US2642450A - Thiolurethane quaternary ammonium salts and processes for preparing them - Google Patents

Description

Patented June 16, 1953 PATENT ner-1 ca iTHIOLURETHANE QUA'IERNARY ,AMMO- :iNIUM' S LTS AND PROCESSESFOR PRE- PARING THEM [hr]. .Weijlard; and Max Tishler, Westfield, N. :J., assignors to Merck & 0.0., 511110., 'IRahway, :.N.,J.,

,a corporation of New Jersey iNo' Dr-awing".

1ApplicationjDecemberI3,1949, Serial No. 132,793

1 9,o,1aims. (ore- 0 45.5)

- "1 This invention is concerned generally with a new group of antispasmodics relatedtoacholine. More particularly, .it relates vto adimethyl-allgyl-B- (carbamylmercapto)ethylqammonium salts wherein;bo,th,of :thehydrogens ,attachedito the nitrogenqatomvof ,thacarbamyl grogpingare recplacedby saturated hydrocarbon radicals; to the g'processior preparing :these; novel quaternary ammonium salts :and ,to thedntermediate products thus, obtained.

Compounds, analogous to the quaternary amomonium ,salts. herein. described but "wherein 50xygen Zis ,substitutedfior sulfur such asrdibutoline -Slllfate 1( imetljiylethyl fiehydroxyethyl-ammoniv,um ,sulfate :dibutylurethanel, .have previously been found to be effective antispasmodics. The lpresentlyflisclosed quaternary; Saltsare, ;however, greatlysuperior in antispasmodic effectiveness {to-said -oxygen;analo gs, and areat the same time much less toxic. eMoreoiler these noyel :quaternary, salts :have been found-to be far superior to any. other ;know is asmodics, -su. ,h.:;.as pa- ;paverine, Pavatrine gand Syntropan. Ifhese new salts haye -,also heengf und rto havelzantitubercuwlar'activity.

'Iihes n ve qua ernar zdimcthylealky fi 4.(N,N disubsti.tuted earhamylmercaptwethyl anunonium salts may .be ,Chemically represented as follows:

wherein R. is an alkylradicaLiRvand Rzare saturated. hydrocarbonradicals and ii is -ananion.

. 1:2 "W e :have discovered that these dimethyhalkylfi-(N,N=disubstituted.r-rcarbamylmercapto) ethyl .ammonium'salts, wherein the substituents attached to the nitrogen atom of theI-carbamyl grouping :are :saturated hydrocarbon radicals, can be prepared by reacting dimethyl-aminoethylthiol with an N,N-disubstituted carbamyl chloride of the formula:

-wherein "R1 and R2 are saturated hydrocarbon -radicals, for example-adialkyl carbamylchloride such :as dibutyl carbamyl chloride, diamyl car- #bamyl chloride, and "the like, or a-dicycloalkyl carbamyl-chloride, such as dicyclohexyl carbamyl chloride, to produce a thiolurethane of the formula:

-wherein-R1and R2 are saturated hydrocarbon radicals, and reacting said thiolurethanewith an --alky1-ester *of an inorganic acid,;for example an a alk-yl iodide, such as ethyl -iodide, propy1 iodide,

-butyl iodide, amyl iodide, and the like, a dialkyl sulfate, ysuch as diethyl sulfate, and the *like,

--to produce-a quaternary-salt of the formula:

wherein '?R 'is an alkyl radical, R1 and R2 vare -saturated 'li drocarbon .radicals and X is an anion.

