KR800001176B1 - Process for the preparation of acetic amine derivatives - Google Patents

Abstract

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Description

Process for preparing acetamide derivative

The present invention relates to a method for preparing acetamide derivatives and derivatives obtained by the present invention.

According to the method of the present invention, di-n-propylacetonitrile is hydrolyzed in 80% sulfuric acid solution at a ratio of 2-2.5 g / nitrile dilute acid at a temperature of 80 ° -130 ° Di-n-propyl acetamide is obtained.

Di-n-propyl acetamide prepared according to the present invention can be used, in particular, as an antiepileptic agent and a psychotic agent (Psychor-thotic Agents). The present invention generally relates to a new process for preparing acetamide derivatives and derivatives obtained according to the present invention. The present invention relates in particular to a new process for the preparation of di-n-propylacetamide of the above-mentioned formula.

Di-n-propylacetamide is B.S.M No. It is a known product with pharmacological properties, particularly notable anticonvulsant properties, as evidenced by 2442M (French Pharma 2442M). In addition, the substance gave rise to a new class of neuropsychiatric drugs, sacorotics or brain stabilizers. For this reason, di-n-propylacetamide, with respect to behavior and psychology, can stabilize disturbed mental functions without the need to control and stimulate or disrupt confused mental functions.

The most classical and most widely used method for preparing di-n-propylacetamide is to treat diethylmalonate in methanol, first with sodium methylate and then with aryl chloride under pressure. In this case, the two operations are performed according to two different usages.

)하고 형성된 염은 디아릴말론산으로 하기위하여 산성화되며, 가열에 의하여 디아릴초산으로 탈카복실화한 다음, palladie 탄소상에서 디-n-프로필초산으로 수소 첨가한다.Next, diethyldiaryl malonate was converted into sodium hydroxide and saponified (

The salt formed is acidified to diarylmalonic acid, decarboxylated to diarylacetic acid by heating, and then hydrogenated with di-n-propylacetic acid on palladie carbon.

This final acid is converted to its chloride, which is finally treated with ammonia to obtain di-n-propylacetamide. This method is a seven-step process including the first two steps, characterized in that the main preparation step is carried out using the malonic acid ester as a starting material. On the other hand, the observable manufacturing conditions can be applied to a number of difficult technical conditions, such as heating under pressure in the first stage, hydrogenating on a catalyst, and often raising the manufacturer's safety concerns with the production of generally toxic acyl chlorides. Cause problems.

On the other hand, the secondary reaction may cause the generation of impurities, for example, the production of aryl-2-valerolactone, which is an impurity that needs to be removed, such as diarylmalonic acid. All of these drawbacks adversely affect the yield and cost of the final product. Of particular interest is the study of methods for preparing di-n-propyl acetamide, which can be corrected by the foregoing.

Up to now, the synthesis of acetamide substituted at the α position by two groups of profiles using the corresponding nitrile as a starting material has been studied only in the case where the profiles of the two groups are each one group of isopropyl.

Attempts to obtain diisopropylacetamides using diisopropyl acetonitrile as starting materials have been reported in 1956 by J. Am. Chem. Soc., (American Union Society, Vol. 78), pages 5416-5420 and by TSAI et al., 1957 J. Am. Chem. Soc. 79, pages 2530-2533.

According to their method, SAREL et al. Hydrolyze diisopropylacetonitrile in a 96% aqueous solution of sulfuric acid (dilute acid 2.1g / nitrile) for 96 minutes at a temperature of 145 ° -155 ° C to diisopropyl. Acetamide is prepared.

TSAI et al. Similarly produce diisopropyl acetamide by hydrolyzing diisopropyl acetonitrile in 75% aqueous sulfuric acid solution (1.7 g dilute acid / g nitrile g) at 140 ° C. for 30 minutes. Since the chemical structures between diisopropyl acetamide and di-n-propyl acetamide are very similar, the previous method for the preparation of diisopropyl acetamide was intended to be applied to the preparation of the latter compounds.

Using exactly the production conditions recommended by TSAI et al., A yield of 86.1% of di-n-propyl acetamide was determined, which was determined to be 81.3% of pure product. This represents the final yield of the operation, such as 69.9% pure di-n-propyl acetamide. The product, on the other hand, exhibits up to 18.5% di-n-propyl acetate as impurities. On the contrary, di-n-propylacetamide was not obtained according to the manufacturing conditions mentioned by SAREL et al. With reference to the foregoing. The hydrolysis product became caramel with the strong odor of sulfuric anhydride during synthesis.

