CA1083607A - Cyclohexyl and cyclohexenyl alkylene polyamines. - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Novel dicyclohexyl, dicyclohexenyl and cyclohexyl-cyclohexenylalkyl polyamines are useful antimicrobial agents, as well as algae inhibitors. They are especially useful in agriculture to protect plants against diseases such as leaf, stem, and fruit spotting, internal discoloration and decay of fruits and vegetables. These compounds are particularly active against diseases caused by the genera Pseudomonas, Xanthomonas, Erwinia, and Corynebacterium.

Description

:; ~
, ~ 8 ;3 61~

Disclosu.re oE the Invention: ;
This invention relates to a new class of substituted polyamines which are useful as algae, inhibitors and as broad spectrum antimicrobial agents, especially against bacteria causing plant diseases. The novel compounds of this invention have the structural formula:

1 ~ :
CH-NH-Z
A-(Rl)n (I) where A is independently a cyclohexyl or Cl to C6 alkyl substituted cyclohexyl, or an unsubstituted or Cl to C6 alkyl substituted cyclohexenyl of the formula:

(R)l ~

~ 1 ~

~ 1575~

~83607 1 where each ~ i9 either hyarosen or Cl to C~ alkyl and the

2 dashed line indica~es either saturation or a single

3 olefinic bond in the ring and provided that if A is cyclo-

4 hexenyl, no more than 9 of R are Cl to C6 alkyl~ ;
Most ~uitably, less than five of R are Cl to C6 6 alkyl ~nd preferably the total of carbon atoms in all of 7 the R group~ does not exceed eight. Most preferably, only 8 three of the R groups are Cl to C4 alkyl, and as such are ; !
g desirably methyl or ethyl.
Each n is ali~e or different and i5 the integer 11 0 or 1;
12 Each R1 i8 alike or different and i8 Cl to C4 13 alkylene7 14 Z is -Y-N-R6, where 16 R5 13 hydrogen, aminoe~hyl, aminopropyll Cl ~o 17 C4 hydroxyalkyl, or C2 to C4 dihydroxyalkyl; and 18 R6 i8 hydrogen, Cl to C4 hydroxyalkyl or C2 to C4 _ 19 dihydroxyalkyl; and Where Y i 8 2 ~ 4J . R7 ~ R8-, or R2.

21 When Y is -R2-N-R
22 ~ R3 23 R2 is 2-hydroxy-1,3-trime~hylene, or Rl as 24 previously de~ined;
~3 is hydrogen, Cl to C4 alkyl, C2 to C~ amino-26 alkyl or Cl to C4 hydroxyalkyl, C2 to C~ dihydroxyalkyl, 27 e.g., 2,3-dihydroxypropyl and 3,4-dihydroxybutyl;

: -- 2 ~

~ 1575 ~9836~7 1 R4 is 2-hydroxy-l,3-trimethylene, or Rl as 2 previously defined;
3 or when R3 and R6 taken together are ethylene, 4 R4 is also ethylene, and R5 is aminoe1~hyl, aminopropyl, or aminohydroxypropyl;
6 When Y is 7{~}R8-- , 7 R7 is R2, methylene, or a chemical bond between 8 the cyclohexylene moiety and a first nitrogen~ R8 is R4 _J 9 methylene or a chemical bond between the cyclohexylene iety and a second nitrogen~
ll 2 ~ R2~ R5 and R6 are as previously 12 defined. Most suitably R3, R5 and R6 are not simultaneously 13 dihydroxyalkyl, and when R3, R5 and R6 are simultaneously 14 dihydroxyalkyl, it i5 preferable that they are C3 or C4 dihydroxyalkyl.
16 Preferred polyamines I are those where the sum 17 of the carbon atoms in both of Rl are from 2 to 8.
18 The utility of the compounds of our invention is 19 generally their broad spectr~m antibacterial and antifungal properties. Especially useful is their activity against 21 bacteria and ungi responsible for stunting the growth and 2~ even destruction of many types of crop-producing plants, 23 and f~r those causing the degradation and deterioration of 24 many ~ypes of materials. This includes papers, leather, textiles, aqueous preparations such as latex paints, 26 adheslves, resins, pigment dispe~sion-Y and oleoresinous 27 coati~gs whose films are particularly vulnerable to the 28 destructive action of fungi. ~he large economic losses /r- ~ 157~

1 encountered ~n papermaking operations caused ~y the 2 accumulation of bacterial and fungal slimes in variou~
3 parts of the water system can be eliminated to a 4 significant extent by the use of the compounds herein describedO In agriculture, a severe problem faced in the 6 raising of cotton, beans, corn and other crop is the 7 loss of yield per acre due to the action of soilborne 8 fungi on seed and on the roots of the young plants.
9 Control or elimination of these losses can be accomplished by the use of the compounds herein described as soil dis-11 infectants in accordance with the invention. They can 12 also be used on foliage and trees for the control of 13 bacterial and fungal diseases.
14 They are especially useful a~ an agent active again~t bacterial disease of fruit~ such as fireblight.
16 Tha prime agent presently useful $B streptomycin, which 17 is not only expensive but being an antibiotic useful in 18 human medicine, its use in agriculture is regarded by some 19 as a source of streptomycin resistant species of pathogens.
The c~mpounds of this invention are preferably 21 prepared according to the following sequence of reactions:

f~ r~ 157 ~ C=O ~ Z
A- (Rl) n (IV) (V) A-~Rl)n ~ C-N-Z -A-(Rl)n (VI) A-~R ) 1 n ~ ~ (HX)__________~

A-(Rl)n (I) (Rl) n ,~ ~ HC-~-Z . HX
A~ tRl) n (Ia) 1 where A, Z and n have their previously def~ned meanings, ~ HX is a mono or polyba~ic organic or inor~anic acid, where 3 sufficient HX is provided to protonate at least one amino 4 group of compound I.
~ The preparation of polyamine I comprises the 6 straightforward Schiff ~a~e reaction of the appropxiate 7 ketone rv and the appropriate amine V.

