US2161212A

US2161212A - Substituted barbituric acids con

Info

Publication number: US2161212A
Authority: US
Publication date: 1939-06-06
Anticipated expiration: 1956-06-06

Description

Patented June 6, 1939 UNITED STATES SUBSTITUTED BARBITURIG V ACIDS CON- TAINING QUATEENARY CARBON ATOMS Frank O. Whitmore, State College, Pa., and Melvin A. Thorpe, St. Louis, Mo., assignors to Mallinckrodt Chemical Works, St. Louis, Mo;

No. Drawing.

ApplicationNovember 3, 1934, Serial No. 751,416 L Y Claims. (or. 260- 257) This invention relates to substituted barbituric acids, and with regard to certain'rnore specific" wherein Y indicates hydrogen or alkali metal; and the Rs indicate alkyl or othersubstituent groups (as pointed out'more fully hereinafter),

but at least one of the Rs indicates an alkyl substituent containing a quaternary carbon'atom, that is, a carbon atom to which are linked four other carbon atoms; or the ordinary substitution products thereof. Other objects will be in part obvious and in part pointed out hereinafter. The invention accordingly comprises the elements and combinations of elements, and features of composition, which will be exemplified in the substances hereinafter described, and the scope of the application of which will be indicated in the following claims.

It has heretofore been determined that the effectiveness of substituted barbituric acid derivatives as hypnotics, jsedatives, or soporifics, depends in part upon the composition of the substituent groups, and it has also been noted that the more branched the substituent groups are, the more effective is the hypnotic or sedative or soporific action, without correspondingincrease in undesirable qualities. It is the purpose of the present invention to provide for substituted barbituric acids having substituents including a considerable number .of branches through the use of substituents containing a quaternary carbon atom, which substituents are all broadly new. Such derivatives have not heretofore been prepared because no satisfactory method has been known for obtaining the quaternary carbon-containing substituent in such form as to permit of its joining to: the barbituric acid nucleus. However, such a method has now been provided, and, as set forth in the'copendi-ng application of the present applicant Whitmore, and Walter E. Trent, Serial No. 666,510, filed April 17, 1933, now Patent No. 2,022,485, dated November 26, 1935, halides including a quaternary carbon atom, such as 3,3-dimethyl-l-bromobutane, may readily be prepared. In the copending application of the present applicant Whitmore and August H. I-Iomeyer, Serial No. 36,132 filed An gust 14, 1935, the preparation of higher homologous halides, such as 4,4-dimethyl-1-bromopentane,is disclosed.

Numerous examples of substances within the scope of the invention are set forth hereinafter, and for an exemplary number of these examples, details of procedure for the preparation thereof are set forth. It is to be understood, however, that the invention is by no means limited to the specific examples set forth.

The first group of examples, numbered 1 through 5, show variations in the structure of the substituent R' (in the above type formula) containing the quaternary carbon atom, while the other R. is uniformly the substituent ethyl.

. EXAMPLE 1 5 -ethyl, 5- (3,3'-dimethylbutyl) barbituric acid The structural formula of this substance is as follows: 7

CHa-CH2 OZ-CNH The above substance is prepared in the following manner:

Ethyl ethylmalonate, commercially obtainable, is used as a starting material. This substance is condensed, in absolute ethyl alcohol in the presence'of an alkali alcoholate, with 3,3- dir'nethyl-l-bromobutane, according to the following reaction:

The product of this reaction, the formula for which is given above, is then condensed with urea, the reaction proceeding in the following manner:

onion; o=c-:o'r'r;6ii;"fi[-Nn the product being the desired substituted barbituric acid.

Procedure 150 cc. of ethyl alcohol were distilled from a solution of absolute ethyl alcohol plus onetwentieth of its weight of metallic sodium into a three-neck flask. The flask was placed in an oil bath and a condenser holding a drying tube at the upper end, and a stirrer with a mercury seal, and a dropping funnel were placed in the three necks. 6.9 grams of metallic sodium weighed in toluene were added in small pieces through the condenser over a period of about 7 minutes. Then, with the oil bath at a temperature of about C., 56.4 grams of ethyl ethylmalonate (boiling point, 112 to 115 at 30 to 32 mm. pressure) were added and the mixture was stirred for about one-half hour. Then, during the next two hours, 49.5 grams of 3,3-dimethyll-bromobutane (boiling point, 137 to 138 C. at 746 mm. pressure), were added to the mixture. After about one-half hour, sodium bromide began to settle out. The mixture was then stirred and refluxed for 56 hours, at the end of which time the mixture was just faintly alkaline to litmus paper. The flask was then attached to a fractionating column and the excess alcohol distilled oii. The residual mixture was washed with cc. of water and the oily layer allowed to separate. The water layer was extracted once with ether, and the ether was then added to the oily fraction, which was then dried with sodium carbonate. The dried oily fraction was then fractionated, and the product ester (see structural formula above), was obtained to the extent of 36.1 grams, boiling at from 148 to 151 C. The yield was 44% of theoretical. The index of refraction of the product ester was about 1.4320 at 20 C., with respect to the sodium-D line.

