US3683040A - Certain bi-{11 or tricycloalkyl methylbenzenes - Google Patents

Abstract

Compounds such as WHEREIN R3 is bicycloalkyl (C7 to C10) or tricycloalkyl (C10 to C11), useful as intermediates for making N-acylcyclohexylamines of the formula:

WHEREIN R is hydrogen, methyl or ethyl; R1 is hydrogen, or alkyl of 1 through 4 carbon atoms; and R2 is straight chain or branched alkyl of 3 through 8 carbon atoms, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl useful as animal repellants are disclosed, bicycloalkyl, cycloalkylalkyl, or tricycloalkyl. Typical are phenyl-2-(2.2.1)-bicycloheptylmethane, 4cyclobutylmethylbenzoic acid, 4''-cyclobutylmethylacetophenone, 4-cyclobutylmethylcyclohexane carboxylic acid, and 4-nhexylcyclohexylamine.

Description

United States Patent Knowles [S4] CERTAIN 81- OR TRICYCLOALKYL METHYLBENZENES [72] inventor: Richard N. Knowles, l-lockessin,

Del.

[73] Assignee: E. I. du Pont de Nemours and Company, Wilmington, Del.

[22] Filed: April 20, 1967 [21] Appl. No.: 635,304

Related US. Application Data [63] Continuation-in-part of Ser. Nos. $74,499, Aug. 18, i966, and Ser. No. 574,276, Aug. l8, 1966.

[52] US. Cl ..260/668 R, 2601514 R, 260/514 B, 260/515 R, 260/56l R, 260/563 R, 260/592,

Primary Examiner- Leland A. Sebastian Attorney-Herbert W. Larson [15] 3,683,040 1 Aug. 8, i972 [57] ABSTRACT Compounds such as wherein R is bicycloalkyl (C to C or tricycloalkyl (C to C11), useful as intermediates for making N- acylcyclohexylamines of the formula:

R O I ll 1r wherein R is hydrogen, methyl or ethyl; R is hydrogen, or alkyl of 1 through 4 carbon atoms; and R is straight chain or branched alkyl of 3 through 8 carbon atoms, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl useful as animal repellants are disclosed, bicycloalkyl, cycloalkylalkyl, or tricycloalkyl. Typical are phenyl-2-[ 2.2. l l-bicycloheptylmethane, 4- cyclobutylmethylbenzoic acid, 4-cyclobutylmethylacetophenone, 4-cyclobutylmethylcyclohexane carboxylic acid, and 4-n-hexylcyclohexylamine.

1 Claim, No Drawings 1 2 CERTAIN Bl- R TRICYCLOALKYL wherein METHYLBENZENES R is cycloalkyl of four through nine carbon atoms, CROSSREFERENCE bicycloalkyl of seven through 10 carbon atoms,

cycloalkylalkyl of five through 10 carbon atoms, or This application is a continuation-in-part of U.S. Pat. 5 y y of through 1 1 carbon atomsapplications Ser. No. 574,499, filed Aug. 18, 1966 and Ser. No. 574,276, filed Aug. 18, 1966.

U 1. BACKGROUND OFTHEINVENTION """li""""" Application Ser. No. 532,544, filed Mar. 1, I966 h abandoned and a f i alkyl of three throug eight carbonv atoms :Ziigfiglggfi gg g ag fi gfi giz nng cycloalkyl of four through nine carbon atoms, cycloal- The present application is directed to those kylalkyl of fivethrough l0carbon atoms, bicycloalkyl pounds useful as intermediates for making the animal g fi l carbon atoms or mcycloalkyl of 10 repellants described in application Ser. Nos. 532,544 rough cm H atoms and 574,276.

(0) ll II R C- SUMMARY OFTHEINVENTION 2o 2-H wherein R is hydrogen, methyl or ethyl;

R is alkyl of three through six carbon atoms, cycloalkyl of four through nine carbon atoms, cycloalkylalkyl of five through 10 carbon atoms, bicycloalkyl of seven through 10 carbon atoms, or tricycloalkyl of 10 This invention relates to five classes of intermediates for making N-acylcyclohexylamines.

More specifically, this invention refers to intermediates for synthesizing potent animal inhalation irritant compounds of the formula:

( through 11 carbon atoms, with the limitation that the NUR| one and four groups on the cyclohexyl ring must be in 1 l the cis configuration. z-fi Preparation The animal repellant compounds are prepared using the intermediates of formulas (2) through (6) and the whefem following synthetic route:

R15 y 8 b methyl or y R, R, and R, in the following reactions are as defined R is hydrogen or alkyl of one through four carbon above i f rm l atoms; and

R is straight chain or branched alkyl of three through eight carbon atoms, cyclobutyl, cyclohexyl, I if A101, ii cyclopentyl, cycloheptyl, cyclooctyl, cyclononyl, R2001 Q cycloalkylalkyl of five through 10 carbon atoms, bicycloalkyl of seven through 10 carbon atoms, or H o tricycloalkylof 10 through ll carbonatoms. [Q KOH Q The intermediate compounds are described in the R20 mm RPCHP following formulas: 4s

. 111 MC] (2) LLQ mom-Q olmicl n on ()CH 2 L'- wherem (1) R is bicycloalkyl of seven through 10 carbon atoms or tricycloalkyl of 10 through I 1 carbon atoms. Iv

wherein V Pt R is cycloalkyl of four through nine carbon atoms, R2CHC om 3H: m cycloalkylalkyl of five through 10 carbon atoms, 3 2

bicycloalkyl of seven through 10 carbon atoms, or R2OH2 @CO2H tricycloalkyl of 10 through l1 carbon atoms.

v1 H2 S 04 RzCH1--CO H NaN; 01101.1 4

Those compounds where R is methyl or ethyl are prepared according to the following reactions where R; becomes R during react-ion IX.