~ <ff~ 1575' 1~836~7 1 If amine V ha~ two primary ~mino group~, it can 2 either be symmetrical or un~ymmetrical~ An ~mine V, which 3 i~ a symmetrical amlne, e.g., where R2 and Rj are 4 alike when R5 and R6 are hydrogens or where R2 and R4 are ethylene, R5 i~ aminoethylf and R6 i~ hydrogen; or 6 where R2 is trimethylene when R5 is 3-aminopropyl and R6 7 is hydrogen; forms a single Schiff base VI. This i5 8 because regardless of which terminal primary amino group 9 of amine V reacts with ketone IV, the same product re~ults.
However, where amine V is unsymmetrical two pxoducts can 11 result. One is Schiff ba~e VI. The other products have 12 the formula VI(a) when R5 and R6 are hydrogen;
A~(Rl)n l3 A (R ~ C N R4 N R2 N~2 (VI(a)) 13 or VI~b) when R5 is a~inoethyl or aminopropyl:
A-(Rl)n ~ C=N(CH 3~2`-3)R4-N-R2-NH~ ~VI~b)) A-(Rl)n 3 14 where A, Rl_6 and n are as pre~iou~ly defined. Note that both product~ VI(a) and VI(b) come within the scope of 16 the definition given for Schiff ~ase VI. Where Schiff 17 bases of formulas VI and VI(a) or VI(b) are produced 18 they can be separated, if desired, by the usual and well 19 known separation techniques, i.e., di~tillation and the like.
21 A~ an alternative to obtaining a mixture of Schiff 22 bases VI and YI(a) or VI(b), the reaction can be conducted 23 stepwi~e. For example, 1,2-diaminoethane may be converted 24 to a Schiff base with 1,5-di-~4-isopropylcyclohexyl)-. ~

r~ 157' :~08~7 1 3-pentanone, catalytic~lly reduced, t~en the ring nitrogen 2 selectively cyanoethylated w~th acry]onitrile, followed by 3 catalytic hydrogenation to furnish [1,5-di~ isopropyl-4 cyclohexyl)-3-pentyl]-1,4,8-triazaoct:ane.
To prepare Schiff base VI, ketone IV and amine V
6 are dissolved in a suitable inert solvent, for example, 7 toluene, and heated to reflux, until reaction is substan-8 tially comple~e. Usually 5 to 20 hours is sufficient for 9 water removal by azeotropic distillation. The solvent is then removed under reduced preqsure and the residue com-11 prising the Schiff ba~e VI is dissolved in an inert solvent 12 preferably an alkanol, such as ethanol or isopxopanol.
13 After dissolution, the Schiff base VI is 14 catalytically or chemically reduced.
If reduction is cat~lytic, any unsaturated carbon 16 to carbon bond in A will also be reduced or hydrogenated, 17 as well a3 the carbon to nitrogen bond of the Schiff base 18 VI. In ~uch catalyt~c reductions, hydrogen saturates an 19 alkanol solution of Schiff base VI using agitation in the 20 presence of the usual hydrogenation catalysts, such as ;~
21 transition metals and their reducible oxides. Especially 22 effective catalysts are the no~le metals and their oxides.
23 A particularly preferred catalyst is platinum oxide.
24 Generally, the hydrogenation reaction is carried out in a manner well known in the art. Small particles, e.g., 100-300 26 mesh of catalyst are admixed with the Schiff base and excess 27 amine in alcohol and placed in a closed sys~em pressurized 28 with from 3-5 atmo~pheres of hydrogen gas preferably at 29 ambient temperature, and generally at such pressures and a temperature of from 15C. to 45C. At higher temperatures -- 7 _ ~`` r~ 157 1(~83607 1 the pre3sure preerab1y need not exc:eed lS atmospheres.
2 After reaction is complete, the pressure is released and 3 the catalyst separated from the reaction mixture by filtra-4 tion. The filtrate containing the cyclohexyl polyamine I,

5 is then further purified by usual techniques. Preferably,

6 whatever solvent may be present is removed under reduced

7 pressure, the residue then dissolved in a water-immiscible

8 solvent, washed with water, followed by a further washing

9 with a saturated aqueous inorganic salt solutionO After

10 drying, the solvent is removed by evaporation under reduced

11 pressure giving the cyclohexylpolyamine I usually as an

12 oil. The cyclohexylpolyamine can then be redissolved in

13 loweralkanol~, mixtures of loweralkanols and water, diethyl~

14 ether, dioxane and then neutralized with an acid, e.g.,

15 hydrogen chloride, or neutralized directly with aqueous 3

16 acids.

17 Acid addition salts are then isolated, if de3ired,

18 by precip~tation, evaporation or other usually employed

19 technique~.

20 Suitable anion~ X for the salt I(a) include anions

21 derived fr~m ~norganic acids as well as those of or~anic

22 acids such for example as halide, i.e., chloride, bromide

23 or iodide or sulfate, nitrate, bisulfate, phosphate,

24 acetate, propionate, maleate, succinate, laurate, palmitate,

25 oleate, stearate, ascorbate, gluconate, citrate, carbonate,

26 bicarbonate, benzoate, salicylate, pamoate, phthalate,

27 furoate, picolinate, dodecylbenzenesulfonate, laurylether- ¦~

28 sulfon te, nicotinate and the like. Generally, any anion

29 derived from an acid is suitable and satisfactory when the polyamine salt anion X , e.gD, chloride is replaced with 31 other anions, by well known anion exchange techniques.