At the present time, a very surprising method has been found, which is much higher yield of di-n-propyl acet than that obtained by the method implied by the technical report by hydrolysis of di-n-propyl acetonitrile with aqueous sulfuric acid solution. Amide can be obtained and this yield is close to 90% as pure product and nearly 96% after reprocessing.

In addition, according to the method of the present invention, di-n-propylacetonitrile is hydrolyzed with 80% sulfuric acid solution at a temperature of 80 ° -130 ° C at a ratio of 2-2.5 g / nitrile dilute acid. Prepare n-propylacetamide.

A temperature of 80 ° -85 ° C is used in particular for the hydrolysis reaction which leads to a 90% yield of the di-n-propyl acetamide. Likewise, the reaction is carried out for 60-90 minutes using a ratio of 2.5 g of dilute acid / g of nitrile. The starting material di-n-propyl acetonitrile is a known product, especially cited in 1947 Z. Physiol, Chem 282 pages 137-142. This can be achieved by, for example, n-pro in a reaction medium containing the cyanide acetate ester and brominated or iodide n-propyl in question at a temperature of 45 ° -55 ° Celsius as a starting material, such as methyl acid or ester. The sodium n-propyl acid salt of panol was introduced, the temperature was maintained at reflux for about 3 hours, and then the di-n-propyl cyanide acetate formed was 10-20 for 3 hours at a temperature of 60-70 degrees Celsius. Saponified with a hydroxide solution of sodium or potassium in%. And the obtained salt is acidified with strong acid such as 36% hydrochloric acid at a temperature slightly lower than 40 ° C, for example, to obtain di-n-propylcyanic acetic acid, and decarboxylation by heating at a temperature of 140 ° -190 ° C. Can be prepared.

)단계는 실제로 예를들면, 브롬화 트리메틸 세틸암모니움과 같은 4급 암모니움의 존재하에 실시할 수 있다. 이러한 실시방법은 에스테르작용의 가수분해 시간을 감소케하며, 디-n-프로필시안화초산에스테르의 나이트릴 작용의 가수분해를 최대로 피하게 한다. 이 방법에 따라, 시안화초산에스테르의 출발물질로 계산한, 적어도 85%의 수율로 순수한 디-n-프로필 아세토 나이트릴을 얻을 수 있다.Sacred flower

The step) may actually be carried out in the presence of a quaternary ammonium, for example trimethyl cetylammonium bromide. This practice reduces the hydrolysis time of the esterification and maximally avoids the hydrolysis of the nitrile action of the di-n-propylcyanide acetate. According to this method, pure di-n-propyl acetonitrile can be obtained in a yield of at least 85%, calculated as starting material for cyanide acetate.

The previous method for the preparation of the starting material di-n-propylaceto nitrile likewise results in a product containing a minimum amount of valeronitrile and ethylpropylaceto nitrile that are particularly obstructive and need to be removed. Phosphorus cyanide acetate is a known product published in J. Am. Chem. Soc., Vol. 43, pp. 205-208, 1921.

Advantageous acquisition of di-n-propylacetamide according to the method of the present invention is such that, in tests conducted while maintaining the minimum operating conditions of the aforementioned technical report, results similar to those obtained by the method of the invention cannot be reproduced. It is surprising.

In addition, hydrolysis of di-n-propylaceto nitrile by sulfuric acid was carried out according to the following scheme, where the first paraliter was changed.

-Molar ratio of sulfuric acid / nitrile,-concentration of sulfuric acid used,-hydrolysis conditions,-hydrolysis temperature of nitrile

Into a 500 ml spherical flask, add the amount of sulfuric acid in the concentration required for the test. While stirring, 125.2 g of di-n-propyl acetonitrile are added at a temperature of 40 degrees Celsius or less for about 15 minutes. Then, hydrolysis was performed under the following test conditions.

Temperature rise time, hydrolysis temperature, temperature hold time, 2000 ml spherical flask containing enough purified water to cool the flask to ambient temperature and obtain about 16% sulfuric acid. The reaction medium is poured into the reaction medium while stirring and cooling. The temperature of the mixture is limited to 25 ° C. during this operation. The mixture is cooled and the crystals are kept for 1 hour at 0 ° C to minus 5 ° and then drained. The crystals are washed on a Buchner funnel with cold purified water at 125g each.

The moist product is placed back into a 1000 ml spherical flask containing 620 g of toluene and the mixture is treated at reflux with toluene / water azeotropy (boiling point: 84 ° C.) until complete dissolution under stirring. The lower aqueous phase was tilted and the organic layer was washed under reflux for 15-30 minutes with stirring and 6.25 g of sodium bicarbonate and 125 g of purified water were continuously tilted, where 125 g of purified water was needed to dissipate the sulfate ions in the effluent.

Next, the toluene solution is treated by refluxing with 4.4 g of activated carbon for 30 minutes while removing water according to Dean-Stark method. After filtration and washing with heating to 62g of toluene. The filtrate and the washed liquid are combined in a second 1000 ml spherical flask, crystallized while stirring and cooling, and maintained at a temperature of minus 5 ° to minus 10 ° for about 2 hours and drained. The draining is carried out by two parts of 62 g of toluene each filtered and cooled in a Buchner funnel. Drain as much as possible and dry in a ventilated dryer at 50 ° C until dry to a certain weight. This gives the first di-n-propyl acetamide. Finally, the toluene-water mother liquor resulting from draining or washing is dried under reduced pressure (50 ° C, 20 mmHg) to obtain a dry extract of di-n-propylacetamide. The following table compares the results obtained by the method of the present invention with the results obtained according to the operating conditions recommended in the technical report.

[table]

Several experimental results shown above show that the method according to the present invention is superior to that of the technical report.

The temperature considered within the scope of the present invention is a condition that can be used for industrialization and is very accessible.

In fact, heating from 120 ° to 130 ° C can be easily achieved by steam at a pressure of 3 kg / cm ² . However, temperatures between 145 ° and 155 ° Celsius are quite expensive as they cannot be achieved with such vapor pressures and are possible by steam at a pressure of 10 kg / cm ² . After all, the method of the present invention is superior to the classical method described above.

For example, only five steps are included because the method of the present invention is implemented with only one use per step.

The method of the present invention, on the other hand, allows the production of only minimal impurities that are easy to remove elsewhere.

Moreover, the method of the present invention is particularly inexpensive, and the cost of di-n-propylacetamide prepared by the method of the present invention is about 2-2 times less than that of the classical method.

Referring to the method of the present invention through the following examples.

Example 1

[Preparation of di-n-propylacetamide]

(A) Di-n-propyl cyanide acetate

First, sodium 7.42 g (0.322 mole) and 180 ml of anhydrous n-propanol are prepared by heating to mild reflux until the sodium is completely dissolved.

Add 16.95 g (0.141 mole) of ethyl cyanate and 40.69 g (0.33 mole) of brominated n-propyl in a 500 ml spherical flask equipped with an input ampoule, a mechanical stirrer, a thermometer, and a chiller equipped with a calcium chloride trap. . The mixture is heated to 45 ° C., and then slowly added the previously prepared sodium n-propyl propyl salt solution while stirring.

In this case, the temperature of the reaction medium is maintained at 50 ° -55 ° C by light cooling of the outside. After the addition, the temperature of the mixture is kept at reflux for 30 minutes and then in this state for 3 hours. Next, the distillation is stopped when the temperature of the material remaining after distilling n-propanol reaches 115 degrees Celsius.

The ester obtained by this method is treated with a solution containing 7.5 g of scaled sodium hydroxide in 67.5 ml of water.

The mixture is placed in a 250 ml spherical flask equipped with a cooler and slowly brought to a reaction medium of 60 ° -70 ° C. This temperature is maintained for 3 hours, then cooled to about 50 ° C. and the rest of ethanol and n-propanol formed under a pressure of 70 mm Hg is removed. The solution obtained is then cooled to 20 ° C. and acidified by addition of 26.25 g of 36% hydrochloric acid under stirring. During this operation, the temperature of the reaction medium is kept below 40 ° C by cooling. Stir for 30 minutes and then stand still for 30 minutes.

The oil layer of di-n-propyl cyanic acid is inclined, and the liquid phase is extracted with 35 ml of toluene. The toluene extract was added to the decanted di-n-propyl cyanide acetic acid, and the toluene solution was washed with a solution of 1.5 g of sodium chloride in 14 ml of water in the decanted ampoule. The toluene phase is decanted and then toluene is distilled off under atmospheric pressure. In this way, 25 g of di-n-propylcyanide acetic acid is obtained.

(B) di-n-propylacetonitrile

Into a 100 ml spherical flask equipped with a thermometer and a cooler, 25 g of di-n-propyl cyanide acetate obtained by the above-mentioned method was added. This mixture is heated with an oil bath.

Decarboxylation starts at temperatures close to 140 ° C.

This mixture is then maintained at reflux, i.e., at about 160 ° C and for 2 hours at 190 ° C. This temperature is maintained until the end of the gas discharge, which takes about 2 hours. Next, the di-n-propyl acetonitrile formed is slowly distilled off, and collected by a distillation after collecting a fraction sorted between 165 ° -175 ° C.

In this manner, 14.7 g of di-n-propylacetonitrile was obtained.

