CA1088098A - Isobutyramides and preparation thereof - Google Patents
Isobutyramides and preparation thereofInfo
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- CA1088098A CA1088098A CA274,001A CA274001A CA1088098A CA 1088098 A CA1088098 A CA 1088098A CA 274001 A CA274001 A CA 274001A CA 1088098 A CA1088098 A CA 1088098A
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- isobutyramide
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- chlorophenoxy
- cyanoethyl
- sodium
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Abstract
ABSTRACT OF THE DISCLOSURE
The invention relates to nove1 isobutyramides of the formula:
The invention relates to nove1 isobutyramides of the formula:
Description
10~809~
This invention relates to new isobutyramides and to a method for their preparation.
The novel isobutyramides I of this invention have the following general formula:
Rl ~ O - C - CO - NH - (CH2) - CN
wherein Rl represents a halogen atom and n is an integer from
This invention relates to new isobutyramides and to a method for their preparation.
The novel isobutyramides I of this invention have the following general formula:
Rl ~ O - C - CO - NH - (CH2) - CN
wherein Rl represents a halogen atom and n is an integer from
2 to 6. The new compounds may be prepared by various methods hereinafter described.
In a first method an acyl chloride II of the formula:
Rl ~ O - C - COCl II
wherein Rl is as described above is reacted with an aminoalkyl nitrile derivatives III of the formula:
NH2 - (CH2)n - CN III
n being as defined above. The reaction is carried out in a suitable solvent such as a mixture of polar and non-polar solvents such as a mixture of dichloroethane and triethylamine and the like.
Another method for preparing the compounds of the present invention comprises reacting a substituted sodium phenolate IV of the formula:
Rl ~ ONa IV
with an N-cyanoalkyl-~-bromo-isobutyramide V of the formula:
Br - C - CONH - (CH2)n - CN V
10~09~
wherein Rl and n are as previously defined. The reaction is preferably carried out in the presence of a non-polar solvent such as ethanol. The N-cyanoalkyl-a-bromo-isobutyramide V may be obtained by interacting a-bromo-isobutyryl chloride VI with an aminoalkyl nitrile III as illustrated in the following reaction scheme:
fH3 Br - f - COCl + NH2 ~ (CH2)n - CN >
VI III
fH3 Br - f - CONH(CH2)nCN V
The starting phenolate IV is obtained by reacting the corresponding phenol with sodium in solution in ethanol. The ethanol is then diluted with an excess toluene after reaction of the sodium phenolate with the isobutyramide followed by distillation of the azeotrope.
The compounds of the present invention can also be prepared by the reaction in dioxane of the correspondingly substituted phenoxy isobutyramide of the formula:
Rl~o - f-- C0 - NH2 on the appropriate N-cyanoalkylene CH2=CH-(CH2)p-CN wherein p is an integer from 0 to 4 in the presence of a basic agent such as soda, at a temperature between 50 and 65C.
The reaction scheme is as follows:
10~09~
~ fH3 Basic agent 1 ~ 0 f - C0 - NH2 + CH2 = CH- (CH2)p CH
Rl ~ 0 - C - C0 - NH - (CH2jn - CN
The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention only.
N-cyanoethyl-p-chlorophenoxy isobutyramide In a 2.5 litre reactor fitted with cooling and stirring means there were poured 1 litre of dry dichloroethane, 74 9 of triethylamine and 52 9 ~0.74 mol) of 3-aminopropio-nitrile. The mixture was stirred and there was then slowly added over a period of 30 minutes, a solution of 172 9 (0.74 mol) of p-chlorophenoxy isobutyryl chloride in 0.5 litres of dry dichloroethane. The temperature was maintained below 10C
during the addition period and then the mixture was refluxed for 4 hours and evaporated to dryness. The product obtained was washed with a sodium carbonate solution, treated with water, extracted with chloroform, dried, treated with diethyl ether and crystallized from di-isopropylether.
There was thus obtained 128 9 (yield 65%) of a white crystalline product melting at 70C, the composition of which is in complete agreement with the formula C13H15N202Cl (molecular weight 266.7).
This compound is insoluble in water but soluble in many organic solvents. The p-chlorophenoxy isobutyric acid chloride was obtained from p-chlorophenoxy isobutyric acid treated by SOC12 in anhydrous benzene.