~ 157 1~836~'7 1 When preparing cyclohexenylpolyamines, that is 2 the product I where olefinic un~aturation in ring A i~
3 retained, a selective chemical rather than a catalytic 4 reduction is employed to reduce Schiff base VI to product I.
6 In this chemically reductiv~ procedure, the 7 ketone 1~ is reacted with the appropriate amine a~ before, 8 but the Schiff base VI dissolved in an inert alkanol or g ether-type solvent is reacted with a chemical reductant such as sodium borohydride or lithium aluminum hydride, 11 respectively.
12 Although as little as an equivalent of the chemical 13 reductant can be used succe~5fully, more satisfactory results 14 are obtained if at }east two lar exce~ of and preferably at least a 2.5 molar excess of the chemical reductant is 16 employed. After any initial reaction has subsided, the 17 reaction mixture of Schiff base VI and reductant may be 18 heated to reflux for an hour or ~wo, then cooled to room 19 temperature, and afterwarcls concentrated under vacuum.
The residue obtained is then further purified as by 21 treatment with mineral acid or inorganic base as was 22 described for polyamines I and the salt may thereafter 23 be formed as previously described.
24 The cyclohexyl and cyclohexenyl ketones rv are readily prepared and two alternative methods, are set 26 forth below.
27 (A) The Condensation of Acids - This n~thod 28 involves the following reaction scheme:

If ~ ;~ 1575~

6~7 Fe b 2 A-~Rl~ -COOH
(VII) A-(Rl)~
C-O ~ ~2 + ~2 ( 1 n 1 Acylative decarboxylation of acids ~II is employed - 2 ~y heating the acid at elevated temperatures ~ither with 3 transition metals, preferably iron, transition metal oxides, 4 alkaline earth oxides, with polyphosphoric acid or with boron trifluoride. Most suitably, acylative reaction i~ achieved 6 by passage of acid vapors over catalysts such a~3 heated 7 thoria aerogel.
8 Conden3ation-decarboxylation of an acid is the 9 preferred method for preparing ~etone IV when each A-(Rl)n group i~ alike, a mixture of products being obtained when 11 several different acids are combined in a reaction. The 12 preferred reaction comprises admixing carboxylic acid VII
13 with reduced iron powder and stirring in an inert atmos-~, 14 phere at 195C. to 200C. for 1-6 hours to form an iron salt.
16 Preferably, the carboxylic acid VII and iron are 17 agitated under an inert atmosphere of nitrogen for at 18 least 2 hours at 195C. to 200C.
19 After 2 hour~, the temperature is increased suitably to 290C. to 310C. and agitation continued for 21 at least another three hour period, four hours usually ~eing 22 sufficient. The reaction mixture i5 allowed to cool, and 23 then is extracted with a suitable inert solvent such as di-24 ethylether and filtered. The solvent extracts are concen-trated ~nder reduced pressure. The residual liquid is 26 distilled undex vacuum to isolate the ketone IV

~ 1575' ~(~8~6V7 1 The carboxylic acids VIX ernployed above are 2 prepared by various means well known in the art. One 3 particularly u-~eful technigue is the addition of a cyclo-4 hexene to an aliphatic acid anhydride!.
In thiq procedure, a mixture of thè cyclohexene 6 and a catalytic quantity, e.g., 0.2-0.3 mole for each 7 mole of cyclohexene of a free radical-forming catalyst, 8 such as di-tert-butyl peroxide, is added dropwise over 9 3-5 hours to a 5-15 molar excess of refluxing aliphatic acid anhydride. After complete addition, the reaction is 11 heated at reflux for 5-10 hours, concentrated under reduced 12 pressure and the liquid residue is mixed with aqueous 13 sodium hydroxide and stirred with heating on a steam bath 14 for about 2-5 hours. The cooled alkaline solution is then extracted with ether~ the ether layer is discarded and the 16 a~ueous solution acidified, and then extracted well with 17 ether. The combined ether extracts are washed with water, 18 dried over anhydrou~ 80dium sulfate, and concentrated 19 under reduced pressure. The residual liquid or solid is distilled under vacuum to give the corresponding carboxylic ~ ;
21 acid, VII.
22 Other carboxylic acids are readily obtained, for 23 example, by the Diels-Alder reaction of a diene and alkyl 24 substituted diene with various unsaturated aliphatic co~pounds or carboxylic acids, as are later referred to 26 in greater detail.

.

~ 15 .
~ 836f~7 1 (B) Condensation of a Gricrnard and a Nitrile 2 Dicyclohexyl, dicyclohexenyl, or cyclohexyl-cyclo-3 hexenyl alkanones can be obtained according t;o the following 4 reaction scheme:
( l)n X M~ _ ~ A-(Rl)nMgX
A-(Rl)n-C-N + A-(Rl)nMgx 3 A~(Rl)nCI~(Rl) A
H 3O 3 n ~ 1 n NMgX
where A or (Rl)n of each reactant may be the same or different 6 and are as previously defined.
7 This general procedure utilizes the reaction -~ 8 of a Grignard reagent prepared from a chloro- or bromo-9 substituted cyclohexane or cyclohexene derivative with a cyanosubstituted cyclohexane or cyclohexene derivative. The 11 resultant disuhstituted iminoalkane salt complex is hydroly-12 zed with a~ueous mineral acid to the corresponding ketone.
13 The Grignard reagent i~ obtained by reaction of 14 the halide with magnesium metal, usually in the form of turnings or powder and may be-catalyzed by very small con-16 centrations of iodine or methyl iodide. Solvents which are ~ 17 useful include diethyl ether, dibutyl ether, tetrahydrofuran, 18 dioxane and benzene. Usually, gentle warming suffices to 19 initiate the reaction and the halide is gradually added to the metal-solvent mixture. After complete addition the dis-21 appearance of practically all magnesium metal signifies the 22 end of the reaction. A small excess of halide is used and 23 moisture must be excluded; a nitrogen atmosphere is benefi-24 cial. The Grignard reagent is then added to the nitrile which is previously dissolved in two or thxee times its volume 26 of solvent over a period of 15 minutes to 1 hour at ambient ~_~ 1575 361D~

