IE51429B1 - Trimethylsilyl cyanohydrin intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones - Google Patents
Trimethylsilyl cyanohydrin intermediates for hypoglycemic 5-substituted oxazolidine-2,4-dionesInfo
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- IE51429B1 IE51429B1 IE419/85A IE41981A IE51429B1 IE 51429 B1 IE51429 B1 IE 51429B1 IE 419/85 A IE419/85 A IE 419/85A IE 41981 A IE41981 A IE 41981A IE 51429 B1 IE51429 B1 IE 51429B1
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- trimethylsiloxyethanenitrile
- fluoro
- methylene chloride
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Description
This application is a divisional from Patent Application No. filed 27th July, 1981. It relates to certain intermediates useful in the preparation of 5phenyl·-and 5-naphthyl-oxazolidin-2,4-dione derivatives which are hypoglycemic agents.
Thus the invention provides a compound of the formula :,CN ,8
OSi(CH3)3
or
5142»
T is fluoro;
T1 is benzyloxy, chloro, phenoxy, nitro or trifluoromethyl;
T2 ia benzyloxy, phenoxy, nitro or trifluoromethyl;
T3 is methyl, (C^-C^alkoxy, methylthio, chloro or fluoro;
T4 and T5 are each independently hydrogen, methyl, bromo, chloro, fluoro, cyano, nitro or trifluoromethyl;
Y is hydrogen, methyl, benzyloxy, (Cj-C^alkoxy, chloro, bromo or fluoro;
Y1 is hydrogen or methoxy; and
Y2 is fluoro or chloro;
with the proviso that when T is chloro, at least one of T4 and T5 is other than hydrogen.
The compound excluded by the proviso clause, namely 2-(2-chlorophenyl)-2-trimethylsiloxyethanenitrile,' is described in Synthesis, 1978, page 220. This article merely describes the preparation of the compound for chemical interest.
The trimethylsilyl cyanohydrins can be prepared by reaction of an aldehyde R^.CHO with trimethylsilylcarbonitrile in the presence of a catalytic quantity of a Lewis acid, e.g., zinc iodide. A reaction inert solvent (e.g. methylene chloride, ether) is generally used when the aldehyde is a solid, but is optional when the aldehyde is a liquid. The temperature of the reaction is not critical, it being conveniently made up at reduced temperature (e.g. 0-5eC.) and allowed to proceed at room temperature for a matter of hours or days, as necessary to achieve complete reaction.
The trimethylsilyl cyanohydrins can be converted into oxazolidin-2,4-diones as described in Patent Application No. .
- 4 The aldehydes required for the above synthesis are broadly available either commercially, or by literature methods, such as the Sommelet reaction [e.g., o-tolualdehyde, Weygand, Organic Preparations,
Interscience, New York, 1945, p. 156; 1-naphthaldehyde, Angyal et al. Org. Syntheses 30, p. 67 (1950); 2naphthadehyde, Badgen, J. Chem. Soc., p. 536 (1941)], decomposition of arylsulfonylhydrazides [e.g., ochlorobenzaldehyde, McCoubrey and Mathieson, J. Chem.
Soc., p. 701 (1949)], hydrolysis of gem-dihalides [e.g., o-fluorobenzaldehyde, Marvel and Hein, J. Am. Chem. Soc. 70, p. 1896 (1948)], replacement of a diazonium group with halogen [e.g., m-chlorobenzaldehyde and m-bromobenzaldehyde, Buck and Ide, Org.
Syntheses IX, 130 (1943)], oxidation of a primary alcohol [e.g. 1-naphthaldehyde, West. J. Am. Chem.
Soc. 44, p. 2658 (1922)], Rosenmund reduction [e.g., 2-naphthaldehyde, Eershberg and Cason, Org. Syntheses 21, p. 84 (1941)], Stephen reduction of nitriles [e.g., m-tolualdehyde, Bowen and Wilkinson, J. Chem. Soc., p. 750 (1950)), vie reaction of Grignard reagents with orthoformic esters or ethoxymethyleneaniline [e._g. 2naphthaldehyde and o-tolualdehyde, Sah, Rec. trav.
chim. 59, p. 1024 (1940)]; or alkylation of hydroxy aldehydes [e.g. o-ethoxybenzaldehyde, Icke et al Org. Syntheses 29, p. 63 (1949)]. Additional methods are noted in the. Preparations detailed hereinafter.
The following Examples illustrate the invention:EXAMPLS 1
2-(2-Methoxyphenyl)-2-trimethylsiloxyethanenitrile
2-Methoxybenzaldehyde [25 g., 0.18 mole; Reiche 5 al., Ber. 93, p.88 (1960)] was dissolved in 150 ml.
of methylene chloride and cooled to 0-5®C. Zinc iodide (500 mg.) was added, followed by dropwise addition of trimethylsilylcarbonitrile (21.8 g., 0.22 mole). The reaction mixture was stirred for about 65 hours at room temperature. The reaction mixture was washed twice with saturated sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated to yield 2-(2-methoxyphenyl)-2-trimethylsiloxyethanenitrile as an oil [41 g., 97%? ir(CH2Cl2) 1600, 1486,
1460, 1075 cm-1; ra/e 235b
EXAMPLE 2
2-(2-Ethoxyphenyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 1, 2-ethoxybenzaldehyde (25 g., 0.166 mole was converted to 2-(2-ethoxyphenyl)20 2-trimethylsiloxyethanenitrile as an oil [40.6 g.; ir (CH2C12) 1594, 1481, 1073 cm-1; m/e 249].
