US2200538A

US2200538A - Barbituric acid compound

Info

Publication number: US2200538A
Authority: US
Publication date: 1940-05-14
Anticipated expiration: 1957-05-14

Description

Patented May 14, 1940 NlTED STATES PATENT OFFICE BARBITURIC ACID COMPOUND William G. Bywater, Detroit, Mich., assignor to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Application February 2, 1938, Serial No. 188,396

13 Claims.

The invention relates to new barbiturates, that is, barbituric acids and their salts, and more particularly to barbiturates having two hydrocarbon radicals attached to the 5-carbon atom of the barbituric acid ring, at least one of which hydrocarbonradicals is an isopropenyl alkyl carbinyl radical.

The general formula for the compounds of the invention may be written as follows,

as cyclopentenyl or cyclohexenyl; aryl, such as phenyl, etc.

From the above definition of R, it will be seen that the compounds of the invention are secondary alkyl substituted barbiturates where the secondary alkyl radical,

CH3 R contains at least five and not more than ten carbon atoms.

In carrying out the invention, one may use any of the known methods for forming barbituric acid where R has the same significance as given in the previous formulas, and react the halide either with an alkali compound of a malonic ester of formula, 1

M COORs or with the corresponding barbituric acid compound of formula, 1

where R1 has the significance already given above, R3 and R4 are alkyl radicals,'and M represents an alkali metal such as sodium.

When the halide reacts with the alkali compound of the malonic ester a di-substituted malonic ester of formula, Y CH 0GH is obtained. This malonic ester can then be re.-

GOORs OOOR4 acted in known manner with urea to form the new barbituric acids of the invention. The acids are readily converted by reaction with basic or alkaline salt-forming compounds into their corresponding barbituric acid salts, included in the general formula given above.

When the halide reacts with the alkali compound of the mono-substituted barbituric acid, the di-substituted barbituric acid of the invention is directly produced.

Instead of carryingout the above described reaction between the halide, III, and the alkali metal compound, V, the same barbituric acid compounds can be prepared by reacting the halide, III, with an alkali compound of an unsubstituted malonic ester of formula,

11 \COOBA VII to form the corresponding mono-substituted malonic ester having the isopropenyl alkyl carbinyl radical attached to the methylene carbon atom. The mono-substituted ester can then be converted into its alkali metal compound and reacted with an alkyl halide, Rl-l-Ial, where R1 is a hydrocarbon radical containing not more than six carbon atoms as already described. The latter reaction results in the di-substituted malonic ester, VI, described above and which is then converted into a barbituric acid by reaction with urea. Likewise, the halide R1-I-Ial can be reacted with an alkali metal compound of an isopropenyl alkyl carbinyl barbituric acid of formula,

where R is a hydrocarbon radical containing not more than six carbon atoms, to directly form the new barbituric acids of the invention.

The invention can also be carried out by reacting the halide, R1-Ha-l, as given above, or the isopropenyl alkyl carbinyl halide, III, with cyanoacetic ester by the known methods to obtain, respectively, mono-substituted cyanoacetic esters,

CH3 R H 0003s (I: l

or CH2= CH COOR; /o R1 GEN IX X Either of the compounds, IX and X, can then be reacted with alkali metal to replace the methylene hydrogen atom by alkali metal and the resulting compounds reacted with the halide, III (in the case of IX), or with the halide, R1-Hal (in the case of X), to give a di-hydrocarbon substituted cyanoacetic ester of formula,

This di-substituted ester is then reacted in the known manner with an alkali alcoholate and a suitable urea compound, such as urea or guanidine, to give an imino barbituric acid compound such as,

The imino compound can be hydrolyzed, for example, by using a solution of a strong mineral acid such as hydrochloric acid. The hydrolysis generates the desired barbituric acid of the formula given above.

The compounds of the invention are useful not only because they constitute a new group of chemical substances having special properties by virtue of the kind of hydrocarbon groups substituted at the methylene carbon atom of the barbituric acid ring, but are also valuable pharmaceutically, especially as soporifics and hypnotics.

It has been found that barbiturates having an ethylenic hydrocarbon radical attached to the barbituric acid methylene carbon atom are prone to produce a convulsant action when administered to the animal organism. On the other hand, the compounds of the present invention are remarkably free from such convulsant action and this is believed to be due to the presence of the isopropenyl group, as well as to the fact that the substituting radical containing the isopropenyl group is a secondary alkyl radical.

Although the invention includes preparation of a large class of chemical compounds, I have found that the preferred compounds from the standpoint of hypnotic. properties, which are low in toxicity and lacking in other undesirable physiological properties, but high in effectiveness as hypnotics and soporifics, are those in which R1 of the general formula, I, is a member of the group ethyl and allyl.