The 'dimethyl am'inoethylthiol starting material-can be prepared by reactingdimethylaminoethyl chloride ,andfiodium 'hydrosulfide as described in Example '1 hereinbelow. ,"Ihe dialkyl -or dicycloalkyl 'carbamyl chloride can be prepared-by reacting "the appropriate secondary amine with "phosgene according to the procedure =set*;-forth in the illustrative examples and describedjin J. "Chem. fSoc. 'l94f7, 3113. The jdimethyl aminoethylthiol and the dis ubstituted carbamyl chloride can be preparedin purified form, if desired, by fractional 'distillationflin vacuo. v The reaction between the dimethyl aminoethylthiol and the,.calflfiiitfl yl chloride having twosaturated hydrocarbon substituents attached to the nitrogen atom of the carbamyl grouping, for

example a-dialkyl-carbamyl"chloride such as dimove impurities.

about 3 hours.

butyl carbamyl chloride, diamyl carbamyl chloride, and the like, or a dicycloalkyl carbamyl chloride such as dicyclohexyl carbamyl chloride, and the like, is ordinarily conducted in the presence of a hydrogen chloride acceptor. The hydrogen chloride acceptor is preferably an organic base such as a compound containing a pyridine ring, such as pyridine, quinoline, picoline, and the like, and preferably an acceptor that also acts as a solvent for the reactants. The reaction is conveniently carried out by heating wherein R1 and Riare saturated hydrocarbon radicals. I

'This thiolurethane is then reacted with an 7 alkyl'ester of an inorganic acid as, for example a dialkyl sulfate, such as diethyl sulfate, an alkyl iodide, such as ethyl iodide, n-propyl iodide, n-butyl iodide, n-amyl iodide and the like, to

produce the corresponding quaternary ammonium salt of the formula:

wherein R, R1, R2 and X have the significance defined hereinabove. 1

The reaction between the-thiolurethane and l the dialkyl sulfate (preferably diethyl sulfate) is conveniently conducted by bringing the reactants together in diethyl ether solution at substantially room temperature. Under these conditions the reaction is ordinarily substantially complete in about 15 hours and the quaternary dimethylalkyl ,3 (N,N disubstituted -'-carbamyl-mercapto)ethyl ammonium ethyl sulfate which precipitates can be recovered by filtration.

When the thiolurethane. is'reacted withf an "alkyl iodide the reaction is ordinarily carried out by mixing the reactants in the absence of a solvent and agitating the resulting mixturelat a temperature of about 25-30 C(foraperiod'of The mixture is ordinarily allowed to stand overnight to insure completion of the reaction. The product, which is the corresponding dimethyalkyl B (N,N disubstitutedcarbamylmercapto) ethyl-ammonium ence of ethanol. r V

Examples of these quaternary salts having the wherein R is an alkyl radical R and. B12 Lar e iodide isthen converted to the corresponding sulfate by reaction with powdered silver sulfate in the pres- 4 saturated hydrocarbon radicals and X is an anion, are the following:

(1) Dimethyl ethyl-QB (N,N dicyclohexylcarbamylmercapto) ethyl ammonium ethyl sulfate, also named dimethylethyl-B-thiob ethyl ammonium ethyl sulfate dicyclohexylurethane;

Dimethyl n propyl {3 (N,N dicyclohexyl carbamylmercapto ethyl ammonium sulfate, also named dimethyl-n-propyl-c-thiolethyl ammonium sulfate dicyclohexylurethane Dimethyl n butyl e 3 (N,N dicyclohexyl carbamylmercapto)ethyl ammonium sulfate, also named dimethyl-n-butyl- .fi-thiolethyl' ammonium sulfate dicyclohexylurethane;

(4) Dimethyl n amyl B (N,N dicyclohexyl carbamylmercapto) ethyl ammonium sulfate, also named dimethyl-n-amyl- B-thiolethyl ammonium sulfate dicyclohexylurethane; r e Dimethyl ethyl B (N,N diamyl carbamylmercapto) ethyl ammonium sulfate, also named dimethylethyl-B-thidlethYl ammonium sulfate diamylurethane; Dimethyl ethyl ,6 (N,N diamyl --carbamylmercapto) ethyl ammonium ethyl sulfate, also named dimethylethyl-B-thiolethyl ammonium ethyl sulfatediamylurethane; 1 Dimethyl ethyl [3 -;(N,N dicyclohexylcarbamylmercapto) ethyl ammonium sulfate, also named dimethylthyl-B-thiolethyl ammonium sulfate dicyclohexylurethane; Dimethyl ethyl B (N,N dibutyl carbamylmercapto)ethyl ammonium iodide, also named dimethylethyl-B-thiolethyl ammonium iodide dibutylurethane; Dimethyl {ethyl ,8 (N,N- dibutyl carbamylmercapto ethyl ammonium sulfate, also nameddimethylethyl ,8 thiolethyl ammonium sulfate dibutylurethane.