RgClIr- S Nlllt llCOaClI; rcllux The Friedel-Crafts reaction (I) is run by carefully adding the acid chloride to a stirring mixture of aluminum chloride and benzene. A slight molar excess of catalyst is used; benzene serves as both a solvent and reactant. The acid chloride is added at such a rate so as to keep the temperature of the slurry at about 30-40 C. The mixture is stirred for one additional hour after all of the acid chloride is added, and then water is slowly added to decompose the catalyst. Sufficient water is added so that all the solids are dissolved. The phenylalkyl ketone is isolated from the benzene solution and is purified by distillation.

The WoliT-Kishner reduction (II) is run in 2-(2- ethoxyethoxy)ethanol using a modification of the procedure given by J. Cason, et al. in Organic Synthesis, Collective Vol. IV, John Wiley and Sons, New York, (1963), p. 510. Once the reactants are mixed, they are heated to reflux for a period of 3 to 5 hours. The reflux temperature is generally in the l30-l40 C. range. After completion of the reflux period, the solution is cooled and poured into 3 to 4 volumes of water. The al- RrCHzeis kylbenzene product is extracted with pentane and purified by distillation.

The Friedel-Crafts reaction (III) is run by mixing approximately equimolar quantities of the reactants together in hexane or nitromethane at less than 5 C. The stirring mixture is slowly allowed to warm to room temperature, and when hydrogen chloride evolution subsides, the mixture is refluxed several hours. Water is then added slowly to decompose the catalyst. A sufiicient quantity of water is then added so that all of the solids are dissolved. The desired acetophenone derivative is isolated from the organic phase, and purified by distillation. Gas-liquid chromatography on an F & M Model 500 Gas Chromatographer using a 20 X V4" O.D. stainless steel column, containing 10 percent Carbowax 20M on 60-80 mesh Diatoport T indicates that about 98 percent of the acetophenone is the 1,4 isomer and 2 percent is the 1,2 isomer. The 1,2 isomer has the shorter retention time.

The haloforrn reaction (IV) is run by slowly adding a cold sodium hypochlorite solution to a stirring solution of the acetophenone derivative in methanol. This is a modification of the procedure used by E. E. Royals (J. Am. Chem. Soc., 69, 841 (1947) for the haloform reaction of a-ionone. After the sodium hypochlorite solution is added, the mixture is warmed to room temperature, and left standing over night. Thereafter, the mixture is heated to reflux, and the distillate collected until the pot temperature rises to 97C.; most of the methanol is distilled. The pot is then cooled to room temperature. In those reactions where R has a low molecular weight such as cyclobutyl the sodium benzoate derivative remains dissolved; however, when R becomes larger, such as bicycloheptyl the sodium benzoate derivative precipitates as a soapy solid. Sulfur dioxide is bubbled into the alkaline pot concentrate until the pH drops below 3. The precipitated benzoic acid derivative is either filtered and washed with water, or extracted with methylene chloride depending on whether or not the benzoic acid is easily filterable or is of a soapy nature. Some of these benzoic acid derivatives can be recrystallized from acetonitrile or pentane, and some are purified merely by trituration with cold pentane.

The catalytic hydrogenation (V) is performed at two to three atmospheres of hydrogen using platinum oxide as catalyst and glacial acetic acid as solvent. A Parr Hydrogenation Apparatus is suitable for these reactions. This reaction produces a eis/trans isomer mixture of about 2 or 3/ l The cis and trans designation refers to the relationship of the 4-alkyl substituent and carboxylic acid group on the cyclohexane ring, this is illustrated below COZH trans The Schmidt reaction (VI) is performed by dissolving the cyclohexane carboxylic acid derivative in a mixture of chloroform and concentrated sulfuric acid. Sodium azide is then added in small portions to the stirring mixture at a rate sufiicient to keep the reaction temperature between 35 and 45C. The mixture is stirred at about 45 to 50C. until the bubbling nearly stops (1 to 3 hours). The mixture is then transferred to a separatory funnel, and the lower, gelatinous sulfuric acid layer is slowly dripped onto ice. The amine sulfate precipitates as a soapy material which slowly crystallizes. The chloroform should be kept away from the ice water mixture since it makes the work-up much more difficult. Those amines which crystallize as the hemisulfates or sulfates are filtered and washed with water. It is convenient to store these amines as their salts. Those amine salts which fail to crystallize are converted to the free bases by making the sulfuric acid solution alkaline, and extracting the amine with dichloromethane. The amine is then purified by distillation. The Schmidt reaction proceeds without changing the cis/trans product ratio.

The acylation (VII) can be performed by dissolving the free amine in an equal volume of dimethylacetamide (DMAC) or dimethylformamide (DMF) and adding an excess of the desired acid anhydride to the stirring solution. This reaction is very exothermic. The solution is stirred for ten minutes, and then it is poured into to I00 volumes of water. The amide separates as an oil which subsequently crystallizes.

The acylation (VII) can also be performed using the amine sulfate directly according to the following procedure. The amine sulfate is ground into a powder, and added to a 1:1 mixture of DMAC and 20 percent aqueous sodium hydroxide solution; there should be a large excess of base. The mixture is stirred for 10 to minutes, and then an excess of the desired acid anhydride is added. The mixture warms to about 60 to 65 C. The sulfate entirely dissolves in 10 to minutes. The solution is then poured into 10 to 100 volumes of water. The amide is isolated by the usual procedures given above.

The formamides of reaction VHI are prepared by refluxing the amine with methylformate for several hours. The excess methylformate is stripped from the reaction, and the residual formamide is purified by recrystallization.

These acylations proceed without changing the cis/trans product ratio.

In those cases where R is methyl or ethyl, the formamide or acetamide respectively is reduced by lithium aluminum hydride in refluxing ether according to reaction IX. The amine is isolated from the reaction after the lithium aluminum hydride is destroyed. These amines are purified by distillation.

Reactions X and XI are run according to the procedures described for reactions VII and VIII respectively.

An alternative synthesis route can be used when the appropriately substituted aniline derivatives are available. This route is illustrated below.