The invention may be illustrated by the following examples.

EXAMPLE 1.Preparation of isop'ropenylethylcarbinol Ethyl magnesium bromide is first prepared in the usual manner (Organic Syntheses 2H, 98, John Wiley liz Sons, Inc., 1931). 52.8 grams (2.2 moles) of magnesium turnings are covered with 500 cc. of anhydrous ether. added 20 cc. of ethyl bromide and a crystal of iodine. After the reaction has started, the remainder of the ethyl bromide (total of 238 grams or 2.2 moles) in 300 cc. of anhydrous ether is added to the reaction vessel while the reaction mixture is stirred vigorously and the vessel cooled in an ice-bath. When all the ethyl bromide has been added the reaction mixture is heated for one-half hour at roomtemperature. The ether solution at this point is dark colored and has in it a slight grey precipitate. To it is added dropwise, while stirring and cooling in an ice-bath, grams (2 moles) of methylacrolein in 200 cc. of ether. The reaction mixture is stirred for onehalf hour after the methylacrolein has been added. All of the Grignard reagent is used up as shown by the Gilman color 'test (Gilman and Schultz, J. Am. Chem. Soc. 4'7, 2002 (1925) The reaction mixture is-allowed' to stand for. 15 to 18 hours then the product is hydrolyzed by first adding cold wateruntil the first vigorous reaction has subsided, thenneutralizing the mixture with 2.2 equivalents of hydrochloric aciddiluted with ice. 'The grey solid in the flask slowly dissolves. The ether layeris separated in a large separatory funnel, and the aqueous phase extracted with 250 cc. of ether. The extract is added to the original ether solution and dried over powdered lime, filtered and fractionated. The fraction boiling at 129-134 at 753 mm. is collected. The index of refraction is and the yield is 58.2 percent based on the methylacrolein used.

The reactions used in the above example may be represented as follows:

(1113 (EH: CHz' C-CHO-f-CzHsMEBI ClipC-CHCHgCH;

OMgBr CH3 H2 27 UHF -OHCH1CHI (RC1) H To the flask is then EXAMPLE z Pre'paratz'on of isopropenylethylcarbinyl chloride 160 grams (1.6 moles) of isopropenylethylcarbinol and 193 grams (1.6 moles) of dimethylaniline are mixed in a one-liter three-necked flask equipped with a mechanical stirrer, dropping funnel and thermometer. The flask and contents are cooled in an ice-bath and while the solution is stirred vigorously, 190 grams of thionyl chloride is slowly added through the dropping funnel. The temperature of the reaction mixture does not rise above that of the room. When all the thionyl chloride has been added, the reaction mixture is stirred for two hours at room temperature then transferred to a separatory funnel and the lower dark layer removed. The upper layer is washed first with cold Water, then with 25 cc. of 5 percent hydrochloric acid, finally with 50 cc. of 10 percent sodium carbonate solution and dried with anhydrous calcium chloride. The crude isopropenylethylcarbinyl chloride is first fractionated under reduced pressure then finally distilled at atmospheric pressure. The chloride is a colorless liquid possessing a strong characteristic odor. It rapidly attacks rubber and cork stoppers and is best handled in all-glass apparatus. It boils at 121-124" 0.;

EXAMPLE 3.Prepamtion of ethyl ethyl- (isopropenylethylcarbinyl) malonate A sodium ethylate solution is prepared from 4.6 grams (0.20 moles) of freshly cut metallic sodium and 70.5 cc. of absolute ethyl alcohol to which is added 38.1 grams (0.20 moles) of ethyl ethylmalonate. The temperature of solution is adjusted to about 40 C. and the addition of isopropenylethylcarbinyl chloride started. As salt begins to separate from the solution the temperature rises. The chloride is added in small portions, with shaking after each portion. When i all the chloride has been introduced into the flask, the mixture is allowed to stand for fifteen minutes at room temperature, then it is gently heated at -110", at the same time removing half of the alcohol by distillation. The desired ester is isolated by first adding sufficient water to the reaction mixture to dissolve the precipitated sodium chloride, and then separating the aqueous and oily layers. The aqueous layer is extracted with a small quantity of ether which is added to the main portion of ester. The oil, after drying with anhydrous calcium chloride, is fractionated under reduced pressure. Ethyl isopropenylethylcarbinylethylmalonate is a colorless liquid possessing a pleasant fruity odor. It distills at l1'7.5-1l9 at about 3.5 mm. pressure;

The reactions in this example may be represented as follows:

EXAMPLE 4.-Preparation of ethyl isopropenylethylcarbinyl barbituric: acid To a solution of sodium ethylate prepared from 4 grams of sodium and 63 cc. of anhydrous ethyl alcohol there is added 16.5 grams (0.06 mole) of ethyl ethylisopropenylethylcarbinyl malonate and 5.4 grams (.09 mole) of urea. The solution is then concentrated by distilling 38 cc. of alcohol from thereaction flask. It is then gently refluxed in an oil bath. The total time consumed for these two operations is 3 hours. The reaction mixture is diluted with water and the alkaline solution filtered until clear. Dilute hydrochloric acid is then used to precipitate ethyl isopropenylethylcarbinyl barbituric acid as a white crystalline solid which, after several recrystallizations from alcohol, melts at 146-147.5.

