Patented Jan. 30, 1951 2,539,428

*w------UNITED STATES PATENT OFFICE

2,539,428 - 3,3'-DITHOLISOBUTYRIC ACED Eugene F. Jansen, Berkeley, Calif., assignor to SecretaryUnited States of Agriculture of America as represented by the No Drawing. Application April 15, 1949, Serial No. 87,823 10 Claims. (C. 260-526) (Granted under the act of March 3, 1883, as amended April 30, 1928; 30 O. G. 757) 1. 2 This application is nade under the act of employed, whereas for the reverse transfer, acidic March 3, 1883, as amended by the act of April 30, conditions are employed. The number of trans 1928, and the invention hereindescribed, if fers to be carried out depends, of course, on the patented in any country, may be manufactured degree of purity desired. For some purposes, it and used by or for the Government of the United is Sufficient to transfer the compound from or States of America for governmentai purposes ganic Solvent to water and then back to or throughout the World without the payment to me ganic Solvent, and then evaporate the solvent of any royalty thereon. - to obtain the product. In other cases where This invention relates to organic sulphur com highly purified product is desired, the transfers pounds, in particular to Sulphur-containing de O can be repeated to eliminate all impurities. For rivatives of , and has among its complete and exhaustive purification, the follow objects the provision of processes for isolating an ing procedure is used: Asparagus juice is ex Organic disulphide compound contained in tracted with a polar solvent whereby a polar asparaguS and for converting this material, or Solvent extract is obtained which contains the other raw materials, into 3,3'-dithiolisobutyric 15 desired Organic disulphide compound plus im acid and derivatives thereof. Other objects will purities Such as phenolic compounds, non-acidic be apparent from the description of the inven compounds, and so forth. This extract is then tion. extracted with an aqueous alkaline solution. By The products of the invention, which are novel this treatment the disulphide compound is trans Sulphur-containing derivatives of isobutyric acid, 20 ferred to the aqueous phase, but various im may be represented by the formulae purities, particularly phenolic compounds, re main in the Solvent phase. The aqueous extract is then acidified and extracted with a polar sol YoH-cooM vent whereby the disulphide compound is trans R-s-off, 25 ferred to the Solvent phase and a further elim and ination of impurities is effected. The solvent R S-CH phase is then concentrated, preferably under Yo Yo H-cooM Vacuum, to remove all the water therefrom. The concentrated solution is then mixed with R? Ys-o?, 30 an excess of an organic fat solvent whereby im wherein R and R' are radicals selected from the purities low in Sulphur content are precipitated. group consisting of hydrogen and hydrocarbon, The disulphide compound is again transferred to and M is a cation. aqueous solution by extraction with aqueous al One phase of this invention involves the pro kaline solution and this aqueous phase, after vision of a process for isolating an organic di 35 acidification, is extracted with an organic fat Sulphide compound from asparagus. This com Solvent. The resulting extract contains the di pound, the existence of which has not been here Sulphide compound in substantially pure form tofore known, is useful as an intermediate for and it can be recovered in solid form by evapo chemical Syntheses and for other purposes as ration of the solvent. will appear hereinafter. The process by which 40 In the foregoing isolation technique many al this disulphide compound is isolated involves ex ternative materials may be used. For example, tracting asparagus juice with an organic polar butanol (i.e., normal butyl ) is the pre solvent whereby a polar solvent extract is ob ferred polar Solvent; however, other polar sol tained which contains the disulphide compound Vents can be employed which are miscible with together with