PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE ISOXAZOLINE COMPOUNDS

Abstract

The present invention relates to a process for the preparation of a compound of formula (I) wherein A.sub.1 and A.sub.2 are C—H, or one of A.sub.1 and A.sub.2 is C—H and the other is N; R.sub.1 is C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl or C.sub.3-C.sub.6cycloalkyl; each R.sub.2 is independently bromo, chloro, fluoro or trifluoromethyl; R.sub.3 is hydrogen; R.sub.4 is hydrogen, halogen, methyl, halomethyl or cyano; or R.sub.3 and R.sub.4 together form a bridging 1,3-butadiene group; R.sub.5 is chlorodifluoro-methyl or trifluoromethyl; n is 2 or 3; by reacting a compound of formula (II) wherein A.sub.1, A.sub.2, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n is as defined under formula (I) above, with hydroxylamine, a base and a chiral catalyst, characterized in that the chiral catalyst is a dimeric chiral catalyst of formula (III) wherein R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10 and X are as defmed in claim 1.

##STR00001##

Claims

1. A process for the preparation of a compound of formula I ##STR00024## wherein A.sub.1 and A.sub.2 are C—H, or one of A.sub.1 and A.sub.2 is C—H and the other is N; R.sub.1 is C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4haloalkyl or C.sub.3-C.sub.6cycloalkyl; each R.sub.2 is independently bromo, chloro, fluoro or trifluoromethyl; R.sub.3 is hydrogen; R.sub.4 is hydrogen, halogen, methyl, halomethyl or cyano; or R.sub.3 and R.sub.4 together form a bridging 1,3-butadiene group; R.sub.5 is chlorodifluoromethyl or trifluoromethyl; n is 2 or 3; by reacting a compound of formula II ##STR00025## wherein A.sub.1, A.sub.2, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5 and n is as defined under formula I above, with hydroxylamine, a base and a chiral catalyst, characterized in that the chiral catalyst is a dimeric chiral catalyst of formula III ##STR00026## wherein each R.sub.6 is ethyl or vinyl; R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6haloalkylthio, C.sub.1-C.sub.6alkylsulfonyl or C.sub.1-C.sub.6haloalkylsulfonyl; and X is a halogen anion or BF.sub.4-, PF.sub.6.sup.−, HSO.sub.4-or an C.sub.1-C.sub.3alkylsulfonate, benzenesulfonate or methyl-benzenesulfonate.

2. A process according to claim 1, wherein in the catalyst of formula III each R.sub.6 is vinyl; each of the substituents R.sub.7, R.sub.8, R.sub.9 and R.sub.10 has the same meaning and represent halogen and X is chloride or bromide or BF.sub.4-or PF.sub.6.sup.−.

3. A process according to claim 1, wherein in the catalyst of formula III each R.sub.6 is vinyl; each of the substituents R.sub.7, R.sub.8, R.sub.9 and R.sub.10 has the same meaning and represent fluoro or chloro; and X is chloride or bromide.

4. A process according to claim 1, wherein the amount of hydroxylamine is from 1 to 10 equivalents.

5. A process according to claim 1, wherein the amount of base is from 0.05 to 2 equivalents.

6. A process according to claim 1, wherein the amount of catalyst is from 0.01 to 0.4 equivalents

7. A compound of formula III ##STR00027## wherein each R.sub.6 is ethyl or vinyl; R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are halogen, cyano, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.6alkylthio, C.sub.1-C.sub.6haloalkylthio, C.sub.1-C.sub.6alkylsulfonyl or C.sub.1-C.sub.6haloalkylsulfonyl; and X is a halogen anion, BF.sub.4-, PF.sub.6.sup.− or an C.sub.1-C.sub.3alkylsulfonate, benzenesulfonate or methyl-benzenesulfonate.

8. A compound of formula III according to claim 7, wherein each R.sub.6 is vinyl; each of the substituents R.sub.7, R.sub.8, R.sub.9 and R.sub.10 has the same meaning and represent halogen; and X is chloride, bromide or BF.sub.4-.