Dimethyl ethyl B (N,N dicyclohexyl carbamylmercapto) ethyl a mm on i u m iodide, also named dimethylethyl-fi-thiolethyl ammonium iodide dicyclohexylurethane; a Dimethyl n propyl B (N,N dicyclohexyl carbamylmercaptmethyl ammonium iodide, also named dimethyl-n-propyl-fi-thiolethyl ammonium iodide dicycloxhexylurethane;-,ix 1' a Dimethyl 9 n butylq- 5 e (N,N dicyclohexyl carbamylmercapto) ethyl ammo- I nium iodide, also named .pli'methyl-ln-butyl e-thiolethyl ammonium iodide dicyclohexylurethane;

Dimethyl namyl p (N,N- dicyc1ohexyl carbamylmercapto)ethyl ammonium iodide, also nameddimethyl-n-amyl- V p-thiolethyl ammonium. idodide dicyclo hexylurethane; U Dimethyl ethyl (3 (N,N.- diamyl carbamylmercapto) ethyl ammonium iodide, also named dimethylethyl p-thiol'ethy1 ammonium iodide diamylurethane.

Of particular interest are the first seven quaternary salts listed on the precedingpa e which have been found to possessoutstanding antispasmodic activity.

These compounds were tested in comparison .with Dibutolinesulfate (dim'ethylethyl -.p.- hydroxyethyl ammonium sulfate dibutylurethanel ecreate on isolated organs-for:ariiitspasmodic activity as .follows: rabbit intestine, ,iorn-inhibition of spon- .taneous. activity; guinea pigluterus', .for inhibition :of spontaneousaacti vity; guinea-,pig izitestineyior 40- me./-kg.ifor f-Di'bu-tolina and stowed-marks.

inhibition -of ..contraction produced .by .spasmo- 15 injections of: compound? over a three-monthpegemc -.a-gents,..urecho1ine acetyl choline, .and in r'iod. -Eaoh injectionwas-2J5mgikg. twice-"daily some instances .b arium; chloride. on' week days, with 2 single inj'ections of 5 mg s/ kg. .The results ,obtained rare summerized in .the -on' saturdaysand Sundays. A-rsimilar group -was following table given thetsame dosa'ge ofiDibutoline, and-a third r r Inhibit-ion ofContraetlons :Irihibitiontoi:Spontaneous; rot G. P. Intestine Tro- .Activity.of v duc'ed by Spasmogenic- -Agents LOOIHIJOHDG Q Urecl-1o1ine Q I R bbt V, BBIHJHI Int estine G P Uterus 'fiifig Chloride ++-l-+.+++ ++L +s+' -1+ .+=+H-.: -+s++ 7 .+.-l.-.++ 1 r +.:i.--:+ 7 (DithiolmaSuliat 5- +.:r "'Dibutoline' Sulfate. I N

As evident from the: above table the novel qua- ;ternary salts described in this application, and especially the dimethylallgyl fi-thiolethyl #ammo- "snium (ethyl) --sulf ate dicyclohexyleurethanes, .are :more effective antispasmodics than Dibutoline. :Of ,particular interest. is the .quaternary salt, di- .methylethyl flathiolethyl-ammonium sulfate .dicyclohexyl urethane (compound "7) which .has beeniound tobe two-to three-times as .potent as -Dibutoline in inhibitingatheaefiectof spasmogenic :agents on. isolatedguinea pig. intestine.