some impurities. This extract is 45 Water to the extent of about 5 percent to about then further treated to separate the desired 20 percent, as for example, isobutyl alcohol, compound from the impurities. It has been Secondary butyl alcohol, n-amyl alcohol, isoamyl found that the disulphide compound has a car alcohol, and so forth. boxylic group and in its acid form is preferentially In the transfers to aqueous solution the al soluble in organic solvents, whereas in its Salified 50 kaline material is preferably sodium bicarbonate, or neutralized form it is preferentially Soluble in but other similar moderate alkaline materials water. Therefore, further purification is ef are Suitable, Such as potassium bicarbonate, po fected by carrying out one or more transfers tassium carbonate, Sodium carbonate, borax, po from solution in organic Solvent to Solution in tassium tetraborate, ammonium hydroxide, am Water and vice Versa. In transferring from 55 monium carbonates, and so forth. organic solvent to water, basic conditions are In the acidification steps, any water-soluble 2,539,428 3. acid may be used, as for example, hydrochloric, carbonates, or other inorganic compounds. For Sulphuric, phosphoric, acetic, and So forth. example, the Sodium Salt of the dithiol acid can As the organic fat Solvent, benzene is prefer be gi'epared by reacting it with Sodium hydroxide red, but , xylenes, carbon tetrachloride, or Sodium carbonate. In the Same manner any , ethylene dichloride, ether, hexane, is desired salt can be prepared by the usual neu octane, and mixtures of hydrocarbons such as tialization or metathetic techniques. Salt for gasoline, petroleum ether, Stoddard Solvent, nation is not limited to inorganic salts as salts benzine, naphtha, and other organic fat Solvents may also be made With Organic baseS Such as may be used. amines, quaternary ammonium compounds, The disulphide compound isolated from ternary sulphonium compounds, for example, asparagus juice is a yellow amorphous material methyl amine, triethanol amine, glyceryl amine, which contains the radical aniline, morpholine, , , pyri dine, piperidine, tetraethyl ammonium hydrox ide, dodecyl trimethyl ammonium hydroxide, YoH-c OOH 5 triethyi Sulphonium hydroxide, and So forth. Ainother phase of the invention involves the Since it contains a carboxylic radical, it forms provision of dialkyl 3,3'-dithiolisobutyric acid, salts just as do other carboxylic acids. It is in the salts thereof, and methods for preparing Soluble in water but Soiuble in aqueous alkaline these compounds. These compounds can be pre Solutions. It is also Soluble in many organic 2) pared in Several ways, as for example, by alkyla Solvents Such as alcohol, benzene, ether, and SO tion of the alkali metal derivative of 3,3'-dithiol forth. It contains approximately 43 percent car isobutyric acid or by alkyl-mercaptization of a bon, 6 percent hydrogen, and 30 percent sulphur 3,3'-dihaloisobutyric acid. and its neutral equivalent is 360-this figure With regard to the first-mentioned method, Signifying that each 360 grams thereof contains 25 the alkali metal derivative of 3,3'-dithioliso one carboxylic radical. The material tends to is reacted with an alkyl halide, or polymerize. On Standing either aS Such or in Solu equivalent alkylating agent, Such as a dialkyl tion, becoming insoluble in organic solvents, sulphate. The alkali metal derivative which is Another phase of this invention involves the used in this synthesis can be prepared by alkali preparation of 3,3'-dithiolisobutyric acid and the 35) metal reduction of the asparagus disulphide con Salts thereof. This acid has the pound or by treatment of 3,3'-dithiolisobutyric acid with an alkali metal. The reaction involv H-s-cl. ing alkylation of the sodium derivative of 3,3'- CH-COOH dihioisobutyric acid is described in Example IV H-s-cé, herein and is shown in the following equation: and can be prepared in Several WayS, as for ex NBSC RSCH N ample, by reduction of the asparagus disulphide Yoh-cooNa+2RI -> CH-COONa -- 2NaI compound heretofore described, or by reaction of a 3,3'-dihaloisobutyric acid with an inorganic Rsc?, hydroSulphide. 