US3297715A - 5-propyl-hygric acid derivatives and intermediates - Google Patents

Description

United States Patent 3,297,715 S-PROPYL-HYGRIC ACID DERIVATIVES AND INTERMEDIATES Ross R. Herr, Kalamazoo, Mich, assignor to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed June 15, 1964, Ser. No. 375,333 3 Claims. (Cl. 260-3263) This invention relates to novel compositions of matter and is particularly concerned with S-proplyhygric acid, derivatives thereof, intermediates in the production thereof and the novel process of production thereof.

The novel compounds and the process of this invention can be illustratively represented by the following sequence Of formulae:

wherein R is an alkyl group containing from 1 to 8 carbon atoms, inclusive. The novel Compounds II, III and IV each possess two asymmetric carbon atoms and are therefore each produced as a mixture of four isomeric forms.

The invention is furthermore concerned with the esters and amides of S-propylhygric acid and the alkyl halide quaternary ammonium salts thereof, having the structure Wherein R is selected from the group consisting of an alkoxy group containing up to and including 12 carbon atoms, and the group NH;,-; and wherein R is defined as hereinbefore and R is an alkyl group having from 1 to 20 carbon atoms, inclusive, and wherein Hal is a halogen atom selected from chlorine, bromine, and iodine.

The process of the present invention comprises: Treating a-caprylolactone (I) [Schwenk et al., Org. Synth. 27, 68-71 (1947)] with phosphorus tribromide and bromine and thereafter with ethanol to obtain ethyl a,6-dibr0mocaprylate (II); treating Compound 11 with an alkyl amine, such as methylamine, ethylamine, propylamine, butylamine, hexylamine, octylamine, or the like, to give the corresponding 1 alkyl propylproline N-alkyl amide (III); and hydrolyzing this a-mide with a mineral acid to obtain the corresponding l-alkyl-S-propylproline mineral acid salt, which can be treated with a base, such as silver carbonate or silver oxide, to give the corresponding 1- alkyl-S-propylproline.

The alkyl halide quaternary ammonium salts of 1- Patented Jan. 10, 1967 ice alkyl-5-propylproline esters and amides of Formula IV are obtained by treating 1-alkyl-5-propylproline amide or esters, prepared as shown in the examples, with an alkyl halide, such as methyl iodide, ethyl iodide, propyl iodide, butyl iodide, hexyl iodide, octyl iodide, decyl iodide, dodecyl iodide, tetradecyl iodide, hexadecyl iodide, octadecyl iodide, eicosyl iodide, methyl bromide, ethyl bromide, butyl bromide, hexyl bromide, heptyl bromide, dodecyl bromide, octadecyl bromide, eicosyl bromide, and the like to give the corresponding methiodide, ethio dide, propyl iodide, butyl iodide, hexyl iodide, octyl iodide, decyl iodide, dodecyl iodide, tetradecyl iodide, hexadecyl iodide, octadecy-l iodide, eicosyl iodide, methyl bromide, ethyl bromide, butyl bromide, hexyl bromide, heptyl bromide, dodecyl bromide, octadecyl bromide, eicosyl bromide, and the like, of l-alkyl-S-propylproline amides and l-alkyl-S-propylproline esters.

The quaternary ammonium salts of Formula V, particularly those on which one of the alkyl groups on the nitrogen atom of the quaternary proline has more than 10 carbon atoms, are active anti-microbial and wetting agents and can be thus used for cleaning instruments, employed in bacteriology and surgery. Moreover, because of their electro-conductivity, these compounds can be used for electrocardiographic jellies.

A suitable composition of an electroca-rdiographic jelly containing the above-indicated salts can "be prepared as follows:

Parts Glycerol 5 Starch 1O Quaternary ammonium salts 60 Water 25 The jelly is prepared by mixing the starch, glycerol and water, and then adding the selected alkyl halide quaternary salt of the amide or esters of a 1-alkyl-5- propylproline.

The novel l-alkyl-S-propylproline per se of Formula IV are also useful as buffers and antacids.

The fiuosilicic acid salts of 1-alkyl-5-propylprolines are particularly useful for rnothproofing according to U.S. Patents 1,915,334 and 2,075,359.

The new '1-alkyl-5-proplyprolines can furthermore be converted to 1-alkyl-5-propyl-2-pyrrolidinepenicillins by condensing the prolines with -aminopenicillanic acid as shown in Example 17. These new penicillins have greater stability, particularly against acids and against penicillinase and are thus more effective than penicillin.

The following examples :are illustrative of the process and products of the present invention, but are not to be construed as limiting.