1 The react~on mixture m~y then b~ heated to reflux to insure 2 complete reaction. Generally, a small excess of Grignard 3 reagent as compared to nitrile is emp:Loyed. From 1 to 10 4 hours at reflux is sufficient for complete cbnversion.
The resultant imine salt is preferably decomposed to the 6 ketone with aqueous mineral acids such as hydrochloric, 7 sulfuric and phosphoric. The ketones are water-insoluble 8 and may be extracted with water-immiscible solvents.
9 Purification is preferably accomplished by fractional distillation under reduced pressure. It is feasible to 11 use the crude ketone reaction mixture for the alkylation 12 of polyamines as the reaction by-products are usually 13 alcohols or hydrocarbons and do not react with amines.
14 The reactant halides, if present in the crude product, should be removed prior to the keto~e-amine alkylatio~
16 process.
17 The concentrations of Grignard reagent and nitrile 18 may be varied over wide limits for securing good yields in 19 the ~rocess.
The halide and cyano, a~ well as carboxylic 21 derivatives of cyclohexanes and cyclohexenes are commonly 22 available;where the re~uisite carboxylic, cyano or halo 23 derivatives as used herein are not readily available they 24 can be obtained through employing knvwn techniques, for example, by means of the Diels-~lder 3ynthesis-~ ~ 15, 8~607 R R R R
CR 1,R R ~ R
~ R
CR I C ~
¦ ¦~D R ~ ~D
CR R /\R
R R
C~
R

1 where D is R, -(Rl)n-COOH, -(Rl)n-Br, or -(R~ CN and 2 where Rl, R, and X have their previou~ meanings. 'Where D
~, 3 is R and each R is alkyl, the resulting cyclohexene 4 can be reacted with an aliphatic acid anhydride as previously described. Where D is (Rl)n-COOH, (Rl)n-CN or (Rl)n-BR, 6 the condensation can proceed as outlined in preparative 7 example~ A and B above. Of course, A(Rl)n-COO}I can be 8 treated by standard technique~ with a phosphorous chloride, 9 e.g., phosph~rous pentachloride, to form A(Rl)n-COCl.
Where R is independently either hydrogen or C
r 11 to C alkyl, the Darzens synthesis Compt. ~end., 150, 707 12 (1910~ can be used:

R R R R
R_ ~ ~ ~ ( l)nA
R ~ + A(~l)ncOcl ~ ~

R R R R

13 where Rl, n, R and A ~re a~ previously defined. Lik~wise, 14 the Blaise-Marie synthetic route can be employedrBull.
Chim. ~4] 7, 215 (1910~ and Compt. Rend. 145, 73 (1907~:
16 A-RlZnCl ~ AIRl)nCCl ~ ARlCO(Rl)n , 17 where A, n and Rl have their previously defined meanings.

1~361~'7 Once the ketone IV is obtained it can then be reacted with a suitable polyamine V. Polyamines V which are exceptionally suitable for reaction with ketone IV include diethylenetriamine, triethylenetetramine, 3,3'-iminobis-(propylamine), 3,3'-methyliminobis-(propylamine), dipropylene-triamine, N,N'-bis-(3-aminopropyl)-1,3-trimethylenediamine, N,N'-bis-(2-aminoethyl)-1,3-trimethylenediamine, N,N'-bis-(3-aminopropyl)piperazine, N-(3-amino-2-hydroxypropyl)-1,3-trimethylenediamine, N-(2-aminoethyl)-1,3-trimethylenediamine, spermidine, spermine, 1,4-bis-(2-aminoethyl)piperazine, tris-(2-aminoethyl)amine, 1-(2-aminoethyl)-4-(3-aminopropyl)-piperazine, l-(3-amino-2-hydroxypropyl)-4-(2-aminoethyl)-piperazine, N-(3-amino-2-hydroxypropyl)-1,3-trimethylene-diamine, N,N'-bis-(3-aminopropyl)-1,4-cyclohexylene-bis-(methylamine), 1-(2,3-dihydroxypropyl)-1,5,9-triazanonane, 1-(2-hydroxyethyl)-1,4,7,10-tetraazadecane, 4-(3,4-dihydroxy-butyl)-1,4,8-triazaoctane, 1-(2-hydroxypropyl)-5-hydroxy-methyl-1,5,9-triazanonane, 1,4-di-~3-aminopropyl)piperidine, : tris-(3-aminopropyl)amine, ethylenediamine, trimethylene- :
2a diamine, and 1,3-diamino-2-hydroxypropane.
. The compounds described herein are excellent broad spectrum antimicrobial agents which are especially effective ~; against gram positive and negative bacteria, particularly the troublesome gram-negative of the genus _seudomonas at aqueous concentrations of 1.0 to 100 ppm. Examples of susceptible species include, inter alia, Staphylococcus aureus, Streptococcus pyogenes, Bordetella bronchiseptica, Pasteurella multocida, Escherichia coli, Salmonella ` typhimurium, S. pullorum, Klebsiella pneumoniae, Aerobacter : 30 aerogenes, Pseudomonas aeruginosa, Desulfovibrio desulfur-"~ 1571 8;~607 1 icans, Bacillus mycoides, fungi ~uch as Aspergillus ni~er 2 and Chaetomium globosum. For use, these compounds can be 3 applied neat or employed in a diluted form. ~atisfactory 4 diluents include any inert material not destr~ctive of the antimicrobial activity and especia}ly liquid formulations 6 comprising aqueous disper~ions, solutions, and emulsions.
7 Solid diluents include talc, corn starch, alumina and 8 diatomaceous earth. The antimicrobial agents of this inven-9 tion can also bs deposed on materials such as natural fibers including paper, cotton, wool and synthetic fibers such as 11 nylon, polypropylene, as well as upon inanimate surfaces 12 including hard surfaces such as wood, glass, metal, tile, 13 rubber, plastic, and porous surfaces such as concrete, 14 leather and the like.
The polyamines of this invention are especially 16 useful in suppressing the growth of aerobic and anaerobic 17 bacteria in fluids employed in cutting and grinding 18 operations, such as metal working, and oil well drilling 19 muds or secondary oil recovery waters and brine~. Anaerobes such as the sulfate-reducer, Desulfovibrio e~ulfuricans, 21 are inhibited at 0.1-10 ppm. concentration of these 22 polyamines. Suppression of these bacteria eliminates 23 hydrogen sulfide production and corrosion of equipment, 24 pluggin~ of oil-bearing sands, malodors and other deleterious actions. These compounds are also useful in ~he preservation 26 against biodeterioration of other a~ueous systems such as 27 aqueous emulsions and dispexsions, paints or coatings, pig-28 ment suspensions, adhesives and the like where proliferation 29 of microorganisms can produce colloid breakdown, pH shifts, malodors, corrosive substances, viscosity loss and other 31 undesirable effects.