40 With regard to the first-mentioned method, the preferred technique involves dissolving the a Sparagus disulphide compound in a Suitable RSCH inert Solvent, as for example, anhydrous liquid YoH-cooH annonia, and then reducing it with an alkali metal such as Sodium or potassium. The alkali wherein R is an alkyl radical. metal derivative of the 3,3'-dithiolisobutyric acid It is apparent that by suitable selection of the So formed is then converted into the acid itself alkylating agent any desired alkylated deriva by addition of a mineral acid. Such as hydro tive may be Synthesized. For example, the chloric, Sulphuric, and So forth. If it is desired alkylating agent may be methyl iodide, inethyl to obtain a purified product, the acidified reaction bromide, ethyl iodide, ethyl bromide, propyl mass is extracted with an inert organic solvent iodide, propyl bromide, butyl iodides, butyl bro such as benzene, toluene, xylene, petroleum inides, and So forth. naphtha, hexane, and so forth, and the dithiol The method of preparing alkyl derivatives of acid recovered therefrom by concentrating and 55 3,3'-dithiolisobutyric acid by reaction of a 3,3'- cooling. This pirocedure is shown in Example II dihaloisobutyric acid with an alkali metal ner herein, and the reactions involved in this syn captide is described in Example V and can be thesis are illustrated by the following equation illustrated by the following equation: NaSCE HSCH. Asparagus Na N acid N 80 ICH RSC disulphide - CH-COONa- CH-COOB N compound liq. NH3 M ? CH-COOH -- 2RSNa - CH-COOH -- 2NaI NaSCE HSCEI. Icí, RSCH The other method for preparing 3,3'-dithiol Wherein R is an alkyl radical. isobutyric acid involves reacting a 3,3'-dihalo It is evident from the above equation that isobutyric acid with an inorganic hydrosulphide. by suitable choice of the mercaptide reactant For example, 3,3'-diiodoisobutyric acid is reacted any desired alkyl derivative may be synthesized. With barium hydroSulphide whereby the iodo For example, Sodium methyl mercaptide, sodium groups are replaced by thiol (SH) groups. This: . ... ethyl mercaptide, sodium propyl mercaptide, 70 Sodium isopropyl mercaptide, sodium butyl mer ICH Hscu, captides, and so forth, may be employed. Po oil-cooh - Ba(SH)2 - CH-COOH -- BaI tassium mercaptides can be used in place of ICH, Hsc?, Sodium mercaptides. With regard to the other 3,3'-dithiolisobutyric acid can be converted reactant, dibromo- or dichloroisobutyric acid can into its Salts by reaction with suitable hydroxides, 75 be used in place of the iodine derivative, 2,539,428 5 - 6 Another aspect of the invention concerns the 1300 ml. of benzene, and the precipitated ma preparation of 1,3-dithiane-5-carboxylie acid, its terial removed by filtration. The butanol-ben salts and the 2-Substituted derivatives thereof. Zene solution was then extracted with 550 ml. of These compounds are prepared by reacting 3,3'- 5 percent sodium bicarbonate solution; the bi dithiolisobutyric acid with an aldehyde or ke carbonate Solution was washed with benzene, and tone, preferably in the presence of an inorganic then acidified to pH 2 with Sulphuric acid. Some acid such as hydrochloric, sulphuric or hydro sticky black insoluble material was removed by bromic acid. The reactions whereby these com filtration and centrifugation. The bicarbonate pounds are produced can be illustrated by the Solution was then extracted with 3 liters of ether following equations: O and the ether extract dried over anhydrous so dium sulphate and then evaporated to a volume Hsce S-CR of 100 ml. CH-cooH + H&H - Cf. CH-COOH grains of theThis disulphide ether solutioncompound. contained 31.7 Hscá, N s-cá,/ - O 5 EXAMPTE Hsce O S-C - - - Reduction of the asparagus disulphide compound CH-cooH + R&B - R-cé CE-COOE to 3,3'-dithiolisobutyric acid Hsc?, w s-cá, + HO To 175 ml. Of liquid ammonia, was added 13 ml. HSCH. O. S-CHs. 20 of the ethereal Solution prepared in accordance YouCH-COOH cant + RCRof - R-C-R'4- N eH-C--. OO}} with Example I above, this ether solution con HSCH.? Ys-offS-CH -- EO taining 4.1 grams of the disulphide compound. Metallic Sodium was added in small pieces until wherein R. and R' are hydrocarbon radicals. 