaline earth metal hydrogen carbonates, alkali metal phosphates, alkaline earth metal phosphates, alkali metal fluorides, or mixtures thereof.

9. Method according to claim 8, wherein the base is used in an amount of 1 to 10 equivalents based on the starting material of the formula VI, preferably in an amount of 2 to 5 equivalents, more preferably in an amount of 2.5 to 3.5 equivalents.

10. Method for purifying the compound of the formula I, wherein this is crystallized from an aromatic hydrocarbon.

11. Method according to claim 10, wherein the aromatic hydrocarbon is selected from toluene, ethylbenzene, ortho-xylene, meta-xylene, para-xylene.

12. Method according to claim 1, wherein a method of purification is executed subsequently to the reaction.

13. Compound of the formula (I), in modification I.

Description

EXAMPLES

[0110] A: Method Examples

[0111] The examples that follow elucidate the method of the invention using the structural unit of the formula VI (where —A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl). The synthesis affords a substantially better yield than the known synthesis based on the known structural unit of the formula II.

Example 1

[0112] 30.0 g of water, 120.0 g of isopropanol and 9.2 g of 2′-methyl-5′-(pentafluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4′-(trifluoromethyl)-2′H-1,3′-bipyrazole (compound of the formula VI where —A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were mixed in a reaction vessel. To this was added 6.0 g of 2-chloro-N-(1-cyanocyclopropyl)-5-bromobenzamide (compound of the formula VII where —X is bromine) and 5.0 g of sodium hydrogen carbonate. Finally, 1.16 g of tetrakis(triphenylphosphine)palladium was added and the mixture was heated under reflux for 5 h. The solids present in the reaction mixture were filtered off by suction and washed with 30 g of isopropanol. The filtrate was concentrated slightly to approx. 75% and the distillation residue metered into 200 ml of water. The precipitated solid was filtered off by suction, washed with water and dried under reduced pressure. This afforded 11.3 g of material having a content of 93.2 area %. Without taking into account the content, the calculated yield was—due to the content of secondary components—102.2% of theory; when taking into account the content, it was 95.3% of theory.

Example 2

[0113] 30.0 g of water, 120.0 g of isopropanol and 9.2 g of 2′-methyl-5′-(pentafluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4′-(trifluoromethyl)-2′H-1,3′-bipyrazole (compound of the formula VI where —A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were mixed in a reaction vessel. To this was added 6.9 g of 2-chloro-N-(1-cyanocyclopropyl)-5-iodobenzamide (compound of the formula VII where—X is iodine) and 5.0 g of sodium hydrogen carbonate. Finally, 1.16 g of tetrakis(triphenylphosphine)palladium was added and the mixture was heated under reflux for 5 h. The solids present in the reaction mixture were filtered off by suction and washed with 30 g of isopropanol. The filtrate was concentrated slightly to approx. 75% and the distillation residue metered into 200 ml of water. The precipitated solid was filtered off by suction, washed with water and dried under reduced pressure. This afforded 10.8 g of material having a content of 97.3 area %. Without taking into account the content, the calculated yield was—due to the content of secondary components—97.7% of theory; when taking into account the content, it was 95.1% of theory.

Example 3

[0114] 150 g of water, 600 g of isopropanol and 46.0 g of 2′-methyl-5′-(pentafluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4′-(trifluoromethyl)-2′H-1,3′-bipyrazole (compound of the formula VI where —A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were mixed in a reaction vessel. To this was added 34.7 g of 2-chloro-N-(1-cyanocyclopropyl)-5-iodobenzamide (compound of the formula VII where —X is iodine) and 25.20 g of sodium hydrogen carbonate. Finally, 1.44 g of tetrakis(triphenylphosphine)palladium was added and the mixture was heated under reflux for 3.5 h. The solid present in the reaction mixture was filtered off by suction and washed with 100 g of isopropanol. The filtrate was concentrated slightly to approx. 50% and the distillation residue cooled to RT. 1000 ml of water was metered into the cooled residue. The precipitated solid was filtered off by suction, washed with water and dried under reduced pressure. This afforded 54.6 g of material having a content of 98.7 area %. Without taking into account the content, the calculated yield was—due to the content of secondary components—98.8% of theory; when taking into account the content, it was 97.5% of theory.