15759y 1~336~7 One particularly useful application of the compounds of this invention is imparting sanitizing properties to fabrics, either woven or non-woven, launderable or disposable which are to be employed, such for example, as diapers, surgical masks, caps, gowns, towels and drapes, covers for hospital furniture and instrument wrappings, aseptic facial tissues and sanitary napkins and bathroom tissue. In this application, the compounds of Formula I can be applied to the fibrous pulp before extracting or strand or thread formation or it can be sprayed upon the finished goods. Either depo-sition technique is satisfactory so long as from 1 x 10 4% or more by weight of the antimicrobial material is retained on the cloth. Greater than 0.1% to 1% by weight is generally excessive and superfluous.
, Another application is alone or in solution or ; suspension or in conjunction with soaps or detergents for use in cleansing the skin, particularly in presurgical scrubbing formulations, or in formulations for controlling the growth of Corynebacterium acnes. C. acnes is a strain of bacteria implicated in acne conditions, especially Acne vulgaris, `~ wherein applications of as little as 1 to 5 ppm. is effective in controlling such skin dwelling bacteria. Larger concen-trations can be used if desired without irritation or dis-comfort such as 2500 ppm and higher. Where the cleansing formulation is diluted with water upon use, the Eormulation can comprise from 0.01% by weight and more of the polyamine of this invention.
In addition, the compounds described herein can be employed in impounded water, such as swimming pools, ponds or industrially-used water such as cooling or paper-mill water to inhibit growth of undesirable bacteria, fungi, and/or algae.

"~ 15 7 L

~IL8836~7 1 In the control of slime-producing microorganisms 2 and ~lga~ in reclrculating industrial waters, particularly 3 cooling operations and especially installations such as 4 cooling towers, the polyamine compounds of this invention are usually employed alone, but can also be used in combina-6 tion with other antimicrobial agents. The compounds are 7 preferably employed as salts to enhance solubility. Con-8 centrations in the recirculating water of as little as 9 1 x 10 % by weight are effective in inhibiting microbial growth. To insure effectiveness, especially against more 11 resistant strains of microorganisms, and also when make-up 12 water is added to replace water lost by evaporation and 13 the like, concentrations of from 1 x 10 4% to 5 x 10 2%
14 by weight are most satisfactory. Dosage may be continuous or as intermittent ''shock treatment'', i.e., addition in a 10-20 minute period every 4-8 hours.
17 An unusual, highly advantageous property of these 18 compounds is high substantivity to all kinds of surfaces;
19 this provides protection against corrosion and acts as a storage depot for continuously dosing the waters in contact.
21 The same proper~ies also are largely responsible for the pre-22 viously stated utility as disinfectants for inanimate 23 surfaces comprising walls and ceilings, equipment, animal 24 pens, hospital facilities, kitchens and bathrooms and the like.
26 In formulating the compounds of this invention for 27 the abo~e uses, these compound~ can be employed in combina-~8 tion with other antimicrobial agents, surfactants, insec-2g ticides, defoamers, odorants, or as chelates of metals such as copper, calcium, magnesium and iron.
31 A~ricultural Applications 32 Wettable powder formulations for use as a dis-33 persion in water represent a practical means for good .~ 157 ~L~83~6)7 1 di~tribution ~n so~l- Other methods of achieving the same 2 result~ include the preparation of dusts. All of the 3 polyamines can be blended as fine powders with the 4 commonly used powder diluent~ such as talc, clay, refined silicates, wood flour, sandl magnesiwm oxide, calcium 6 carbonate, fuller's earth, kaolin, diatomace~us earth, 7 mica, pumice and the like. The powder can h~ve the 8 following formulation:
g Percent 10 Polyamine 1 75 11 Inert diluent (clay, talc, etc.) 25-99 12 The mixtures may be finely powdered, e.g., to the 13 1-10 micron average particle size, or be made by blending 14 the already finely powdered ingredients.
For application as agricultural disinfectants the 16 dust~ may be applied to the seed and surrounding soil at the 17 time of planting. The concentration of the sterilant is 18 adju~ted to give an effective, nonphytotoxic dosage in the 19 ~oil. In general, the ~oil concentration of polyamine 3hould be from 10 to 25 part~ per million (of active ingre-21 dient). For most economical and effective use the dusts can 22 be applied in bands of 6 to 8 inches centered on the rows 23 just prior to seeding. The material can then be rototilled 24 to a depth of several inches. This mode of treatment saves material and protects the root system of young plants 26 against microbial attack. For the protection of a given 27 crop, such as cabbage, the band spread of antimicrobial can 28 vary from 8 inche~ for black root disease to 12-15 inches 29 for club root disease prevention. Similarly, the depth to which the fungicide should be distributed can vary from 2 31 to 6 inche~.