XII

The hydrogenation (XH) can be performed at 1 to 3 atmospheres of hydrogen on a Parr Hydrogenation Apparatus using platinum oxide as catalyst and glacial acetic acid as solvent. Hydrogen up-take is quite slow.

The cis/trans ratio of the cyclohexylamine product is about 1:1.

Reactions XIII and XIV are performed according to reactions VII and VIII discussed above. The cis/trans ratio for the amides from XII and XIH is about 1:1.

The pure amide isomers from reactions VII, VIII, X, XI, XIII and XIV can be separated by chromatography over silicic acid using methylcyclohexane saturated with acetonitrile as the eluting solvent. Isomer mixtures also can be separated by gas-liquid chromatography using 10 percent Carbowax 20M on 60-80 mesh Diatoport T. In both of these chromatography methods, the cis isomer elutes before the trans isomer. The cis amine isomer can be regenerated by alkaline hydrolysis of the purified amide.

The following additional examples describe the invention in greater detail.

EXAMPLE 1 A 23.9 gram quantity of 4-n-butylaniline (from Aldrich Chemical Company) is dissolved in 250 milliliters of glacial acetic acid, and 1 gram of Adams Catalyst (PtO is added. The mixture is then hydrogenated at two to three atmospheres using a Parr Hydrogenation Apparatus. To insure complete reduction, the hydrogenation is run over night. The catalyst is then filtered, and the acetic acid is removed under reduced pressure on a steam bath. The concentrate is taken up in ether and washed with dilute, aqueous sodium bicarbonate. The ethereal solution is dried (MgSO filtered and evaporated in vacuum leaving 21 grams of the 4-nbutylcyclohexylamine (n 1.4574). The amine is taken up in two volumes of dirnethylacetamide and treated with one volume of acetic anhydride. The temperature of the stirring solution rises rapidly to 60-80 C. After having stirred for ten minutes, the solution is poured into 10 volumes of water. The oil which separates is extracted with ether. The ethereal solution is dried (MgSO filtered and stripped leaving an oil which slowly crystallizes. This waxy solid softens at 57C. and melts from 79100C. Gas-liquid chromatography of this cis/trans mixture of N-acetyl-4-nbutylcyclohexyl-amine on an F & M Model 500 Gas Chromatograph over 10 percent Carbowax 20M on 60-80 mesh Diatoport T in a A." X 2' stainless steel column at a temperature of 200 C., a block temperature of 308C, and an injection port temperature of 280C. with a He flow rate of 60 cc./min. shows that the cisztrans ratio is about 1 :1

The retention times for the cis and trans isomers are 28.0 and 32.5 minutes respectively. The cis isomer causes severe burning of the operators nose as it elutes from the column while the trans isomer does not cause much irritation.

XIII

DMAC

The infra-red spectrum (nujol) for this mixture shows characteristic peaks at 3300 cm" for the N-H, 1630 and 1560 cm for the amide carbonyl, 1320 cmfor the trans isomer and 1280 cm" for the cis isomer. Anal. Calcd. for C H NO: C, 73.0; H, 11.8; N, 7.1%

Found: C, 72.9; H, 11.7; N, 6.7%

Mice are treated by aerosol exposure to the cis/trans mixture of N-acetyl-4-n-butylcyclohexylamine (c) in the following manner: The compound is administered as an aerosol into a 2.8 liter chamber. The exposure chamber consists of a 2.8 liter bell jar over a nebullizer inserted through the floor of the chamber. Mice are exposed for five minutes to 200.0 micrograms per liter (1,000Ct). The compound is dissolved in 1.4 ml. of acetone and during a span of 20 seconds the compound is sprayed up into the chamber. No further air is transferred into or out of the chamber during the 5 minute exposure.

After this exposure, irritant effects are observed in all mice exposed. The mice used as controls exposed to 1.4 ml. of acetone alone exhibit no irritant effects. Irritant effects can be described as the presence of one or more of the following reactive signs:

a. hyperemia of the ears, nose and tail b. abnormal gait, including rubbing of the nose on the floor while running about c. blinking d. salivation e. depression f. dyspnea g. hunched posture h. facepawing.

EXAMPLE 2 A mixture consisting of 400 ml. of benzene and 67 g. (0.5 mole) of aluminum chloride is stirred in a one liter round bottom flask fitted with a stirrer, thermometer condenser connected to a scrubber, dropped funnel, and cooling bath. Cyclobutane carbonyl chloride (50 g.; 0.42 mole) is added dropwise while the pot temperature is held below 35 C. The brown slurry is stirred for 1 hour and then water is cautiously added while the pot temperature is held below 30 C. Sufficient water is added so that all the solids dissolve. Two liquid phases are obtained. The mixture is transferred to a separatory funnel, and the benzene layer is separated. The aqueous layer is washed with 100 ml. of benzene which is then combined with the first benzene fraction. The aqueous solution is discarded. The combined benzene fractions are washed sequentially with 200 ml. of 5 percent aqueous sodium hydroxide solution and 250 ml. of water. The benzene solution is dried with magnesium sulfate, filtered, and evaporated in vacuum. The residual oil is distilled at 67 C. at 0.1 mm. of mercury giving cyclobutylphenylketone (11,, 1.5455).

Anal. Calcd. for C H O: C, 82.5; H, 7.6%

Found: C, 81.9; H, 7.6%

EXAMPLES 3 5. 3-Cyclopentylpropiophenone: B 1.5300 Anal. Calcd. for C I-1 0: C, 83.2; H, 8.9%

Found: C, 83.1; H, 8.9% 6. Cycloheptylphenylketone: B 134-136C.; n 1.5415 7. l-Adamantylphenylketone: m. 49-52C. 8. 2-[2.2.2]-Bicyclooctylphenylketone 9. 1-[3.2.1 ]-Bicyclooctylphenylketone 10. 2-[ 3.3. 1 ]-Bicyclononylphenylketone EXAMPLE 11 A solution of potassium hydroxide (140g; 2.5 mole) in 500 ml. of 2-(2-ethoxyethoxyl)ethanol (from Matheson, Coleman & Bell Co.) is prepared by carefully heating the mixture until all of the solids are gone. The solution is cooled to below C. Then 2-[2.2.1 bicycloheptylphenylketone (94.7g.; 0.50 mole) and 99 percent hydrazine hydrate (1 10 g.; 2.2 mole) are added all at once. The reactants are refluxed for 4 hours at 135 C., and then the solution is poured into 2.5 l. of water. The oil which separates is extracted with three- 500 ml. portions of pentane. The aqueous phase is discarded, and the combined pentane fractions are dried with magnesium sulfate, filtered and evaporated in vacuum. The residual oil is distilled at C. at 12 mm. of mercury to give phenyl-2-[2.2.l]-bicycloheptylmethane (n 1.5342).

Anal. Calcd. for C I-1, C, 90.3; H, 9.7%

Found: C, 90.8; H, 9.5%

EXAMPLES 12 22 The following phenylmethane derivatives are prepared according to the procedure given for phenyl- 2-[2.2.1]-bicycloheptylmethane in Example 8 by substituting the like molar amount of the appropriate phenylketone for 2-[2.2. l ]-bicycloheptylpheny1ketone of Example 8.

12. Isobutylbenzene: B 168C; n 1.4800.

13. Cyclobutylphenylmethane: B 89C.; n 1.5150.

14. Cyclopentylphenylmethane: B 92C.; n 1.5165.

EXAMPLE 23 A solution of cyclobutylphenylmethane (20.5 g.; 0.14 mole) and acetyl chloride (12.5 g.; 0.16 mole) in 400 ml. of hexane is cooled to 0C. and aluminum chloride (21.5 g.; 0.16 mole) is added all at once. The reaction equipment is similar to that given in Example 2. The stirring mixture is warmed to about 5 C., and held there for one-half hour. The slurry is then warmed to room temperature for 1 hour, and finally refluxed for 30 minutes. Water is then carefully added to decompose the aluminum chloride. Sufficient water is finally added to dissolve all the solids and obtain two liquid phases The mixture is transferred to a separatory funnel, and the hexane solution is isolated. The aqueous phase is washed with 100 ml. of hexane, and then discarded. The combined hexane fractions are washed sequentially with 100 ml. of percent aqueous sodium hydroxide solution and 100 ml. of water. The hexane solution is dried with magnesium sulfate, filtered and evaporated in vacuum. The residual oil is distilled at 108C. at 1 mm. of Hg to give 4'-cyclobutylmethylacetophenone (n 1.5388).

Anal. Calcd. for C H O: C, 82.9; H, 8.6%.

Found: C, 83.1; H, 8.5%.

The pertinent features in the infra-red spectrum are a very strong peak at 1680 cm (carbonyl) and a peak at 850 cmindicative of two adjacent benzenoid hydrogens thus showing that the benzene ring has substituents in the 1 and 4 positions.

A gas-liquid chromatograrn obtained on an F & M Model 500 Gas Chromatograph using a 2' X W O.D. Stainless Steel column packed with percent Carbowax 20M on 60-80 mesh Diatoport T with a helium flow rate of 60cc/min. a block temperature of 307 C., an injection port temperature of 262 C., and a column temperature of 225 C. shows that the sample consists of 98 percent of the 1,4-isomer and 2 percent of the 1,2-isomer which have retention times of 9.5 and 8.0 minutes respectively.

EXAMPLES 24-42 The following acetophenone derivatives are prepared according to the procedure given for 4' cyclobutylmethylacetophenone in Example 23 by substituting a like amount of the appropriate alkylphenylmethane derivative for the cyclobutylphenylmethane of Example 23. For those compounds where R, is bi-or tricycloalkyl, nitromethane can be used as solvent in place of the hexane. The infra-red spectra for all these compounds are similar to that reported for 4'-cyclobutylmethylacetophenone in Example 23.

24. 4-Isobutylacetophenone: B 110 C.; n,, 1.5 6.

25. 4'-n-Pentylacetophenone: l3 122 C.; n 1.5142.

26. 4'-Cyclopentylmethylacetophenone: B 130- 1 32 C.;

Calcd. for C I-1, 0: C, 83.2; H, 8.9%. Found: C, 83.5; H, 8.9%.

Gas-liquid chromatography under conditions like those in Example 23 at a column temperature of 200 C. gives peaks at 14.0 minutes (2 percent of sample) for the 1,2-isomer at 17.5 minutes (98 percent of sample) for the 1,4-isomer.

27. 4'-(2-Methylpentyl)acetophenone: B 96 C.; n,, 1.5120. Anal. Calcd. for C I-I 0: C, 82.3; H, 9.9%.

Found: C, 82.2; H, 9.8%.

Gas-liquid chromatography under conditions like those in Example 23 gives peaks at 6.0 minutes (1 percent of sample) for the l,2-isomer and 7.5 minutes (99 percent of sample) for the 1,4-isomer.

28. 4'-n-Hexylacetophenone: "D251 .5 106. 29. 4-Cyclohexy1methylacetophenone. 30. 4'-n-l-leptylacetophenone: B -134C.; n 1.5084. 31. 4'-n-Octylacetophenone: B 128C.; n 1.5060. 32. 4'-( 3-Cyclopentylpropyl)acetophenone: B 154C; n 1.5298. Anal. Calcd. for C H O: C, 83.5; H, 9.6%.

Found: C, 83.5; H, 9.6%. 33. 4'-Cycloheptylmethylacetophenone: B 136- 140C; 11,, 1.5426. Anal. Calcd. for C l'l O: C, 83.4; H, 9.6%.

Found: C, 83.6; H, 9.7%. 34. 4'-Cyclononylmethylacetophenone. 35. 4-Cyclooctylmethylacetophenone. 36. 4'-( 2-[2.2.1 ]-Bicycloheptylmethyl)acetophenone: B 117C.;n 1.5511. Anal. Calcd. for Cml-l O: C, 84.2; H, 8.8%.

Found: C, 84.1; H, 8.8%.

Gasliquid chromatography under conditions like those given in Example 23 gives a single peak with a retention time of 29.5 minutes.

37. 4-( l-Adamantylmethyl)acetophenone.

38. 4'-( 2-[ 2.2.2]-Bicyclooctylmethy1)acetophenone. 39. 4'-( 1-[3.2. l ]-Bicyclooctylmethyl)acetophenone. 40. 4'-(2-[ 3.3. l ]-Bicyclononylmethyl)acetophenone. 4 1 4-( 1 -Homoadamantylmethyl)acetophenone.

42. 4'-( 2-[ 3.2.01-Bicycloheptylmethyl )acetophenone.

EXAMPLE 43 A solution of 4'-cyclobutylrnethylacetophenone (20 g.; 0.11 mole) in 225 ml. of methanol is cooled to less than 5C., and 275 ml. of a 1.29M sodium hypochlorite solution (0.35 moles) is slowly added. The temperature is held below 5 C. during the addition. The sodium hypochlorite solution is conveniently prepared according to the procedure given by M. S. Newman, Organic Synthesis, Collective Volume 11, John Wiley and Sons, New York, 1943, p. 429. After about 25 ml. of the hypochlorite solution is added, a white precipitate forms. When all of the hypochlorite solution is added, the stirring mixture is allowed to warm to room temperature, and left standing over night. Some chloroform usually separates during the night. The stirring mixture is heated to reflux 80 C.) and distillate 200 ml.) is collected until the pot temperature rises above 95 C. The pot concentrate is cooled to room temperature, and sulfur dioxide is bubbled into it until the pH falls below 3. The precipitate is extracted with two-300 ml. portions of dichloromethane, and the aqueous phase is discarded. The combined dichloromethane solutions are dried with magnesium sulfate, filtered and evaporated in vacuum. The yellow residue is triturated with cold pentane, and filtered. The 4-cyclobutylmethylbenzoic acid melts at 146149 C. and has an infra-red spectrum showing typical benzoic acid absorption peaks.

Anal. Calcd. for C H O C, 75.8; H, 7.4%.

Found: C, 75.5; H, 7.6%.

Calcd. neutral equivalent weight:

Found: 198

EXAMPLES 44 62 The following 4-alkylbenzoic acid derivatives are prepared according to the procedure given for 4- cyclobutylmethylbenzoic acid in Example 43 by substituting the appropriate 4'-alkylacetophenone in a like molar amount for the 4-cyclobutylmethylacetophenone of Example 43. All of these compounds show the typical benzoic acid absorption peaks in their infra-red spectra.

44. 4'-Isobutylbenzoic acid: m. 143.0144.5 C. Anal. Calcd. for C H O C, 74.2; H, 7.9%.

Found: C, 74.2; H, 7.9%. 45. 4-n-Pentylbenzoic Acid: m. 87.0-88.5 C. 46. 4-Cyclopentylmethylbenzoic acid: in. 143.0145.0 C. Anal. Calcd. for C H O C, 76.5; H, 7.9%

Found: C, 76.1; H, 7.5%. 47. 4-(2-Methylpentyl)benzoic acid: m. 103-1 C. Anal. Calcd. for C H O :C, 75.7; H, 8.8%.

Found: C, 75.9; H, 8.9%. 48. 4-n-Hexylbenzoic acid. m. 7782 C. 49. 4-Cyclohexylrnethylbenzoic acid. 50. 4-n-Heptylbenzoic acid: m. 9396C. 51. 4-n-0ctylbenzoic acid: m. 96-98C. 52. 4-(3-Cyclopentylpropyl)benzoic acid: in 1 l7-1 19 C. Anal. Calcd. for C H O z C, 77.5; H, 8.7%.

Found: C, 77.6; H, 8.7%. 53. 4-Cycloheptylmethylbenzoic acid: m. 171-l73C. Anal. Calcd. for C H O z C, 77.5; H, 8.7%.

Found: C, 77.2; H, 8.7%. 54. 4-qyclooctylmethylbenzoic acid. 55. 4-Cyclononylmethylbenzoic acid. 56. 4-(2-[2.2.1]-Bicycloheptylmethyl)benzoic acid: m. l71173C. Anal. Calcd. for C H O :C, 78.3; H, 7.9%

Found: C, 77.6; H, 7.9%. Calcd. neutral equivalent weight: 230.

Found: 243. 57. 4-(1-Adamantylmethyl)benzoic acid. 58. 4-(2-[2.2.2]-Bicyclooctylmethyl)benzoic acid. 59. 4-( 1-[ 3.2. l ]-Bicyclooctylmethy1 )benzoic acid. 60. 4-(2-[3.3. 1 ]-Bicyclononylmethy1)benzoic acid. 61. 4-( l-Homoadamantylmethyl)benzoic acid. 62. 4-(2-[ 3 .2.0]-Bicycloheptylmethyl)benzoic acid.

EXAMPLE 63 A sample of 4-cyclobutylmethylbenzoic acid (8.3 g.; 0.044 mole) is dissolved in 250 ml. of glacial acetic acid in a 500 ml. pressure bottle and platinum oxide (1 g.) is added. The mixture is then shaken under a hydrogen pressure of 45 p.s.i.g. on a Parr Hydrogenation Apparatus for 24 hours; the final pressure is 33 p.s.i.g. The catalyst is filtered, and the acetic acid removed in vacuum. The residual oil is taken up in 200 ml. of ether, and washed with two-100 ml. portions of water to remove the residual acetic acid. The ethereal solution is then dried with magnesium sulfate, filtered and evaporated in vacuum leaving an oil which subsequently crystallizes. The 4-cyclobutylmethylcyclohexane carboxylic acid is recrystallized from a mixture of ethanol and water, and melts from 59 to 69 C. The cis/trans mixture of carboxylic acids causes the broad melting range.

Anal. Calcd. for C I-1 0 C, 73.5; H, 10.2%.

Found: C, 73.4; H, 10.2%. The infra-red spectrum shows that the benzene ring has been reduced.

EXAMPLES 64 82 The following 4-alkylcyclohexane carboxylic acid derivatives are prepared according to the procedure given for 4-cyclobutylmethylcyclohexane carboxylic acid in Example 63 by substituting the appropriate 4- alkyl-benzoic acid in a like molar amount for the 4- cyclobutylmethylbenzoic acid of Example 63. Infra-red spectra of these compounds also show that the benzene rings have been reduced.

64. 4-Isobutylcyclohexane carboxylic acid: B 118- 119C.;n 1.4638. Anal. Calcd. for C H O C, 71.7; H, 10.9%

Found: C, 72.3; H, 11.3%. 65. 4-nPentylcyclohexane carboxylic acid: B 138 C.; n 1.4652. Anal. Calcd. for C H O- C, 72.8; H, 1 1.2%.

Found: C, 72.8; H, 11.4%. 66. 4-Cyclopentylmethylcyclohexane carboxylic acid; B 140 C.; n 1.4910, m. 38-47 C. Anal. Calcd. for C H O C, 74.2; H, 10.5%

Found: C, 73.9; H, 10.7%. 67. 4-(2-Methylpentyl)cyclohexane carboxylic acid: B03 126 -130 H025 Anal. Calcd. for C H O C, 73.5; H, 11.3%.

Found: C, 73.8; H, 11.2%. 68. 4-n-Hexylcyclohexane carboxylic acid: B 129- l31C.;n 1.4666. Anal. Calcd. for C H O C, 73.4; H, 11.4%.

Found: C, 74.0; H, 11.1%. 69. 4-Cyclohexylmethylcyclohexane carboxylic acid: m. 62-69 C. Anal. Calcd. for C H O C, 74.9; H, 10.8%.

Found: C, 75.2; H, 10.7%. 70. 4-n-Heptylcyclohexane carboxylic acid: B C.; n,, 1.4676. Anal. Calcd. for C H O C, 74.3; H, 1 1.6%.

Found: C, 74.5; H, 11.4%. 71. 4-n-Octylcyclohexane carboxylic acid: m. 3639 C. (from acetonitrile) Anal. Calcd. for C H O z C. 75.0; H, 11.4%.

Found: C, 75.5; H, 11.9%. 72. 4-( 3-(b'clopentylpropyl)cyclohexanecarboxylic acid: B05 D25 Anal. Calcd. for C H o C, 75.5; H, 11.0%.

Found: C, 75.4; H, 10.8%. 73. 4-Cycloheptylmethylcyclohexane carboxylic acid; B 160-162 C.; n 1.4963; m. 45-49 C. Calcd. for C H O z C, 75.5;H, 11.0%. Found: C, 75.5; H, 10.8%. Neutral Equivalent: Calcd. 238. Found: 238. 74. 4-n-Nonylcyclohexane carboxylic acid. 75. 4-Cyclononylmethylcyclohexane carboxylic acid. 76. 4-(2-[2.2. 1 ]-Bicyclohepty1methyl)cyclohexane carboxylic acid: m. 6473 C. (from ethanol). Anal. Calcd. for G i-1 0 C, 76.2; H, 10.2%.

Found: C, 76.1; H, 10.1%. 77. 4-(1-Adamantylmethyl)cyclohexane carboxylic acid. 78. 4-(2-[2.2.2]-Bicyclooctylmethyl)cyclohexane carboxylic acid. 79. 4-(1-[3.2.1 ]-Bicyclooctylmethyl)cyclohexane carboxylic acid. 80. 4-(2-[3.3.1]-Bicyc1ononylmethyl)cyclohexane carboxylic acid.

81. 4-( 1-l-lomoadamantylmethyl)cyclohexane carboxylic acid.

82. 4-(2-[3.2.0]-Bicycloheptylmethyl)cyclohexane carboxylic acid.

EXAMPLE 83 A sample of 4-n-hexylcyclohexane carboxylic acid (24 g.; 0.11 mole) is taken up in a mixture of 200 ml. of chloroform and 1 10 ml. of concentrated sulfuric acid in a 500 ml. Erlenmeyer flask. Sodium azide (9.8 g.; 0.15 mole) is carefully added with a spatula at a rate to keep the temperature of the stirring mixture between 35 and 45 C. After completion of the sodium azide addition, the stirring mixture is heated at 45-50C. for 2 hours; the rate of gas evolution is very slow at this time. The mixture is transferred to a separating funnel and the lower, gelatinous sulfuric acid layer is slowly dripped into one liter of crushed ice. The 4-n-hexylcyclohexylamine hemisulfate crystallizes slowly. The salt is filtered and washed with water; it is almost completely insoluble in water. The melting point is above 300 C.

Anal. Calcd. for C, H N%H SO C, 62.1; H, l 1.3; N, 6.0; S, 6.9%.

The infra-red spectrum shows absorptions characteristic of amine salts and sulfates and has no absorption corresponding to a carboxyl function.

EXAMPLES 84 102 The following 4-alkylcyclohexylamine derivatives or their salts are prepared according to the procedure given for 4-n-hexylcyclohexylamine hemi-sulfate in Example 83 by substituting the appropriate 4-alkylcyclohexane carboxylic acid in like amount by weight for the 4-n-hexylcyclohexane carboxylic acid of Example 83. In those instances where the free amines are prepared, the amine salt is dissolved in 10 percent aqueous sodium hydroxide solution, and the free amine is extracted with dichloromethane. The dichloromethane solution is dried with magnesium sulfate, filtered and evaporated in vacuum. The residual oil is distilled in vacuum through a spinning band column. The infra-red spectra of these compounds all show the loss of the carbonyl function and the presence of an amino function.

84. 4-Isobutylcyclohexylamine: B 56 C.; n 1.4552.

Anal. Calcd. for C H N: C, 77.4; H, 13.6; N, 9.0%.

Found: C, 77.6; H, 13.5; N, 9.1%.

85. 4-n-Pentylcyclohexylamine: B 76 C.; a

Anal. Calcd. for C H N: C, 78.0; H, 13.7; N, 8.3%.

Found: C, 77.9; H, 13.6; N, 8.6%.

86. 4-Cyclopentylmethylcyclohexylamine hemi-sulfate:

Anal. Calcd. for C, H N%H SO,: C, 62.6; H, 10.5; N,

Found: C, 62.0; H, 10.7; N, 6.0%.

87. 4-(2-Methylpentyl)cyclohexylamine: B 80-81 Anal. Calcd. for C H N: C, 78.7; H, 13.7; N, 7.6%.

Found: C, 78.3; H, 13.7; N, 8.1%.

88. 4-Cyclobutylmethylcyclohexylamine.

89. 4cis-Cyclohexylmethylcyclohexylarnine sulfate: m. 300C.

Anal. Calcd. for C, H N%H S C, 64.0; H, 10.8; S,

hemi- Found: C, 63.9; H, 10.6; S. 6.9%. 90. 4-n-Heptylcyclohexylamine hemi-sulfate hemihydrate: m. 300 C. Anal. Calcd. for C, H N%H,S0,%H O: C, 62.3; H, 1 1.5; N, 5.6% Found: C, 62.6; H, 12.0; N, 5.0%. 91. 4-n-Octylcyclohexylamine hemi-sulfate hemihydrate. Anal. Calcd. for C H N%H SO %H O: C, 62.4; H, 11.6; N, 5.2%.

Found: C, 61.8; H, 12.0; N, 5.1%. 92. 4-(3-Cyclopentylpropyl)cyclohexylamine sulfate: m. 300C. Anal. Calcd. for C H N-H SO C, 54.6; H, 9.5; N, 4.6; S, 10.4%.

Found: C, 55.2; H, 9.8; N, 4.5; S. 9.9%.

93. 4-Cycloheptylmethylcyclohexylarnine hemi-sulfate: m 300 C. 94. 4-Cyclooctyhnethylcyclohexylamine hemi-sulfate: m 300 C. 95. 4-Cyclononylmethylcyclohexylarnine hemi-sulfate: m 300C. 96. 4-(2'[2.2. l ]-Bicycloheptylmethyl)cyclohexylami ne hemi-sulfate dihydrate: m. 300 C. Calcd. for C14H25NC14H25N'5QH2S04'2H201 C, H, N, 4.8%. Found: C, 58.5; H, 9.3; N, 4.7%. 97. 4-(1-Adamantylmethyl)cyclohexylamine sulfate: m. 300B C. 98. 4-(2-[2.2.2]-Bicyclooctylmethyl)cyclohexylamine sulfate: m. 300 C. 99. 4-( l-[3.2.1 ]-Bicyclooctylmethyl)cyclohexylarnine sulfate: m. 300 C. 100. 4-(2-[3.3.1 ]-Bicyclononylmethyl)cyclohexylamin e hemi-sulfate: m. 300 C. 101 4-( l-Homoadamantylmethyl)cyclohexylamine sulfate: m. 300 C. 102. 4-(2-[3.2.0]-Bicycloheptylmethyl)cyclohexylami ne hemi-sulfate: m. 300 C.

EXAMPLE 103 A sample of 4-n-hexylcyclohexylamine hemi-sulfate (10 g.; 0.043 mole) is stirred for ten minutes in a mix- 5 ture consisting of 100 ml. of dimethylacetamide and 25 ml. of 20 percent aqueous sodium hydroxide solution. Acetic anhydride (20 ml.) is added with stirring; the temperature rises to -80 C. After the temperature has dropped to about 60 C., the milky suspension is filtered to remove any traces of unreacted 4-n-hexylcyclohexylamine hemi-sulfate. The milky filtrate is poured into 1200 ml. of water, and the oil which separates crystallizes. The crystalline N-acetyl-4-n-hexylcyclohexylamine is filtered and washed with water. It melts from 49 to 87 C.

Anal. Calcd. for C H NO: C, 74.8; N, 12.1; N, 6.2%.

Found: C, 74.7; H, 12.0; N, 6.3%.

Gas-liquid chromatography on an F & M Model 500 Gas Chromatograph using a 2' X V4" O.D. stainless steel column packed with 10 percent Carbowax 20M on 60-80 mesh Diatoport T at a column temperature of 200 C., a block temperature of 308 C. an injection port temperature of 265 C. and a helium flow rate of 60 cc/min. shows that the sample consists of two compounds present to the extent of 64 and 36 percent which have retention times of 53.3 and 61.8 minutes respectively.

A nuclear magnetic resonance spectrum of the mixture shows that the larger component is N-acetyl-cis-4- n-hexylcyclohexylamine and the smaller component is N-acetyl-trans-4-n-hexylcyclohexylamine.

The pure isomers are isolated by adsorption chromatography over silicic acid using methylcyclohexane saturated with acetonitrile as the eluting solvent; the adsorbant to compound ratio is 50: 1. N-Acetyl-cis-4-nhexylcyclohexylamine melts at 550 to 57.0 C., and N-acetyl-trans-4-n-hexylcyclohexylamine melts at 123.0-124.0 C.

The cis/trans mixtures are used for the purposes of this invention without separation of the isomers.

N-Acetyl-4-n-hexylcyclohexylamines are used to treat mice according to the procedures given in Example l with like results. At the time mice are treated in such manner with the pure isomers, the cis isomer is shown to be much more of an irritant than the trans isomer.

EXAMPLES 104 125 The following N-acyl-4-alkylcyclohexylamines are prepared according to the procedure given for N- acetyl-4-n-hexylcyclohexylamine in Example 103 by substituting in a like molar amount the appropriate 4- alkylcyclohexylamine and acid anhydride for the 4-nhexylcyclohexylamine and acetic anhydride of Example 103.

104. N-Acetyl-4-isobutylcyclohexylamine: m. 961 18 C. cis/trans ratio 63(41.0 min.)/37 (47.2 min.) by G.L.C. method like that in Example 103 at a column temperature of 180 C.

Anal. Calcd. for C, H NO: C, 73.0; H, 11.7; N, 7.1%. Found: C, 73.1; H, 12.2; N, 7.0%.

1 N-Butyryl-4-isobutylcyclohexylamine.

106. N-Acetyl-4-n-pentylcyclohexylamine: m. 4595 C. cis/trans ratio 68(34.3min.)/32(39.9min.) by G.L.C. method like that in Example 103 at a column temperature of 200 C.

Calcd. for C H NO: C, 75.0; H, 1 1.9; N, 6.6%. Found: C, 73.6; H, 12.3; N, 6.6%.

107. N-Propionyl-4-n-pentylcyclohexylamine.

108. N-Acetyl-4-cyclopentylmethylcyclohexylamine: m. 65-78 C. cis/trans ratio 74(33min.)/26(37min.) by G.L.C. method like that in Example 103 at a column temperature of 225 C.

Calcd. for C H NO: C, 75.4; H, 1 1.2; N, 6.2%. Found: C, 75.2; H, 11.4; N, 6.2%.

109. N-Propionyl-4-cyclopentylmethylcyclohexylamine.

110. N-Acetyl-4-(2-methylpentyl)cyclohexylamine: m. 5869 C. cis/trans ratio 87(54.5min.)/13(62.6min.) by G.L.C. method similar to that in Example 103 at a column temperature of 190 C.

Calcd. for C H NO: C, 74.7; H, 12.1; N, 6.2%. Found: C, 74.6; H, 11.9; N, 6.0%.

1 l 1. N-Acetyl-4-Cyclobutylmethylcyclohexylamine: m. 4259 C. cis/trans ratio 78(43.5min)/ 22(49.6min) by a G.L.C. method like that in Example 103 at a column temperature of 200 C.

Calcd. for C H NO: C, 74.7; H, 11.1; N, 6.7%. Found: C, 74.7; H, 11.1; N, 6.5%.

1 l2. N-Acetyl-4-n-heptylcyclohexylamine; m. 611 14 C., cis/trans ratio 64(23.5min.)/36(27.0min.) by a G.L.C. method like that in Example 103 at a col. temperature of 230 C.

Calcd. for C ,H NO: C, 75.3; H, 12.2; N, 5.9%. Found: C, 75.0; H, 12.1; N, 5.9%.

113. N-Acetyl-4-n-octylcyclohexylamine; m. 62-82 C. cis/trans ratio (31.5min.)/25(36.5min.) by a G.L.C. method similar to that of Example 1 12.

Calcd. for C H NO: C, 76,0; H, 12.3; N, 5.5%. Found: C, 75.8; H, 12.3; N, 5.4%.

1 17. N-Acetyl-4-cyclooctylmethylcyclohexylamine.

1 18. N-Acetyl-4-cyclononylmethylcyclohexylamine.

1 19. N-Acetyl-4-( 2-[2.2.1 l-bicycloheptylmethyl)cyclohexylamine: m. 1111 13 C. cis/trans ratio 73(55.8min.)/27(63.5min.) by G.L.C. method like that in Example 103 at a column temperature of 225C.

Calcd. for C H NO: C, 77.2; H, 10.9; N, 5.6%. Found: C, 76.9; H, 10.7; N, 5.6%.

120. N-Acetyl-4-( 1-adamantylmethyl)cyclohex ylamine. 121. N-Acetyl-4-(2-[ 2.2.21-bicyclooctylmethyl)cyclohexylamine.

122. N-Acety1-4-( 2-[ 3.2.1 ]-bicyclooctylmethyl)cyclohexylamine.

123. N-Acetyl-4-(2-[ 3.3. l l-bicyclononylmethyl)cyclohexylamine. 124. N-Acetyl-4-( 1-homoadamantylmethyl)cyclohexylamine. 125. N-Acetyl-4-( 2-[3.2.0 l-bicycloheptylmethyl)cyclohexylamine.

EXAMPLE 126 A sample of 4-cyclobutylmethylcyclohexylamine (20 g.; 0.060 mole) is refluxed for 3 hours with 20 ml. of methylformate. The solution is then evaporated in vacuum and the residual N-formyl-4-cyclobutylmethylcyclohexylamine is purified by recrystallization from hexane. This N-formyl-4-cyclobutylmethylcyclohexylamine is used to treat mice and other animals according to the procedures given in U.S. Pat. application Ser. No. 532,544, filed Mar. 1, 1966 now abandoned.

EXAMPLE 127 A mixture of N-formy1-4-cyclohexylmethylcyclohexylamine (7.9g.; 0.035 mole) and lithium aluminum hydride (LAH) (3.8g; 0.10mole) is heated in ml. of refluxing ether for 24 hours. The suspension is cooled, and the lithium aluminum hydride is decomposed using wet ether and then a saturated, aqueous solution of sodium sulfate. This decomposition should be performed cautiously to avoid a fire. The

' precipitated salts are filtered and washed with ether.

The ethereal solution is then dried with magnesium sulfate, filtered and evaporated in vacuum learving an oil. The infra-red spectrum shows the oil to be an amine. The N-methyl-N-cyclohexylmethylcyclohexylamine is purified by vacuum distillation.

EXAMPLES 128-141 The following dialkylamines are prepared according to the procedure described for N-methyl-N-cyclohexylmethyl-cyclohexylamine in Example 127 by substituting in like amount by weight the appropriate N-fonnyl or N-acetyl-4-alkylcyclohexylamine for the N-formyl- N-cyclohexylmethyl-cyclohexylamine in Example 127. 128. N-Methyl-N-(4-cyclobutylmethylcyclohexyl)amine.

129. N-Ethyl-N-(4-n-butylcyclohexyl)amine.