Example 4

[0115] 10.6 g of the product obtained in the previous example was dissolved hot in 94.4 g of toluene in a reaction vessel. The solution was cooled while stirring and the solid filtered off by suction, washed with toluene and dried under reduced pressure. This afforded 8.9 g of material in (84.0% based on starting material used), which had a content of 99.4 area % and a palladium content of under 100 ppm.

Example 5

[0116] 37.5 g of water, 150 g of isopropanol and 11.5 g of 2′-methyl-5′-(pentafluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4′-(trifluoromethyl)-2′H-1,3′-bipyrazole (compound of the formula VI where —A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were mixed in a reaction vessel. To this was added 0.16 g of triphenylphosphine, 8.7 g of 2-chloro-N-(1-cyanocyclopropyl)-5-iodobenzamide (compound of the formula VII where —X is iodine) and 6.3 g of sodium hydrogen carbonate. Finally, 0.2 g of tetrakis(triphenylphosphine)palladium was added and the mixture was heated under reflux for 5 h. The mixture was cooled and the solid present was removed by filtration and washed with a little isopropanol. 250 ml of water was metered into the pooled filtrate and the precipitated solid was filtered off and washed with water. The damp product was mixed with approx. 44 g of toluene and stirred at 70-75° C. for 1 h. The suspension was cooled to RT and the solid filtered off by suction, washed with toluene and dried. This afforded 12.3 g (89.0% of theory) of a slightly yellowish solid having a content of >99 area % (area percent from HPLC chromatogram). The palladium content was under 50 ppm.

Example 6

[0117] In a reaction vessel, 11.1 g of the product obtained in the previous example was mixed with 198 g of toluene and 0.5 g of activated carbon and dissolved hot under reflux. The activated carbon was filtered off hot and the filtrate obtained was concentrated to approx. 40%. This was cooled while stirring and the solid obtained was filtered off, washed with toluene and dried under reduced pressure. This afforded 10.0 g (90.1% based on starting material used) of a colourless, finely crystalline powder having a content of >99.8 area % (area percent from HPLC chromatogram). None of the secondary components were present in a content above 0.10 area %. The palladium content was under 10 ppm.

[0118] The product prepared in example 6 was investigated by TGA. This showed no loss of mass up to 150° C.

[0119] The product prepared in example 6 was analysed by X-ray powder diffractometry (measurement conditions as specified hereinbelow). The product had crystallized in modification I, which is described in detail hereinbelow. The diffractogram of the product from example 6 is shown in FIG. 1.

Example 7

[0120] 37.5 g of water, 150 g of isopropanol and 11.5 g of 2′-methyl-5′-(pentafluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4′-(trifluoromethyl)-2′H-1,3′-bipyrazole (compound of the formula VI where —A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) were mixed in a reaction vessel. To this was added 0.16 g of triphenylphosphine, 8.7 g of 2-chloro-N-(1-cyanocyclopropyl)-5-iodobenzamide (compound of the formula VII where —X is iodine) and 6.3 g of sodium hydrogen carbonate. Finally, 0.2 g of tetrakis(triphenylphosphine)palladium was added and the mixture was heated under reflux for 5 h. The mixture was cooled and the solid present was removed by filtration and washed with 1.8 g of isopropanol. 250 ml of water was metered into the pooled filtrate and the precipitated solid was filtered off, washed with water and dried under reduced pressure. A 2.0 g reserve sample of the water-damp product was taken and dried. This afforded 1.1 g of material (8.0% of theory). The rest of the water-damp product was suspended in 300 g of toluene and the water was removed by azeotropic distillation. Activated carbon was then added and the mixture was stirred under reflux and filtered hot. Approx. 60% of the solvent was distilled from the clear filtrate and the residue left behind was cooled. The precipitated solid in the mixture was filtered off by suction, washed with toluene and dried under reduced pressure. This afforded 10.8 g of a crystalline solid (78.2% of theory). The analytical content of was 99.6 area % (area percent from HPLC chromatogram). The largest secondary component was present in 0.11%. The palladium content was less than 100 ppm.