9. A compound of formula Ill according to claim 7, wherein each R.sub.6 is vinyl; each of the substituents R.sub.7, R.sub.8, R.sub.9 and R.sub.10 has the same meaning and represent fluoro or chloro; and X is chloride or bromide.

Description

PREPARATORY EXAMPLES

[0049] The following abbreviations were used in this section: s=singlet; bs=broad singlet; d=doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, sept=septet; m=multiplet; Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl; M.p.=melting point; RT=retention time, M=molecular mass.

[0050] The following LC-MS methods were used to characterize the compounds:

[0051] Method A

[0052] Spectra were recorded on a Mass Spectrometer from Waters (SQD or ZQ Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 0 L/Hr, Desolvation Gas Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH: gradient: gradient: 0 min 0% B, 100% A; 1.2-1.5 min 100% B; Flow (ml/min) 0.85.

[0053] Method B

[0054] Spectra were recorded on a Mass Spectrometer from Waters (SQD or ZQ Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 150° C., Desolvation Temperature: 350° C., Cone Gas Flow: 0 L/Hr, Desolvation Gas Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 μm, 30×2.1 mm, Temp: 60° C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH: gradient: gradient: 0 min 0% B, 100% A; 2.7-3.0 min 100% B; Flow (ml/min) 0.85.

[0055] Chiral HPLC was conducted on a Waters UPLC—Hclass, DAD Detector Waters UPLC, with a column Daicel CHIRALPAK® ID, 5 μl, 0.46 cm×25 cm, Mobile phase: Hept/EtOAc 70/30, Flow rate: 1.0 ml/min, Detection: 265 nm, Sample concentration: 1 mg/mL in DCM/iPrOH 50/50, Injection: 2 μl. Free radicals represent methyl groups.

##STR00012##

[0056] (XI) was prepared accordina WO 2013/069731.

##STR00013##

[2,3,5,6-tetrafluoro-4-(hydroxymethyl)phenyl] methanol XV (5.0 g) was mixed with HBr in acetic acid (5.7 mol/L, 41 ml). The resulting dark orange solution was stirred for 16 hours at amabient temperature.

[0057] 10 mL of acetic acid was added and the stirring was continued for another 20 hours. Work up: The orange suspension was diluted with ethyl acetate ->orange solution. This solution was transferred into an additional funnel and it was added dropwise to a cold saturated Na.sub.2CO.sub.3 solution (gas evolution). At the end of addition, the reaction mixture was stirred for another 20 minutes. Then the aqueous layer (suspension) was extracted twice with ethyl acetate. The organic layer was washed twice with saturated Na.sub.2CO.sub.3 solution and once with brine. Then it was dried over Na.sub.2SO.sub.4, filtered and evaporated to give 7.5 g of the product XVI as a yellowish solid.

[0058] .sup.1H NMR (400 MHz, CDCl.sub.3) δ=4.52 (s, 4H). .sup.19F NMR (376 MHz, CDCl.sub.3) δ=142.36.

##STR00014##

[0059] Dry acetonitrile (200 ml) was added to a mixture of quinine (6.5 g, Sigma Aldrich) and 1,4-bis (bromomethyl)-2,3,5,6-tetrafluoro-benzene (12.5 g) and it was stirred at 40° C., under argon overnight. The solid was filtered and washed two times with acetonitrile and one time with diethylether. It was dried under reduced pressure to give 18.0 g of the product XVII as a beige solid.

[0060] .sup.1H NMR (400 MHz, DMSO) δ=8.83 (d, 2H, J=4.4), 8.02 (d, 2H, J=8.3), 7.80-7.79 (m, 2H), 7.51 (d, 2H, J=4.9), 7.44 (br.s, 2H), 6.81 (br.s, 2H), 6.58 (br.s, 2H), 5.82-5.76 (m, 2H), 5.62 (d, 2H, J=12.8), 5.13-5.03 (m, 4H), 4.83 (d, 2H, J=12.8), 4.20 (br.s, 6H), 4.03 (s, 6H), 3.86 (br.s, 26H), 3.68 (br.s, 2H), 2.87 (br.s, 2H), 2.24 (br.s, 2H), 2.17 (br.s, 2H), 2.05 (d, 2H), 1.89 (br.s, 2H), 1.44 (t, 2H). LC-MS (ES+): m/z=413 (M-569) RT=0.76 (Method A)