EXAMPLE 1 Ethyl a,t$-a'ibro mocaprylate Into a round-bottomed ml. flask, fitted-with a reflux condenser, there was placed 10.5 ml. of phosphorus tribromide, cooled to 0 C. To the cooled phosphorus tribromide there was added 13 g. of fi-caprylolactone [Schwenk et al., Org. Synth. '27, 6871 (1947)]. After all of the B-caprylolactone had been added, 7.1 ml. of bromine was added under stirring and the resulting mixture was allowed to stand overnight at room temperature. After 20 hours, 1 ml. of phosphorus tribromide and 6 ml. of bromine was added. The mixture was allowed to stand another 4 hours and was then refluxed for a period of 24 hours. The reaction mixture was then cooled to room temperature and cautiously absolute ethanol was added. After all the ethanol had been added, the resulting mixture was refluxed for 1 /2 hours. The mixture was then distilled in vacuo to remove excess ethanol and the resulting residue was dissolved in benzene. The benzene solution (about 250-300 1111., including rinses) was washed, in a larger flask, once with water, then with dilute sodium thiosulfate solution, then with water again until all washings were free of bromine ions. The benzene solution was then dried over anhydrous sodium sulfate, and was distilled in vacuo to give a brown oily residue. This residue was redistilled in vacuo at 0.8 mm. pressure (Hg) at 125-135 C. to give 20 g. (57% of theory) of ethyl a,5-dibromocaprolate.

Analysis.Calcd. for C H o Br C, 36.38; H, 5.49; Br, 48.43. Found: C, 35.43; H, 5.37; Br, 48.75.

EXAMPLE 2 The N-mcthyl amide f -pr0pylhygric acid (cis and trans) A solution of 14.85 g. (0.045 mole) of ethyl a,6-dibromocaprylate, 17.4 g. (0.56 mole) om methyl amine and 85 ml. of methanol were heated at 140 C. for 4 hours in an autoclave. The reaction mixture was filtered and evaporated in vacuo to dryness. The residue was dissolved in chloroform and filtered to remove methyl amine hydrobromide. The filtrate was evaporated to dryness and the residue was distributed countercurrently for 200 transfers using the solvent system ethyl acetatezethanol:cyclohexanezwater, 1:1:1:1. Two main peaks were seen by determination of solids. The first peak was in tubes 80-107. These tubes were combined and evaporated to dryness and the resulting partially crystalline residue was recrystallized from Skellysolve B hexanes to give 1.8 g. of the N-methyl amide of 5-propy1- hygric acid.

AnaIysis.Calcd. for C H N O: C, 65.18; H, 10.94; N, 15.21. Found: C, 65.86; H, 11.27; N, 14.54.

The second peak was found in tubes 118-150, which were pooled and evaporated to dryness. The resulting residue crystallized in the refrigerator between 0 and 5 C. but melted at room temperature. 1 This material was used directly in the next step of the hydrolysis.

EXAMPLE 3 Hydrolysis of the N-methyl amide of (cis and trans) 5- propylhygric acid [5-propylhygric acid (cis and trans)] Eight hundred milligrams of the low-melting methyl amide of S-propylhygric acid was hydrolyzed by refluxing with 40 ml. of 6 N hydrochloric acid for a period of 4 hours. The solution, after the refluxing, was evaporated to dryness in vacuo. The residue was dissolved in water, and a basic exchange resin (Dowex 2) was added until the pH rose to 10. The resin was then collected and eluted with aqueous hydrochloric acid. The eluate was evaporated to dryness and the residue was dissolved in a small amount of anhydrous ethanol. Ether was added until the solution was cloudy and the mixture was then cooled in a refrigerator. Crystals which separated were collected by filtration, washed and recrystallized to give 107 mg. of S-propylhygric acid hydrochloride.

Analysis.Calcd. for C H NO -HCl: C, 52.04; H, 8.73; N, 6.74; Cl, 17.07. Found: C, 51.82; H, 9.33; N, 7.08; Cl, 16.90.

A 200 mg. sample of the higher melting crystalline methyl amide of S-propylhygric acid was refluxed with 10 ml. of 6 N hydrochloric acid for 4 hours. The solution was evaporated to dryness in vacuo, the residue was dissolved in water, and a basic resin, Dowex 2, was added until the pH was 10. The resin was collected and diluted with aqueous hydrochloric acid. The eluate was evaporated to dryness and the residue was dissolved in a small amount of anhydrous ethanol. Ether was added until the solution was cloudy and the mixture was then cooled. A small amount of yellow oil separated. The supernatant was decanted and diluted with several volumes of ether. On cooling, crystals formed slowly.

From two such experiments, 143 mg. of crystalline material was obtained, which was recrystallized from acetonitrile-ether to give mg. of 5-propylhygric acid hydrochloride.

Analysis.Calcd. for C H NO 'HCl: C, 52.04; H, 8.73; N, 6.74; Cl, 17.07. Found: C, 51.12; H, 8.45; N, 7.03; Cl, 16.55.

EXAMPLE 4 5-propylhygric acid A mixture of 800 mg. of 5-propylhygric acid hydrochloride (cis and trans), 2 g. of silver carbonate, and 10 ml. of water were stirred at room temperature (25 C.) for a period of one-half hour. The mixture was then warmed on a steam bath for 30 minutes and filtered. The filtrate was evaporated in vacuo and the thus-obtained residue was recrystallized from ethyl alcoholzethyl acetate to give 5 propylhygric acid.

EXAMPLE 5 N-ethyl amide of J-ethyl-S-propylproline In the manner given in Example 2, 10 g. of ethyl u,8- dibromocaprolate was condensed with 15 g. of ethylamine in 17 ml. of methanol by heating at C. for four hours. The residue was treated as in Example 2 to give the ethyl amide of 1-ethyl-5-propylprolines.

EXAMPLE 6 N-propyl amide 0f 1,5-dipr0pyIproli/1e In the manner given in Example 2, ethyl a,6-dibromocaprolate was condensed with propylamine to give the N-propyl amide of 1,5-dipropylproline.

EXAMPLE 7 N-hexyl amide of 1-hexyLS-propylproline 1-ethyl-S-propylproline hydrochloride In the manner given in Example 3, N-ethyl amide of 1- ethyI-S-propylproline was hydrolized with hydrochloric acid to give l-ethyl-S-propylproline hydrochloride.

EXAMPLE 9 1,5-dipr0pylpr0line hydrochloride In the manner given in Example 3, N-propyl amide of 1,5-dipropylproline was hydrolized in hydrochloric acid to give 1,5-dipropylproline hydrochloride.

EXAMPLE 10 I-hexyI-5-propylpr0line hydrochloride In the manner given in Example 3, N-hexyl amide of 1- hexyl-S-propylproline was hydrolized in hydrochloric acid to give 1-hexyl-5-propylproline hydrochloride.

In the manner given in Example 3, other 1-alkyl-5-propylproline hydrochlorides can be prepared by hydrolizing the corresponding N-alkyl amides of l-alkyl-S-propylproline, representative l-alkyl-S-propylproline hydrochlorides thus prepared include: the l-butyl-S-propylproline hydrochloride, the 1-isobutyl-5-propylproline hydrochloride, the I-pentyl-S-propylproline hydrochloride, the 1- octyl-5-propylproline hydrochloride, and the like.

EXAMPLE ll .1-ethyl-S-propylproline In the manner given in Example 4, 1-ethyl-5-propylproline hydrochloride was reacted with silver carbonate to give 1-ethy1-5-propylpr0line.

EXAMPLE 12 1,5-diprpylpr0line In the manner given in Example 4, 1,5-dipropylproline hydrochloride was treated with silver carbonate to give 1,5-diproplyproline.

EXAMPLE 13 J-hexyl-S propylproline In the manner given in Example 4, 1-hexyl-5-propylproline hydrochloride was treated with silver carbonate to give 1-hexyl-5-propylproline.

In the manner given in Example 4, other l-alkyl-S-propylprolines can be produced by reacting the corresponding hydrochloride salts of l-alkyl-S-propylprolines with silver carbonate. Representative compounds thus produced include: l-butyl-S-propylproline, 1-isobutyl-5-propylproline, 1-pentyl-5-propylproline, 1-octyl-5-propylproline, and the like.

EXAMPLE 14 1 -methyl-S-propylproline amide To a stirred mixture of 1.03 g. (0.006 mole) of 1- rnethyl-S-propylproline, 1.68 ml. (0.006 mole) of triethylamine and 60 ml. of dry acetonitrile at 0 C. is added 0.58 ml. of ethyl chloroformate. The reaction mixture is maintained between 0 and C. for a period of /2 hour and then 6 ml. of concentrated ammonium hydroxide is added. After standing for a period of 18 hours at 25 C. the reaction mixture is evaporated to dryness in vacuo and the resulting residue is dissolved in 50 ml. of Water. The aqueous solution is made acidic with hydrochloric acid and thereupon extracted with four 50-ml. portions of methylene chloride. The methylene chloride extracts are discarded, the aqueous phase is made basic with sodium hydroxide and then extracted with three SO-ml. portions of methylene chloride. The methylene chloride phases are combined, evaporated and the residue recrystallized from Skellysolve B hexanes to give 1-methyl-5-propylproline amide.

EXAMPLE 15 1,5-dipr0pylpr0line amide In the manner given in Example 14, 1,5-dipropylproline in acetonitrile, treated with triethylamine, thereupon with ethyl chloroformate, and subsequently with ammonium hydroxide, gives 1,5-dipropylproline amide.

EXAMPLE 16 1-ethyl-5-pr0pylpr0line amide In the manner given in Example 14, 1-ethyl-5-propylproline dissolved in dry acetonitrile, reacted with triethylamine and ethyl chloroformate and subsequently with ammonium hydroxide gives l-ethyl-S-propylpr-oline amide.

In the manner given in Example 14, other l-alkyl-S-proplyproline amides are obtained by reacting l-alkyl-S-propylproline with triethylamine, ethyl chloroformate, and subsequently treating the mixture with ammonium hydroxide. Representative l-alkyl-S-propylproline amides thus obtained include: 1-butyl-5-propylproline amides, 1- isobutyl-S-propylproline amides, l-pentyl-S-propylproline amides, 1-hexyl-5-propylproline amides, l-heptyl-S-propylproline amides, 1-octyl-5-propylproline amides, and the like.

EXAMPLE 17 Potassium 6- (5-propylhygramid0 penicillanate A mixture of 3.09 g. of S-propylhygric acid, 9.5 ml. of tributyl-amine, 100 ml. of acetonitrile and 40 ml. of acetone is stirred until complete solution has taken place. To this solution, cooled to 0 C., is added 2.05 ml. of isobutyl chloroformate. The reaction mixture is stirred for 30 minutes in an ice bath, then 3.24 g. of 6-aminopenicillanic acid in 50 ml. of water and 1.7 g. of sodium bicarbonate is added, and stirring is continued at room temperature for 2 hours. The mixture is evaporated to dryness.

The residue is partitioned between ether and water, and the ether layer is discarded. The aqueous layer is adjusted to pH 6 with hydrochloric acid, extracted several times with ether and the ether solution is dried over sodium sulfate. The addition of a 40% solution of potassium 2-ethyl hexonate in butyl alcohol precipitates potassium 1-methyl-5-propyl-2-pyrrolidinylpenicillin [potassium 6(5propylhygramido)penicillanate].

EXAMPLE 18 Methyl ester of 1-methyl-5-propylpr0line To a solution of 1.5 g. of1-methyl-5-propylproline in 20 ml. of ethanol is added under stirring, during a period of 10 minutes, an excess of diazomethane. The mixture is decomposed by the addition of acetic acid, evaporated to dryness, and the resulting residue dissolved with 20 ml. of water. This solution is made basic by the addition of aqueous sodium hydroxide and then extracted with three 25-ml. portions of methylene chloride. The methylene chloride extracts are evaporated to give 500 mg. of crude 1-methyl-5-pro pylproline methyl ester.

This material is redissolved with hydrochloric acid, the solution is evaporated and recrystallized from ethanoltether to give the hydrochloric acid salt of the methyl ester of l-methyl-S-propylptroline.

EXAMPLE 19 Ethyl 5-propylhygrate hydrochloride (l-elhyl-S-propylproline ethyl ester hydrochloride) A solution is prepared containing 1 g. of l-methyl-S- propylproline in 25 m1. of ethanol. Through this solution is passed dry hydrogen chloride gas for a period of 15 minutes. The solution is thereupon evaporated and the resulting material recrystallized twice from ethanol and Water to give the hydrochloric acid salt of ethyl 5- propylhygrate.

Treatment of the hydrochloric acid salts of ethyl 5- propylhygrate with a weak base, e.g., silver carbonate, as shown in Example 4, gives the free ester, ethyl 5- propylhygrate.

In the manner given in Example 19, other esters of 1-alkyl-5-propy1prolines and the hydrochlorides can be made by reacting a selected 1-alkyl-5-propylproline in an alkanol, such as methanol, ethanol, propanol, butanol, pentanol, hexanol, heptanol, octanol, decanol, dodecanol and the like, with hydrogen chloride to obtain the corre sponding alkyl ester of 1-alkyl-5-propylproline hydrochloride, which can be converted with silver carbonate or silver oxide to the corresponding free ester. Representative esters thus obtained include: methyl 1,5-dipropylproline, methyl l-butyl-S-propylproline, methyl l-isobutyl- 5-propylproline, ethyl 1-pentyl-5-propylproline, butyl 1- hexyl-5-propylproline, octyl 1-octyl-5-propylproline, dodecyl l-ethyl-S-propylproline, and the like.