, .A large number of experiments. have "been perrformed on :isolated vvuteri of 'aboth pregnant and -non .pregnant :guinea pigs.- Direct -eomparisons .have been ,made of the activity onthe isolated uter-us between compound 7, .Dibutoline, papav- ='erine,.Pavatrine, andssyntropan. In nearlyevery :test :compound 7 proved .to the :the most effective .of-:allof these agents, sometimes-being active .on

an organ which was relatively refractory to the:

other compounds. Moreover, compound 7 proved to be very effective in relaxinguterine contractions stimulated (by urecholine, acetyl choline, histamine, pitocum, or'ergotamine tartrate. Compound 7 has been administered orally, 'subcutaneously, and intravenously to the dog with exteriorized intestinal loop. Good intestinal =antispasmodic effects have been 'ob'serve'dafter administration by 'all "three :routes, ithough Jon --some;occasions oral administration. failed. {When -Pavatrine :was administered .orall yffor compari- ''son in two experiments, -it succeededfsonce iand failed;once. When Dibutoline iodide has been -administered orally in comparable .doses '(up to trials. In a'single experiment, :compound '7 (-2 -mg./kg. .sucutaneouslyl, relaxed .the uterus of -anzintact anesthetized guinea pig.

Compound 7 produces :mydriasis similar to .that dbserved with Dibutoline when applied topically itoathezcats eye, .in..5.% ;or .1-,% solution. vMydri- 'asis was :not produced; by administration of ;oral doses upto 2 mg./kg. I

tithe acute toxicity :of compound 7 was tested umdiound 'to be approximately;one =ha1f as. toxic aas .Dibutoline in mice treated with single doses "subcutaneously. Determination of .LDauw (the dosage .that ":will kill Nonehalf of I the animals :treated). pf. the. atwoIzdr-ugs simultaneously on two grouprserved as luninjectedaoontrols. At the- .end -of three months, rtheigrowthratezof allrgroup was [identical and there .was...no evidence 10i toxicity. --Examination- .of ther-ats after administration;ior ,threemonths showed no divergence from normal in hemoglobin -red .cell count, .and wwhite cell count (total-anddifierential). .Nogross morphorlogicalchanges were. found-.atautopsy; except/for a'moderate degree vof local tissue: irritationzatrthe !site of injection (rats are particularly susceptible to local irritation). .iNolocal irritation was observed in dogs-receiving repeated injections.

.The antitubercular utility of the new :quaternary-salts illustratedibyetheactivitiestobserved when compounds .-1 and .9 were tested .for in -vitr.o iactivityragainsta human .typezstrainofiM tuberculosis designated .aswI-IB'Z-RV. 'II-hesecompounds were activeat-lll micrograms ,peizmilliliter.

The following examples illustrate methods of carrying out the presenttimrention but it is to be understood that these examples are :given for fpurposes or-illustration an'd not :of limitation.

xEmmv e chloride hydrocliloride wasdissolved sins-850ml. of-'watereand 8-50 m l.-oi' aqueous sofdium' hy- 'drexi'de sdlution was a'dded. :The resultingsolution was-extracted successively :with -1000;ml., 500-1111., an'd aOO ml. :portions fof di'ethyl .eth'er'.

"The: extracts awere rcombine'cl and theu-ether iwas evaporated :under .ireduced .pressure toizproduce :approximatelyz'iOOagme. of crndesdimethylamin'o- :ethylchloride. 7 a

