Process for the stereoselective preparation of a pyrazole-carboxamide

Abstract

The present invention relates to a process for the enantioselective preparation of the compound of formula (Ib), which process comprises a) reducing the (E)- or (Z)-form of a compound of formula (II), with an enantioselective reagent to a compound of formula (IIIa), and b) acylating the compound of formula (IIIa) with the compound of formula (IV), or c) coupling the compound of formula (IV) with the compound of formula (II), to give a compound of formula (V) and d) reducing compound of formula (V) in the presence of hydrogen, a catalyst and a chiral ligand, to the compound of formula (Ib). ##STR00001##

Claims

1. A process for the enantioselective preparation of the compound of formula (Ib) ##STR00025## which process comprises a) reducing the (E)- or (Z)-form of a compound of formula (II) ##STR00026## with an enantioselective reagent to give a compound of formula (IIIa) ##STR00027## and b) acylating the compound of formula (IIIa) with the compound of formula (IV) ##STR00028## or c) coupling the compound of formula (IV) with the compound of formula (II), to give a compound of formula (V) ##STR00029## and d) reducing the compound of formula (V) in the presence of hydrogen, a catalyst and a chiral ligand, to give the compound of formula (Ib).

2. The process for the enantioselective preparation of the compound of formula (Ib) according to claim 1, which process comprises a) reducing the (E)- or (Z)-form of a compound of formula (II) ##STR00030## with an enantioselective reagent to a compound of formula (IIIa) ##STR00031## and b) acylating the compound of formula (IIIa) with the compound of formula (IV) ##STR00032##

3. The process for the enantioselective preparation of the compound of formula (Ib) according to claim 1, which process comprises c) coupling the compound of formula (IV) with the compound of formula (II), to give a compound of formula (V) ##STR00033## and d) reducing the compound of formula (V) in the presence of hydrogen, a catalyst and a chiral ligand, to the compound of formula (Ib).

4. The process for the enantioselective preparation of the compound of formula (Ib) according to claim 1, ##STR00034## which process comprises a) reducing the (E)- or (Z)-form of a compound of formula (II) ##STR00035## with a borane complex as a reducing agent, in the presence of a single enantiomer of a chiral 1,2-amino-alcohol, in an inert solvent and at temperatures ranging from 0 C. and 60 C., to a compound of formula (IIIa) ##STR00036## and b) acylating the compound of formula (IIIa) with the compound of formula (IV), in an inert solvent, in the presence of a weak base and at temperatures ranging between 20 C. and 120 C. ##STR00037## or c) coupling the compound of formula (IV) with the compound of formula (II), by deprotonation of compound of formula (II) with 1 to 5 equivalents of a suitable base in an inert aprotic solvent, wherein the suitable base is selected from KN(iPr).sub.2, LiN(iPr).sub.2, KN(trimethylsilyl).sub.2, BuLi, and KN(iPr).sub.2/KOtBu, at temperature ranging from 78 C. to 25 C., followed by treatment with compound of formula (IV), to give a compound of formula (V), ##STR00038## and d) reducing the compound of formula (V) in the presence of hydrogen at pressures ranging from 0.1 bar to 15 MPa, in the presence of 0.1 to 0.0001 equivalent of a metal catalyst and a single enantiomer of a suitable chiral ligand, in ratio of metal catalyst to chiral ligand ranging from 0.8 to 1.5, in a suitable solvent and at temperatures ranging from 20 C. to 100 C., to give the compound of formula (Ib).

5. The compound of formula (V) ##STR00039##

6. The process of claim 2, wherein the reduction of the compound of formula (II) is performed via the action of borane in the presence of a single enantiomer of a chiral amino-alcohol.

7. The process according to claim 6, wherein the source of borane is borane diethylaniline.

Description

PREPARATORY EXAMPLES

Gcms

(1) GCMS was conducted on a Thermo, MS: DSQ and GC: TRACE GC ULTRA with a column from Zebron phenomenex: Phase ZB-5 ms 15 m, diam: 0.25 mm, 0.25 m, H.sub.2 flow 1.7 ml/min, temp injector: 250 C., temp detector: 220 C., method: start at 70 C., 25 C./min until 320 C., hold 2 min at 320 C., total time 12 min. Cl reagent gas: Methane, flow 1 ml/min.
Chiral HPLC Analysis: Method A

(2) Autopurification System from Waters: 2767 sample Manager, 2489 UVNisible Detector, 2545 Quaternary Gradient Module. Column: Daicel CHIRALPAK AS-3R, 3 m, 0.46 cm15 cm. Mobile phase: ACN/MeOH/Water 35/5/60. Flow rate: 1.0 ml/min. Detection: DAD Sample concentration: 1 mg/mL in ACN/Water 80/20. Injection: 5 L.

(3) Chiral HPLC Analysis: Method B

(4) HPLC Waters UPLCHclass. DAD Detector Waters UPLC. Column: Daicel CHIRALPAK IC, 3 m, 0.46 cm10 cm. Mobile phase: EtOH/MeOH 50/50. Flow rate: 1.0 ml/min. Detection: DAD. Sample concentration: 1 mg/mL in Hept/iPrOH 70/30. Injection: 24.

Example P1: preparation of enantiomerically enriched (2S)N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine of formula IIIa

(5) ##STR00021##

(6) Under an atmosphere of argon, ()-norephedrine-(1R,2S)-2-amino-1-phenyl-propan-1-ol-(76 mg, 0.5 mmol) was dissolved in tetrahydrofuran (5 ml) and cooled to 0 C. Borane-N,N-diethylaniline complex (0.18 ml, 0.5 mmol) was then added and the resulting mixture was stirred at 0 C. for 2 hours after which a solution of (E)-N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-imine (0.267 g, 1 mmol) in 3 ml of tetrahydrofuran was added dropwise. Upon warming to 35 C., additional borane-N,N-diethylaniline complex (0.18 ml, 0.5 mmol) was added dropwise and the reaction mixture was then stirred for 2 hours at 35 C. and for 16 hours at ambient temperature. Upon quenching the reaction mixture with 1 ml methanol (dropwise addition) the volatile components were removed on a rotary evaporator and the mixture was treated with hydrochloric acid (10 ml, 2M) and stirred for 2 hours at ambient temperature.

(7) The aqueous solution was subsequently washed with ether, basified with NaOH (2M) and extracted three times with tBuOMe. The organic layer was washed with brine, dried over sodium sulfate, and evaporated to give the enriched N-methoxyamine as a yellow oil (0.271 g, 0.827 mmol, 82% yield, estimated by quantitative HNMR)

(8) .sup.1HNMR: (CDCl.sub.3, 400 MHz) : 0.91-0.93 (d, 3H); 2.72-2.77 (dd, 1H); 2.98-3.03 (dd, 1H); 3.25-3.30 (m, 1H); 3.93 (s, 3H); 7.15 (s, 2H).

(9) Enantiomeric excess: Method A

(10) R stereoisomer: Peak 1: 26.89 min; 3.94%

(11) S Stereoisomer: Peak 2: 28.35 min; 96.06%

Example P2: Preparation of the Enantiomerically Enriched Compound of Formula Ib

(12) ##STR00022##

(13) A solution of 3-difluoromethyl-1H-pyrazole-4-carbonyl chloride (0.91 g; 4.7 mmol) in dichloromethane (5 ml) was added dropwise to a stirred solution of N-[2-(2,4-dichlorophenyl)-1-methyl-ethyl]-O-methlyhydroxylamine (1.0 g; 4.27 mmol)prepared as described aboveand triethylamine (0.90 ml; 6.4 mmol) in dichloromethane (7 ml) at 0 C. The cooling bath was removed and the reaction mixture was stirred for 1.5 hours at ambient temperature. The reaction mixture was then washed sequentially with 1M NaOH (20 ml), 1M HCl (20 ml), brine (20 ml) and then dried over sodium sulfate. After removal of the solvent the residue was purified by flash chromatography over silica gel (eluent: hexane/ethyl acetate 7:3) giving 1.35 g of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,4-dichlorophenyl)-1-methyl-ethyl]-methoxy-amide as a white solid (m.p. 98-102 C.).