- 6 51420
EXAMPLE 3
2-(2-Fluorophenyl)-2-trimethylsiloxyethanenitrile
Except that a 16 hour reaction time was employed, the procedure of Example 1 was employed to react 25 fluorobenzaldehyde (10 g., 0.081 mole) in 50 ml. of methylene chloride with trimethylsilylcarbonitrile (9.6 g., 0.097 mole) in the presence of zinc iodide (300 mg.) to yield 2-(2-fluorophenyl)-2-trimethylsiloxyethanenitrile as an oil [16.1 g., 89%; m/e 223; ir (C^C^)
1709, 1621, 1600, 1176 cm-1].
EXAMPLE 4
2-(5-Chloro-2-methoxyphenyl)-2-trimethylsiloxyethaneni trile
By the procedure of Example 3, 5-chloro-2-methoxy15 benzaldehyde (6 g., 35 mmoles) in 100 ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (4.16 g., 42 mmoles) in the presence of 200 mg. of zinc chloride. The reaction was diluted with 50 ml. of methylene chloride immediately prior to the isolation sequence which produced 2-(5-chloro—2-methoxyphenyl) —2trimethylsiloxyethanenitrile as an oil [9.1 g., 97%, m/e 271/269, ir (CHjClj) 1613, 1493, 1105 cm-1].
- 7 EXAMPLE 5
2-(5-Fluoro-2-methoxyphenyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 1, except that a reaction time of 4 days at room temperature was employed, 5-fluoro-2-methoxybenzaldehyde (9.5 g., 0.062 mole) in 50 ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (7.3 g., 0.074 mole) in the presence of a catalytic amount of zinc iodide to produce 10 2-(5-fluoro-2-methoxyphenyl)-2-trimethylsiloxyethanenitrile [12.5 g., 79%; oil; m/e 253; ir (CHjClj) 1504, 1200 cm-1].
EXAMPLE 6
2-(3-Chlorophenyl)-2-trimethylsiloxyethanenitrile 15 Following the procedure of Example 16 of Patent
Application No. , 3-chlorobenzaldehyde (25 g., 0.178 mole) was reacted with trimethylsilylcarbonitrile (21.2 g., 0.214 mole) in the presence of zinc iodide (500 mg.) to yield 2-(3-chlorophenyl)-2-trimethyl2q siloxyethanenitrile as an oil (39.2 g., 92%; ir (CH2C12) 1592, 1570, 1468, 1183 cm-1].
- 8 51428
EXAMPLE 7
2- (2-Methaxy-5-n.itroph.enyl) -2-trimethylsiloxy-ethanenitrile
2-Methoxy-5-nitrobenzaldehyde (3.4 g., 0.019 mole) was dissolved in 125 ml. of methylene chloride. Zinc iodide (50 mg.) and then trimethylsilylcarbonitrile were added and the mixture stirred for 2 hours at room temperature. The reaction mixture was washed with two portions of saturated sodium bicarbonate and then one portion of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness to yield 2(2-methoxy-5-nitrophenyl)-2-trimethylsiloxyethanenitrile [5.0 g.., 94%; m.p. 108-111 °C., m/e 280; ir (KSr) 1610, 1592, 1511, 1342, 1269 cm1].
EXAMPLE 8
2- (2-Methylphenyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 16 of Patent Application No. 1 ι except that a reaction time of 5 days at room temperature was employed, 2-methylbenzaldehyde (15 g., 0.125 mole) was reacted with trimethylsilylcarbonitrile (14.9 g., 0.15 mole) to produce 2-(2-methylphenyl)-2-trimethylsiloxyethanenitrile as an oil (25.6 g., 93%; m/e 219, ir (CHjC^) 1600, 1484, 1450, 1124 cm1].
- 9 EXAMPLE 9
2-(2-Trifluoromethylphenyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 16 of Patent Application No. , 2-trifluoromethylbenzaldehyde (10 g., 0.057 mole) was reacted with trimethylsilylcarbonitrile (6.73 g., 0.068 mole) in the presence of zinc iodide (250 mg.) to yield
2- (2-trifluoromethylphenyl)-2-trimethylsiloxyethanenitrile as an oil (15.1 g., 97%; ir (CH2C12) 1316, 1170, 1124 cm-1].
EXAMPLE 10
2-(3-Phenoxyphenyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 16 of Patent Application No. \ , 3-phenoxybenzaldehyde (15 g., 0.076 mole) was reacted with trimethylsilylcarbonitrile (9.01 g., 0.091 mole) in the presence of zinc iodide (500 mg.) to yield
2-(3-phenoxyphenyl)-2-trimethylsiloxyethanenitrile as an oil (21.8 g., 96%; m/e 297; ir (CHjClj) 1587, 1481, 1140 cm1].
- 10 EXAMPLE 11
2-(2-Benzyloxyphenyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 1, 2-benzyloxybenzaldehyde (25 g., 0.118 mole) in 250 ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (14.06 g., 0.142 mole) in the presence of zinc iodide (500 mg.) to yield 2-(2-benzyloxyphenyl)-2—trimethylsiloxyethanenitrile as an oil [35.6 g., m/e 311, ir (CH2C12) 1605, 1493, 1418, 1220 cm-1].
EXAMPLE 12
2-(3-Trifluoromethylphenyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 16 of Patent Application No. , 3-trifluoromethylbenzaldehyde (10 g., 0.057 mole) was reacted with trimethylsilylcarbonitrile (6.73 g.,
0.068 mole) in the presence of zinc iodide (250 mg.) to yield 2-(trifluoromethylphenyl)-2-trimethylsiloxyethanenitrile as an oil [15.6 g., m/e 273; ir (CH.C1_) 1342, 1170,
-1 t ί
1136 cm x] .