.2700 gm. (1-1.-2 :moies)1.oi sodium sulfide mono- -hydrate iw'asmelted in a five-liter flask provided withialmeehanical stirrer,.reflux. condenser, ther- .mometecr .and gas inlet .tube. Hydrogen sulfide -wa-s,passed.into-.the molten mixture over aperio'd of 6 to 7..hours during which time the mixture stirred. rapidly and maintained at a' 'tem- Lperature' between "about '50 and The di- ..methylacminoethylchloride (760 gms:) was-added dropwise 'to t'he reaction-mixture over --a period of approximately --2 hours during which time' the -'contents of the flask-were stirred rapidly maintained at-a tempe'rature Lflf :5.0eB.0. C. .Llhe -resulting mixture was' then ,heatedtou-QOx-lflfi 1 $0., th'eatediunder. reflux for ;1;hour;andccooled. The

diffierentistrains ;oi'.;:mice :gavemfigure ein-about action m xt w extracted u e i elrwith -600 ml 300 ml., and 3001111. portions of diethyl ether, the extracts were combined and dried over anhydrous calcium sulfate (Drierite) The ether was then evaporated from the dry ether solution, and the-residual material was fractionally distilled. The fraction distilling at 120-140", C.

, (temperature in distilling flask 140-190 G.) was collected to produce 199 gms. of crude dimethylaminoethylthiol (yield approximately ,30% of theory).

85'0 gms. of crude dimethylaminoethylthiol (from several preparations) was distilled in vacuo using a 6-8 inch Vigreux column to produce 748 gms. of substantially pure dimethylaminoethylthiol; B. P. 37-43 61/20 mm.; recovery yield approximately 88%. Analysis. Calcd for C iI-IuNS: C, 45.66; H, 10.54; N, 13.32.

Found: C, 45.44; H, 10.56; N, 13.06.

Example 2 1800 ml. of xylene were placed in a five-liter, three-necked flask provided with a mechanical stirrer and thermometer. The xylene wascooled to 10 C. and 297 gms. (3 moles) of phosgene Was added. A solution containing 516 gms. (4 moles) of n-dibutylamine dissolved in 1030 ml. of xylene was added to the phosgene solution over a period of approximately 5 hours, said addition 1 being carried out while rapidly stirring the flask. contents and maintaining the reaction temperature at approximately 5-10 C. .The reaction 'mixture was stirred at room temperature for an additional period of about 18 hours, the dibutyl Example 3 I 35 gms. (0.33 mole) of pure dimethylah inoethylthiol (B. F. 37-43" C./20 mm.) prepared as described in Example 1, was dissolved in 250 ml.

of pyridine contained in a one-liter, three-necked flask equipped with a mechanical stirrer and reflux condenser. 57.5 g. (0.30 mole) of n-dibutylcarbamylchloride, prepared as described in Example 2, was added to the flask contents. The resulting mixture was heated under reflux for approximately 3 hours and was then evaporated to. dryness in vacuo. The residual material was dissolved in 200 ml. of water and the pH was adjusted to 3 by adding 30 ml. of concentrated aqueous hydrochloric acid solution. The resulting solution was extracted with four 100 ml. porti-ons of diethyl ether and the ether extracts were discarded. The aqueous solution was made a1- kaline by adding thereto an'excess of sodium carbonate, and the resulting solution was extracted with three 100 ml. portions of chloroform. The chloroform extracts were combined, dried over anhydrous calcium sulfate (Drierite) and the chloroform evaporated. The residual material was heated at 100-110 C. at a pressure of 1 mm. to remove all traces of solvent thereby producing approximately '76 gms. of dimethylaminoethylthioldibutylurethane; yield approximately 97%; of theory. 1

0 ethylammonium l pared as described in Example 4, was dissolved in Emmrlepel 75 gms.'(0;29 mole) of dimethylaminoethyl- 'thioldibutylurethane, prepared as described in Example 3, was mixed with 235 g.. (1.5 moles) of ethyl iodide. The mixture was stirred until solution was effiected and the resulting solution was ,M. P. 56 0.; yield approximately 96.6% of theory.

Example 5 116 gms. (0.278 mole) ofdimethylethyl-B-thiol iodide dibutylurethane, pre- 1100 ml. of 90% aqueous ethanol, and 60 gms.

dissolved in 2000 m1. of pyridine. was stirred andv heated under reflux at a tem- (0.19 mole) ofpowdered silver sulfate was added to the solution.