The same flask arrangement was used for the second step. 65.97 grams of absolute ethyl alcohol were placed in the flask, and 3.84 grams of clean metallic sodium were added to form sodium ethylate. The resulting ethylate was cooled to 20 C., and 15.15 grams of the ester prepared as above were added, followed by 4.81 grams of pure, crystalline urea. The reaction mixture was heated to refluxing temperature by means of a water bath, and the refluxing was continued for four hours. A straight condenser was then attached to the flask, and the excess alcohol was removed by distillation. This required two hours. The residue in the flask was then cooled to 25 C., and then dissolved by adding 50 cc. of distilled water. The resulting solution was then extracted with two portions of ether, 50 cc. and 25 cc. respectively. The extracted solution was then diluted with an additional 50 cc. portion of water and the barbituric acid derivative precipitated out by adding dilute hydrochloric acid until the solution was. acid to blue litmus paper. The almost white crystalline precipitate was washed with water, sucked free of excess water, and then dried in an electric drying oven over night at 105 C. The product weighed 9.35 grams, which was 70% of the theoretical yield. This product was then dissolved in 107 cc. of boiling 50% ethyl alcohol. On cooling, 8.5 grams of pure white crystals were obtained. These crystals had a melting point of about 192 C., and constituted the desired product, 5-ethyl, 5-(3',3'dimethy1 butyl) barbituric acid.

EXAMPLE 2 5 -ethyl, 5- (4',4-dimethylpentyl) barbitzm'c acid 'The structural formula of this substance is as follows:

omen? O:ONH

O C: (oflosocmomom o ;c1 u1 from which it is seen that it is the same as the preceding compound, Example 1, except for the addition of one further -CH2- group in the alkylene chain connecting the quaternary carbon atom to the barbituric acid nucleus.

The synthesis of this substance is substantially the same as that of the next lower homologue (Example 1) as described, but involving the use of 4,4-dimethyl-l-bromopentane in place of the 3,3-dimethyl-1-bromobutane. First, the 4,4-dimethyl-l-bromopentane is condensed with ethyl ethylmalonate to obtain the ester having the formula:

and that is in turn condensed with urea to obtain the desired product. Because of the similarity of procedures, no detailed example of the synthesis of this material will be given.

The product, 5-ethyl, 5-(4',4-dimethylpentyl) barbituric acid, is a crystalline solid'having a melting point of about 184 to 185 C.

, EXAMPLE 3 5-e thyl, 5-(4,4'-dimethylhea:yl) barbiturz'c acid The structural formula of this substance is as. follows:

O:C-NH' 0 C20 I CHaCHa.C(CHa)2.CHz.OHz.CH2 0ZC'NH anionic(cnmcmomonf c ooomorn and that is in turn condensed with urea to obtain the desired product which has the form of long, colorless. fluffy needles melting at 154 to 155 C.

EXAMPLE 4 5 ethyl, 5- (7',7"dimethyloctyl) barbituric' acid The structural formula of this substance is as follows:

CHLOE?! O:C-NH

o l (CH3)3C.CH2.CHa.OHz.CH2.CHz-CH2 OZC-NH from which it is seen that it is the same as the substances of Examples 1 and 2, except for the addition of four, and three, respectively, further -CH2 groups in the alkylene chain connecting the quaternary carbon atom to the barbituric acid nucleus.

The synthesis of this substance is substantially the same as that of the preceding examples, but involving the use of .7,7-dimethyl-1-bromooctane as the quaternary carbon-containing starting material. This, is first condensed with ethyl ethylmalonate to obtain the ester having the formula:

- (CH1)3C.CH2.GH2.CH2.CHLCH2-CH2 OZC-OCHzCHs and that is in turn condensed with urea to obtain the desired product.

The foregoing examples illustrate the possibility of numerous variations in the structure of the substituent group containing the quaternary carbon atom. For illustrative purposes, the other substituent group has, throughout these examples, been held as ethyl. In the next thirteen examples, numbered 5 through 17, inclusive, the substituent containing the quaternary carbon atom remains the same, namely, 4',4'-dimethylpentyl- (see Example 2), while the other substituent is subjected to wide variations.

EXAMPLE 5 5- (4',4dimethylpentyl) barbituric acid This substance has the following structural formula:

H\ (yo-tin a 0 0:0

l (CH3)3C.CH2.CH2.CH2 OZC-NH It represents a substance where the second substituent is hydrogen.

This substance is synthesized by first condensing ethyl malonate with 4,4-dimethyl-l-bromopentane, in absolute ethyl alcohol in the presence of an alkali alcoholate, according to the following reaction:

+NaBr The product of this reaction, the formula for which is given above, is then condensed with urea, the reaction proceeding in the following manner:

the product being the desired substance, 5-(4',4'-

dimethylpentyl) barbituric acid.

Ethyl malonate, the starting material, is commercially obtainable.

v EXAMPLE 6 5-methyl, 5- (4,4-dimethylpentyl) barbituric acid This substance has the following structural formula:

- OzC-NH It is representative of a class of substances where the second substituent is an alkyl, specifically, methyl. Examples 1 through 4 also fall in this category, the second substituent there being ethyl.

It is prepared by the same method of synthesis as that of Example 5, but using ethyl methylmalonate in place of the ethyl malonate. Ethyl methylmalonate is commercially obtainable.

EXAMPLE '1 5-n-pr0pyl, 5 (4 ',4'-dimethylpentyl) barbituric acid This substance has the following structural formula:

CHa.GH2.0Hz -NH o l (CH3 80.0Hfl.CHq-CH2 O:C-NH

It is likewise a substance in which the secondsubstituent is an alkyl, specifically, n-propyl.

It is prepared by the same method of synthesis as that of Example 5, but using ethyl n-propylmalonate in place of the ethyl malonate. Ethyl n-propylmalonate is commercially obtainable.

EXAMPLE 8 5 -n-batyl, 5- (4',4-dimethylpentyl) barbituric acid This substance has the following structural formula GHLCHI-GHi-GHz (pC-NH (CHalaQOHaCHsCHa O:C--N

It is likewise a substance in which the second substituent is an alkyl, specifically, n-butyl.

It is prepared by the same method of synthesis as that of Example 5, but using ethyl n-butylmalonate in place of the ethyl malonate. Ethyl n-butylmalonate is commercially available.

EXAMPLE 9 5-allyl, 5- (4',4'-dimethylpentyl) balrlnturz'c acid EX MPLE 10 5-propargyl, 5- (4,4 -dimethylpentyllbarbituric acid 5 -cyclopentyl, 5 (43 4. -dime.thylpentyl) barbituric acid This substance has the following structural formula:

CHYIJH OZC-JITH C C20 l (cHoaQcHscHscm OzC-NH This substance is representative of a class of substances in which the second substituent is a cycloalkyl, specifically, cyclopentyl.

It is prepared by the same method of synthesis as that of Example 5, but using ethyl cyclopentylmalonate in place of the ethyl malonate. Ethyl cyclopentylmalonate may be prepared by wellknown methods.

E AMPLE l2 5 -cyclohexyl, 5- (4',4'-dimethylpentyl) barbituric acid This substance has the following structural formula:

It is likewise representative, along with Example 11, of substances in which the second substituent is a cycloalkyl, specifically, cyclohexyl.

It is prepared by the same method of synthesis as that of Example 5, but using ethyl cyclohexylmalonate in place of the ethyl malonate. Ethyl V cyclohexylmalonate may be prepared by wellknown methods.

1 1 EXAMPLE l3 5-phenyl, 5- (4,'4'dimethylpentyl) barbitaric acid The structural formula of this substance is as follows:

C5115 OZCNH It is representative of a class of derivatives in which the second substituent is an' aryl, specificially, phenyl.

It is prepared by the same method of synthesis as that of Example 5, using ethyl phenylmalonate in place of the ethyl malonate. Ethyl phenylmalonate is commercially obtainable. The product has the form of white crystals which melt at 174 to 175 C.