32 The wettable powders can be prepared by the addition 33 of 0.1-5% of a wetting agent to the powder blend~s,. Many 34 di~per~ing agents are commercially available which are non-~ 15, 1~336~7 1 phytotoxic at the required concentrations. These may, for 2 example, be alkali metal and amine salts of ~ulfated and 3 sulfonated acids, alcohols, and oils, or polyethoxylated 4 alkyl phenols, long chain fatty amine quaternary salts, partial fatty acid esters of polyhydr:ic alcohols, etc. Some 6 dispersants can be used in preparing emulsifiable concen- I
7 trates of the polyamines in organic solvents. Many of 8 these agents are available in solvent-soluble form. The 9 manner of application to the soil is similar to the dusts.
Spray equipment is used to spread the suspensions or 11 emulsions over the soil and by discing, the fungicidal 12 agents can be uniformly distributed to varying depths.
13 Spray application i~ also effective for band-limiting the 14 dosages.
Other agricultural uses for these formulations 16 involve the eradication of bacterial blights of plants by 17 application to the involved surface area~. The compounds 18 of this invention show high orders of bacterial inhibition 19 and are especially useful for this purpose. Some of the diseases which are of commercial importance in decreasing 21 yield and quality and are controlled by the compositions 22 of the invention are fire blight of apple and pear, 23 bacterial spot on stone fruit, cherry leaf spot, walnut 24 blight, common blight of bean, bacterial spot of tomato and pepper, and potato seed piece decay. The effective 26 concentration of polyamines required varies from 5-200 27 parts per million; they may be applied as dusts, powder 2a dispersions in water as emulsions in water, or as aqueous ~ 157' 1~836~7 1 dipping baths. Other plant disease~ which can be controlled 2 by treatment with these formulations are fungal in origin, 3 such as the many kinds of powdery mildew and leaf scabs.
4 For seed treatment, proportions as low as 1 to 4 ounces per hundred weight (550 to 600 ppm on seed) are 6 effective against various fungi.
7 The compounds of the invention can ~e used in form ~;~ 8 of aqueous suspen~ion~ or emulsions, the base products being 9 generally insoluble in water. For this type ~f formulation various powdered carriers can be employed to aid in achieving 11 uniform distribution. Talc, fullerls earth, calcium silicate, 12 calcium carbonate, clays and the like are admixed with the 13 agent along with wetting and dispersing agents and sticking 14 agents. For maximum chemical compatability those which are non-ionic in character are preferred. Other nonionic or ; , 16 cationic surfactants are also satisfactory.

17 Additional applications for the compounds of this 18 invention include inhibiting formation of dental plaque ~;

19 especially when used as an oral rinse, e.g., a mouth wash, or in combination with a toothpaste or tooth powder con-21 taining from 50-1,000 ppm.

22 The following specific examples are further 23 illustrative of our invention, but should not be construed 24 as any limitation on the compound presented in formula I

or the appended claims.

~836~)7 PREPARATION A

Free Radical Addition of Acetic Anhydride to ~-Pinene . . . _ To 1,000 g. (10 moles) of refluxing acetic anhydride ;
is added dropwise a mixture of 136 g. ~-pinene (1.0 mole) and

30 g. t-butyl peroxide (0.2 mole) over a period of 2.5 hours.
The reaction mixture is then heated at reflux for an addition-al 5 hours. The acetic anhydride is then removed under vacuum and the residue hydrolyzed by treatment with 40 g. NaOH in 250 ml. water and 150 ml. ethanol. The mixture is heated at reflux for 2 hours, then acidified with hydrochloric acid, extracted with ether and dried over sodium sulfa-te. The dried extracts are evaporated to leave a residue which is distilled under vacuum giving 43.1 g. (22~) of 3-(4-isopropylcyclo-hexenyl)propionic acid having a b.p. 135-137C. (0.3 mm.).
PREPARATION B
3-(4-Isopropylcyclohexyl)propionic Acid The unsaturated acid from the previous preparation is dissolved in ethanol and hydrogenated with PtO2 at room temperature and 40 psi hydrogen pressure. The platinum catalyst is filtered off and the ethanol removed under reduced pressure. The saturated product 3-(4-isopropylcyclohexyl)-propionic acid is obtained as a colorless liquid 42.3 g.
(97%).

~ 1575~

~83607 P~EPARATION_C
2 Preparation of 1,5-Di-~4-Isopropylcyc ~
3 3-(4-Isopropylcyclohexyl)propionic acid (39.7 g., 4 0.20 mole) and iron thydrogen reduced, 6.15 g., ~.11 mole) is heated or 1.5 hours at 195C. under a nitrogen 6 atmosphere. After that time, the temperature is increased 7 to 290C. and maintained at that temperature for thxee 8 hours. The cooled reaction mass is extracted well with 9 ether, filtered through Celite, and the ethereal extracts concentrated under vacuum. The residue is stripped under 11 vacuum to leave the product, 17.3 g. (51%).
12 Similarly in an analogous manner there are 13 obtained the following ketones.
14 1,9-Dicyclohexyl-5-nonanone;
1,5-Dicyclohexyl-3-pentanone;
16 1,3-Dicyclohexylacetone;
17 1,7-Dicyclohexyl-4-heptanone;
18 1,3-Di-(3-methylcyclohexyl)acetone;
19 1,7-Di-(4-ethylcyclohexyl)-4-heptanone;
~, 1,5-Di-(2-isopropylcyclohexyl)-3-pentanone;

21 1,9-Di-(2-ethylcyclohexyl)-5-nonanone;

22 1,5-Di-(4-t-butylcyclohexyl)-3-pentanone;

23 1,5-Di-(2,4,6-trimethylcyclohexyl)-3-pentanone;

24 1,;-Di-(3,5-diethylcyclohexyl)-3-pentanone;

1,7-Di-(2,6-dimethyl-4-t-butylcyclohexyl)-4-26 heptanone;

27 1,7-Di-(2,3,4,5,6-pentamethylcyclohexyl)-4-28 heptanone;

29 when un~a~urated acids are subjected to the above procedure the following representative ketones are obtained:

31 1,7-Dicyclohex-3 enyl-4-heptanone;

32 2,8-Di-(4-methylcyclohex-3-enyl)-5 nonanc)ne and

33 1,5-Di-[4-isopropylcyclohex-1-enyl]-3-p~sntanone.

~ 15~

~3607 2 Preparation of 4 Cyclohexyl-1-(4-lsopropylcyclohexyl)-3 butanone-2 4 A Grignard reagent was prepared fro~ 2-cyclohexyl-; S ethyl bromide 21 gm. (0.11 mole) and magnesiuff~, 2.4 g.
6 (0.1 gram atom~. The magnesium is covered with 25 ml. of 7 anhydrous ether~ a crystal of iodine added and in a nitrogen 8 atmosphere, the halide dissolved in 50 ml. of anhydrous 9 ether is added, once initial raaction i~ obtalned, at reflux temperature over a period of 1-2 hours. After complete 11 addition, refluxing is continued for 1/2 hour.
12 In a nitrogen atmosphere, the Grignarcl solution 13 i8 clarified by passage through a glass wool filter plug 14 and added slowly to an agitated solution of 4-isopropyl-cyclohexylacetonitrile, 14.9 gm. ~0.09 mole~ in 200 ml. of 16 anhydrous diethyl ether. A gentle reflux is maintained 17 during the additio~ which re~uires 1/2 to 1 hour. After 18 complete addition and an additional 15 minutes at reflux, 19 the reaction mixture is cooled and poured onto a mixture of 50 ml. of concentrated hydrochloric acid and 200 gms. of 21 ice using good mixing. Upon warming the ether is removed 22 by distillation and the residue heated at 70-100C. for 23 1 hour. The product is extracted with two portions, 250 24 ml. each of e~her, the ether solution dried over anhydrous magnesium sulfate and the solvent removed. Any of the 26 reactants, i.e., halide and nitrile, are separated from 27 the ketone by fractional distillation under reduced 28 pressure along with by-products.

- 24 ~

, ~ 157 1~36~7 1 In a similar procedure, the follow~ng ketones are 2 prepared:
3 1-(2-Methylcyclohexyl)-4-cyclohexylpentan-2-one;
4 1-(4-t-Butylcyclohexyl)-5-(4-isopropylcyclohexyl)-pentan-3-one;
6 2-(3-Methylcyclohexenyl)-8-(2-isopropylcyclohexyl)- ;
7 octan-4-one;
8 1-(2,6-Dimethyl-4-t-butylcyclohexyl)-5-(3,5-di-9 ethylcyclohexyl)pentan-3-one.
PREPA~ATION E
11 ~repaxation of N-(3-Aminopropyl)~1,4-cyclohexanebis-12 (methylamine) 13 Acrylonitrile (26.5 g., 0.5 mole) is added dropwise 14 over a 45 minute period to 1,4-cyclohexanebis(methylamine) (2.84 g., 2.0 mole) with stirring and ice bath cooling.
16 After complete addition, the reaction mixture is stirred an 17 additional 1 hour at 5C., gradually warmed to 45C. and 18 kep 2 hours at that temperature followed by 1 hour at 90C.
19 The reaction mixture is stripped of any unreacted acrylo-20 nitrile and excess non-cyanoethylated bis(methylamine) ~ ;
21 starting material which was remo~ed at an internal tempera-22 ture of 110C. and 1 mm. The residue is then dissolved in 23 1.5 1. of ethyl alcohol (ammonia gas saturated) mixed with 24 50 ml. of sponge nickel catalyst and hydrogenated at 150 psi. After removal of catalyst by filtration, the solvent 26 and ammonia is stripped off and the triamine product 27 purified by fractionation under reduced pressure.
28 A higher homolog, N-(3-aminopropyl~-1,4-cyclo-29 hexanebis-(2-ethylamine) is synthe~ized using the above 30 procedure with 1,4-bis ~2-aminoethyl)cyclohexane prepared ~`
31 according to P.P~ Garcia and J.H. Wood, J. Org. Chem., 26, 32 4167 (1961). Excess staring amine in this example may be 33 separated from product at a boiling point of 122C.-126C./

34 1 mm.

1~8;~6~7 1 PREpARAT-IoN F
2 Preparation of N-(3-Aminopropyl)-N'-(2-hydrQx~ethyl1-1,4-3 cyclohexanebis(methylamine) 4 Acrylonitrile (10-6 ~-, 0.2 mole) is added dropwise over a 15 minute pexiod to N-(2-hydroxyethyl)-1,4-cyclo-6 hexanebis(methylamine) (37.2 g~, 0.4 mole) with stirring and 7 ice bath cooling. After complete add:ition, the reaction 8 mixture is stirred an additional 2 hours at 5C., allowed 9 to gradually warm over a 1 hour period, heated 2 hours at 45C. and finally 1 hour at 90C. It is then fractionated 11 under reduced pressure up to an internal temperature of 12 170C. The residue is dissolved in 200 ml. ethyl alcohol~
13 cooled in an ice bath and saturated with ammonia gas at 0C.
14 Approximately 5 ml. of sponge nickel catalyst tW.R. Grace Co., Davison Chem~ Division) is added and the mixture shaken 16 under hydrogen at lS0 psi until no further hydrogen uptake.
17 The catalyst is removed by suction, filtration under nitrogen, 18 the solvent stripped away and the residue fractionally dis-19 tilled under reduced pressure. The triamine product is readily distinguished from cyanoethylated diamine by its 21 lower ~f on silica gel using a solution of 1 volume concen-22 trated aqueous ammonium hydroxide in 4 volume methyl alcohol.
23 The synthesis is an adaptation of the method of M. Israel 24 et al, J ed. Chem., 7, 710 (1964) for the preparation of polymethylenepolyamines.