. ~, .~ Ø
.~
10~8098 N-cyanoethyl-p-fluorophenoxy isobutyramide The procedure of Example 1 was repeated except that the p-chlorophenoxy isobutyryl chloride was replaced by p-fluorophenoxy isobutyryl chloride.
There was thus obtained, with a yield of 71%, a white crystalline product melting at 75C. The composition of the product was in agreement with the formula C15Hl5N202F;
(molecular weight 250.2).
N-cyanobutyl-p-chlorophenoxy isobutyramide The procedure of Example 1 was repeated except that
In a first method an acyl chloride II of the formula:
Rl ~ O - C - COCl II
wherein Rl is as described above is reacted with an aminoalkyl nitrile derivatives III of the formula:
NH2 - (CH2)n - CN III
n being as defined above. The reaction is carried out in a suitable solvent such as a mixture of polar and non-polar solvents such as a mixture of dichloroethane and triethylamine and the like.
Another method for preparing the compounds of the present invention comprises reacting a substituted sodium phenolate IV of the formula:
Rl ~ ONa IV
with an N-cyanoalkyl-~-bromo-isobutyramide V of the formula:
Br - C - CONH - (CH2)n - CN V
10~09~
wherein Rl and n are as previously defined. The reaction is preferably carried out in the presence of a non-polar solvent such as ethanol. The N-cyanoalkyl-a-bromo-isobutyramide V may be obtained by interacting a-bromo-isobutyryl chloride VI with an aminoalkyl nitrile III as illustrated in the following reaction scheme:
fH3 Br - f - COCl + NH2 ~ (CH2)n - CN >
VI III
fH3 Br - f - CONH(CH2)nCN V
The starting phenolate IV is obtained by reacting the corresponding phenol with sodium in solution in ethanol. The ethanol is then diluted with an excess toluene after reaction of the sodium phenolate with the isobutyramide followed by distillation of the azeotrope.
The compounds of the present invention can also be prepared by the reaction in dioxane of the correspondingly substituted phenoxy isobutyramide of the formula:
Rl~o - f-- C0 - NH2 on the appropriate N-cyanoalkylene CH2=CH-(CH2)p-CN wherein p is an integer from 0 to 4 in the presence of a basic agent such as soda, at a temperature between 50 and 65C.
The reaction scheme is as follows:
10~09~
~ fH3 Basic agent 1 ~ 0 f - C0 - NH2 + CH2 = CH- (CH2)p CH
Rl ~ 0 - C - C0 - NH - (CH2jn - CN
The present invention will be more readily understood by referring to the following examples which are given to illustrate the invention only.
N-cyanoethyl-p-chlorophenoxy isobutyramide In a 2.5 litre reactor fitted with cooling and stirring means there were poured 1 litre of dry dichloroethane, 74 9 of triethylamine and 52 9 ~0.74 mol) of 3-aminopropio-nitrile. The mixture was stirred and there was then slowly added over a period of 30 minutes, a solution of 172 9 (0.74 mol) of p-chlorophenoxy isobutyryl chloride in 0.5 litres of dry dichloroethane. The temperature was maintained below 10C
during the addition period and then the mixture was refluxed for 4 hours and evaporated to dryness. The product obtained was washed with a sodium carbonate solution, treated with water, extracted with chloroform, dried, treated with diethyl ether and crystallized from di-isopropylether.
There was thus obtained 128 9 (yield 65%) of a white crystalline product melting at 70C, the composition of which is in complete agreement with the formula C13H15N202Cl (molecular weight 266.7).
This compound is insoluble in water but soluble in many organic solvents. The p-chlorophenoxy isobutyric acid chloride was obtained from p-chlorophenoxy isobutyric acid treated by SOC12 in anhydrous benzene.
. ~, .~ Ø
.~
10~8098 N-cyanoethyl-p-fluorophenoxy isobutyramide The procedure of Example 1 was repeated except that the p-chlorophenoxy isobutyryl chloride was replaced by p-fluorophenoxy isobutyryl chloride.
There was thus obtained, with a yield of 71%, a white crystalline product melting at 75C. The composition of the product was in agreement with the formula C15Hl5N202F;
(molecular weight 250.2).
N-cyanobutyl-p-chlorophenoxy isobutyramide The procedure of Example 1 was repeated except that
3-aminopropionitrile was replaced by 5-amino pentanonitrile;
yield 81% of a white crystalline product melting at 88C the analysis of which shows a good correspondence with the formula C15HlgN202Cl~
The compounds obtained according to this invention have been submitted to toxicological, pharmacological and clinical studies which are summarized thereafter.