EXAMPLE 14 s-b'enzyz, 4,'4-dimethylpentyl) barbituric acid The structural formula of this substance is as follows:

CaHt.CH2 A O:CNH

O cnmdcraomom sic-i111 It is representative of a class of derivatives in which the second substituent is an arylalkyl, specifically, benzyl.

It is prepared by the same method of synthesis as that of Example 5, but using ethyl benzylmalonate in place of ethyl malonate. Ethyl benzylmalonate is commercially obtainable.

EXAMPLE 5- (beta-phenyletii'yl) 5- (4';4'-dimethylpentyl) barbiturz'c acid The structural formula of this'substance is as follows:

CtH5.CH2.CH2 -O:C-NH.

0 1 I (CHa)aC.CH2.CHz.CHz OzC-NH It is representative, along with Example 14, of derivatives in which the second substituent is an arylalkyl, specifically, beta-phenylethyl,

It is prepared by the same method of synthesis as that of Example 5, but using ethyl .betaphenylethylmalonate in place of the ethyl malonate. Ethyl beta-phenylethylmalonate is commercially obtainable.

7 EXA PLE 16 5 -phenoxyethyl, 5- (4 ,4 -dzmethylpentyl) barbituric acid The structural formula of this substance'is as follows: 4

CaHLOlCHLQHz O:O-NH

. c r l (CH3)3C.CE2.CH2.CH2 OIC-NH 7 It is exemplary of a class of derivatives in which the second substituent is an aryl-oxy-alkyl, specifically, phenoxyethyl.

It is prepared by the same method of synthesis as that of Example 5, but using ethyl phenoxyethylmalonate in place of the ethyl malonate. Ethyl phenoxyethylmalonate may be prepared by well-known methods.

EXAMPLE 1'7 5 -etho.ryethyl, 5- (4,4dimcthylpentyl) barbituric acid The structural formula of this substance is as follows:

(cmboomcmcm O:CNH

It is exemplary of a class of derivatives in which the second substituent is an alkyl-oxy-alkyl, specifically, ethoxyethyl.

It is prepared by the same method of synthesis as that'of Example 5, but using ethyl ethoxyethylmalonate in place' of the ethyl malonate. Ethyl ethoxyethylmalonate may be prepared by well-known methods.

A still further generic class of derivatives coming within the scope of the invention comprises the monobasic alkali metal salts of any of the cHicHtocHacHi acids falling within the scope of the invention. For example, if sodium ethylate be allowed to react, in molecular proportions, by well-known methods, with any of the foregoing acids, the monobasic sodium salt of the corresponding acid is obtained. The same is of course true of the other alkali metals. It is unnecessary herein to set forth specifically all of these alkali-metalsalts of all of the foregoing acids, but a few will suffice for the lot:

EXAMPLE 18 (From Example 1.) Monobasic sodium salt of -ethyl, 5-(3',3'-dimethylbutyl) barbituric acid.

EXAMPLE 19 (From Example 2.) Monobasic sodium salt of 5-ethyl, 5-(4,4'-dimethylpenty1)barbituric acid.

EXAMPLE 20 (From Example 13.) Monobasic sodium salt of 5-phenyl, 5-(4,4-dimethylpentyl) barbituric acid, which is an amorphous White powder that decomposes on heating, yielding no well-defined melting point.

The malonic esters described in this application are claimed in the copending application of the present applicant Whitmore, and David M. Jones and Clarence I. Noll, Serial No. 63,212, filed February 10, 1936.

In View of the above, it will be seen that the several objects of the invention are achieved and other advantageous results obtained.

As many changes could be made in carrying out the above syntheses and in compounding the above substances without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limit- 7 ing sense.

5- (3',3' -dimethylbutyl) barbituric 5- (4',4' -dimethylpentyl) barbituric wherein Y indicates a substituent selected from a class composed of hydrogen and the alkali metals, R indicates a substituent selected from a class composed of hydrocarbon radicals, aryloxy-alkyls, and alkyl-oxy-alkyls, R1 is an aliphatic hydrocarbon radical, and R2, R3, and R4 are each alkyls attached to the same carbon atom of R1.

4. A 5-substituted barbituric acid having a single barbituric acid nucleus, in which one of the substituents in the 5-position is an aliphatic hydrocarbon radical having a quaternary carbon atom in its structure.

5. A 5-substituted barbituric acid having a single barbituric acid nucleus, in which one of the substituents in the 5-position is an alkyl having a quaternary carbon atom in its structure.

FRANK C. WHITMORE. MELVIN A. THORPE.