3, relatively permanent blue color was obtained. It is evident from the above, equations that 25 As the reduction proceeded the material Went. any desired derivative can be prepared by selec into Solution. The annonia, was allowed to tion of the proper aldehyde 0 ketone. Thus, evaporate spontaneously. The residue was taken to prepare 1,3-dithiane-5- the up in 40 ml, of water and quickly acidified with proper reactant is formaldehyde. This Synthesis concentrated hydrochloric acid to pH 2. This is illustrated by Example III herein. To prepare 30 aquéous material was frozen, then dried under 1,3-dithiane-2,2-dimethyl-5-carboxylic acid the Vacult. Ehe residue Was allowed to Stand over proper reactant is ; to prepare 1,3-di night with 600 ml. of petroleum ether (B. P. thiane-2-methyl-5-carboxylic acid the proper 92-109°) and then re-extracted with 200 ml of reactant is acetaldehyde. Use may be made of petroleum ether. The combined petroleum ether any aldehyde, or ketone, such as propionaldehyde, extract was coaled to -18° for several days: butyraldehyde, , Valeraldehydes, ColorleSS crystals of 3,3'-dithiolisobutyric acid benzaldehyde, methyl ethyl ketone, methyl propyl Separated. Upon recrystallization from 800 ml. of ketone, diethyl ketone, acetophenone, and So petroleum ether, 1.97 grams of 3,3'-dithioliso forth. butyric acid was obtained corresponding to a 48 The dialkyl derivatives of 3,3'-dithiolisobutyric 40 pereeit yield on a solid basis. The product melted acid as well as the dithiarae carboxylic acids can a 6-62. be converted into salts in the same manner and with the same materials as set forth above in Analysis: C4H8O2S2 Connection with Salts of 3,3'-dithiolisobutyric Calculated: C, 31.56; H, 5.30; S, 42.12, mol, wt. 152 acid itself. 45 Found: C, 32.3; H, 5.30; S, 41.6, neutral equivalent The compounds prepared in accordance. With l:52; mol. Wit. 155; equivalent weight by - SH this, invention are useful as intermediates for titration 77...... the preparation of diverse types of derivatives. Moreover, the compound 3,3'-dithiolisobutyric EXAMPLE III Preparation of 1,3-dithiane-5-carboacylic acid acid and its Salts are useful as anti-lewisite agents 50 and as regulators for enzymic reactions. To a solution of 0.25 grams (.0016 mole) of 3,3'- The following examples are illustrative of the dithioisobutyric acid in 50 ml of O. normal invention: hydrochloric acid was added 0.14 m. of formalin EXAMPLE I (.0019 mole of formaldehyde) and the reaction Isolation of the asparagus disulphide compound 55 mixture WaS refluxed for two hours. The reaction mixture was then evaporated to dryness under A Supply of a Sparagus concentrate Was pro Vacuum. Whereupon a Crystalline residue was ob cured. This concentrate was prepared by evap tained. The crystals were recrystallized from orating the juice pressed from a Sparagus butts 12 ml. of hot Water and a yield of 0.19 grams (70 until the solids content was 62.5 percent. A 9 O percent of theoretical) of 1,3-dithiane-5-car gallon sample of the concentrate (40 kilos) was boxylic acid was obtained. The product had a diluted with an equal weight of water. This of 146-148° C. solution, which had a pH of 4.5, was extracted with 7 gallons of butanol by agitation for 20 minutes. After standing for 2 hours the liquid Calculated: C, 36.56%; H, 4.91%; S, 39.04%; inol, was centrifuged, the butanol phase thus being wt. 164 separated from the aqueous phase. The butanol Found: C, 36.7%; H, 5.04%; S, 39.8%; neutral phase was then extracted with 3 gallons of dilute equivalent 161. aqueous sodium bicarbonate Solution (4 lbs. EXAMPLE IV NaHCO3 per gallon). The bicarbonate extract O was separated and