The resulting mixture was stirred rapidly for 2 hours, the silver iodide was removed by filtration and washed with three 50 ml. portions of ethanol. The combined filtrate and washings were evaporated in vacuo to a syrup. The syrup was dissolved in 4'00 n11. of water, the solution was extracted with two 200 ml. portions of diethyl ether, and the extracts were discarded. The pH of the aqueous solution was adjusted to 6.7 by the-addition of aqueous barium hydroxide solution, hydrogen sulfide was passed into the solution to'precipitate residual silver, 5 gm. of activated charcoal was added, and the mixture was filtered. The filtrate was evaporated in vacuo to a syrup and .the residual material was subjected to benzene distillation using three 150 ml. portions of benzene. The residual material was dried over sulfuric acid at a pressure of 1 mm. to produce 83.8 gms. of dimethylethyl-p-thiolethyl ammonium sulfate dibutylurethane: yield approximately 89.3% of theory. Analysis.C'alcd for c', 51.99;.H, 9.39; N, 8.08. Found: 0, 51.78; H,

Example 6 Dicyclohexylamine was reacted with phosgene according to the procedure described for reacting phosgene with n-dibutylamine in Example 2. -After evaporation of the-xylene solvent, the rehexylcarbamylchloride; M. P. -86" C.

781 gms.. (3.2 moles) of powdered dicyclohexylcarb-amylchloride was added to a solution containing 350 gms. (3.3 moles) of dimethylaminoethylthiol (prepared as described in Example 1) The mixture perature of -105 C. for a period of 3 hours,

and the mixture was then cooled to room temperature. The nearly-solid mass was dissolved in 1000 ml. of water and the aqueous solution "was evaporated in vacuo at a temperature below '50 C.'until a mush resulted. This residual-material was treated in the manner described in Example 3 to produce948 gms. of dimethylaminodescribed in Example- 4 161 reactingdimethylethyltlfioldicyclohexylurethane; P.: 48.450?- 6.;

yield approximately 95% of theory. Example 7 948 gms. of dimethyl'aminoethylthioldicyclohexylurethane; prepared as described in Example 6, .Was .reacted with. ethyl iodide, according. tothe procedure described :in:-Examp le .4,,to produce-l465 gms.. of. dimethylethylrd -thiolethyl ammonium iodide dicyclohexylurethane; Pel90-19l9 C.;; yield approximately 98% of theory. Analysis. Calcd for O19Hs7O'N'2SL H2O; :.C, 47.79; H, 8.02; N, 5.87. Found-:10; 4-790';HZ 7.78v';.N, 5.63.

7 Example 8 2715i ms. of?dimethylethyleg-thiolethylj an'1 monium iodide dicyclohexylurethane,.preparedlas described in Example 7, was reacted'with silver sulfate according. to the procedure described in Example 5 to produced-188 gms. of-dimethylethyl- 2U B-thiolethyl ammonium sulfate dicyclohexylurethane; M. P. 1'43'-144 C.; yield approximately 97% "of'theory. AnalysisP-Calcd'for.

31 gms. of dimethyl'aminoethylthioldicyclo hex-ylureth'a-ne prepared as describedii'n': Example 6, was reacted with- '85 -gm's5- of n=propyliodide',*. utilizingsubstantially-the same procedure 1 as that amino'ethylthioldibutylurethanewith ethyl iodide, to produce gmsz of dimethyl -n-rpropyl-p thiolethyl ammonium iodide dicyclohexy-lurethane; M. P. 149-151 CI; yieldapproximately 41.7% of theory. Analysis.Calcd for C, 49.78; H, 8.15; N, 5.80. Found: C, 49.63; H, 7.99% N", 5.82} 1 20 gms; of dimethyl-n-propy-ll-B-thiolethyl.am monium: iodide. dicyclohexylurethane was .ireacted with silver. su1fate,.accordingtoythe procedure describedr in Example. 5,.to. produce 16.41 gms.-of dimethyl-n-propy1=prthiolethyl ammonium sulfate dicyclohexylurethane; 137-139 C.; yield ap proximately 85% of theory. Analysis.'-Calc"d for GwI-IvaOtNtSa-fififi (33521482 11; 9.91 N,- 6512 H2O, 11.80. Eound .-:'5?r.61 H; 9. 0; N, 6.37; H2,O.,,11 .44.,