- 11 EXAMPLE * 5 * * * * 10 * * 13 * 15 * * * * 20
2-(5-Chloro-2-methoxy~3-meth.ylph.enyl) -2-trimethylsiloxyethanenitrile
By the procedure of Example 1, 5-chloro-2-methoxy5 3-methylbenzaldehyde (1.98 g., 10.7 mmole) in 50 ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (1.27 g., 12.8 mmole) in the presence of zinc iodide (50 mg.) to yield 2-(5-chloro-2-methoxy-3methylphenyl)-2-trimethylsiloxyethanenitrile as an oil 10 (3.0 g., 99%; m/e 285/283? ir (CHjClj) 1471, 1117, 1096 cm-1).
EXAMPLE 14
2- (2-Chloro-6-methoxyphenyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 25 of Patent Application
No. , except that a 1 hour reaction time at room temperature was employed, 2-chloro-6-methoxybenzaldehyde (3.6 g., 0.021 mole) in 100 ml. of ether was reacted with trimethylsilylcarbonitrile (4.30 g., 0.042 mole) in the presence of zinc iodide (100 mg.), affording 2-(2-chloro6-methoxyphenyl)-2-trimethyl-siloxyethanenitrile as an oil (5.62 g., 99%, pnmr/CDClg/delta includes trimethylsilyl peak at 0.3 ppm., C-H product peak at about 6.7 ppm, no C-H aldehyde peak in the 10.4 region).
51428
- 12 EXAMPLE 15
2- (2-Chloro-6-fluorophenyl) -2-trimethyls iloxyethanenitrile_
Following the procedure of Example 25 of Patent 5 Application No. , except for use of a reaction time of
2.5 hours at room temperature, 2-chloro-6-fluorobenzaldehyde (10 g., 0.063 mole) in 150 ml. of ether was reacted with trimethylsilylcarbonitrile (12.5 g., 16 ml., 0.126 mole) in the presence of zinc iodide (100 mg.) to produce 2-(21q chloro-6-fluorophenyl)-2-trimethylsiloxyethanenitrile as an oil [18.2 g., incompletely dry; pnmr/^R^) j^/delta includes C-H at 5.55 ppm (split by fluorine), no aldehyde C-H (near
.4 ppm)].
EXAMPLE 16
2-(5-Bromo-2-methoxyphenyl)-2-trimethylsiloxyethanenitrile * 20 * * * * 25
-Bromo-2-methoxybenzaldehyde (15 g., 0.069 mole) in 100 ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (8.2 g., 10.5 ml., 0.083 mole) in the presence of 100 mg. of zinc iodide according to
Example 1. After 24 hours at room temperature, the reaction mixture was diluted with 100 ml.--=of methylene chloride and further isolated according to Example 1 to yield 2-(5-bromo-2-methoxyphenyl)-2-trimethylsiloxy25 ethanenitrile [21.1 g., solids; Rf- (1:1 ethyl acetate, chloroform) 0.78; pnmr/CDCl3/delta: 0.3 (9H), 4.0 (3H), 5.7 (1H), 6.7-7.8 (3H)]. '
- 13 EXAMPLE 17
2-(5-Chloro-2-ethoxyphenyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 1, 5-ehloro-2-ethoxy5 benzaldehyde (10 g., 0.054 mole) in 100 ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (6,4 g., 8.2 ml., 0.065 mole) in the presence of 100 mg. of zinc iodide. After 2.5 hours at room temperature, isolation was according to Example 52, yielding 10 2-(5-chloro-2-ethoxyphenyl)-2-trimethylsiloxyethanenitrile as an oil which crystallized on standing (14.8
g.; pnmr/ CH2Cl2:CHCl3/delta: 0.3 (9H) , 1.5 (3H), 4.2 (2S), 5.8 (1H), 6.7-7,.6 (3H)].
EXAMPLE 18
2-(2-Ethoxy-5-fluorophenyl)-2-trimethylsilyl.ethanenitrile
By the procedure of Example I* 5 * 7 * * 10 * * * * 15 * * * * 20, 2-ethoxy-5-fluorobenzaldehyde (10.2 g., 0.06 mole) in 120 ml. of methylene chloride was reacted with trimethylsilylcarbo20 nitrile (12 g., 15.3 ml., 0.12 mole) in the presence of zinc iodide (150 mg.) to yield 2-(2-ethoxy-5-fluorophenyl) -2-trimethylsilylethanenitrile as an oil [14.1 g., 88%; pnmr/CDC13/delta: 0.3 (s, 9H), 1.5 (t, 3B),
4.1 (c, 2Ξ), 5.8 (s, 1H), 6.8-7.6 (m, 4H)).
- 14 EXAMPLE 19
2-(2-Methoxy-5-methylphenyl)-2-trimethylsiloxyethaneni tr il e
By the procedure of Example 1, 2-methaxy-5-methyl5 benzaldehyde (15 g., 0.1 mole) in 300 ml. of methylenechloride was reacted with trimethylsilylcarbonitrile (19.8 g., 0.2 mole) in the presence of 200 mg. of zinc iodide to produce 2-(2-methoxy-5-methylphenyl)-2-tri— methylsiloxyethanenitrile as an oil [24.7 g., 99%, m/e
249, ir (CH2C12) 2899, 1613, 1497, 1050 cm_1j.
EXAMPLE 20
2-(5-Fluoro-2-methylphenyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 1, but using a stirring time of 16 hours at room temperature, 5fluoro-2-methylbenzaldehyde (8.2 g., 0.059 mole) in 200 ml. of methylene chloride was reacted with trimethyl silylcarbonitrile (8.9 g., 0.09 mole) in the presence of zinc iodide (100 mg.) to yield 2-(5-fluoro-2-methyl20 phenyl)-2-trimethylsiloxyethanenitrile as an oil (13.6 g., pnmr/CDCl3 includes 0.2 ppm peak due to protons of the trimethylsilyl group).
- 15 EXAMPLE 21
2-(3-Fluoro-2-methoxy-5-methylphenyl)-2trimethylsiloxyethanenitrile
3y the procedure of Example 20, 3-fluoro-2-methoxy~ 5 5-methylbenzaldehyde (0.5 g., 3 mmoles) in 25 ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (0.5 g., 0.6 ml., 4.5 mmoles) in the presence of zinc iodide (10 mg.) to yield 2-(3-fluoro-2-methoxy5-methylphenyl)-2-trimethylsiloxyethanenitrile as an 10 oil [0.49 g., pnmr (CHjClj) shows loss of the aldehyde peak at 10 ppm].
EXAMPLE 22
2-(3-Chloro-5-fluoro-2-methoxyphenyl)-2trimethylsiloxyethanenitrile
3y the procedure of Example 15 * * * * 20» 3-chloro-5fluoro-2-methoxybenzaldehyde (1.5 g., 8 mmoles) in ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (0.95 g., 9.6 mmoles) in the presence of 15 mg. of zinc iodide to yield 2-(3-chloro20 5-fluoro-2-methoxyphenyl)-2-trimethylsiloxyethanenitrile [2.13 g., 93%; ir (CH2C12) 1600, 1587, 1464, 1121 cm1].
- 16 EXAMPLE 23
2-(2-Ethoxy-6-fluorophenyl)-2-trimethylsiloxyethanenitrile
3y the procedure of Example 1, using a reaction 5 time of 1 hour at rodm temperature, 2-ethoxv-6-fluorobenzaldehyde (1.3 g., 7.7 mmoles) in 30 ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (1.5 g., 1.9 ml., 15.5 mmoles) in the presence of 30 mg. of zinc iodide to yield 2-(2-ethoxy-6-fluorophenyl)-210 trimethylsiloxyethanenitrile as an oil [1.21 g., Rf 0.7 (3:1 hexane:ethyl acetate)].
EXAMPLE 24
2-(2,5-Dimethylphenyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 16 of Patent Application
No. , using a 64 hour reaction time, 2,5-dimethylbenzaldehyde (10 g., 0.075 mole) was reacted with trimethylsilylcarbonitrile (8.91 g., 0.09 mole) in the presence of 200 mg. of zinc iodide to produce 2-(2,520 dimethylphenyl)-2-trimethyl-siloxyethanenitrile as an oil (15.4 g., 88%; m/e 233).
- 17 EXAMPLE 25
2-(2-Nitrophenyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 1,. using a stirring time of 2.5 hours at room temperature, 2-nitrobenzalde5 hyde (33 g., 0.22 mole) in 400 ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (43.3 g., 55.3 ml., 0.44 mole) in the presence of zinc iodide (125 mg.) to produce 2-(2-nitrophenyl)-2-trimethylsiloxyethanenitrile as an oil [54.7 g., 100%, pnmr/
CH^Cl^/delta includes 6.2 (s) and 7.4-8.3 (m); Rf (CHC13) 0.75].
EXAMPLE 26
2-(2-Methoxy-6-nitrophenyl)-2-trimethylsiloxyethanenitrile
By the procedure of Example 1, 2-methoxy-6-nitrobenzaldehyde [10 g., 0.055 mole; J. Org. Chem. 32, p. 1364 (1969)] in 250 ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (6.54 g., 0.066 mole) in the presence of 100 mg. of zinc iodide to yield 2-(2~methoxy-6-nitrophenyl)-2-trimethylsiloxyethanenitrile as an oil [13.3 g., 86%; m/e 280; ir (CH2C12) 1608, 1534, 1464, 1361 cm1].
- 18 EXAMPLE 27
2- {2,6-Difluorophenyl) -2-trimethylsiloxyethanenitrile
By the procedure of Example 1, except to use a 15 5 hour reaction period at room temperature, 2,6-difluoro benzaldehyde (9.1 g., 0.064 mole) in 100 ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (7.13 g., 0.072 mole) in the presence of 100 mg. of zinc iodide to yield 2-(2,6-difluorophenyl)-210 trimethylsiloxyethanenitrile as an oil [14.34 g., 93%; ir (CH2C12) 1626, 1600, 1471, 1190, 1081 cm”1]
- 19 EXAMPLE 28
2- (2-Methoxy-l-naphthyl)-2-trimethylsiloxyethanenitrlle
By the procedure of Example 3, employing ether in 5 place of methylene chloride, 2-methoxy-l-naphthaldehyde (25 g., 0.134 mole) in 100 ml. of ether was reacted with trimethylsilylcarbonitrile (15.8 g., 0.16 mole) in the presence of 2inc iodide (0.266 g.) to yield solid 2-(2methoxy-l-naphthyl)-2-trimethylsiloxyethanenitrile [36.7 g., pnmr/CDCl3/deltas 0.2 (s, 9H), 3.9 (s, 3E),
6.6 (s, IB), 7.0-8.0 and 8.4-8.6 (m, 6Ξ)].