EXAMPLE 20 Methiodide of methyl 5-pr0pylhygrate To 3 g. of methyl S-propylhygrate is added with cooling and continuous stirring 4.25 g. of methyl iodide; a vigorous reaction ensues. After addition cooling, 2.5 g. of methyl iodide is added and the mixture is allowed to stand overnight at room temperature. Excess methyl iodide is removed under reduced pressure, and the solid obtained is dissolved in 50 ml. of anhydrous ethanol. The ethanol is removed under reduced pressure and the residue is recrystallized three times from a 1:1 mixture of ethanolzether to yield crystals of the methiodide of methyl 5- propylhygrate.

EXAMPLE 21 Methiodide of 1-ethyl-5-pr0pylproline methyl ester To 2 g. of 1-ethyl-5-propylpro1ine methyl ester is added 2.5 .g. of methyl iodide. After standing at room temperature for a period of 22 hours, the reaction mixture is dissolved in 20 ml. of methanol, treated with decolorizing carbon and filtered. The filtrate is evaporated to dryness under reduced pressure and the residue is recrystallized twice from ethyl acetate to give crystals of the methiodide f l-ethyl-S-propylproline methyl ester.

EXAMPLE 22 Methiodide of I-methyl--propylproline amide (methiodide of 5-propylhygramide) A solution of 2.5 g. of l-methyl-S-propylproline amide (S-propylhygramide) in 20 ml. of methanol is treated with 3 ml. of methyl iodide with cooling. After the initial vigorous reaction has abated, 20 ml. of methanol and 5 ml. of methyl iodide are added. After stirring until the exothermic reaction is over, the methiodide of 5- propylhygramide is filtered and washed with methanol. The filtrate is evaporated to dryness in vacuo and the residue is dissolved in 50 ml. of acetone and seeded with a small amount of crystal, preformed in acetone and ethyl acetate. The mixture is then cooled in a refrigerator overnight and the crystals thus obtained are collected by filtration, washed with acetone and ether and dried in vacuo at 40 C. to 'give methiodide of 1-methyl-5-propylproline amide (methiodide of S-prOpylhygramide).

In the manner given in Examples 20, 21 and 22, alkyl quaternary ammonium salts of the esters and amides of l-alkyl-S-propylproline can be obtained by reacting alkyl chlorides, bromides or iodides with selected l-alkyl-S- propylproline esters or amides. Representative compounds thus obtained include: ethiodide, propyl iodide, butyl iodide, pentyl iodide, hexyl iodide, octyl iodide, decyl iodide, dodecyl iodide, tetradecyl iodide, octadecyl iodide, eicosyl iodide, methyl chloride and bromide, ethyl chloride and bromide, propyl chloride and bromide, butyl chloride and bromide, hexyl chloride and bromide, octyl chloride and bromide, decyl chloride and bromide, dodecyl chloride and bromide, tetra-decyl chloride and bromide, octadecyl chloride and bromide, eicosyl chloride and bromide of, e.g., the methyl ester of 1-methyl-5-propylproline, the ethyl ester of l-methyl-S-propylproline, the octyl ester of l-ethyl-S-propylproline, the propyl ester of 1,5-dipropylproline, the butyl ester of l-octyl-S-propylproline, the dodecyl ester of 1-butyl-5-propylproline, the undecyl ester of 1-isobutyl-S-propylproline, the amide of l-methyl-S- propylproline, the amide of 1-ethyl-5-propylproline, the amide of 1,5-dipropylproline, the amide of 1-butyl-5-propylproline, the amide of 1-pentyl-5-propylproline, the amide of l-hexyl-S-propylproline, the amide of 1-octyl-5- propylproline, the amide of 1-isooctyl-5-propylproline, and the like.

I claim:

1. Ethyl a,6-dibromocaprylate.

2. A compound of the formula wherein R is an alkyl group containing from 1 to 8 carbon atoms, inclusive.

3-. The N-methyl amide of 1-methyl-5-propylproline.

References Cited by the Examiner Fieser et al.: Organic Chemistry, OD 251 F5, 1956, C6, pages 226, 227, 242,

Noller, Chemistry of Organic Compounds, OD 253 N65, 1957, page 237.

Wagner et al.: Synthetic Organic Chemistry, OD 262, W24 02, 1953, page 496.

Winterfeld et al.: Archiv. der Pharmazie, 274: 40-7, 1936, RS 1.A7.

ALEX MAZEL, Primary Examiner.

HENRY R. IILES, Examiner.

J. A. NARCAVAGE, Asisstant Examiner.

Claims (1)

1. 2. A COMPOUND OF THE FORMULA