The barbituric acid in this example has the EXAMPLE 5. -P'repamtion of salts of ethyl 2'80 propenylethylcarbmyl barbituric acid A solution containing a mole of alkali metal hydroxide or alcoholate, such as sodium hydroxide of sodium ethylate, is added to one mole of the barbituric acid of Example 4 in a solvent,

such as water or alcohol, to given a solution of the alkali salt of ethyl isopropenylethylcarbinyl barbituric acid. The solution is filtered, if necessary, and then evaporated, preferably at a low The solutions of the sodium salts when treated with acids regenerate the corresponding barbituric acids. They produce an excellent hypnotic effect when administered to the animal organism. They may be prepared in the form of clear aqueous solutions for injection purposes.

Instead of reacting the barbituric acid in this example with an alkaline solution of an alkali metal compound, an aqueous or other suitable solution of ammonium hydroxide or a monoalkylamine or dialkylamine or a basic solution of an alkaline earth metal compound, such as calcium hydroxide or barium hydroxide may be reacted to give the corresponding moncalkyl ammonium, dialkyl ammonium and alkaline earth metal salts.

propenylethylcarbinyl) malocwte A solution of sodium ethylate is prepared by adding 4.5 grams of sodium to 70 cc. of anhydrous ethyl alcohol and to it is added 39.2 grams (0.196 mole) of ethyl allylmalonate. With the temperature of the solution at 55-60", 23 grams (0.23 mole) of isopropenylethycarbinyl chloride is added in small portions, shaking after each portion is added. Salt separates from the solution immediately after a small amount of the halide has been added. The mixture is allowed to stand at room temperature for one-half hour, then 35 cc. of alcohol is slowly distilled from the solution. The reaction mixture becomes very viscous during the 8 hours it is heated at -110". The product is isolated by diluting with sufiicient water to dissolve the precipitated solid, separating the oily layer from the water, and extracting the aqueous solution with ether. The ether extract and the ester are combined. The ether is removed by dis- I tillation and the residue distilled under reduced pressure. Ethyl allyl- (isopropenylethylcarbinyl) malonate is a colorless liquid distilling at 132- l32.5 under 4 mm. pressure for which was found to be 1.4555.

The reactions in this example may be represented as follows:

C O O CgHs CH3 CH2=CHCH2CH +CH2=C-CHCH2CH3 C O O C2115 C1 CH2=CHCH2 CH3 C O O C2115 CH2=( ;CH-C

GE -CH2 00002115 EXAMPLE 7.-Prepamtion of allyl isopmpenylethylcarbinyl barbituric acid To a solution of sodium ethylate made by dissolving 3.5 grams (0.15 mole) of sodium in 54 cc. of anhydrous alcohol in a cc. round-bottom flask, 14 grams (0.05 mole) of ethyl allyl isopropenylethylcarbinyl malonate and 4.7 grams (0.075 mole) of urea are introduced and the mixture heated to boiling. Twenty-seven cc. of alcohol is removed from the solution by distillation, then the mixture is refluxed for 4.3 hours. The product is dissolved in water and filtered until clear. On acidification with dilute hydrochloric acid an oil separates which slowly solidifies while standing for 18-26 hours in an ice box. Purification is done by crystallization from aqueous alcohol followed by several recrystallizations from a benzene-petroleum ether mixture. Allyl isopropenylethylcarbinyl barbituric acid is secured as a White crystalline solid melting at 107-1105".

The barbituric acid of this example may be represented by the formula:

EXAMPLE 8.Preparatz'on of salts of allyl isopropcnylethylcarbinyl barbituric acid A solution containing a mole of alkali metal hydroxide or alcoholate, such as sodium hydroxide or sodium ethylate, is added to one mole of the barbituric acid of Example 4 in a solvent, such as Water or alcohol, to give a solution of the alkali salt of allyl isopropenylethylcarbinyl barbituric acid. The solution is filtered, if necessary, and then evaporated, preferably at a low temperature and under diminished pressure, until the salt is obtained in solid form.