EXAMPLE 29
2-(2-Ethoxy-l-naphthyl)-2-trimethyls Hoxyetha nenitr ile 15 * * * * 20 * * ay the procedure of Example 28, 2-ethoxynaphthaldehyde (4.5 g., 22.5 mmoles) in 50 ml. of ether was reacted with -trimethylsilylcarbonitrile (2.6 g., 27 mmoles) in the presence of zinc iodide (50 mg.) to yield 2- (2-ethoxy-l-aaphthyl)-2-trimethylsiloxyethane20 nitrile as an oil [5.8 g.; pnmr/CDCl3/deltas 0.2 (s,
9H),‘1.4 (t, 3S), 4.0 (q, 2H), 6.5 (s, IB), 7.0-8.0 (m,
5H), 8.5 (s, 1BH ·
- 20 EXAMPLE 30
2-(2-Benzyloxy-l-naphthyl) -2-trimethylsiloxyethanenitrile;
By the procedure of Example 28 , using a 48 hour reaction time, 2-benzyloxy-l-naphthaldehyde (9.0 g.,
0.034 moles) in 80 ml. of ether was reacted with trimethylsilylcarbonitrile (4.0 g., 0.041 moles) in the presence of about 65 mg. of zinc iodide to yield 2-(2benzyloxy-1-naphthyl)-2-trimethylsiloxyethanenitrile as a viscous oil [10.0 g., pnmr/CDCl^/delta: 0.2 {s, 9H), 5.2 (s, 2Ξ), 6.6 (s, 1H), 7-8.4 (m, UH) J .
EXAMPLE 31
2-(2-Fluoro-l—naphthyl)-2-trimethylsiloxyethanenitrUe
Following the procedure of Example 1, 2-fluoro-lnaphthaldehyde (2.0 g., 11 mmoles) in 80 ml. of methylene chloride was reacted with trimethylsilylcarbonitrile (1.4 g., 1.8 ml., 14 mmoles) in the presence of zinc iodide (20 mg.) to yield 2-(2-fluoro-l-naphthyl)-220 trimethylsiloxyethanenitrile as an oil (2.7 g., Rf 0.62 (CHClj)].
By the same method 2-chloro-l-naphthaldehyde is converted to 2-(2-chloro-l-naphthyl)-2-trimethylsiloxyethanenitrile .
- 21 EXAMPLE 32 .
2-(2-Methyl-1-naphthyl)-2-trimethylsiloxyethanenitrlle
Except for use of a reaction time of 12 hours at room temperature, the procedure of Example 1 was em5 ployed to react 2-methyl-l-naphthaldehyde (0.52 g., 3 mmoles) in 20 ml. of methylene chloride with trimethylsilylcarbonitrile (0.40 g., 3.9 mmole) in the presence of zinc iodide (10 mg.) to yield solid 2-(2-methyl-lnaphthyl)-2-trimethylsiloxyethanenitrile [0.71 g., Sf 10 0.35 (chloroform)].
EXAMPLE 33.
2-(2,5-Dimethoxy-l-naphthyl)-2-trimethylsiloxyethanenitrile ·
By the procedure of Example 25 of Patent Application 15 No. , 2,6-dimethoxy-l-naphthaldehyde (2.3 g., 10.6 mmoles) in 80 ml. of ether was reacted with trimethylsilylcarbonitrile (1.2 g., 12.7 mmoles) in the presence of 50 mg. of zinc iodide to yield solid 2-(2,6-dimethoxy-lnaphthyl)-2-trimethylsiloxyethanenitrile [3.5 g., Rf 0.75 (1:1 chloroform: ethyl acetate) pnmr/ether includes delta 6.8).
- 22 EXAMPLE 34
2-(7-Fluoro-l-naphthyl)-2-trimethylsiloxy'ethanenitrile
7-Fluoro-l-naphthaldehyde (4.7 g., 0.026 mole) in 5 150 ml. -of methylene chloride was reacted with, trimethylsilylcarbonitrile (3.4 g., 0.033 mole) in the presence of 50 mg. of zinc iodide by the procedure of Example 3,to. yield solid 2-(7-fluoro-l-naphthyl)-2trimethylsiloxyethanenitrile [6.2 g.; pnmr/CDCl^/delta 10 0.2 (s, 9H); 6.0 (s, 1H)? 7.2-8.0 (m, 6H)].
3y the same method, 7-chloro-l-naphthaldehyde is converted to 2-(7-chloro-l-naphthyl)-2-trimethylsiloxyethanenitrile .
EXAMPLE 35 15 2-(4-Fluorophenyl)-2-trimethylsiloxyethanenitrile
4-Fluorobenzaldehyde (20 g., 0.16 mole) and zinc iodide (200 mg.) were combined with. 100 ml. of ether and the mixture cooled to 0-5®C.. Trimethylsilylcarbo20 nitrile (19.1 g., 0.19 mole) was added dropwise and the mixture stirred overnight. The reaction pivVnrp was diluted with 100 ml. of ether and furt-h^v isolation following the methods' of Example 1 gave 2-(4-fluorophenyl) -2-trimethylsiloxyethanenitrile as an oil (31.7
- 23 The following illustrate the synthesis of certain intermediates:PREPARATION 1
-Bromo-2-methoxybenzaldehyde g-Bromoanisole (15 g., 0.08 mole) in 350 ml. of methylene chloride was cooled to 0*C. Titanium tetrachloride (30 g., 17.4 ml., 0.16 mole) was added dropwise. After 10 minutes 1,.1-dichloromethyl methyl ether (12.7 g., 0.088 mole) was added dropwise and the re10 action stirred for 90 minutes at 0-10*C., then quenched into excess saturated sodium bicarbonate and methylene chloride. The organic layer was separated and combined with a further methylene chloride extract of the aqueous phase. .The combined organic layers were back washed with saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to yield 5-bromo-2-methoxybenzaldehyde (16.4 g., m.p. 107-110’C.).
- 24 PREPARATION 2
4-Ethoxyphenyl· Chloride
D-Chlorophenol (10 g., 0.077 mole), ethyl iodide (13.1 g., 0.084 mole) and anhydrous potassium carbonate (10.6 g., 0.077 mole) were combined in 130 ml. of acetone and the stirred mixture heated to reflux for 16 hours. The reaction mixture was filtered and the filtrate evaporated to dryness. The residue was taken up in 300 ml. of chloroform, washed in sequence with two
120 ml. portions of IN sodium hydroxide, 50 ml. of brine and 50 ml. of water, dried over anhydrous magnesium sulfate, filtered and evaporated to yield 4ethoxyphenyl chloride as an oil [10.5 g.; pnmr/CDCl^/ delta 1.4 (t, 3H), 4.0 (q, 2H), 6.6-7.3 (in, 4H) ].
PREPARATION 3
-Chloro-2-ethoxyben'zaldehyde
By the procedure of Preparation 1, using a reaction t-imp of 2.5 hours at 0°C. after addition of reagents was complete, 4-ethoxyphenyl chloride (10 g.,
0.064 mole) in 300 ml. of methylene chloride was converted to solid 5-chloro-2-ethoxybenzaldehyde [11 g.,
Rf 0.12 (3:1 hexane:chloroform)].
- 25 PREPARATION 4
2-Ethoxy-5-fluorobenzaldehyde
By the procedure of Preparation 3, using a reaction time of 2 hours at 5-10’C., 4-ethoxyphenyl fluoride (9.4 g., 0.067 mole) was converted to solid 2-ethoxy5-fluorobenzaldehyde [10.4 g., Rf 0.65 (CHCl^)].
PREPARATION 5
2-Methoxy-5-methylbenzaldehyde
4-Methylanisole (12.2 g., 0.1 mole) in 300 ml. of methylene chloride was cooled to 0’C. Titanium tetrachloride (3.8 g., 0.2 mole) was added followed by the dropwise addition of 1,1-dichloromethyl methyl ether (13.8 g., 0.12 mole) over 3 minutes. After stirring for 30 minutes at 0*C., the reaction mixture was poured
IS into 600 ml. of water. The aqueous phase was extracted with two further portions of methylene chloride. The combined organic phase/extracts was washed with brine, dried over anhydrous magnesium sulfate and evaporated to yield 2-methoxy-5-methylbenzaldehyde as an oil [15 g., 100%; ir (0¾¾) 1678, 1608, 1488 cm1].
- 26 PREPARATION 6
-F luo r ο - 2-methyIben z aldehyde
By the procedure of Preparation 1, allowing the reaction mixture to warm to room temperature and stir for 16 hours after addition of reagents was complete, £-fluorotoluene (10 g., 0.09 mole) in 300 ml. of methy lene chloride was converted to S-fluoro-2-methylbenzaldehyde [8.2 g., Rf 0.6 (CHC13)].
PREPARATION 7
R-Fluoro-I-methoxy-S-methylbenzaldehyde
By the procedure of Preparation 5, 2-fluoro-4methylanisole (2.0 g., 14.2 mmoles) in 70 ml. of methylene chloride was converted to crude product (2.3 g.). Chromatography on‘300 g. of silica gel,
IS eluting with 1:1 chloroform: hexane, monitoring by tic, gave, as the minor, less polar of two components, 3fluoro-2-methoxy-5-methylbeazaldehyde [0.5 g., oil, Rf 0.25 (1:1 chloroform: hexane)].
- 27 PREPARATION 8
3-Chloro-5-fluoro-2-hydroxybenzaldehyde
Sodium hydroxide (50 g.) was dissolved in 70 ml. of water. 2-Chloro-4-fluorophenol (10 g., 0.068 mole) was added and then chloroform (30 ml.) The mixture was refluxed for two hours. Addition of chloroform (30 ml.) and reflux for 2 hours was twice repeated. The reaction mixture was cooled to room temperature and crude product recovered as the sodium salt by filtration. The crude was taken into water and acidified with IN hydrochloric acid to yield product (6.6 g.) in the free phenolic-form. The latter was chromatographed on 200 g. of silica gel, with 1:1 methylene chloride: hexane as eluant. The column was monitored by tic. Clean product containing fractions were combined and evaporated to dryness to yield purified 3-chloro-5-fluoro-2-hydroxybenzaldehyde [3.08 g.; m.p. 81-83*C., Rf 0.49 (1:1 methylene chloride: hexane); ir (CH2C12) 1658, 1460, 1439, 1289, 1230, 1116 cm1].
51425
- 28 PREPARATION 9
3-Chloro-5-fluoro-2-methoxybenzaldehyde
3-Chloro-5-fluoro-2-hydroxybenzaldehyde (2.5 g., 0.014 mole) was taken into 25 ml. of acetone. Potas5 sium carbonate (2.48 g., 0.018 mole) and methyl iodide (2.55 g., 0.018 mole) were added in sequence and the mixture stirred for 16 hours at room temperature. The reaction mixture was filtered and the filtrate concentrated to an oil. The oil was partitioned between methylene chloride and water. The organic layer was washed in sequence with fresh water, IN sodium hydroxide and brine, dried over anhydrous magnesium sulfate, and concentrated to yield 3-chloro-5-fluoro-215 methoxybenzaldehyde (1.83 g., 69%; m.p. 59-62°C.).