Example 8

[0121] A reaction vessel was charged with 25.1 g of a crude product prepared in analogous manner to example 5. To this was added 195.5 g of toluene, 80.0 g of acetone and 1.26 g of activated carbon. The crude product was dissolved hot under reflux. The activated carbon was filtered off hot and the filtrate obtained was concentrated by distillation at standard pressure to a residue of approx. 167 g. This was cooled (<approx. 54° C.) while stirring until crystallization was largely complete. The suspension was heated to an internal temperature of approx. 95° C. and stirred briefly at this temperature without allowing complete dissolution to occur. The resulting hot suspension was cooled slowly to 5° C., stirred further at this temperature and the solid obtained was filtered off, washed with toluene and dried under reduced pressure. This afforded 23.7 g (94.4% based on starting material used) of a colourless, finely crystalline powder having a content of >99.8 area % (area percent from HPLC chromatogram). None of the secondary components were present in a content above 0.10 area %. The palladium content was under 1 ppm.

Example 9

[0122] Preparation of the structural unit of the formula C (corresponding to the structural unit of the formula VI where —A is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl).

##STR00017##

[0123] 2.6 kg of structural unit B and 22.88 litres of acetonitrile were mixed at 22° C. in a reaction vessel. To this was added 2.78 kg of ground potassium carbonate, 3.64 kg of the structural unit of the formula A and 1.91 kg of acetonitrile. The reaction mixture was stirred under reflux for 7 hours and then cooled to RT. The solid in the reaction mixture was filtered off and washed with 4.03 kg of acetonitrile. 23.75 kg of solvent was distilled from the pooled filtrate. The distillation residue was mixed with 7.53 kg of isopropanol, after which 47.85 kg of water was metered in at approx. 22° C., the mixture was cooled to 3-5° C. and the precipitated solid was filtered off. The solid was washed with water and dried under reduced pressure. This afforded 4.99 kg of the product of the formula C as a light yellow solid. This was equivalent to 85.2% of theory. The analytical content was 99.6% ESTD (HPLC evaluation with external standard).

[0124] B. Crystal Forms of the Compound of the Formula (I)

[0125] B.1. Preparation of Modification I

[0126] Approx. 400 mg of the compound of the formula (I) was in each case dissolved hot in the specified volume of one of the solvents specified below and filtered hot: [0127] 80 ml of diisopropyl ether+5 ml of ethanol [0128] 40 ml of toluene [0129] 40 ml of tetrahydrofuran [0130] 40 ml of acetone [0131] 40 ml of ethyl acetate [0132] 40 ml of acetonitrile [0133] 40 ml of 2-propanol [0134] 40 ml of ethanol [0135] 40 ml of methanol [0136] 40 ml of 1,4-dioxane [0137] 40 ml of DMSO

[0138] The solutions were allowed to stand at room temperature until dryness. Modification I was characterized by X-ray diffractometry.

[0139] B.2. Preparation of Modification II

[0140] Approx. 400 mg of the compound of the formula (I) was dissolved hot in 4 ml of solketal. The solutions were allowed to stand at room temperature until dryness. Modification II was characterized by X-ray diffractometry.

[0141] B.3. Preparation of the Ethanol-Water Inclusion Complex

[0142] Approx. 400 mg of the compound of the formula (I) was dissolved hot in 100 ml of EtOH/H.sub.2O 1:1 and filtered hot. The solution was allowed to stand until dryness. The ethanol-water inclusion complex was characterized by X-ray diffractometry.

[0143] B.4. Characterization of the Crystal Forms

TABLE-US-00001 TABLE 1 XRPD data for crystal forms of the compound of the formula (I) Reflection positions (signal maxima) [°2 theta] Ethanol-water Mod. I Mod. II inclusion complex 5.6 5.5 5.6 8.1 7.8 8.1 8.7 9.5 8.7 9.6 11.0 9.6 10.4 12.3 9.7 11.2 14.1 10.4 12.2 14.6 10.5 12.7 16.1 11.2 14.1 16.6 12.4 14.5 17.5 12.7 15.2 18.4 14.1 15.9 19.6 14.3 16.8 21.8 14.4 17.7 22.5 15.2 18.2 23.5 15.9 18.6 23.8 16.8 18.8 24.8 17.6 19.1 25.1 18.0 19.3 26.4 18.2 19.7 27.8 18.4 20.0 28.4 18.6 20.8 28.9 18.8 21.1 30.0 19.1 21.7 30.8 19.3 22.0 31.9 19.7 22.5 33.2 20.0 22.8 35.9 20.8 23.0 21.1 23.5 21.5 23.8 21.6 24.3 22.0 24.6 22.5 24.9 22.8 25.2 23.0 25.4 23.5 25.5 23.8 26.2 24.3 26.4 24.6 26.5 24.9 27.1 25.3 27.7 25.5 29.2 26.2 29.8 26.4 30.3 26.6 31.0 26.8 31.4 27.0 32.7 27.6 35.2 28.0 28.8 29.1 29.5 29.8 30.9 31.0 31.8 32.5 32.8 35.3 35.7 36.2 36.5 36.8

[0144] Measurement conditions:

TABLE-US-00002 Anode material Cu K-Alpha1 [Å]  1.54060 Generator 40 mA, 40 kV Sample rotation Yes Scan-axis Gonio Start position [°2theta] 2.0066 End position [°2theta] 37.9906 

[0145] FIG. 1: X-ray powder diffractogram of modification I

[0146] FIG. 2: X-ray powder diffractogram of modification II

[0147] FIG. 3: X-ray powder diffractogram of the ethanol-water inclusion complex

[0148] FIG. 4: X-ray powder diffractogram of the amorphous form

TABLE-US-00003 TABLE 2 IR spectroscopic data of the crystal forms of the compound of the formula (I) Bands [signal maxima in cm.sup.−1] Ethanol-water Mod. I Mod. II inclusion complex Amorphous form 3249 3274 3252 3420 3120 3123 3119 3278 3019 3019 3097 3211 1660 1662 1730 3186 1599 1593 1661 2995 1562 1559 1600 2948 1509 1540 1585 2915 1474 1506 1561 1617 1430 1472 1509 1604 1399 1429 1473 1576 1375 1395 1429 1545 1341 1374 1394 1519 1308 1339 1374 1501 1276 1303 1343 1463 1255 1251 1307 1445 1218 1217 1275 1419 1180 1178 1255 1382 1145 1142 1218 1347 1099 1097 1205 1304 1060 1059 1187 1284 1053 1025 1137 1240 1027 991 1099 1226 993 966 1080 1200 968 941 1060 1180 943 897 1052 1169 899 866 1027 1143 864 837 992 1128 839 819 968 1089 821 802 943 1069 804 782 899 1047 184 769 865 1036 772 745 839 997 760 731 821 940 745 719 803 923 731 695 784 874 698 667 771 854 667 660 745 808 660 635 731 788 636 626 720 753 626 591 697 744 592 570 681 726 572 564 667 721 564 557 659 685 557 636 659 626 609 604 580 592 563 573 564 557

[0149] Measurement conditions:

[0150] ATR IR spectra were recorded at room temperature in a Tensor 37 FT-IR spectrophotometer from Bruker using an ATR unit and without further sample preparation. The resolution was 4 cm.sup.−1.

[0151] The spectra are shown in the figures:

[0152] FIG. 5: IR spectrum of modification I

[0153] FIG. 6: IR spectrum of modification II

[0154] FIG. 7: IR spectrum of the ethanol-water inclusion complex

[0155] FIG. 8: IR spectrum of the amorphous phase