acidified to pH 3 with phos Preparation of dimethyl-3,3'-dithioisobutyric phoric acid, and extracted with 4 gallons of bu acid from the disulphide compound tanol. The butanol extract was evaporated at A metallic SOdium reduction of 15 ml. Of the 35° C. and under vacuum to a volume of 270 ml. ethereal Solution of the disulphide compound was This concentrate was filtered and to it was added 75 carried out as described in Example II. After 2,589,428 7 8 the reduction was complete, 15 ml. of methyl Having thus described the invention, what is iodide were slowly added to the liquid ammonia, claimed is: - solution. The ammonia was allowed to evaporate 1. A compound of the formula, spontaneously. The residue was dissolved in water, acidified with hydrochloric acid to pH 2, and evaporated under vacuum to dryness. The Yoh-c OOM. residue was extracted with 400 ml. of benzene, and the benzene evaporated, leaving 3.14 grams of an wherein R, and R' are radicals selected from the oily product. This oil was dissolved in 200 ml of group consisting of hydrogen and hydrocarbon, petroleum ether (B. P. 92-100° C.) at 25° C. and 10 and M is a cation. cooled to -18° C. whereupon the dimethyl-3,3'- 2. The compound of claim 1 wherein R, R and dithiolisobutyric acid crystallized out in elon Mare each hydrogen. gated rectangles. The product was obtained in a 3. The compound of claim 1 wherein R and yield of 60 percent and had a melting point of R" are alkyl radicals and M is hydrogen. 23.5-25 C. 4. The compound of claim 1 wherein R and R" are both methyl groups, and M is hydrogen. Analysis: C6H12O2S2 5. A process for preparing 3,3'-dithiolisobutyric Calculated: C, 39.97%; H, 6.71%; S, 35.57%; CH3, acid comprising reacting a 3,3'-dihaloisobutyric 16.67%; mol, wt. 180 acid with an inorganic hydrosulphide. Found: C, 40.0%; H, 6.83%; S, 34.9%; CH3, 20 6. A process for preparing 3,3'-dithiolisobutyric 14.3%; neutral equivalent 179, mol. Wit. 183. acid comprising reacting 3,3'-diiodoisobutyric EXAMPLE W acid with barium hydroSulphide. Preparation of dimethyl-3,3'-dithiolisobutyric 7. A process for preparing a dialkyl derivative (tcid from 3,3'-diiodoisobutyric acid of 3,3'-dithiolisobutyric acid comprising reacting 25 a 3,3'-dihaloisobutyric acid with an alkali metal To 125 ml of a cold ethanol solution of sodium mercaptide. ethylate prepared by reaction of 0.5 gram (0.022 8. A process for preparing dimethyl-3,3'-di mole) of sodium with ethanol was added 9.5 grams thiolisobutyric acid comprising reacting 3,3'-di (0.195 mole) of methyl mercaptan. After a few iodioisobutyric acid. With Sodium methyl mercap minutes, the resulting solution of sodium methyl 30 tide. mercaptate was mixed with 2 grams (0.006 mole) 9. A process for preparing a dialkyl derivative of 3,3'-diiodoisobutyric acid and the mixture re of 3,3'-dithiolisobutyric acid comprising reacting fluxed for 6 hours. After acidification, the reac the alkali metal derivative of 3,3'-dithioliso tion mixture was evaporated to dryneSS under butyric acid with an alkyl halide. vacuum. The residue was extracted with 100 ml. 35 10. A process for preparing dimethyl-3,3'-di of warm petroleum ether (B. P. 92-100° C.) and thiolisobutyric acid comprising reacting the alkali the extract filtered. On cooling the filtrate to metal derivative of 3,3'-dithiolisobutyric acid -18° C. overnight, an oil separated. This oil With methyl iodide. was removed and the mother liquor was evapo EUGENE. F. JANSEN. rated to a volume of 25 ml. On cooling again to 40 -18°C., 0.311 grams (30 percent yield) of crystal REFERENCES CITED line dimethyl-3,3'-dithiolisobutyric acid was ob The following references are of record in the tained. The melting point was 23.5° to 25 C. file of this patent: Analysis: C6H12O2S2 Calculated: C, 39.97%; H, 6.71%; S, 35.57%; CH3, 45 UNITED STATES PATENTS 16.67%; mol. wt. 180 Number Name Date Found: C, 39.8%; H, 6.76%; S, 35.0%; CH3, 2,183,860 Coltof ------Dec. 19, 1939 14.3%; neutral equivalent 179. 2,477,327 Blake ------July 26, 1949