Boiling Point: 170 ° C Yield: 83% compared to Ethyl Cyanate Tape used

(C) di-n-propylacetamide

Into a 100 ml spherical flask equipped with a mechanical stirrer, a cooler and a thermometer, 10 g (0.08 mol) of di-n-propylaceto nitrile obtained according to the above-described method and 25 g of 80% sulfuric acid are mixed.

The mixture is heated to 80 ° -82 ° Celsius and held at this temperature for 2 hours. Cool the reaction medium to about 15 degrees Celsius and pour it into 100 ml of water at such a rate that the temperature of the medium does not exceed 25 degrees Celsius. Cool down to 0 ° -2 ° C and let the mixture stand still for 1 hour at this temperature. Next, the water is removed from the crystal of the formed di-n-propylacetamide. And wash with 20 ml of water. The crystals are dried to give 10.98 g of di-n-propylacetamide. This represents a yield of 96%.

In addition, the obtained di-n-propyl acetamide is purified by a hot solution of toluene and a water wash in an aqueous solution of sodium bicarbonate until the liquid PH group is near 7, and purified by water until the sulfate ion is completely removed. The toluene phase is then cooled to 60 ° C. and decolorized by the addition of activated carbon. It is heated to reflux for 1 hour and the toluene solution is dried by azeotropic distillation of water.

Activated charcoal is filtered and the filtrate is cooled to minus 10 ° Celsius. Drain the formed precipitate and dry. Purification of di-n-propyl acetamide can be carried out in a similar manner in methylene chloride to remove sulfate ions. This solvent is then removed and the residue is extracted with dichloroethane under heating to decolorize the solution with activated charcoal.

In this way, that is, using either of the purification methods, 10.1-8.92 g of di-n-propyl acetamide is obtained. This is shown in 91.5% and 90.5% yield, respectively. The yield of hydrolysis was 87-88% compared to the di-n-propylaceto nitrile used.

Example 2

[Preparation of Di-n-propylamide]

Into a 500 ml spherical flask equipped with a stirrer, a thermometer, a reflux condenser and an input ampoule, 312 g of 80% sulfuric acid (2.5 g of acid / nitrile g) were added and di-n- at a temperature of about 40 ° C. for 15 minutes under stirring. 125.2 g of propyl acetonitrile are added. Raise the temperature of the reaction medium to 80 ° -85 ° C for 30 minutes and maintain this temperature for 90 minutes. Cool to ambient temperature and gradually add to a 2000 ml spherical flask containing 1250 g of cold purified water. And keep stirring while obtaining about 16% dilute acid.

During this operation, the temperature of the mixture is limited to 25 degrees Celsius. Next, cool and hold for 1 hour from 0 ° C to minus 5 ° and drain the crystals formed. The draining operation is carried out on a Buchner funnel with each 125 g of two parts of cold purified water.

The damp product is placed in a 1000 ml spherical flask containing 620 g of toluene. The mixture is treated by azeotropic reflux with toluene / water until complete dissolution with stirring. (Boiling point: 84 ° C)

The aqueous phase of the lower layer was decanted and the organic layer was washed for 15-30 minutes at reflux with stirring.

Continue to tilt to 125 g of purified water and 6.25 g of sodium bicarbonate. 125 g of purified water is needed to dissipate the sulfate ions in the effluent. Next, the toluene solution was treated by refluxing with 4.4 g of activated carbon for 30 minutes while removing water according to Dean-Starke method. Filter and wash with 62 g of toluene.

The filtrate and the washed liquid are placed in a second 1000 ml round flask. Cool with stirring to crystallize and hold at 5 ° C--10 ° C for 2 hours, then drain. The draining is carried out by two parts of 62 g of cold toluene, filtered on a Buchner funnel. Drain it to the maximum and dry it to a constant weight in a ventilated drying room at 50 ° C. In this way, a primary portion of di-n-propylacetamide is obtained. This shows a yield of 88.0% compared to the di-n-propylacetonitrile used. Dry the toluene-water mother liquor used to drain or wash under reduced pressure (50 ° C, 20mmHg).

Obtain 4 g of dry extract of di-n-propylacetamide in crystalline form as well.

This represents an additional yield of 2.8%.

Di-n-propylacetamide is obtained with a total yield of 90.8% compared to di-n-propylaceto nitrile used in this way.

Retreatment of the toluene-water mother liquor can yield di-n-propylacetamide in 96% yield.

Claims (1)

To obtain acetamide derivatives, di-n-propylacetonitrile is hydrolyzed in an aqueous solution of 80% sulfuric acid at a rate of 2 to 2.5 g / nitrile g at a temperature of 80 ° to 130 ° C. The method for producing di-n-propylacetamide of the following formula.