Example 1 2 28.5 gms. of dimethyl-n-butyl-p-thiolethyl ammonium iodide dicyclohexylurethane was reacted with silver sulfate, according to the procedure described in Example 5, to produce 23.7 gms. of dimethyl-n-butyl-fl-thiolethyl ammonium sulfate dicyclohexylurethane; M. P. 99-99.5 C.; yield approximately 87% of theory. Analysis.-Calcd for C42Ha2OsN4Sa.6H2O; 'C, 53.47; H, 10.04; N,

Emdmple'id 31- gms.: ofdimethylamino'ethylthioldicycloe hexylurethane; prepared asrdescribed in: Example:

6;=w.as reacted with: neamyl'iodide; utilizing'thesubstantially. sameeprocedure as thatdesc'ribed in Example 4;. to. produce? 36' gms; of; dimethyli-neamyl-fi-thiolethyl ammonium." iodide? dicyclohexylurethane; M.-P. 179-18050; yield approximately 71% of theory: Analysis.-Calcd for Cal-1439172315; C,- 51:75:1Hy8z49; 5248. Found: C,file-96;.151;..82331N 6.4 i

" EwdmpleMV mcnium iodide; dicyclohexylurethane, prepared I Eem 'li i" 31 gms.. (0.1:mole) of dimethylam-inoethylthiol dicyclohexylurethane, preparedias described in? Example 6,..Was? dissolved in: 200. mlz; of d-iethyl: I ether,. 31-. gms. 0.2 i mole) O'fe dicthy1 sulfate. was

added;. and. ther-mix-turerwasmllowedate standlat room' temperaturevoyernight; -The; crystalsi thatf formed.- were-recoyered byrfiltrationy.washedawithi Q n-Diamylamine was reacted with phosgenednr the. presence. ofxylene,. utilizing. substantially the; same procedure described-for reacting; n.-di-:-

butylamine with.phos ei e 'inrExample 2;;and;;the-

residual. material 01012911116617. after evaporation .of. the. xylene. was fractienally; dis'tilledr in:v vacud using a Vigreux column tovproducer diamyl.--- carbamylchloride; B. P. 112-114 C./1:mmi

' 62.6 .gmsof .diamylcarbamylchloride; prepared asdescribed.on--:theapreeedingg page; was. reacted with.v 33;. gms., of: .dimethyla-minoethylthiol;, prepared. as :describedvimExample r1, and 1 the; react-- tion product was treated in substantially the same manner as described in Example 6, to pro-v duce 75.6 gms. of dimethylaminoethylthioldiamylurethane, which was obtained as a liquid;

yield approximately 94% of theory.

Example 17 60.6 gms. of dimethylaminoethylthioldiamylurethane, prepared as described in Example 16, was reacted with ethyl iodide, utilizing substantially the same procedur as that described in Example 4, to produce gms. of dimethylethylc-thiolethyl ammonium iodide diamylurethane which was obtained as an amorphous mass; yield approximately 97% of theory. Analysis.-Calcd for C17H3'1ON2SI2 C, 45.94; H, 9.39; N, 6.30. Found: C, 45.89; H, 8.02; N, 638.