N-cyanoethyl-p-chlorophenoxy isobutyramide Into a 25 litre reactor fitted with cooling and stirring means there were poured 3 litres of ethanol, 60 9 of sodium and 250 g of p-chlorophenol (1.944 mol). After stirring for 1 hour there were added 3 litres of toluene and the ethanol/toluene azeotrope was removed by distillation; 2 more litres of toluene were added and also 425 9 of N-cyanoethyl-~-bromo-isobutyramide, (1.944 mol).
The mixture was refluxed for 10 hours, and 2 litres of toluene were then removed by distillation. The resulting mixture was treated with water which gave a precipitate which ~u~o9~
was separated, washed with water, made acid with HCl until it was neutral, dried and crystallized from di-isopropylether.
There were thus obtained 348 9 (yield 67%) of a white crystalline product melting at 71C. The composition of the product corresponded to the formula C13H1502N2Cl (molecular weight 266.72). The compound was insoluble in water but solu-ble in most common organic solvents.
N-cyanoethyl-p-fluorophenoxy isobutyramide The procedure of Example 4 was repeated except that the p-chlorophenol was replaced by p-fluorophenol, which after the sodium treatment was reacted with N-cyanoethyl-~-bromo-isobutyramide.
There was thus obtained, with a yield of 67% a hhite crystalline product melting at 75C. The analysis shows a good correspondence with the formula C13H1502N2 (molecular weight 250.2).
N-cyanobutyl-p-chlorophenoxy isobutyramide The procedure of Example 4 was repeated except that N-cyanoethyl-~-bromo-isobutyramide was replaced by N-cyanobutyl-~-bromo-isobutyramidej yield 87% of a white crystalline product melting at 88C the analysis of which shows a good corre-spondence with the formula C15HlgN202Cl.
N-cyanoethyl-p-chlorophenoxy isobutyramide In a 5 1 reactor fitted with warming, cooling and stirring means is prepared, at 60C, a solution of 1.220 9 (5.71 mol) of p-chlorophenoxy isobutyramide in 1.81 of dioxane.
There is then added 23 g of powdered soda and slowly (in 15 minutes), while maintaining the temperature between 60 and iOt~8098 65C, 394 ml of acrylonitrile. The reaction mixture is stirred for 15 minutes at the same temperature, then treated by 60 g of carbon black, filtered. 1.6 1 of dioxane are added to the filtrate and after stirring, there is slowly added 10 1 of demineralized water, stirring is maintained for 2 hours and the reaction mixture is allowed to rest for 12 hours. After sepa-ration of the precipitate, washing with water and drying at 40C, there is obtained 1.380 9 at a beige product which, after recrystallization (isopropanol ~ water) leads to 1.001 9 (yield 73%) of a white crystalline product melting at 71C, the analysis of which shows a very good correspondence with the formula C13H1502N2Cl N-cyanoethyl-p-fluorophenoxy isobutyramide The procedure of Example 7 was repeated but p-chloro-phenoxy isobutyramide was replaced by p-fluorophenoxy isobutyr-amide. Yield 64% of a white crystalline product melting at 75C, the analysis of which shows a good correspondence with the formula C13Hl502N2F.
N-cyanobutyl-p-chlorophenoxy isobutyramide The procedure of Example 7 was repeated but acrylo-nitrile was replaced by pentylenonitrile; yield 77% in a white crystalline product melting at 88C, the analysis of which shows a good correspondence with the formula C15HlgN202Cl.
TOXICITY
The acute toxicity has been determined per os on mice and rats, by the usual technics. The LD 50 values are respectively 1 g/kg for mice and over 2.4 g/kg for rats for the compound of Example 1.
For the compounds of Examples 2 and 3, the LD 50 was 10~8098 1.2 g/kg for both, on mice and over 2.5 g/kg for both, on rats.
The subacute toxicity of the compound of Example 1 was researched on rats at the doses of 40, 80 and 160 mg/kg (per os) and no difference was noticed between treated and control animals.
PHARMACOLOGY
C Triton test.