- 29 PREPARATION 10
2-Fluoro-6-hydroxybenzaldehyde
According to the procedure of Preparation 9, 3fluorophenol (19.2 g.) in sodium hydroxide/water (120 g./133 ml.) was reacted with chloroform (three ml. portions). The reaction mixture was cooled and filtered. The resulting solids were partitioned between saturated brine and ethyl acetate, the pH was adjusted to 7.0 with diluted hydrochloric acid, and the ethyl acetate layer separated and held. The earlier filtrate was adjusted to pH 7.0 with cone, hydrochloric acid and extracted with ethyl acetate. The earlier and later ethyl acetate extracts were combined, back washed with water and then brine, dried over anhydrous mag15 nesiua sulfate, filtered and evaporated to partially solid crude product (14.6,g.). The crude product was chromatographed on 200 g. of silica gel, eluting with 6:1 hexane: ether, monitoring hy tic. The less polar component was collected .in early fractions, which were combined and evaporated to yield 2-fluoro-6-hydroxybenzaldehyde, as an oil which partially crystallized on standing [1.4 g.j Rf 0.8 (2:1 chloroform: hexane)].
S1429
- 30 PREPARATION 11
2-Ethoxy-6-fluorobenzaldehyde
By the procedure of Preparation 9, 2-fluoro-6hydroxybenzaldehyde (1.4 g., 10 mmoles), ethyl iodide (1.7 g., 11 mmoles) and potassium carbonate (1.38 g., mmoles) in 18 ml. of acetone were ..converted to 2ethoxy-6-fluorobenzaldehyde as an oil [1.37 g., ir (CH2C12) 1681, 1600, 1471, 1282, 1111, 1064 cm-1];.
PREPARATION 12
2-Chloro-6-methoxybenzaldehyde
2-Chloro-6-fluorobenzaldehyde (51.5 g., 0.030 mole) was taken into 500 ml. of methanol. Sodium hydroxide (14.4 g., 0.35 mole) was added and the stirred reaction mixture heated to reflux for 3 hours.
X5 The mixture was cooled to room temperature, and the volume reduced.to 200 ml. by distillation in vacuo. Water (400 ml.) and methylene chloride (200 ml.) were added and the two phase system equilibrated. The organic phase was separated and the aqueous phase ex20 tracted with two additional 100 ml. portions of methylene chloride. The combined organic layers .were dried over anhydrous sodium sulfate, filtered and the •methylene chloride removed by distillation at atomspheric pressure with displacement by hexane (450 ml.) to a final volume of 300 ml. The product layer, initially present as an oil, began to crystallize at 45°C. The-mixture was cooled to room temperature, granulated for 16 hours, and filtered to yield 2-chloro
6-methoxybenzaldehyde [35.6 g., 64.2%; Rf 0.2 (CHClj)].
- 31 PREPARATION 13
2-Methoxy-5-nitrobenzaldehyde £-Nitroanisole (25 g., 0.163 mole) was dissolved in 400 ml. of methylene chloride and cooled to 10°C.
S Titanium tetrachloride (61.8 g., 36 ml., 0.326) was added, followed by 1,1-dichloromethyl methyl ether added over 2 minutes. The mixture was warmed to room temperature and stirred for 42 hours. The reaction mixture was diluted with 1 liter of ice and water and extracted with three 500 ml. portions of methylene chloride. The organic extracts were combined, washed with two portions of water and one of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil (20 g.). The oil was chromatographed on 600 g. silica gel, using 2:1 methylene chloride: hexane as eluant, collecting 15 ml. fractions, and monitoring by tic.. Clean product fractions 79-185 were combined and evaporated to yield 2-methoxy-5nitrobenzaldehyde (3.8 g.; m.p. 87-89, literature m.p.
89-90·).
- 32 PREPARATION 14
2,6-Difluorobenzaldehyde
1,3-Difluorobenzene (25 g., 0.22 mole) was dissolved in 150 ml. of tetrahydrofuran and cooled to -50°C
Butyl lithium (99 ml. of 2.3M in hexane, 0.228 mole) was added over 20 minutes, maintaining the temperature at -50-C. After 1.5 hours of stirring at the same temperature, N-methylformanilide (29.7 g., 0.22 mole) in 50 ml. of tetrahydrofuran was added over 20 at “50°C. After an additional 1.5 hours of stirring at -50°C., the reaction mixture was poured slowly into 1 liter of cold IN sulfuric acid, and extracted with three portions of ether. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was distilled. Middle cuts were combined to yield 2,6difluorobenzaldehyde. (18.2 g., 58%; b.p. -72-74-/12 mm.) .
51489
- 33 PREPARATION 15
2-Sthoxy-l-naphthaldeh.yde
2-Bydroxy-1-naphthaldehyde (10 g., 0.058 mole) was combined with acetone (120 ml.), iodoethane (9.9 g.,
0.063 mole) and anhydrous potassium carbonate (8.0 g.,
0.058 mole) and the mixture heated to reflux for 48 hours. The reaction mixture was cooled to room temperature, filtered and filtrate evaporated to solids (9.0 g.) Recrystallization from isopropyl ether af10 forded purified 2 -etho'xy-1 -naphthaldehyde in two crops (4.5 g. and 0.5 g., m.p. 106-109C.).