The alkali metal salts, such as the sodium salt, are white solids soluble in water and alcohol and insoluble in water immiscible solvents. The solutions of the sodium salts when treated with acids regenerate the corresponding barbituric acids. They produce an excellent hypnotic efiect when administered to the animal organism. They may be prepared in the form of clear aqueous solutions for injection purposes.

Instead of reacting the barbituric acid in this example with an alkaline solution of an alkali metal compound, an aqueous or other suitable solution of ammonium hydroxide or a monoalkylamine or dialkylamine or a basic solution of an alkaline earth metal compound, such as calcium hydroxide or barium hydroxide may be reacted'to give the corresponding monoalkyl ammonium, dialkyl ammonium and alkaline earth metal salts.

Although the above examples illustrate the invention, it is not limited to the specific compounds or conditions or reactions described therein, since other compounds embodied in the formulas given may be utilized and prepared, and the other reactions or methods of preparation mentioned in the description above can be made use of.

Some of the barbituric acids of the invention are as follows: Methyl isopropenylethylcarbinyl barbituric acid, n-propyl isopropenylethylcarbinyl barbituric acid, isopropyl isopropenylethylcarbinyl barbituric acid, butyl isopropenylethylcarbinyl barbituric acid, amyl isopropenylethylcarbinyl barbituric acid, isoamyl isopropenylethylcarbinyl barbituric acid, l-methyl-butyl isopropenylethylcarbinyl barbituric acid, hexyl isopropenylethylcarbinyl barbituric acid, Z-methyl amyl isopropenylethylcarbinyl barbituric acid, ethyl isopropenylmethylcarbinyl barbituric acid, allyl isopropenylmethylcarbinyl barbituric acid, ethyl isopropenylallylcarbinyl barbituric acid, allyl isopropenylallylcarbinyl barbituric acid, amyl isopropenylamylcarbinyl barbituric acid, hexyl isopropenylhexylcarbinyl barbituric acid, phenyl isopropenylethylcarbinyl barbituric acid, phenyl isopropenylphenylcarbinyl barbituric acid, ethyl isopropenylphenylcarbinyl barbituric acid,

allyl isopropenylphenylcarbinyl barbituric acid,

oyclohexyl isopropenylethylcarbinyl barbituric acid, cyclopentenyl isopropenylethylcarbinyl barbituric acid, cyclohexenyl isopropenylethylcarbinyl barbituric acid and di-isopropenylethylcarbinyl barbituric acid.

The salts, for example the sodium salts, of each of the barbituric acid compounds given in the last paragraph above may be readily prepared, for instance as illustrated in Examples 5 and 8.

Inaddition to the new barbiturates, the inter- Y mediate malonic esters illustrated by Formula VI and in the examples constitute a new class of chemical substances of value.

What I claim as my invention is: 1. A barbiturate represented by the formula,

R1 C0-NI1 where R and R1 represent hydrocarbon radicals containing not more than six carbon atoms.

3. A barbiturate represented by the formula,

where R and R1 represent alkyl radicals containing not more than six carbon atoms and M represents a member of the group hydrogen, an alkali metal, an equivalent of an alkaline earth metal, ammonium, alkylammonium and dialkylammonium.

4. A barbituric acid represented by the formula,

CHz=O-CH CO-NH Rx CO-NH Where R and R1 represent alkyl radicals containing not more than six carbon atoms.

5. A barbiturate represented by the formula,

CH3 1'! CH:=CCH CO-NH o oo R1 C0-NM where R is a hydrocarbon radical containing not more than six carbon atoms, R1 is a member of the group ethyl and allyl radicals and M is a member of the group hydrogen, an alkali metal, an equivalent of an alkaline earth metal, ammonium, alkylarnmonium and dialkylammonium. 6. A barbituric acid represented by the for mula,

where R is a hydrocarbon radical containing not more than six carbon atoms and R1 is a member of the group ethyl and allyl radicals.

7. A barbiturate compound of formula,

where R1 represents a member of the group ethyl and allyl radicals and M represents a member of the group hydrogen, an alkali metal, an equivalent of an alkaline earth metal, ammonium, alkylammo-nium and dialkylammonium.

8. A barbituric acid of formula,

where R1 represents a member of the group ethyl and allyl radicals.

9. A barbiturate of formula,

OH: 02115 CHz=C-OE /CO-NH CIH6/ OO-Nl\ /I where M is a member of the group hydrogen, an alkali metal, an equivalent of an alkaline earth metal, ammonium, alkylammonium and vdialkylammonium.

10. A barbiturate of formula,

. c 0H=oHo2 o 0-N having a melting-point of about l0'7-ll0.5 C.

13. Sodium ethyl isopropenylethylcarbinyl barbiturate which has the formula,

CH2 CzHa CHz=C-CH (JO-NH and which has hypnotic properties.

WILLIAM G. BY WATER.