An experimental hyperlipemia and hypercholesterolemia are induced in male rats by an intraperitoneal injection of t~
triton (dose: 5 ml/kg); these rats are treated immediately per os, either by the product of Example 1 or by 2-(4-chloro-phenoxy) 2-methylpropanoïc acid ethyl ester or by nicotinic acid (three batches of each 10 animals) at the same doses. The best hypocholesterolemic activities are found for the compound of the invention and the first reference compound whereas the best hypotriglyceridemic activities are found for the second reference compound and the compound of invention.
CLINIC
20 patients were treated comparatively, successively by 2-(4-chlorophenoxy) 2-methylpropanoïc acid ethyl ester -reference compound - (30 days, 2 g/day) and, after 15 days without treatment, by the compound of Example 1 - invention compound - (30 days, 2 g/day); the average figures in 9/1 for initial values final values and decrease for triglycerids, total cholesterol and total lipids are listed in the following table I.
10~09t~
TABLE I
.__ __ REFERENCE COMPOUND INVENTION COMPOUND
Tri~lycerids Initial 1.611 (+ 0.098) 1.59 (+ 0.155) Final 1.137 (+ 0.085) 1.082 (+ 0.101) Decrease 0.474 (+ 0.102) 0.507 (+ 0.088) Total cholesterol ..
Initial 3.31 (+ 0.121) 3.17 (+ 0.151) Final 2.85 (+ 0.170) 2.70 (+ 0.169) Decrease 0.46 (+ 0.107) 0.47 (+ 0.058) Total lipids Initial 9.985 (+ 0.342) 9.94 (+ 0.454) Final 8.775 (+ 0.491) 8.367 (+ 0.431) Decrease 1.210 (+ 0.244) 1.572 (+ 0.198) The activity of the compound of the invention appears similar on the total cholesterol rate but more favourable on the triglycerids and total lipids rate.
PRESENTATION - POSOLOGY
The compound of the invention may be presented in any suitable form for use in human therapy. For instance, a form for oral administration may be a gelatin capsule containing:
- compound of any of the examples 0.500 9 - silicic acid 0.018 9 - talc 0.042 9 0.560 9 As to the posology, according to the patients, it may be comprised between 0.5 and 4 9 per day.
yield 81% of a white crystalline product melting at 88C the analysis of which shows a good correspondence with the formula C15HlgN202Cl~
The compounds obtained according to this invention have been submitted to toxicological, pharmacological and clinical studies which are summarized thereafter.
N-cyanoethyl-p-chlorophenoxy isobutyramide Into a 25 litre reactor fitted with cooling and stirring means there were poured 3 litres of ethanol, 60 9 of sodium and 250 g of p-chlorophenol (1.944 mol). After stirring for 1 hour there were added 3 litres of toluene and the ethanol/toluene azeotrope was removed by distillation; 2 more litres of toluene were added and also 425 9 of N-cyanoethyl-~-bromo-isobutyramide, (1.944 mol).
The mixture was refluxed for 10 hours, and 2 litres of toluene were then removed by distillation. The resulting mixture was treated with water which gave a precipitate which ~u~o9~
was separated, washed with water, made acid with HCl until it was neutral, dried and crystallized from di-isopropylether.
There were thus obtained 348 9 (yield 67%) of a white crystalline product melting at 71C. The composition of the product corresponded to the formula C13H1502N2Cl (molecular weight 266.72). The compound was insoluble in water but solu-ble in most common organic solvents.
N-cyanoethyl-p-fluorophenoxy isobutyramide The procedure of Example 4 was repeated except that the p-chlorophenol was replaced by p-fluorophenol, which after the sodium treatment was reacted with N-cyanoethyl-~-bromo-isobutyramide.
There was thus obtained, with a yield of 67% a hhite crystalline product melting at 75C. The analysis shows a good correspondence with the formula C13H1502N2 (molecular weight 250.2).
N-cyanobutyl-p-chlorophenoxy isobutyramide The procedure of Example 4 was repeated except that N-cyanoethyl-~-bromo-isobutyramide was replaced by N-cyanobutyl-~-bromo-isobutyramidej yield 87% of a white crystalline product melting at 88C the analysis of which shows a good corre-spondence with the formula C15HlgN202Cl.
N-cyanoethyl-p-chlorophenoxy isobutyramide In a 5 1 reactor fitted with warming, cooling and stirring means is prepared, at 60C, a solution of 1.220 9 (5.71 mol) of p-chlorophenoxy isobutyramide in 1.81 of dioxane.
There is then added 23 g of powdered soda and slowly (in 15 minutes), while maintaining the temperature between 60 and iOt~8098 65C, 394 ml of acrylonitrile. The reaction mixture is stirred for 15 minutes at the same temperature, then treated by 60 g of carbon black, filtered. 1.6 1 of dioxane are added to the filtrate and after stirring, there is slowly added 10 1 of demineralized water, stirring is maintained for 2 hours and the reaction mixture is allowed to rest for 12 hours. After sepa-ration of the precipitate, washing with water and drying at 40C, there is obtained 1.380 9 at a beige product which, after recrystallization (isopropanol ~ water) leads to 1.001 9 (yield 73%) of a white crystalline product melting at 71C, the analysis of which shows a very good correspondence with the formula C13H1502N2Cl N-cyanoethyl-p-fluorophenoxy isobutyramide The procedure of Example 7 was repeated but p-chloro-phenoxy isobutyramide was replaced by p-fluorophenoxy isobutyr-amide. Yield 64% of a white crystalline product melting at 75C, the analysis of which shows a good correspondence with the formula C13Hl502N2F.
N-cyanobutyl-p-chlorophenoxy isobutyramide The procedure of Example 7 was repeated but acrylo-nitrile was replaced by pentylenonitrile; yield 77% in a white crystalline product melting at 88C, the analysis of which shows a good correspondence with the formula C15HlgN202Cl.
TOXICITY
The acute toxicity has been determined per os on mice and rats, by the usual technics. The LD 50 values are respectively 1 g/kg for mice and over 2.4 g/kg for rats for the compound of Example 1.
For the compounds of Examples 2 and 3, the LD 50 was 10~8098 1.2 g/kg for both, on mice and over 2.5 g/kg for both, on rats.
The subacute toxicity of the compound of Example 1 was researched on rats at the doses of 40, 80 and 160 mg/kg (per os) and no difference was noticed between treated and control animals.
PHARMACOLOGY
C Triton test.
An experimental hyperlipemia and hypercholesterolemia are induced in male rats by an intraperitoneal injection of t~
triton (dose: 5 ml/kg); these rats are treated immediately per os, either by the product of Example 1 or by 2-(4-chloro-phenoxy) 2-methylpropanoïc acid ethyl ester or by nicotinic acid (three batches of each 10 animals) at the same doses. The best hypocholesterolemic activities are found for the compound of the invention and the first reference compound whereas the best hypotriglyceridemic activities are found for the second reference compound and the compound of invention.
CLINIC
20 patients were treated comparatively, successively by 2-(4-chlorophenoxy) 2-methylpropanoïc acid ethyl ester -reference compound - (30 days, 2 g/day) and, after 15 days without treatment, by the compound of Example 1 - invention compound - (30 days, 2 g/day); the average figures in 9/1 for initial values final values and decrease for triglycerids, total cholesterol and total lipids are listed in the following table I.
10~09t~
TABLE I
.__ __ REFERENCE COMPOUND INVENTION COMPOUND
Tri~lycerids Initial 1.611 (+ 0.098) 1.59 (+ 0.155) Final 1.137 (+ 0.085) 1.082 (+ 0.101) Decrease 0.474 (+ 0.102) 0.507 (+ 0.088) Total cholesterol ..
Initial 3.31 (+ 0.121) 3.17 (+ 0.151) Final 2.85 (+ 0.170) 2.70 (+ 0.169) Decrease 0.46 (+ 0.107) 0.47 (+ 0.058) Total lipids Initial 9.985 (+ 0.342) 9.94 (+ 0.454) Final 8.775 (+ 0.491) 8.367 (+ 0.431) Decrease 1.210 (+ 0.244) 1.572 (+ 0.198) The activity of the compound of the invention appears similar on the total cholesterol rate but more favourable on the triglycerids and total lipids rate.
PRESENTATION - POSOLOGY
The compound of the invention may be presented in any suitable form for use in human therapy. For instance, a form for oral administration may be a gelatin capsule containing:
- compound of any of the examples 0.500 9 - silicic acid 0.018 9 - talc 0.042 9 0.560 9 As to the posology, according to the patients, it may be comprised between 0.5 and 4 9 per day.
Claims (20)
1. The process for preparing an isobutyramide of the formula:
wherein R1 is a halogen atom and n is an integer of from 2 to 6, which comprises:
(a) reacting an acid chloride of the formula:
wherein R1 is as defined above, with an aminoalkyl nitrile derivative of the formula:
NH2 - (CH2)n - CN
wherein n is as defined above in a mixture of polar and non-polar solvents; or (b) reacting a sodium substituted sodium phenolate of the formula:
with an N-cyanoalkyl-.alpha.-bromo-isobutyramide of the formula:
wherein n is as defined above, in a polar solvent, or (c) reacting a substituted phenoxy isobutyramide of the formula:
wherein R1 is as defined above, with an N.-cyanoalkylene of the formula:
CH2 = CH - (CH2)p - CN
wherein p is an integer of from 0 to 4, the reaction being carried out at a temperature of from 50 to 65°C and in the presence of a basic agent.
wherein R1 is a halogen atom and n is an integer of from 2 to 6, which comprises:
(a) reacting an acid chloride of the formula:
wherein R1 is as defined above, with an aminoalkyl nitrile derivative of the formula:
NH2 - (CH2)n - CN
wherein n is as defined above in a mixture of polar and non-polar solvents; or (b) reacting a sodium substituted sodium phenolate of the formula:
with an N-cyanoalkyl-.alpha.-bromo-isobutyramide of the formula:
wherein n is as defined above, in a polar solvent, or (c) reacting a substituted phenoxy isobutyramide of the formula:
wherein R1 is as defined above, with an N.-cyanoalkylene of the formula:
CH2 = CH - (CH2)p - CN
wherein p is an integer of from 0 to 4, the reaction being carried out at a temperature of from 50 to 65°C and in the presence of a basic agent.
2. The process of Claim 1, which comprises reacting an acid chloride of the formula:
wherein R1 is as defined above, with an aminoalkyl nitrile derivative of the formula:
NH2 - (CH2)n - CN
wherein n is as defined above in a mixture of polar and non-polar solvents.
wherein R1 is as defined above, with an aminoalkyl nitrile derivative of the formula:
NH2 - (CH2)n - CN
wherein n is as defined above in a mixture of polar and non-polar solvents.
3. The process of Claim 1, which comprises reacting a sodium substituted sodium phenolate of the formula:
with an N-cyanoalkyl-.alpha.-bromo-isobutyramide of the formula:
wherein n is as defined above, in a polar solvent.
with an N-cyanoalkyl-.alpha.-bromo-isobutyramide of the formula:
wherein n is as defined above, in a polar solvent.
4. The process of Claim 1, which comprises reacting a substituted phenoxy isobutyramide of the formula:
wherein Rl is as defined above, with an N-cyanoalkylene of the formula:
CH2 = CH - (CH2)p - CN
wherein p is an integer of from 0 to 4, the reaction being carried out at a temperature of from 50 to 65°C and in the presence of a basic agent.
wherein Rl is as defined above, with an N-cyanoalkylene of the formula:
CH2 = CH - (CH2)p - CN
wherein p is an integer of from 0 to 4, the reaction being carried out at a temperature of from 50 to 65°C and in the presence of a basic agent.
5. The process of Claim 2, wherein 3-aminopropio-nitrile is reacted with p-chlorophenoxy isobutyryl chloride to form the N-cyanoethyl-p-chlorophenoxy isobutyramide.
6. The process of Claim 2, wherein 3-aminopropio-nitrile is reacted with p-fluorophenoxy isobutyryl chloride to form the N-cyanoethyl-p-fluorophenoxy isobutyramide.
7. The process of Claim 2, wherein 5-amino pentano-nitrile is reacted with p-chlorophenoxy isobutyryl chloride to form the N-cyanobutyl-p-chlorophenoxy isobutyramide.
8. The process of Claim 3, wherein sodium p-chloro-phenolate is reacted with N-cyanoethyl-.alpha.-bromo-isobutyramide to form the N-cyanoethyl-p-chlorophenoxy isobutyramide.
9. The process of Claim 3, wherein sodium p-chloro-phenolate is reacted with N-cyanoethyl-.alpha.-bromo-isobutyramide to form the N-cyanoethyl-p-fluorophenoxy isobutyramide.
10. The process of Claim 3, wherein sodium p-chloro-phenolate is reacted with N-cyanobutyl-.alpha.-bromo-isobutyramide to form the N-cyanobutyl-p-chlorophenoxy isobutyramide.
11. The process of Claim 4, wherein p-chlorophenoxy isobutyramide is reacted with acrylonitrile to form the N-cyanoethyl-p-chlorophenoxy isobutyramide.
12. The process of Claim 4, wherein the p-fluoro-phenoxy isobutyramide is reacted with acrylonitrile to form the N-cyanoethyl-p-fluorophenoxy isobutyramide.
13. The process of Claim 4, wherein the p-chloro-phenoxy isobutyramide is reacted with pentylenonitrile to form the N-cyanobutyl-p-chlorophenoxy isobutyramide.
14. The isobutyramides of the formula:
wherein Rl is a halogen atom and n is an integer of from 2 to 6, when prepared by the process defined in Claim 1, 2 or 3 or by an obvious chemical equivalent.
wherein Rl is a halogen atom and n is an integer of from 2 to 6, when prepared by the process defined in Claim 1, 2 or 3 or by an obvious chemical equivalent.
15. The isobutyramides of the formula:
wherein Rl is a halogen atom and n is an integer of from 2 to 6, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.
wherein Rl is a halogen atom and n is an integer of from 2 to 6, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.
16. The N-cyanoethyl-p-chlorophenoxy isobutyramide, when prepared by the process defined in Claims 5, 8 and 11 or by an obvious chemical equivalent.
17. The N-cyanoethyl-p-fluorophenoxy isobutyramide, when prepared by the process defined in Claims 6, 9 and 12 or by an obvious chemical equivalent.
18. The N-cyanobutyl-p-chlorophenoxy isobutyramide, when prepared by the process defined in Claims 7, 10 and 13 or by an obvious chemical equivalent.
19. A process for the preparation of an isobutyr-amide of the formula:
wherein Rl is a halogen; and n is an integer from 2 to 6 said process comprising:
(a) forming a sodium phenolate by reacting in ethanol sodium with a phenol of the formula:
wherein Rl is a halogen;
(b) adding an excess of toluene to the ethanol solution of sodium phenolate of step (a) whereby an ethanol/toluene azeotrope is formed;
(c) removing the azeotrope of step (b) by distillation;
(d) forming a reaction mixture by adding to the solution of sodium phenolate in toluene remaining from step (c) an N-cyanoalkyl .alpha.-bromoisobutyramide of the formula:
wherein n is an integer from 2 to 6;
(e) refluxing the reaction mixture of step (d) for a period of from 6 to 15 hours;
(f) adding water to the refluxed reaction mixture whereby a precipitate is formed in the reaction mixture; and (g) separating the precipitate of step (f) from the reaction mixture.
wherein Rl is a halogen; and n is an integer from 2 to 6 said process comprising:
(a) forming a sodium phenolate by reacting in ethanol sodium with a phenol of the formula:
wherein Rl is a halogen;
(b) adding an excess of toluene to the ethanol solution of sodium phenolate of step (a) whereby an ethanol/toluene azeotrope is formed;
(c) removing the azeotrope of step (b) by distillation;
(d) forming a reaction mixture by adding to the solution of sodium phenolate in toluene remaining from step (c) an N-cyanoalkyl .alpha.-bromoisobutyramide of the formula:
wherein n is an integer from 2 to 6;
(e) refluxing the reaction mixture of step (d) for a period of from 6 to 15 hours;
(f) adding water to the refluxed reaction mixture whereby a precipitate is formed in the reaction mixture; and (g) separating the precipitate of step (f) from the reaction mixture.
20. The process of Claim 19 further including the following additional steps: (a) neutralizing the separated precipitate by addition of acid until a neutral pH is obtained; and (b) drying the neutralized precipitate.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB10643/76A GB1577413A (en) | 1976-03-17 | 1976-03-17 | Growth of crystalline material |
| GB1063576 | 1976-03-17 | ||
| GB10635 | 1976-03-17 | ||
| GB10643 | 1976-03-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1088098A true CA1088098A (en) | 1980-10-21 |
Family
ID=26247660
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA274,001A Expired CA1088098A (en) | 1976-03-17 | 1977-03-15 | Isobutyramides and preparation thereof |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1088098A (en) |
-
1977
- 1977-03-15 CA CA274,001A patent/CA1088098A/en not_active Expired
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| Date | Code | Title | Description |
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| MKEX | Expiry |