PREPARATION 16
2-Benzyloxy-l-napttthaldehyde
By the procedure of Preparation I5, substituting IS equivalent benzyl bromide (10.7 g., 0.063 moles) for ethyl iodide and recrystallizing the crude product from a mixture of isopropyl ether and toluene, 2-hydroxy-lnaphthaldehyde was converted to 2-benzyloxy-l-naphthaldehyde [9.2 g,, m..p. 111-113’C., pnmr/CDCl^/deltas
.2 (s, 2H), 7.0-8.0 (m, 11H). 8.7 (s, 1H)J.
51439
-. 34 PREPARATION· 17
7-Fluoro-l-naphthaldehyde and 2-Fluoro-l,naphthaldehyde
By the method o£ Preparation 1, 2-fluoronaphthalene 5 (10 g., 0.068 mole) in 200 ml. of methylene chloride was reacted with titanium tetrachloride (25.5 g.,
14.7 ml. 0.136 mole) and 1,1-dichloromethyl methyl ether (10.1 g., 0.088 mole). The resulting crude . product (11 g.) was first recrystallized from hexane 10 to yield 7-fluoro-l-naphthaldehyde [2.5 g., m.p.
95-96°C., Rf 0.25 (1:1 chloroform: hexane)J. The mother liquor was evaporated·to dryness and the residue chromatographed on 400 g. of silica gel, eluting initially with 3:1 hexane: chloroform and then with 3:2 15 hexane: chloroform. The column was monitored by tic. Fractions contain clean 2-fluoro-l-naphthaldehyde [Rf 0.31 (3:2 hexane: chloroform)] were combined and evaporated to dryness, yielding purified 2-fluoro-lnaphthaldehyde (2.8 g., m.-p. 60-62“C.).
By the same method, 2-chloronaphthalene is converted to 7-chloro-l-naphthaldehyde and 2-chloro-l-naphthaldehyde
- 35 PREPARATION 18
2-Methyl-l-naphthaldehyde
By the method of Preparation 1, except that a reaction time of 1 hour at 0°C. was employed, 2-methyli naphthalene (10 g., 0.070 mole) in 200 ml. of methylene chloride was reacted with titanium tetrachloride (52.6 g., 30.5 ml., 0.28 mole) and 1,1-dichloromethyl methyl ether (24.1 g., 0.21 mole). The crude product, obtained as an oil, was distilled, yielding 12.2 g. of distillate b.p. 155-160Ό./2.3-3.0 mm. On standing, crystalline product separated from the distillate. Filtration gave purified 2-methyl-l-naphthaldehyde (0.53 g., m.p. 48-50’C.).
PREPARATION 1?
2,6-Dimethoxy-l-naphthaldehyde
By the method of Preparation 1, 2,6-dimethoxynaphthalene (5 g., 26 mmoles) in 150 ml. of methylene chloride was reacted with titanium tetrachloride (19.7
g., 11.4 ml., 104 mmoles) and 1,1-dichloromethyl methyl ether (8.9 g., 78 mmoles). The resulting crude product was recrystallized from toluene, affording purified
2,6-dimethoxy-l-naphthaldehyde (1.0 g., m.p. 285288*C.).
Claims (2)
1. CLAIMS :1. A compound of the formula or 5142» - 37 T is fluoro; T 3 is benzyloxy, chloro, phenoxy, nitro or tri fluoromethyl ; T is benzyloxy, phenoxy, nitro or trifluoro5 Diethyl; is methyl, (C^-Cg)alkoxy, methylthio, chloro or fluoro; i) 5 T and T are each independently hydrogen, methyl, bromo, chloro, fluoro, cyano, nitro or trifluor'omethyl ; Y is hydrogen, methyl, benzyloxy, (C^-Cg)alkoxy, chloro, bromo or fluoro; Y 1 is hydrogen or methoxy; and Y is fluoro or chloro? with the proviso that when T 3 is chloro, at least one of T and T is other than hydrogen.
2. A compound of the formula given and defined in Claim 1, which is any one of those specifically hereinbefore mentioned.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US17320680A | 1980-07-28 | 1980-07-28 | |
| US06/222,202 US4367234A (en) | 1980-07-28 | 1981-01-02 | Hypoglycemic 5-substituted oxazolidine-2,4-diones |
| IE1695/81A IE51427B1 (en) | 1980-07-28 | 1981-07-27 | Hypoglycemic 5-substituted oxazolidine-2,4-diones |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE51429B1 true IE51429B1 (en) | 1986-12-24 |
Family
ID=27270387
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE3015/84A IE51428B1 (en) | 1980-07-28 | 1981-07-27 | Intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones |
| IE419/85A IE51429B1 (en) | 1980-07-28 | 1981-07-27 | Trimethylsilyl cyanohydrin intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones |
| IE850419A IE850419L (en) | 1980-07-28 | 1981-07-27 | Intermediates |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE3015/84A IE51428B1 (en) | 1980-07-28 | 1981-07-27 | Intermediates for hypoglycemic 5-substituted oxazolidine-2,4-diones |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE850419A IE850419L (en) | 1980-07-28 | 1981-07-27 | Intermediates |
Country Status (1)
| Country | Link |
|---|---|
| IE (3) | IE51428B1 (en) |
-
1981
- 1981-07-27 IE IE3015/84A patent/IE51428B1/en unknown
- 1981-07-27 IE IE419/85A patent/IE51429B1/en unknown
- 1981-07-27 IE IE850419A patent/IE850419L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE850419L (en) | 1982-01-28 |
| IE843015L (en) | 1982-01-28 |
| IE51428B1 (en) | 1986-12-24 |
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