Catalytic Hydrogenation Process for Preparing Pyrazoles

Abstract

The present invention relates to a catalytic process for preparing pyrazoles comprising the step of cyclizing hydrazone substituted ?,?-unsaturated carbonyl compounds by reacting them with hydrogen in a reaction mixture comprising as components (a) a hydrogenation catalyst, (b) an acid selected from Br?nsted acids, ammonium salts of Br?nsted acids, and Lewis acids, (c) a protic solvent, and optionally (d) an aprotic solvent.

Claims

1-22. (canceled)

23. A process for preparing a pyrazole compound of formula V, or a salt, stereoisomer, tautomer or N-oxide thereof ##STR00027## comprising the step of cyclizing a hydrazone substituted ?,?-unsaturated carbonyl compound of formula IV ##STR00028## by reacting it with hydrogen, wherein the compound of formula IV is provided in a reaction mixture comprising as components: (a) a hydrogenation catalyst; (b) an acid selected from Br?nsted acids, ammonium salts of Br?nsted acids, and Lewis acids; (c) a protic solvent; and optionally (d) an aprotic solvent; and wherein R.sup.1 is C(O)OR.sup.c, wherein R.sup.c is C.sub.1-C.sub.4-alkyl or benzyl; R.sup.2 is CH.sub.3, or fluoromethyl; R.sup.3 is H; R.sup.4 is selected from C.sub.1-C.sub.4-alkyl, which group is unsubstituted, or partially halogenated, and R.sup.5 is selected from C.sub.1-C.sub.4-alkyl.

24. The process of claim 23, wherein R.sup.2 is CH.sub.3; and R.sup.5 is CH.sub.3.

25. The process of claim 23, wherein R.sup.1 is C(O)OCH.sub.2CH.sub.3; R.sup.2 is CH.sub.3; R.sup.4 is CH(CH.sub.3).sub.2; and R.sup.5 is CH.sub.3.

26. The process of claim 23, wherein the hydrogenation catalyst comprises palladium or platinum.

27. The process of claim 26, wherein the hydrogenation catalyst is Pt/C.

28. The process of claim 23, wherein the hydrogenation catalyst is present in the reaction mixture in an amount of at least 0.05 mol % based on the molar amount of the compound of formula IV.

29. The process of claim 23, wherein the acid is selected from the group consisting of H.sub.2SO.sub.4, methylsulfonic acid, trifluoroacetic acid, trichloroacetic acid, H.sub.3PO.sub.4, and AlCl.sub.3.

30. The process of claim 23, wherein the protic solvent is selected from the group consisting of C.sub.1-C.sub.4-alkanols, C.sub.2-C.sub.4-alkandiols, water, acetic acid, formic acid, and mixtures thereof.

31. The process of claim 23, wherein the protic solvent is selected from the group consisting of methanol and ethanol, and mixtures thereof.

32. The process of claim 23, wherein the aprotic solvent is selected from the group consisting of aromatic solvents, alkane solvents, ether solvents, ester solvents, and mixtures thereof.

33. The process according of claim 23, wherein the compound of formula IV is present in the reaction mixture in an amount of at most 50 wt.-%, based on the total weight of the reaction mixture.

34. The process of claim 23, wherein the reaction with hydrogen is performed at a temperature of from 0? C. to 40? C.

35. The process of claim 23, wherein hydrogen is provided with a pressure of from 5 to 80 bar.

36. The process of claim 23, wherein a solution of compound of formula IV, wherein the solvent is selected from the group consisting of C.sub.1-C.sub.4-alkanols, C.sub.2-C.sub.4-alkandiols, water, acetic acid, formic acid, and mixtures thereof, is dosed to the reaction mixture comprising components a), b), c), and optionally d) wherein component a) is Pt/C, b) is H.sub.2SO.sub.4, c) is MeOH, and d) is, if present, toluene, MTBE, or EtOAc.

37. The process of claim 23, wherein the process further comprises the step of preparing the hydrazone substituted ?,?-unsaturated carbonyl compound of formula IV ##STR00029## by reacting an ?,?-unsaturated carbonyl compound of formula III ##STR00030## with a hydrazone compound of formula II ##STR00031## wherein X is halogen, OH, C.sub.1-C.sub.10-alkoxy, C.sub.3-C.sub.10-cycloalkoxy, C.sub.1-C.sub.10-alkyl-S(O).sub.2O, C.sub.1-C.sub.10-haloalkyl-S(O).sub.2O, phenyl-S(O).sub.2O, tolyl-S(O).sub.2O, (C.sub.1-C.sub.10-alkyloxy).sub.2P(O)O, C.sub.1-C.sub.10-alkylthio, C.sub.3-C.sub.10-cycloalkylthio, C.sub.1-C.sub.10-alkyl-C(O)S, NH.sub.2, C.sub.1-C.sub.10-alkylamino, C.sub.1-C.sub.10-dialkylamino, morpholino, N-methylpiperazino, or aza-C.sub.3-C.sub.10-cycloalkyl; and R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are defined as in claim 20.

38. The process of claim 37, wherein X is OCH.sub.2CH.sub.3.

39. The process of claim 37, wherein the step of preparing the pyrazole compound of formula V and the step of preparing the compound of formula IV are performed in a one-pot procedure, wherein the compound of formula IV is subjected to the cyclization reaction without previous purification.

40. The process of claim 37, wherein (i) if the step of preparing the compound of formula IV is performed in a protic solvent or in a solvent mixture comprising a protic solvent and an aprotic solvent, the step of preparing the pyrazole compound of formula V is performed in the same solvent or solvent mixture as used in the step of preparing the compound of formula IV; or (ii) if the step of preparing the compound of formula IV is performed in an aprotic solvent, the aprotic solvent is replaced by a protic solvent, or a protic solvent is added before the step of preparing the pyrazole compound of formula V.

41. The process of claim 23, wherein the compound of formula V is a compound of formula Va or Vb ##STR00032## and wherein the process further comprises the step of converting the compound of formula Va or Vb into a compound of formula Vc ##STR00033## wherein R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as defined in claim 23; and wherein R.sup.c in formula Va is C.sub.1-C.sub.4-alkyl or benzyl; and wherein the compound of formula Vc is converted into a compound of formula VI ##STR00034## wherein X.sup.1 is a leaving group selected from halogen, N.sub.3, p-nitrophenoxy, and pentafluorophenoxy, and wherein R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are as defined in claim 20.

42. The process of claim 41, wherein X.sup.1 is chlorine.

43. The process of claim 41, wherein the process further comprises the step of converting the compound of formula VI into a compound of formula VIII ##STR00035## by reacting the compound of formula VI with a compound of formula VII ##STR00036## wherein R.sup.2 is CH.sub.3, or fluoromethyl; R.sup.3 is H; R.sup.4 is selected from C.sub.1-C.sub.4-alkyl, which group is unsubstituted, or partially halogenated, and R.sup.5 is selected from C.sub.1-C.sub.4-alkyl, and wherein U is N or CH; R.sup.P1, R.sup.P2, and R.sup.P3 are H; and R.sup.1N is H, C.sub.1-C.sub.2-alkyl, or C.sub.1-C.sub.2-alkoxy-C.sub.1-C.sub.2-alkyl.

44. A composition comprising (1) a compound of formula IV ##STR00037## wherein R.sup.1 is C(O)OCH.sub.2CH.sub.3; R.sup.2 is CH.sub.3; R.sup.3 is H; R.sup.4 is CH(CH.sub.3).sub.2; and R.sup.5 is CH.sub.3; and (2) at least one component selected from (a) a hydrogenation catalyst comprising palladium or platinum, (b) an acid selected from Br?nsted acids, ammonium salts of Br?nsted acids, and Lewis acids, and (c) methanol or ethanol.

45. The process of claim 23, wherein a solution of compound of formula IV, wherein the solvent is selected from the group consisting of methanol and ethanol, and mixtures thereof, is dosed to the reaction mixture comprising components a), b), c), and optionally d) wherein component a) is Pt/C, b) is H.sub.2SO.sub.4, c) is MeOH, and d) is, if present, toluene, MTBE, or EtOAc.

Description

EXAMPLES

[0585] I Characterization/Detection

[0586] The detection of the compounds can be done by coupled High Performance Liquid Chromatography (HPLC). The following method has been used:

[0587] Agilent XDB-C18, 4.6?50 mm, 1.8 ?m; mobile phase: A: water+(0.1% H.sub.3PO.sub.4); B: acetonitrile (MeCN)+(0.1% H.sub.3PO.sub.4); 0-10 min: 5% A, 95% B; 10-10.1 min: 95% A, 5% B; flow: 1.2 mL/min in 10.1 min at 60? C.; UV detector 210 nm.

[0588] II Screenings

[0589] The following reaction is performed in all screening experiments.

##STR00026##

[0590] All screening experiments were run in a hastelloy pressure vessel.

[0591] Analytics were run using HPLC and all results are presented in area % (=proportion of the area of a specific HPLC peak to the total area of all peaks in percent). Conversion was measured by determining the area % of the starting material, compound IV.1. Furthermore, the area % values of both, the pyrazole V.1 and the corresponding NH-pyrazole V.sup.H.1, are in each case determined. The retention times are as follows:

TABLE-US-00005 IV.1 (1,4-adduct): 6.3 min V.1 (pyrazole): V.sup.H.1 (NH-pyrazole): 6.1 min 3.2 min

Example 1: Screening Experiments

[0592] Compound IV.1, ethyl 2-[[2-(2,2-dimethyl-1-methyl-ethylidene)hydrazino]methylene]-3-oxo-butanoate (5 g, 0.02 mol), was dissolved in 95 g EtOH. To the solution was first added Pt/C (0.7 g) followed by acid (H.sub.2SO.sub.4, 0.5 equiv, 0.9 g). The reaction vessel was pressurized with hydrogen to 10 bar and heated to 30? C. The reaction mixture was stirred for 2 hours. Following the reaction, a sample was taken and the conversion was measured by HPLC. Furthermore, the area % values of the pyrazole V.1, ethyl 1-(2,2-dimethyl-1-methyl-ethyl)-5-methyl-pyrazole-4-carboxylate, and the NH-pyrazole V0.1 were determined. The results are provided in entry 1 of Table 1A.

[0593] Further acids as listed in Table 1A below were tested analogously or according to the modified reaction conditions provided in the respective entry of Table 1A.

TABLE-US-00006 TABLE 1A NH-pyrazole Acid Time Conversion Pyrazole V.1 V.sup.H.1 No* Acid [equiv] [h] [%] [area %] [area %] 1 H.sub.2SO.sub.4 0.5 2 >95 74 17 2 MSA 1 2 >95 51 48 3 AcOH 25** 2 64 39 4 4 TFA 0.5 2 >95 85 16 5 TCAA 0.5 2 >95 67 27 6 ClAcOH 0.5 2 33 14 18 7 H.sub.3PO.sub.4 1 3 42 31 <1 8 H.sub.3PO.sub.4 1 8 >95 90 10 9 AlCl.sub.3 0.1 3 >95 >90 2 10 BF.sub.3*OEt.sub.2 0.1 3 52 44 2 11 MSA*Pyr 1 3 45 34 9 *All reactions run with 0.7 g Pt/C in EtOH at 30? C., 10 bar pressure **EtOH/AcOH = 1:1

[0594] Furthermore, the influence of the presence of an aprotic solvent was analyzed analogously by using a solvent mixture as defined in Table 1B below and MSA (1 equiv) as the acid.

TABLE-US-00007 TABLE 1B NH-pyrazole Solvent Time Conversion Pyrazole V.1 V.sup.H.1 No* mixture [h] [%] [area %] [area %] 1 EtOH/Toluene 3 >95 53 47 2 EtOH/EtOAc 3 >95 62 34 3 EtOH/MTBE 3 >95 49 45 *All reactions run with 0.7 g Pt/C and with 1 equivalent MSA at 30? C., 10 bar pressure

Example 2: Screening Experiment

[0595] To a suspension of Pt/C (0.7 g) in 31 g MeOH 1.8 g (0.5 equiv) H.sub.2SO.sub.4 were added. The reaction vessel was pressurized with hydrogen to 15 bar and cooled to 10? C. To the reaction mixture was dosed a solution of 9 g ethyl 2-[[2-(2,2-dimethyl-1-methyl-ethylidene)hydrazino]methylene]-3-oxo-butanoate (0.04 mol, compound IV.1) in 20 g MeOH over 240 min using an HPLC pump. The reaction mixture was stirred for an additional hour following the dosing. Then the conversion was measured by HPLC: the area % values of the pyrazole V.1, ethyl 1-(2,2-dimethyl-1-methyl-ethyl)-5-methyl-pyrazole-4-carboxylate, and NH-pyrazole V.sup.H.1 were determined. The results are provided in entry 1 of Table 2C.

[0596] Further trials were run analogously or according to Example 2; the results are listed in Tables 2C to 2G. All trials run with 0.7 g Pt/C catalyst in same amounts of solvent and compound IV.1.

TABLE-US-00008 TABLE 2C Dosing Post stirring NH-pyrazole Acid Time time Conversion Pyrazole V.1 V.sup.H.1 No* Solvent [equiv] [h] [h] [%] [area %] [area %] 1 EtOH H.sub.2SO.sub.4 (0.50) 4 1 >95 93 7 2 MeOH H.sub.2SO.sub.4 (0.50) 4 1 >95 93 7 3 EtOH H.sub.3PO.sub.4 (1.0) 4 4 72 47 17 *All reactions run at 10? C., 15 bar pressure

TABLE-US-00009 TABLE 2D Dosing/post NH-pyrazole Temp Pressure stirring time Conversion Pyrazole V.1 V.sup.H.1 No * Solvent [? C.] [bar] [h] [%] [area %] [area %] 4 EtOH 10 15 4/1 >98 80.1 19.9 5 MeOH 10 15 4/1 >98 90.5 9.5 6 i-propanol 10 15 4/1 >95 53.8 46.2 7 n-butanol 10 15 4/1 >95 43.9 56.1 8 EtOH/Toluene (1:1) 10 15 4/1 >98 78.7 21.3 Concentration of IV.1 in total amount of solvent = 15 wt.-%; Acid = H.sub.2SO.sub.4, 0.5 equiv.

TABLE-US-00010 TABLE 2E Dosing Post stirring NH-pyrazole Temp Pressure Time time Conversion Pyrazole V.1 V.sup.H.1 No* [? C.] [bar] [h] [h] [%] [area %] [area %] 9 10 5 4 1 >98 55.9 44.1 10 10 10 4 1 >98 70.0 30.0 11 10 15 4 1 >98 80.1 19.9 12 10 20 4 1 >98 86.0 14.0 Solvent = EtOH, Concentration of IV.1 in total amount of solvent = 15 wt.-%; Acid = H.sub.2SO.sub.4, 0.5 equiv.

TABLE-US-00011 TABLE 2F Dosing Post stirring NH-pyrazole Temp Concentration* Time time Conversion Pyrazole V.1 V.sup.H.1 No* [? C.] [%] [h] [h] [%] [area %] [area %] 13 10 10 4 1 >98 91.3 8.7 14 10 15 4 1 >98 80.1 19.9 15 10 20 4 1 >98 69.7 30.3 Solvent = EtOH; Acid = H.sub.2SO.sub.4, 0.5 equiv.; Pressure 15 bar *concentration of IV.1 in total amount of solvent

TABLE-US-00012 TABLE 2G Dosing Post stirring NH-pyrazole Temp Pressure Time time Conversion Pyrazole V.1 V.sup.H.1 No* [? C.] [bar] [h] [h] [%] [area %] [area %] 16 10 15 4 1 >98 80.1 19.9 17 10 15 10 1 >98 90.6 9.3 Solvent = EtOH, Concentration of IV.1 in total amount of solvent = 15 wt.-%; Acid = H.sub.2SO.sub.4, 0.5 equiv.

TABLE-US-00013 TABLE 2H Dosing Post stirring NH-pyrazole Temp Acid Time time Conversion Pyrazole V.1 V.sup.H.1 No* [? C.] [equiv] [h] [h] [%] [area %] [area %] 18 10 0.5 4 1 >98 80.1 19.9 19 10 1 4 1 >98 79.0 21.0 Solvent = EtOH, Concentration of IV.1 in total amount of solvent = 15 wt.-%; Acid = H.sub.2SO.sub.4, 0.5 equiv.; Pressure = 15 bar