PROCESS FOR THE PREPARATION OF TRIAZOLES

Abstract

The present invention discloses the efficient preparation of 2-substituted-4-amido-1,2,3-triazoles.

Claims

1. A process for preparation of one or more compounds of formula 1 ##STR00038## wherein R.sup.2 is an alkyl, aromatic, or heterocyclic group, R.sup.3 is an alkyl, aromatic, or heterocyclic group, by conversion of one or more compounds of formula 4 ##STR00039## in which R.sup.2 and R.sup.3 have the above mentioned meanings, into one or more compounds of formula 1.

2. A process according to claim 1 wherein the conversion is effected thermally or in the presence of an activating agent.

3. A process according to claim 2 wherein the activating agent comprises one or more inorganic bases, alkali metal salts of simple alcohols, aliphatic or aromatic amines, strong acids and/or copper salts.

4. A compound of formula 4 ##STR00040## wherein R.sup.2 is an alkyl, aromatic, or heterocyclic group, R.sup.3 is an alkyl, aromatic, or heterocyclic group.

5. A compound of formula 10 ##STR00041## wherein X is either sulfur or oxygen, R.sup.1 is C.sub.1-8-alkyl (which may be straight-chained, cyclic, or branched), phenyl (which is unsubstituted or is substituted with 1-5 groups independently chosen from the following list: C.sub.1-8-alkyl groups (which may be straight-chained, cyclic, or branched), halogens, C.sub.1-4-alkoxy (which may be straight-chained or branched), or nitro groups), or the two R.sup.1-groups may be joined by a C.sub.1-3-alkyl group or be part of a 1,2-disubstituted phenyl group to form a cyclic unit, which cyclic unit may be further substituted with 1-6 groups chosen from the following list: C.sub.1-6-alkyl groups (which may be straight-chained, cyclic, or branched), halogens, benzyl, trimethylsilyl, acetoxy, phenyl, 4-methoxyphenyl, 2-nitrophenyl, C.sub.1-4-alkoxycarbonyl (which may be straight-chained or branched), carboxylic acids, or groups of the structure C(O)NR.sup.aR.sup.b (where R.sup.a and R.sup.b are independently chosen between H or a C.sub.1-4-alkyl group (which may be straight-chained or branched)), and R.sup.2 is an alkyl, aromatic, or heterocyclic group.

Description

EXAMPLES

[0100] Abbreviations used:

[0101] RT=room temperature, Me=methyl, Et=ethyl, Ph=phenyl, h=hour(s), min=minute(s)

[0102] The present invention is illustrated in detail by the following examples, although the examples should not be interpreted in a manner that restricts the invention.

Example 1: Preparation of an Amidoxime of the General Structure 8: 2,2-Diethoxy-N-hydroxyethanimidamide 8a

[0103] ##STR00021##

[0104] A solution of hydroxylamine hydrochloride (59.3 g, 827 mmol) and diethoxyacetonitrile (73.5 g, 551 mmol) in water (180 mL) and ethanol (360 mL) was treated portionwise at RT with solid Na.sub.2CO.sub.3 (45.6 g, 430 mmol). After 1 h the ethanol was removed from the mixture by distillation at reduced pressure. The resulting mixture was diluted with water (250 mL) and extracted with dichloromethane (1300 mL, 2100 mL). The combined organic extracts were dried (Na.sub.2SO.sub.4) and concentrated at reduced pressure to give the title compound as a white solid (87.0 g, 536 mmol, 97%). .sup.1H NMR (400 MHz, CD.sub.3CN): 7.51 (br s, 1H), 4.73 (br s, 2H), 4.62 (s, 1H), 3.55 (m, 4H), 1.17 (t, J=7.1 Hz, 6H).

Example 2: Acylation of an Amidoxime to Give a Compound of the General Structure 10: 2,2-diethoxy-N-[(4-methoxybenzoy)oxy]ethanimidamide 10a

[0105] ##STR00022##

[0106] A solution of pyridine (6.44 g, 81.3 mmol) and 2,2-diethoxy-N-hydroxyethanimidamide (12.0 g, 73.9 mmol) in CH.sub.2Cl.sub.2 (100 mL) was treated between 0-5 C. with a solution of 4-methoxybenzoyl chloride (13.4 g, 77.6 mmol) in CH.sub.2Cl.sub.2 (20 mL). The resulting mixture was brought to RT and stirred for 45 min before water (75 mL) was added. The phases were separated and the organic layer was washed with water (20 mL), dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to give the title compound as a beige solid (22.0 g, 95% purity, 70.6 mmol, 95%).

TABLE-US-00001 TABLE 1 Examples of acylated amidoximes of the general structure 10 prepared according to or in analogy to this procedure [00023] Structure X R.sup.1 R.sup.2 Yield .sup.1H NMR (CD.sub.3CN, 400 MHz) 10a O Et 4-MeOPh 95% 8.02 (d, J = 9 Hz, 2H), 7.00 (d, J = 9 Hz, 2H), 5.49 (br s, 2H), 4.85 (s, 1H), 3.86 (s, 3H) 3.70-3.50 (m, 4H), 1.21 (t, J = 7 Hz, 6H) 10b O Et 2-ClPh 89% 7.80 (m, 1H), 7.53 (m, 2H), 7.43 (m, 1H), 5.50 (br s, 2H), 4.86 (s, 1H), 3.70-3.50 (m, 4H), 1.21 (t, J = 7 Hz, 6H) 10c O Et 2-CF.sub.3Ph 97% 7.83 (m, 2H), 7.73 (m, 2H), 5.46 (br s, 2H), 4.85 (s, 1H), 3.70-3.50 (m, 4H), 1.21 (t, J = 7 Hz, 6H) 10d O Et 2-Cl-3-pyridyl 92% 8.52 (m, 1H), 8.19 (m, 1H), 7.46 (m, 1H), 5.55 (br s, 2H), 4.86 (s, 1H), 3.70-3.50 (m, 4H), 1.21 (t, J = 7 Hz, 6H) 10e O Et Me 95% 5.39 (br s, 2 H), 4.76 (s, 1H), 3.70-3.50 (m, 4H), 2.08 (s, 3H), 1.18 (t, J = 7 Hz, 6H)

Example 3: Cyclization of an Acylated Amidoxime to a Protected 1,2,4-oxadiazole of the General Structure 11: 5-(4-methoxyphenyl)-3-(diethoxymethyl)-1,2,4-oxadiazole 11a

[0107] ##STR00024##

[0108] A solution of 2,2-diethoxy-N-[(4-methoxybenzoyl)oxy]-ethanimidamide (500 mg, 1.60 mmol) in toluene (4 mL) was treated with TBAF (1 M in THF, 320 L, 0.320 mmol) and stirred overnight at 60 C. The resulting mixture was then cooled to RT, and washed with 10% NaOH (1 mL). The organic phase was separated and the remaining aqueous phase was extracted with toluene (2 mL). The combined organic phases were filtered through a pad of silica gel, dried (MgSO.sub.4), and concentrated under reduced pressure to give the title compound as a colourless oil (400 mg, 98% purity, 1.41 mmol, 88%).

TABLE-US-00002 TABLE 2 Examples of 1,2,4-oxadiazoles of the general structure 11 prepared according to or in analogy to this procedure [00025] Structure X R.sup.1 R.sup.2 Yield .sup.1H NMR (CD.sub.3CN, 400 MHz) 11a O Et 4-MeOPh 93% 8.07 (d, J = 9 Hz, 2H), 7.10 (d, J = 9 Hz, 2H), 5.67 (s, 1H), 3.88 (s, 3H), 3.80-3.62 (m, 4H), 1.21 (t, J = 7 Hz, 6H) 11b O Et 2-ClPh 98% 8.08 (m, 1H), 7.64 (m, 2H), 7.52 (m, 1H), 5.74 (s, 1H), 3.82-3.65 (m, 4H), 1.23 (t, J = 1 Hz, 6H) 11c O Et 2-CF.sub.3Ph 93% 8.03 (m, 1H), 7.96 (m, 1H), 7.86 (m, 2H), 5.75 (s, 1H), 3.71-3.65 (m, 4H), 1.22 (t, J = 7 Hz, 6H) 11d O Et 2-Cl-3-pyridyl 91% 8.62 (m, 1H), 8.45 (m, 1H), 7.56 (m, 1H), 5.76 (s, 1H), 3.72-3.57 (m, 4H), 1.23 (t, J = 7 Hz, 6H) 11e O Et Me 87% 5.59 (s, 1H), 3.75-3.58 (m, 4H), 2.55 (s, 3H), 1.18 (t, J = 7 Hz, 6H)

Example 4: Deprotection of a Protected 1,2,4-Oxadiazole to an Aldehyde of the General Structure 12: Preparation of 5-(4-methoxyphenyl)-1,2,4-oxadiazole-3-carbaldehyde 12a

[0109] ##STR00026##

[0110] A solution of 5-(4-methoxyphenyl)-3-(diethoxymethyl)-1,2,4-oxadiazole (13.0 g, 45.5 mmol) in MeCN (130 mL) was treated with 10% HCl (55 mL, 160 mmol) and stirred at 60 C. for 1.5 h. The majority of the acetonitrile was removed by distillation under reduced pressure and the resulting white suspension was diluted with water (130 mL), cooled to RT, and filtered. The filter cake was washed with water (20 mL) and dried overnight in a vacuum oven (50 C., 20 mbar) to give the title compound as a white solid (8.64 g, 42.3 mmol, 93%).

TABLE-US-00003 TABLE 3 Examples of aldehydes of the general structure 12 prepared according to or in analogy to this procedure [00027] Structure R.sup.2 Yield .sup.1H NMR (CD.sub.3CN, 400 MHz) 12a 4-MeOPh 93% 10.09 (s, 1H), 8.14 (d, J = 8.9 Hz, 2H), 7.13 (d, J = 8.9 Hz, 2H), 3.9 (s, 3H) 12b 2-ClPh 92% 10.14 (s, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.68 (m, 2H), 7.56 (m, 1H) 12c 2-CF.sub.3Ph 99% 10.13 (s, 1H), 8.10 (m, 1H), 8.04 (m, 1H), 7.88 (m, 2H)

Example 5A: Condensation of an Aldehyde with a Hydrazine of the General Structure 13 to a Hydrazone of the General Structure 4: Preparation of 3-[((2,4-dichlorophenyl)hydrazono)methyl]-5-(4-methoxyphenyl)-1,2,4-oxadiazole 4a

[0111] ##STR00028##

[0112] A mixture of 5-(4-methoxyphenyl)-1,2,4-oxadiazole-3-carbaldehyde (500 mg, 2.40 mmol) and 2,4-dichlorophenylhydrazine (450 mg, 2.52 mmol) in MeCN (15 mL) was treated with 31% HCl (300 L, 2.64 mmol) and stirred at RT for 3 h. The resulting white suspension was diluted with water (15 mL) and filtered. The filter cake was washed with water (10 mL) and dried overnight in a vacuum oven (50 C., 20 mbar) to give the title compound as a white solid (860 mg, 2.37 mmol, 99%, ca. 10:1 mixture of stereoisomers).

Example 5B: Condensation of an Aldehyde with a Salt of a Hydrazine of the General Structure 13 to a Hydrazone of the General Structure 4: Preparation of 2-(2-[[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methylene]hydrazino)-5-(trifluoromethyl)pyridine 4b

[0113] ##STR00029##

[0114] A mixture of 5-(4-methoxyphenyl)-1,2,4-oxadiazole-3-carbaldehyde (500 mg, 2.40 mmol) and 2-hydrazino-5-(trifluoromethyl)pyridine hydrochloride (877 mg, 2.52 mmol) in MeCN (10 mL) was stirred at RT for 3 h. The resulting suspension was diluted with water (10 mL) and filtered. The filter cake was washed with water (10 mL) and dried overnight in a vacuum oven (50 C., 20 mbar) to give the title compound as a brown solid (630 mg, 1.73 mmol, 72%, ca. 90:10 mixture of stereoisomers).

Example 5C: Tandem Preparation of a Hydrazone of the General Structure 4 from a Protected Oxadiazole of the General Structure 11: Preparation of 2-[2-[(5-(6-chloropyridin-2-yl)-1,2,4-oxadiazol-3-yl)methylene]hydrazino]-5-(trifluoromethyl)-pyridine 4g

[0115] ##STR00030##

[0116] A solution of 2-chloro-6-[3-(diethoxymethyl)-1,2,4-oxadiazol-5-yl]pyridine (750 mg, 2.58 mmol) in MeCN (10 mL) was treated with 10% HCl (3 mL, 9 mmol) and stirred at 85 C. for 3 h. The resulting solution was then cooled to RT and treated with 2-hydrazino-5-(trifluoromethyl)pyridine hydrochloride (943 mg, 2.71 mmol). After stirring for 1.5 h at RT the fine suspension was diluted with water (15 mL) and filtered. The filtercake was washed with water (10 mL) and dried at room temperature to give the title compound as a brown solid (790 mg, 92% purity, 1.97 mmol, 76%, >95:5 mixture of stereoisomers).

TABLE-US-00004 TABLE 4 Examples of hydrazonyl-1,2,4-oxadiazoles of the general structure 4 prepared according to or in analogy to these procedures [00031] Structure R.sup.2 R.sup.3 Yield .sup.1H NMR 4a 4-MeOPh 2,4-Cl.sub.2Ph 98% 11.50 (s, 1H), 8.16 (d, J = 9 Hz, 2H), 7.68 (d, J = 2 Hz, 1H), 7.65 (s, 1H), 7.63 (d, J = 3 Hz, 1H), 7.44 (m, 1H), 7.24 (d, J = 9 Hz, 2H), 3.90 (s, 3H) 4b 4-MeOPh 4-CF.sub.3-2-pyridyl 72% 10.02 (s, 1H), 8.50 (s, 1H), 8.13 (d, J = 9 Hz, 2H), 8.04 (s, 1H), 7.95 (m, 1H), 7.42 (d, J = 9 Hz, 1H), 7.13 (d, J = 9 Hz, 2H), 3.90 (s, 3H) 4c 4-MeOPh 6-Cl-2-pyridyl >99% 11.17 (s, 1H), 8.52 (s, 1H), 8.25 (m, 1H), 8.13 (d, J = 9 Hz, 2H), 7.86 (m, 1H), 7.20 (d, J = 9 Hz, 2H), 6.99 (m, 1H), 3.89 (s, 3H) 4d 4-MeOPh Me 65% 8.08 (d, J = 9 Hz, 2H), 7.32 (s, 1H), 7.09 (m, 3H), 3.88 (s, 3H), 2.95 (s, 3H) 4e 2-CF.sub.3Ph Ph 66% Z-Isomer: 10.93 (s, 1H), 8.16 (m, 1H), 8.02 (m, 1H), 7.89 (m, 2H), 7.34 (m, 2H), 7.30 (s, 1H), 7.27 (m, 2H), 7.00 (m, 1H) E-Isomer: 9.42 (s, 1H), 8.07 (m, 1H), 7.98 (m, 1H), 7.87 (m, 2H), 7.83 (s, 1H), 7.30 (m, 2H), 7.14 (m, 2H), 6.94 (m, 1H) 4f 2-CF.sub.3Ph 2,6-F.sub.2Ph 58% 11.84 (s, 1H), 8.45 (s, 1H), 7.87 (d, J = 8 Hz, 1H), 7.77 (m, 4H), 7.47 (t, J = 8 Hz, 2H) 4g 2-Cl-3-pyridyl 4-CF.sub.3-2-pyridyl 76% 10.06 (s, 1H), 8.64 (m, 1H), 8.51 (d, J = 2 Hz, 1H), 8.49 (d, J = 2 Hz, 1H), 8.08 (s, 1H), 7.95 (m, 1H), 7.58 (m, 1H), 7.41 (d, J = 9 Hz, 1H) 4h 2-ClPh 2,4-Cl.sub.2Ph 85% 11.35 (s, 1H), 8.19 (m, 1H), 7.68 (m, 3H), 7.58 (m, 1H), 7.50 (m, 2H), 7.35 (m, 1H) .sup.1H NMR spectra were recorded at 400 MHz in CD.sub.3CN except for examples 4a and 4f, which were recorded in DMSO-d.sub.6. All hydrazones except example 4e were isolated with an isomeric purity of >90:10 as determined by .sup.1H NMR. The NMR data is reported for the major isomer of these examples; the exact structure of this major isomer has not been experimentally determined. Example 4e was isolated as a ca. 1:1 mixture of stereoisomers, the structures of which were determined after chromatographic separation.

Example 6A: Rearrangement of a hydrazonyl-1,2,4-Oxadiazole of the General Structure 4 to a 1,2,3-triazole of the General Structure 1 Under Basic Conditions: Preparation of N-[2-(2,4-dichlorophenyl)-2H-1,2,3-triazol-4-yl]-4-methoxybenzamide 1c

[0117] ##STR00032##

[0118] A white suspension of 3-[(2,4-dichlorophenyl)carbonohydrazonoyl]-5-(4-methoxyphenyl)-1,2,4-oxadiazole (650 mg, 1.80 mmol) in (i)-PrOH (10 mL) was treated with 10% NaOH (0.65 mL, 1.8 mmol), and the resulting light yellow suspension was stirred at 80 C. for 1 h. The solvents were then removed by distillation at reduced pressure, and the residue was taken up in water (5 mL) and extracted with CH.sub.2Cl.sub.2 (220 mL). The combined extracts were dried (MgSO.sub.4), concentrated under reduced pressure, and dried overnight in a vacuum oven (50 C., 20 mbar) to give the title compound as a beige solid (610 mg, 1.65 mmol, 92%).

Example 6B: Rearrangement of a hydrazonyl-1,2,4-oxadiazole of the General Structure 4 to a 1,2,3-triazole of the General Structure 1 Under Acidic Conditions: Preparation of 4-methoxy-N-[2-[5-(trifluoromethyl)pyridin-2-yl]-2H-1,2,3-triazol-4-yl]benzamide 1d

[0119] ##STR00033##

[0120] A suspension of 2-[2-[(5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl)methylene]hydrazine]-5-(trifluoromethyl)pyridine (10:1 mixture of stereoisomers, 620 mg, 1.70 mmol) in MeCN (10 mL) was treated with MeSO.sub.3H (335 L, 5.12 mmol) and stirred at 85 C. for 6 h. The resulting red suspension was cooled to RT, diluted with water (10 mL) and filtered. The filter cake was washed with water (5 mL) to give the title compound as a light brown solid (0.60 g, 1.6 mmol, 97%).

Example 6C: Rearrangement of a hydrazonyl-1,2,4-oxadiazole of the General Structure 4 to a 1,2,3-triazole of the General Structure 1 in the Presence of a Lewis Acid Catalyst: Preparation of N-[2-phenyl-2H-1,2,3-triazol-4-yl]-2-(trifluoromethyl)benzamide 1g

[0121] ##STR00034##

[0122] A solution of 3-[(Z)-phenylhydrazonolmethyl]-5-[2-trifluoromethylphenyl]-1,2,4-oxadiazole (50 mg, 0.15 mmol) in MeOH (1 mL) was treated with Cu(OAc).sub.2 (3 mg, 0.02 mmol). After stirring for 3 h at RT the mixture was diluted with water (4 mL) and extracted with MTBE (15 mL). The organic phase was washed with water (5 mL), dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to give the title compound as a colourless oil (40 mg, 0.12 mmol, 83% yield).

Example 6D: Tandem Preparation of a 1,2,3-triazole of the General Structure 1 from an Aldehyde of the General Structure 12 without Isolation of the Intermediate Hydrazone: Preparation of N-[2-(2,6-difluorophenyl)-2H-1,2,3-triazol-4-yl]-2-(trifluoromethyl)-benzamide 1 h

[0123] ##STR00035##

[0124] A suspension of 5-(2-trifluoromethylphenyl)-1,2,4-oxadiazole-3-carbaldehyde (1.00 g, 3.88 mmol) and (2,6-difluorophenyl)hydrazinium chloride (0.817 g, 4.20 mmol) in acetonitrile (7.5 mL) was treated with 20% sulfuric acid (170 L, 0.396 mmol) and stirred for 2 h at RT. The resulting solution (ca. 1:1 mixture of hydrazone stereoisomers) was then warmed to 50 C., treated with 32% NaOH (0.8 mL, 9 mmol) and stirred overnight. The resulting red solution was diluted with water (10 mL) and the acetonitrile was removed by distillation under reduced pressure. The resulting suspension was extracted with CH.sub.2Cl.sub.2 (150 mL, 110 mL), dried (MgSO.sub.4) and purified by flash chromatography to give the title compound as a beige solid (1.20 g, 96% purity, 3.13 mmol, 81%).

Example 6E: Tandem Preparation of a 1,2,3-triazole of the General Structure 1 from a Protected Oxadiazole of the General Structure 11 without Isolation of the Intermediate Aldehyde or Hydrazone: Preparation of N-[2-(2,6-difluorophenyl)-2H-1,2,3-triazol-4-yl]acetamide 1k

[0125] ##STR00036##

[0126] A mixture of 5-methyl-3-(diethoxymethyl)-1,2,4-oxadiazole (102 mg, 0.545 mmol), (2,6-difluorophenyl)hydrazinium chloride (103 mg, 0.568 mmol) and 96% H.sub.2SO.sub.4 (5 L, 0.09 mmol) in water (1 mL) was stirred at 80 C. for 3 h. The resulting yellow suspension was then treated with 10% NaOH (300 L, 0.83 mmol) and (n)-BuOH (1 mL), and stirred at 80 C. for 1 h. The two phases were then separated and the aqueous phase was extracted with MTBE (31 mL). The combined organic phases were dried (Na.sub.2SO.sub.4) and concentrated under reduced pressure to give the title compound as a brown powder (114 mg, 0.478 mmol, 88%).

TABLE-US-00005 TABLE 5 Examples of 1,2,3-triazoles of the general structure 1 prepared according to or in analogy to these procedures [00037] Structure R.sup.2 R.sup.3 Yield .sup.1H NMR (CD.sub.3CN, 400 MHz) 1c 4-MeOPh 2,4-Cl.sub.2Ph 92% 9.45 (br s, 1H), 8.40 (s, 1H), 7.95 (d, J = 7 Hz, 2H), 7.71 (d, J = 2 Hz, 1H), 7.62 (d, 9 Hz, 1H), 7.51 (m, 1H), 7.04 (d, J = 9 Hz, 2H), 3.87 (s, 3H) 1d 4-MeOPh 4-CF.sub.3-2-pyridyl 97% 9.68 (br s, 1H), 8.86 (s, 1H), 8.51 (s, 1H), 8.24 (d, J = 2 Hz, 1H), 8.22 (d, J = 2 Hz, 1H), 7.99 (d, J = 9 Hz, 2H), 7.05 (d, J = 9 Hz, 2H), 3.88 (s, 3H) 1e 4-MeOPh 6-Cl-2-pyridyl 97% 9.57 (br s, 1H), 8.53 (d, J = 4 Hz, 1H), 8.43 (s, 1H), 8.09 (m, 1H), 7.97 (d, J = 9 Hz, 2H), 7.56 (m, 1H), 7.04 (d, J = 9 Hz, 2H), 3.87 (s, 3H) 1f 4-MeOPh Me 68% 9.22 (br s, 1H), 7.98 (s, 1H), 7.92 (d, J = 9 Hz, 2H), 7.02 (J = 9 Hz, 2H), 4.01 (s, 3H), 3.87 (s, 3H) 1g 2-CF.sub.3Ph Ph 83% 9.71 (br s, 1H), 8.33 (s, 1H), 7.99 (d, J = 8 Hz, 2H), 7.83 (d, J = 8 Hz, 1H), 7.71 (m, 3H), 7.52 (t, J = 8 Hz, 2H), 7.38 (t, J = 8 Hz, 1H) 1h 2-CF.sub.3Ph 2,6-F.sub.2Ph 81% 9.68 (br s, 1H), 8.43 (s, 1H), 7.84 (d, J = 8 Hz, 1H), 7.73 (m, 3H), 7.62 (m, 1H), 7.25 (t, J = 8 Hz, 2H) 1i 2-Cl-3-pyridyl 4-CF.sub.3-2-pyridyl 59% 10.01 (s, 1H), 8.64 (m, 1H), 8.50 (m, 2H), 8.08 (s, 1H), 7.95 (m, 1H), 7.59 (m, 1H), 7.40 (d, J = 9 Hz, 1H) 1j 2-ClPh 2,4-Cl.sub.2Ph 86% 9.63 (br s, 1H), 8.39 (s, 1H), 7.72 (d, J = 2 Hz, 1H), 7.62 (d, J = 9 Hz, 2H), 7.53 (m, 3H), 7.46 (m, 1H) 1k Me 2,6-F.sub.2Ph 88% 9.12 (br s, 1H), 8.27 (s, 1H), 7.59 (m, 1H), 7.22 (m, 2H), 2.17 (s, 3H)