(14) .sup.1HNMR: (CDCl.sub.3, 400 MHz): 1.41-1.46 (d, 3H); 2.99-3.04 (dd, 1H); 3.17-3.23 (dd, 1H); 3.60 (s, 3H); 3.95 (s, 3H); 4.68-4.70 (m, 1H); 7.10-7-62 (m, 5H). MS [M+H]+ 392/394/396.

(15) In case of the acylation of the (S)-enriched O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]hydroxylamine the retentions times are (S)-stereoisomer (2.41 min), (R)-stereoisomer (2.97 min) and the enantiomeric ratio is conserved from (S)-enriched O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]hydroxylamine to (S)-enriched 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [2-(2,4-dichlorophenyl)-1-methyl-ethyl]-methoxy-amide.

Example P3: Preparation of the Compound of Formula V

(16) ##STR00023##

(17) The compound of formula II (a mixture of isomers E/Z=1:1.5) (2.67 g) was dissolved in THF (20 ml) under argon and cooled to 30 C. To this solution, a 0.5M toluene solution of KN(trimethylsilyl).sub.2 (40 ml) was added at a rate allowing the temperature to stay below 25 C. The resulting solution was stirred for additional 10 min and the compound of formula VI (3.89 g) dissolved in THF (10 ml) was added at a rate allowing the temperature to stay below 20 C. The resulting solution was stirred for 0.3 hours at 20 to 30 C. A saturated aqueous solution of NH4Cl (100 ml) was added, the reaction was stirred an additional 10 min. The resulting mixture was extracted with EtOAc (270 ml) and the combined organic layers were washed with brine, then dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The resulting brown mass was purified by flash chromatography (silica gel, EtOAc: heptan=1:1). The product containing fractions were concentrated under vacuum and the resulting oil was crystallized from ether to give colorless crystals (1.93 g) of compound V. This reaction is very selective towards the (E)-isomer, as the (Z)-isomer of compound of formula V is not observed in significant amount after the reaction.

(18) 1H NMR (CDCl3, 500 MHz) =7.94 (t, J=1.46 Hz, 1H); 7.39 (s, 1H); 7.30 (t, J=54.20 Hz, 1H); 6.41 (s, 1H); 4.00 (s, 3H); 3.82 (s, 3H); 1.91 (s, 3H).

Example P4: Preparation of the Enantiomerically Enriched Compound of Formula Ib

(19) ##STR00024##

(20) 16.9 mg (0.031 mmol) SL-J002-1 and 10.6 mg (0.028 mmol) [Rh(nbd).sub.2]BF.sub.4 were placed in a 10 ml Schlenk flask that was previously set under an atmosphere of argon. Then 4 ml degassed methanol was added and this orange solution stirred for 30 min at room temperature. In a second 25 ml Schlenk flask, 0.3 g (0.706 mmol) of compound V was placed, followed by 3.5 ml degassed THF and 10 ml degassed MeOH. The clear solution was stirred for 10 min. Then, both the substrate and the catalyst solution were transferred via cannula into a 50 ml stainless steel reactor that was previously set under an atmosphere of argon. The reactor was sealed, purged with argon in three cycles (1 bar/20 bar) and finally, the argon replaced by hydrogen (4 cycles 0.1 MPa/2 MPa). The reactor pressure was set to 5 MPa hydrogen, heating to 50 C. and stirring started. IPC sample have been collected after 1.5 hours, 6 hours and 21 hours. After 48 hours reaction time, the pressure was released. The crude product was analyzed with respect to conversion, chemoselectivity and enantiomeric excess using the HPLC. The conversion after 48 hours was 99.8%, product Ib was formed with 87% chemoselectivity and 69% enantiomeric excess.

(21) .sup.1HNMR: (CDCl.sub.3, 400 MHz):

(22) 1.41-1.46 (d, 3H); 2.99-3.04 (dd, 1H); 3.17-3.23 (dd, 1H); 3.60 (s, 3H); 3.95 (s, 3H); 4.68-4.70 (m, 1H); 7.10-7-62 (m, 5H).

(23) MS [M+H]+ 392/394/396.