##STR00015##

1,2,4,5-tetrachloro-3,6-bis(chloromethyl)benzene (482 mg) and quinine (1.0 g, Sigma Aldrich) was mixed with dry acetonitrile (15 mL). The reaction mixture was stirred one night at room temperature and 5 days at 65° C. Then, it was filtered and the solid was washed twice with cold acetonitrile to give 959 mg of the product XIX as a beige solid.

[0061] .sup.1H NMR (400 MHz, DMSO) δ=8.83 (d, 2H, J=4.4), 8.02 (d, 2H, J=9.2), 7.80 (d, 2H, J=4.4), 7.50 (d, 2H), 7.40 (m, 2H), 6.99 (d, 2H), 6.60 (br.s, 2H), 5.89-5.74 (m, 4H), 5.08-5.00 (m, 6H), 4.51-4.45 (m, 3H), 4.26-4.24 (m, 2H), 4.07-4.00 (m, 7H), 3.77 (br.s, 2H), 2.78 (d, 2H), 2.17 (br.s, 2H), 2.07 (m, 4H), 1.98 (br.s, 2H), 1.84 (br.s, 2H), 1.41-1.38 (m, 2H). LC-MS (ES−): m/z=445 (M-513) RT=0.83 (Method A)

##STR00016##

1,4-bis(chloromethyl)-2,3,5,6-tetramethyl-benzene (428 mg) and quinine (1.2 g, Sigma Aldrich) were mixed with dry acetonitrile (18.5 mL) under argon. It was stirred at room temperature overnight and for 2 days at 55° C. The reaction ixture was cooled down to room temperature and poured into diethylether slowly. The suspension was filtered to give 1.07 g of XXI as a light brown solid.

[0062] .sup.1H NMR (400 MHz, DMSO) δ=8.85-8.83 (m, 2H), 8.02 (d, 3H, J=9.2), 7.82 (t, 2H, J=2×5.4), 7.52-7.49 (m, 4H), 7.04 (d, 1H, J=3.7), 6.98 (d, 1H, J=3.7), 6.78 (d, 2H, J=12.1), 5.81-5.72 (m, 4H), 5.09-5.00 (m, 5H), 4.86 (d, 2H, J=14.3), 4.23 (br.s, 4H), 4.04 (d, 6H, J=12.1), 3.55 (d, 4H, J=9.9), 3.37-1.37 (m, 24 H). LC-MS (ES−): m/z=484 (M-394) RT=0.72 (Method A)

##STR00017##

[0063] To a suspension of XVII (500 mg, 0.508 mmol) in acetonitrile (4 ml) was added KBF.sub.4 (0.320 g, 2.54 mmol). The reaction mixture was stirred at room temperature for 2.5 days. Diethyl ether was added to the reaction mixture. The resulting precipitate was filtered off and washed with water. The precipitate was dissolved in a mixture of methanol and dichloromethane and evaporated under reduced pressure to afford XXXII (474 mg) as a beige solid.

[0064] IR (thin film) 1621, 1496, 1292, 1241, 1025 cm.sup.−1

##STR00018##

[0065] To a suspension of catalyst XVII (500 mg, 0.508 mmol) in acetonitrile (4 ml) was added KPF.sub.6 (0.467 g, 2.54 mmol). The reaction mixture was stirred at room temperature for 2.5 days. Diethyl ether was added to the reaction mixture. The resulting precipitate was filtered off and washed with water. The precipitate was dissolved in a mixture of methanol and dichloromethane and evaporated under reduced pressure to afford XXXIII (433 mg) as a brown solid.