Example 18 90 gms. of dimethylethyl-p-thiolethyl ammonium iodide diamylurethane, prepared as describedovernight.

in Example 17, was reacted with silver sulfate,

utilizing substantially the same procedure as that described in Example 5, toproduce 69 gms. of dimethylethyl-;8 thiolethyl ammonium sulfate diamylurethane; M. P. 124125 0.; yield approximately 91% of theory. Analysis.-'Ca1cd for C34H7406N4S3.1.5H20'2 H20, 3.56. Found: H20, 3.85. Sample dried to constant weight at 80 C./1 mm. AnaL-Calcd for C34H74O6N'4S32 N, 7.67. Found: N, 8.18.

' Example 19 15 gms. of dimethylaminoethylthioldiamylurethane, prepared as described in Example 16, was dissolved in 100 ml. of diethyl ether, 15.4 gms. of diethyl sulfate was added to the solution and the resulting mixture was allowed to stand No crystallization took place. The mixture was then heatedunder reflux for an additional 24 hours, without any formation of crystals.

The ethereal mixture was extracted with two 25 ml. portions of water, the combined aqueous extracts were washed with ether and the ether layers were-discarded. The pH of the aqueous" solution was adjusted to 6.4 by the addition of 10% aqueous barium hydroxide solution, a small amount of activated charcoal was added, and the mixture was filtered. The traces of barium ion were removed'from the filtrate by adding a minute amount of ammonium sulfate and a slight turbidity was removed by adding activated charcoal and filtering. The solution was evaporated invacuo to a syrup and the syrup was air-dried toconstant weight. During the drying period, the syrup crystallized slowly, and the crystalline masses were broken up during the drying pe-' riod. There was thus obtained 12 gms. of dimethyl-fi-thiolethyl ammonium ethyl sulfate diamylurethane; M. P. 55-56 C.; yield approximately 55% of theory. Analysis.'Calcd for C19H42O5N2Sa /gI-I2O: C, 50.51; H, 9.59; N, 6.19; E20, 1.99. Found: C, 50.20; H, 9.08; E20, 1.85.

' Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims they are to be considered part of our invention. I

We claim: I 7

lqThe process which comprises reacting dimethylaminoethyl thiol with-a carbamyl chloride having two saturated hydrocarbon substituents attached to the nitrogen atom of thecarbamyl- 5 12 grouping to produce a thiolurethane er: the for-=- mula:

R1\ (I? I CH3 N-CSOH2CH:N'

R, CH3 V wherein R1 and R are saturated hydrocarbon radicals, and reactingsaid thiolurethane with an alkylester of an inorganic acid to produce a quawherein R1 and R2 have the significance abovedefined, R is an alkyl radical, and X is an anion.

2. Quaternary salts having'the formula: T

N OS-CHaCHaNOHz QR, f V x @H. Y wherein R1 and R2 are saturated hydrocarbon radicals, R is an alkyl radical, and X is an anion.

3. Dimethylalkyl-fi-thiolethyl' ammonium sulfate dialkylurethanes. 4. Dimethylalkyl-fi thiolethyl ammonium sulfate dicycloalkylurethanes.

5. Dimethylethyl-fi-thiolethyl ammonium sul, fate dicyclohexylurethane.

6. Dimethylethyl-p-thiolethyl ammonium eth-I yl sulfate dicyclohexylurethane.

7. Dimethyl-n-propyl- 8-th.iolethyl ammonium sulfate dicyclohexylurethane.

8. Dimethyl-n-butyl- 8-thio1ethy1 ammonium sulfate dicyclohexylurethane.

9. Dimethyl n amyl-fl-thiolethyl ammonium sulfate dicyclohexylurethane. 7

Q JOHN WEI JLARD.

' f OTHER REFERENCES" Soc. Chem. Ind. (Br.). 537,105, April 14,1947.

Claims (1)

1. THE PROCESS WHICH COMPRISES REACTING DIMETHLAMINOETHYL THIOL WITH A CARBAMYL CHLORIDE HAVING TWO SATURATED HYDROCARBON SUBSTITUENTS ATTACHED TO THE NITROGEN ATOM OF THE CARBAMYL GROUPING TO PRODUCE A THIOLURETHANE OF THE FORMULA: