Method of obtaining ester of 1-tert-alkyl 5-cyano-1h-pyrazole-4-carboxylic acid

专利摘要:
The present invention provides a novel process for selectively alkylating pyrazoles comprising reacting a 3(5)-cyano-1H-pyrazole-4-carboxylic acid ester with a C4-C11 alkene, or a C5-C6 cycloalkene, and a strong acid in a solvent which contains a strong electron withdrawing group. Also provided are new 3(5)-cyano-1H-pyrazole-4-carboxylic acid esters.
公开号:SU1579457A3
申请号:SU884355378
申请日:1988-03-28
公开日:1990-07-15
发明作者:Абрахэм Айкинс Джеймс；Ричард Бек Джеймс；Вай-Пинг Тао Эдди
申请人:Эли Лилли Энд Компани (Фирма)；
IPC主号:

专利说明:

ate j
This invention relates to an improved process for the preparation of 1-alkyl-5-cyano-1H-pyrazole-4-carboxylic esters, which are used in the synthesis of carboxamide herbicides and algaecides.
The purpose of the invention is to increase the yield of the target product and increase the efficiency of the process.
This goal is achieved by the fact that the 3 (5) -cyano-1H-pyrazole-4-carboxylic acid ester is alkylated with a C-C-alkene or C5-C6-cycloalkene, substituted in position I by a C-C-alkyl group in the presence of strong acid in a solvent that contains a strong electroacceptor group.
Example 1. 3 (5) -cyano-1H-pyrazole-4-carboxylic acid ethyl ester.
A 22 liter three-necked flask was charged with 5.72 L of acetonitrile, 1.048 g (5.72 mol) of 3 (5) -carbamoyl-1H-pyrazole-4-carboxylic acid ester and 791 g (5.72 mop) of potassium carbonate . The resulting mixture is heated to 75-80 ° C and added over 1 hour.
SP
i
 cm
315
g (8.58 mol) oxychloride phos- |
1,316 handicap.
The resulting mixture is stirred at a temperature of about 80 ° C for 3 hours, then cooled to room temperature (25 ° C) and stirred for another 1 hour. The reaction mixture is then filtered to remove salts of potassium chloride and excess potassium carbonate and the filter cake is washed with 500 ml of acetonitrile. The resulting filtrate and acetonitrile washes were combined and the resulting solution was concentrated to dryness under reduced pressure to obtain 3 (5) -cyano-1H-pyrazole-4-carboxylic acid solid ester. To the solid product is added 3 l of cold deionized water and the resulting mixture is stirred for about 15 minutes and then filtered. The isolated solid is washed with 1 l of cold deionized water and dried under vacuum at a temperature of about 40 ° C to obtain 818 g (yield 86.5%) of the above compound, m.p. 149 - 152 ° .С.

Calculated,%: C 50.91; H 4.27; N 25.44;
C7H7N, 02
Found,%: C 51.15; H 4.39; N 25.63.
EXAMPLE 2 3 (5) -cyano-1H-pyrazole-4-carboxylic acid ethyl ester.
In a 1-liter three-neck flask containing a suspension of 96.8 g (0.5 mol) 94.5% (wt.%) Of pure ethyl ester 3 (5) -carbamoyl-1H-pyrazole-4-carboxylic acid and 35 , 0 g (0.33 mol) of sodium carbonate in 500 ml of acetonitrile added 75 ml (0.8 mol) of phosphorus oxychloride. The resulting mixture is heated to reflux and then stirred at this temperature for about 90 minutes. The reaction mixture is cooled to room temperature (25 ° C) and filtered to remove sodium chloride salts and unreacted sodium carbonate.
The filtrate is concentrated to dryness under reduced pressure to give a solid. 500 ml of deionized water is added to it and the mixture is stirred for about 15 minutes and then filtered. Selected solid product is dried in vacuum at a temperature of about 40 ° C. 76.8 g (yield, 93.1%) of the title compound are obtained, m.p. 148-150 ° C. H NMR (300 kHz, DMSO - de, tetramethylsilane), o: 1.3 (triplet, 3N); 4.3 (quadruplet, 2H); 8.65 (singlet, 1H). Calculated,%: C 50.91; H 4.27;
5 0 5
0
five
0
five
N
25.44; С, Н, ЫЛ0 „
C 51.09; H 4.23;

Found,% N 25.30.
Example 3. 1-tert.-butyl-5-cyano-1H-pyra-aol-4-carboxylic acid ethyl ester.
A cold (-70 ° C) mixture containing 8.3 g (0.05 mol) of 3 (5) -cyano-1H-pyrazole-4-carboxylic acid ethyl ester 10 ml (0.1 mol) isobut Tetylene and 3.1 g (0.015 mol) of para-toluenesulfonic acid monohydrate in 100 ml of acetonitrile are placed in a Parr bottle. The resulting mixture is gradually heated to reflux and stirred for about 18 hours. The reaction is completed by monitoring high performance liquid chromatography, the reactor is cooled and its pressure is reduced to atmospheric (0 psi excess). The solution is concentrated to an oil, removing acetonitrile under reduced pressure.
The resulting oil is dissolved in 200 ml of diethyl ether. The ether solution is washed successively with water, a saturated solution of sodium bicarbonate and brine, and then dried over magnesium sulfate. The solvent is removed under reduced pressure to obtain 8.4 g (84.3% yield) of 1-tert-butyl-5-cyano-1H-pyrazole-carboxylic acid ethyl ester as an oil.
(H NMR (300 MHz., Tetramethylsilane, DMSO-a6), 5: 1.3 (triplet, 3N); 1.72 (singlet, 9H); 4.3 (quadruplet, 1H).
Calculated,%: C 59.71; H 6.83;
N
18.79, C, H, SN, 04
Found,%: C 59.50; H 6.57; N 18.84.
PRI me R 4. 1-tert-butyl-5-cyano-1H-pyrazole-4-carboxylic acid ethyl ester.
In an autoclave containing 0.5 g (3.0 mmol) of 3 (5) -cyano-1H-pyrazole-4-carboxylic acid ethyl ester, dissolved in 100 ml of acetonitrile, 7.13 g (127.0 mmol) are added. ) isobutylene and 0.2 g (1.0 mmol) of para-toluene sulphonic acid monohydrate. The reaction mixture is heated to 110 ° C (about 50 psi excess pressure) and stirred for 24 hours. The reaction is almost complete according to the highly efficient
chromatography “The reactor is opened, the water is washed with 100 ml of water and dried over
Treatment is reduced to atmospheric (0 psi excess). The solution is concentrated to an oil, removing acetonitrile under reduced pressure.
50 ml of water and 100 ml of di-J5 ethyl ether are added to dissolve the oil. The organic layer is separated and dried over sodium sulfate. The resulting solution is filtered and the solvent is distilled off under reduced pressure to obtain 0.66 g of 1-tert.-butyl-5-cyano-1H-pyrazole-4-carboxylic acid ethyl ester (yield 91.8%) in the form of oil. According to high performance liquid chromatography 25, the title compound has a purity of 93.2%.
magnesium sulfate. The solvent is removed under reduced pressure to half 0.66 g (91.8% yield) of 1-tert-butyl-5-cyano-1H-pyrazole-4-carboxylic acid e-ester as an oil.
PRI me R 6. 1-tert-Butyl-5-C but-N-methyl-1H-pyrazole-4-carboxes
To an autoclave containing 1.257 g of 96.1% purity of ethyl ethyl 3 (5) -cyano-1H-pyrazole-4-carbonic acid (7.62 mol) dissolved in 17.300 ml of acetonitrile, is added to 9.900 g ( 51.7 mol) isobutyl and 483.15 g (2.54 mol) of para-toluenesulfonic acid monohydrate. The reaction mixture is heated to 85-90 seconds (an excess pressure of Ј 45 psi) and stirred for 17.5 hours. After the reaction, according to high performance liquid chromatography, the reactor is opened, the pressure is reduced to atmospheric and the acetonitrile is distilled off.
A sample for high performance liquid chromatography was prepared by placing 25 mg of sample in a 50 ml volumetric flask and then diluted with 25 ml of methanol. The column was eluted with a solution containing 10% (vol%) methanol, 18% (vol%) tetrahydrofuran, and 72% (vol%%) buffer solution, diethylamine (phosphoric acid), 1% v / v solution of diethylamine in water and the pH was adjusted to 7, 0 phosphoric acid.
Use a 25 cm column Zorbax CN. The detector at a wavelength of 254 nm, the flow rate in the column is 2.0 ml / min, and the injection volume is 10 μl.
PRI me R 5. Complex 1-tert-butyl ethyl ester, 5-cyano-1H-pyrazole-4-carboxylic acid.
To an autoclave containing 0.5 g (3.0 mmol) of 3 (5) -cyano-1H-pyrazole-4-carboxylic acid ethyl ester dissolved in 50 ml of acetonitrile, 7–13 g (127.0 mol) of isobutylene and 0.2 g (1.0 mmol) of para-toluenesulfonic acid monohydrate. The reaction mixture is heated to 75-80 ° C (an overpressure of approximately 45 psi) and stirred for 18 hours. When the reaction is almost complete according to high performance saturation chromatography, the reactor is opened and
pressure is reduced to atmospheric. The resulting solution was concentrated to an oil, removing acetonitrile under reduced pressure.
Water (100 ml), diethyl ether (100 ml) and brine (100 ml) are added to dissolve the oil. The organic layer is separated.
J5 20 25
0
five
0
five
0
five
magnesium sulfate. The solvent is removed under reduced pressure to obtain 0.66 g (91.8% yield) of 1-tert-butyl-5-cyano-1H-pyrazole-4-carboxylic acid ethyl ester as an oil.
EXAMPLE 6 1-tert-Butyl-5-cyano-N-methyl-1H-pyrazole-4-carboxamide.
To an autoclave containing 1.257 g of 96.1% purity of 3 (5) -cyano-1H-pyrazole-4-carboxylic acid ethyl ester (7.62 mol) dissolved in 17.300 ml of acetonitrile, add 2,900 g (51, 7 mol) isobutylene and 483.15 g (2.54 mol) para-toluenesulfonic acid monohydrate. The reaction mixture is heated to 85-90 seconds (an excess pressure of Ј 45 psi) and stirred for 17.5 hours. After the reaction according to high performance liquid chromatography is completed, the reactor is opened, the pressure is reduced to atmospheric and the acetonitrile is distilled off.
Aqueous methylamine (3.300 g of a 40% by weight solution of methylamine in water, 42.6 mmol of methylamine) and methanol (3.810 ml) are added and the mixture is stirred at 50 ° C for about 4 hours. The resulting solution is cooled to room temperature (25 ° C) and stirred overnight
The resulting solution is concentrated; the unreacted methylamine and methanol are distilled off under reduced pressure. To the concentrated solution was added cold water (7,600 ml). 1-tert-Butyl-5-cyano-M-methyl-1H-pyrazole 4-carboxamide precipitates and is isolated by filtration. The carboxamide obtained is washed with 7.6 ml of cold water, dried under vacuum at 40-50 ° C overnight to obtain 1.316 g (yield 84.7%) of the product, which has a purity of 100% according to high performance liquid chromatography (as described in Example 4). ).
Calculated,%: C 58.24; H 6.84; N 27.17.
C, 0H14N40
Found,%: C 58.14; H 6.84; N 27.44.
Example 7. Ethyl ester of 5-cyano 1- (1,1-dimethylbutyl) - -1H-pyrazole-4-carboxylic acid.
2-Methyl-1-pentene (6.1 g, 0.072 mol); 3 (5) -cyano-1H-pyrazole-4-carboxylic acid ethyl ester (6.0 g, 0.036 mol) and 5 drops of sulfuric acid are combined in 15 ml of acetonitrile and placed in a sealed ampoule. The resulting solution is heated to 120dC and maintained at this temperature for about 8 hours. After 8 hours, the solution is cooled and the acetonitrile is removed under reduced pressure. The resulting oil was purified by somatography (high performance liquid chromatography) using hexane as eluant, followed by elution with ethyl acetate / hexane (1: 4). The solvent was removed under reduced pressure to obtain 4.57 g (50.9% yield ) 5-cyano-1- (1,1-dimetzlbutyl) -1H-pi razol-4-carboxylic acid ethyl ester as an oil.
Hi NMR (250 MHz, CDC1,), b: 0.90 (doublet, 3N); 1.40 (triplet, 311); 1.75 (singlet, 6H) | 1.02 (broad, triplet, 4H); 4.30 (quadruplet, 2H). Calculated,%: C 62.63; H 7.68; N 16.85.
С, 5Н „М, Og
Found,%: C 62.70; H 7.47; N 16.76. Prim
e p
5-Cyano-1- (1t1-diethylpropyl) -M-methyl-1H-pyr azole-4-carboxamide.
Sulfuric acid (4.7 g, 0.048 mol) is added dropwise to a solution containing 8.0 g (0.048 mol) of ethyl ester 3 (5) -cyano-1H-pyrazole-4-carboxylic acid and 9 , 5 g (0.096 mol) of 3-ethyl-2-pentene dissolved in 40 ml of methylene chloride and tO and acetonitrile. The acid is added at such a rate as to maintain the solution temperature below 10 ° C during the addition. The reaction mixture is allowed to warm to room temperature (25 ° C) and stirred for about 16 h.
After 16 hours, an additional 100 ml of methylene chloride is added. The resulting solution is washed twice with 150 ml of 2N
0
five
0
0
five
35
sodium hydroxide and 1 SO ml of brine, then sugaat, is -. benefit sodium sulfate. Methylene chloride and acetonitrile are removed under reduced pressure to give an oil.
This oil is purified by high performance liquid chromatography using hexane and then ethyl acetate / hexane (1: 4) as eluent. The solvent is again removed under reduced pressure, whereby 6.3 g (49.9% yield) of 5-cyano-1- (1,1-diethylpropyl) -H-pyrazole-4-carboxylic acid ethyl ester are obtained.
(H NMR (250 MHz, CDC1,),: 0.75 (triplet, 9H); 1.35 (triplet, 3N); 2.15 (quadruplet, 6H); 4.35 (quadruplet, 2H).
C, 63.85; H 8.04;
40
%:
Calculated, N 15.96.
C HaiNjOa
Found,%: C 64.09; H 7.98; N 16.26.
The above carboxylic ester (2.5 g, 9.5 mmol) and aqueous methylamine (4.5 g 40% by weight, solution of methylamine in water; 57.0 mmol) are combined with 50 ml of methanol. The resulting solution is heated at boiling under reflux for 8 h, then cooled to room temperature (25 ° C).
The resulting solution was concentrated to remove unreacted methylamine and methanol under reduced pressure. The solid obtained is recrystallized from toluene / hexane to give 0.58 g (28.4%) of 5-cyano--1- (1,1-diethylpropyl) -M-methyl-1H-pyrazole 4-carboxamide m.p. 85-87 ° C.
five "
five
N
Calculated, 22.56.
C ,, H20N40
%: C, 62.88; H 8t12;
Found,%: C 62.63; H 7.88; N 22.30.
PRI me R 9. 5-cyano-1- (1-methyl-cyclopentyl) -N-methyl-1H-pyriol sol-4-carboxamide.
Zinc chloride (13.2 g, 0.096 mol), 1-methyl-1-cyclopentene (8.0 g, 0.096 mol) and 3 (5) -cyano-1H-pyrazole-4-carboxylic acid ethyl ester (8, 0 g (0.048 mol) is added to 50 ml of acetonitrile and the mixture is heated under reflux for 24 hours. Then the solution
cooled to room temperature (25 ° C) and the zinc chloride is filtered off. The resulting filtrate is concentrated to an oil, removing the solvent under reduced pressure.
200 ml of water and 200 ml of ethyl acetate are added to dissolve the oil. The organic layer is separated, washed twice with 150 ml of 2N sodium hydroxide and 150 ml of saturated brine, and then dried using sodium sulfate. The ethyl acetate is removed under reduced pressure to give an oil.
This oil was purified by high-performance liquid chromatography according to the method described in Example 4. The solvent was again removed under reduced pressure to obtain
4.2 g (35.4% yield) of 5-cyano-1- (1-methylcyclopentyl) -1K-pyrazole-4-carboxylic acid ethyl ester.
4l NMR (250 MHz, CDC13), Ј; 1.30 (triplet, ZI); 1.65 (doublet, SN); 2.25 (squared square, 4H); 2.60 (width doublet, 4H); 4.35 (quadruplet, 2H).
Calculated by 7-. C 63.14; H 6.93; N 16.99.
C H N-jOz
Found,%: C 63.36; H 6.73; N 16.72.
The above carboxylic acid ethyl ester (2.0 g, 8.0 mmol) and aqueous methylamine (3.6 g, 40% by weight solution of methylamine in water, 48.5 mmol) are combined in 30 ml of methanol. The resulting solution is heated at reflux for 7 h, then cooled to room temperature (25 ° C).
Methanol and unreacted methylamine are removed under reduced pressure. The resulting solid is recrystallized from ethanol to give
1.3 g (70% yield) of 5-cyano-1- (1-methyl- -cyclopentyl) M-methyl-1H-pyrazo-l-4-carboxamide, mp. 139-141 C.
"
Calculated,%: C 62.05; H 6.94; N 24.12.
With, ghlO
Found,%: C 61.83; H 6.95; N 23.93.
Thus, the proposed method makes it possible to more economically obtain 1-tert-alkyl-5-cyano-1H-pyrazole-carboxylic acid ester with high yield (up to 90%).

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining 1-tert-alkyl-5-cyano-1H-pyraol-4-carboxylic ester of the general formula
20
25
thirty
35
40
C02Ri
CN
pg
Nn. .BUT,
N f
Rrc-bz
R2
where R4 is C, -C6-alkyl;
R2 is C-C-alkyl;
Rj and R4 each independently, alkyl or together with the carbon atom to which they are attached form Cg-Cg-cycloalkyl, characterized in that, in order to increase the yield of the desired product and increase the efficiency of the process, the ester 3 cyano-1H-pyrazole-4-carboxylic acid of formula
PgOED
 CN
H
is reacted with a ken or -C-cycloalkene, substituted in position I by a C-O-alkyl group, in the presence of a strong acid and solvent, which contains a strong electron-withdrawing group.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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US07/032,662|US4820845A|1987-04-01|1987-04-01|Alkylation of 3-cyano-1H-pyrazole-4-carboxylic acid esters|

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