[0066] IR (thin film) 1621, 1497, 1293, 1241, 1026, 928, 826 cm.sup.−1

[0067] The selectivity of the catalysts according to this invention was compared with structurally close catalysts according to the prior art. The results are given in Table 1 below (free radicals represent methyl groups):

##STR00019##

[0068] General procedure (based on WO 2013/069731):

[0069] 0.32 mmol of XXIV (E/Z>99:1, R/S=99:1) was dissolved in 4 mL of dichloromethane. Catalyst 0.06 mmol or 0.03 mmol (as indicated below) was dded. The reaction mixture was cooled down to −20° C., 0.7 mmol of 10M sodium hydroxide solution, 0.054 ml of water and 0.64 mmo1 of 50% aqueous hydroxylamine were sequentially added. The reaction mixture was wigorously stirred at −20° C. for 20 h and analysed by chiral HPLC (ratio of diastereomers) and 1H NMR (conversion).

TABLE-US-00001 TABLE 1 comparative data with catalysts known from the prior art: HPLC ratio of diastereomers Catalyst (S,S:R;S:S,R:R,R) Compound XI according to 19:1:77:3 WO 2013/069731 0.06 mmol Compound XXX according to 10:2:72:16 WO 2011/104089 and WO 2011/067272 0.06 mmol Compound XXXI according to 4:2:64:30 (*) WO 2002/05953 Compound XVII according to 3:0:94:3 this invention 0.06 mmol Compound XVII according to 4:1:92:3 this invention 0.03 mmol Compound XIX according to 5:1:90:4 this invention 0.06 mmol Compound XIX according to 5:1:90:4 this invention 0.03 mmol (*) 86% conversion of the starting material. More than >95% conversion of the starting material was observed for all other runs.

##STR00020## [0070] XXX according to WO 2011/104089 and WO 2011/0672726

##STR00021## [0071] XXXI according to WO 2002/05953

TABLE-US-00002 TABLE 2 Examples of catalysts according to the invention with different reaction conditions [00022]

[0072] General procedure:

[0073] 0.32 mmol of XXIV (E/Z>99:1, R/S=99:1) was dissolved in 4 mL of dichloromethane. Catalyst 0.06 mmol was added. The reaction mixture was cooled down to −20° C., 0.7 mmol of 10M sodium hydroxide solution, 0.054 ml of water and 0.64 mmol of 50% aqueous hydroxylamine were sequentially added. The reaction mixture was wigorously stirred at −20° C. for 20 h and analysed by chiral HPLC (ratio of diastereomers) and 1H NMR (conversion).

TABLE-US-00003 HPLC ratio of diastereomers Catalyst (S,S:R;S:S,R:R,R) Compound XXI 0.06 mmol 10:5:59:26

[0074] More than >95% conversion of the starting material was observed for all runs.

TABLE-US-00004 TABLE 3 Selectivity of catalysts according to this invention with different reaction conditions: [00023]

[0075] General procedure:

[0076] XXVI (E/Z>99:1, R/S>99:1) and catalyst XVII were stirred in the given solvent at the reaction temperature. Aqueous 5-10M solution of base and 50% aqueous hydroxylamine were added sequentially. The reaction mixture was wigorously stirred at the given temperature. It was analysed by chiral HPLC (ratio of diastereomers) and 1H NMR using 1,3,5-trimethoxybenzene as a standard (yield determination).

TABLE-US-00005 HPLC ratio of Chemical diastereomers Scale Catalyst/catalysts loading [%] Reaction conditions Yield (S,S:R,S:S,R:R,R) 1 g Compound XVII 0.025 eq 1.1 eq NH2OH, 0.16 eq 86% 1:0:89:9 KOH, DCM solvent, −10° C., 1.5 h 10 g  Compound XVII 0.05 eq 1.1 eq NH.sub.2OH, 0.16 eq 83% 7:1:85:7 NaOH, DCE solvent, RT, 20 min 1 g Compound XVII 0.10 eq 2 eq NH.sub.2OH, 0.1 eq KOH, 60% 0:0:93:7 iPrOH solvent, 0° C., 3 h 1 g Compound XXXII 0.05 eq 1.1 eq NH.sub.2OH, 0.16 eq 79% 3:0:92:5 NaOH, DCE solvent, −10° C., 4.5 h