27 Preparation ~f N-(2-Hydroxyethyl~-1,4-cyclohexanebis(methyl-28 amine) 29 A solution of 14.2 gm. tO.l mole) of 1,4 cyclo-hexanebis(methylamine) in 150 ml. anhydrous methyl alcohol _ 26 _ ~`

~8;36(~7 .~;
; and under an atmosphere of nitrogen is warmed to 45C.-50C.
In a 20 minute period, there is introduced with good agitatlon and beneath the liquid surface a total of 1.1 gm. (0.025 mole) of ethylene oxide in gaseous form. The reaction temperature is maintained at 45C.-50C. for an additional one-half hour ; after stopping the addition of ethylene oxide. The methyl alcohol is removed by distillation at atmospheric pressure;
excess 1,4-cyclohexanebis(methylamine) is readily separated from the product by fractionation under reduced pressure.
Only monoethoxylated compound remained and could be used as such or further purified by distillation at reduced pressure.
PREPARATION H

Preparation of N-(3-Amino-2-hydroxypropyl)-1,4-cyclohexanebis-(methylamine) - - - ------1,4-Cyclohexanebis(methylamine) (14.2 g., 0.1 mole) is dissolved in 50 ml. of anhydrous methyl alcohol and the solution cooled to +5C. in an ice bath. Epichlorohydrin (9.3 g., 0.1 mole) is added in a 2-minute period and the temperature maintained at +5C. for 2 hours; reaction is allowed to continue at 10C.-15C. until thin layer chromatog-raphy of an aliquot (silica gel plate with development using a solution of 1 volume concentrated aqueous ammonium hydroxide in 4 volumes of methyl alcohol) indicated nearly complete conversion of the starting diamine to the propylene chloro-hydrin. The solution is then added to 100 ml. of dry methyl alcohol previously saturated at 0C. with dry ammonia gas by continuous dropwise flow at +5C. with good agitation and external cooling. After stirring 2 hours at +5C., it is allowed to warm to 20C. and mixed overnight. The reaction is competed by heating at 45C.-55C. for 6 hours. The solv~nt and ammonia was removed by stripping and the produc-t purified using fractional distillation under reduced pressure.

~836~

N-(2,3-Dihydroxypropyl)-1,4-cyclohexanebis(methyl-amine) is produced by alkaline hydrolysis of the above propylenechlorohydrin derivative.
The propylene chlorohydrin derivative is dissolved in a lM sodium hydroxide solution containing 50% methyl alcohol and 50% water by weight in a ratio of 5 grams of chlorohydrin to 25 ml. of sodium hydroxide solution. After stirring 24 hours at 20C. the methyl alcohol is removed by distillation and the oil which separates is extracted with 100 ml. of diethyl ether. The extract is washed with approxi-mately 10 ml. of cold water, the ether layer dried over anhydrous sodium sulphate and then filtered. Removal of the ether by distillation leaves the product in good purity as an oil.
PREPARATION I

Preparation of N,N'-bis-(3-Aminopropyl)-1,4-bis-(2-amino-ethyl)cyclohexane Acrylonitrile (10.6 g., 0.2 mole) is added dropwise over a 15 minute period to 1,4-bis-(2-aminoethyl)cyclohexane 20 (17.0 g., 0.1 mole) cooled in an ice bath and with good stirring. The resultant solution is maintained at 5C.-10C.
with agitation for 1 hour, allowed to warm to 25C. over a 2 hour period and finally heated at 90C.-95C. for 4 hours.
The reaction mixture is then freed of any unreacted material and monocyanoethylated product by gradually heating to an internal temperature of 130 C. at a pressure of 0.5-1 mm. The residue is dissolved in 200 ml. ethyl alcohol which had been previously saturated with dry ammonia gas at 0C., mixed with approximately 5 ml. of a sponge nickel catalyst suspension and reduced with shaking under 200 psi hydrogen. The catalyst is removed by suction filtration, the filtrate stripped of ~836~7 solvent and the residue purified by fractional distillation under reduced pressure.
PREPARATION J

Preparation of N-(2-Aminoethyl)-1,4-bis--(2-aminoethyl)cyclo-hexane 1,4-Bis-(2-aminoethyl)cyclohexane (68 gm., 0.4 mole) and ethyleneimine (4.3 gm., 0.1 mole) with 0.4 g. ammonium chloride are mixed in a glasslined pressure reactor and filled with nitrogen to 100 psi. The mixture is shaken and heated at 85C.-95C. for 48 hours. After cooling, it is distilled ~ r rapidly free of the salt and then fractionated under high vacuum. The starting diamine is readily distinguished from the triamine product by thin layer chromatography on silica gel using a mixture of 1 volume concentrated aqueous ammonium hydroxide with 4 volume methyl alcohol, the diamine having a much higher Rf.
PREPARATION K
N,N-Bis-(3-hydroxypropyl)-1,4-cyclohexanebis(methylamine) Preparation of l-Cyano-4- ~i-(3-hydroxypropyl)aminomethy ~-cyclohexane and catalytic reduction a. l-Bromomethyl-4-cyanocyclohexane (20.2 g., 0.1 mole) and di-(3-hydroxypropyl)amine (53.2 g., 0.4 mole) in 400 ml. of anhydrous isopropyl alcohol are heated in an autoclave at 105C.-115C. for 8 hours with continuous agitation. The reaction mixture is stripped of solvent under reduced prQssure and the residue diluted with 500 ml.
of ice water. A cold solution of 5 g. of sodium hydroxide in 100 ml. of water is added and the mixture extracted with two 150 ml. portions of methylene chloride. The ~ 15759 1~83607 1 organic phase is then washed with 50 ml. of iae water, 2 dried overnight with anhydrous sodium 9;ulfate, filtered 3 and freed of solvent by distillation under reduced pressure.
4 b. The residual oil from a.) is ta~en up in 5 200 ml. of anhydrous ethyl alcohol previously saturated 6 at 0C. with dry ammonia gas, mixed with 5 ml. of sponge 7 nickel catalyst suspension and hydrogenated at 25C. under 8 100 psi hydrogen pressure in a stirred autoclave. The 9 reaction completion is readily determined by disappearance of the C~N IR absorption band and measurement of hydrogen 11 uptake. The catalyst is removed by suction filtration, 12 the solvent with mild heating under reduced pressure and 13 the product obtained pure with fractional distillation at 14 reduced pressure.
PREPARATION L
16 N,N-Di-t2,3-dihydroxypro~yl)trimethylenediamine 17 Bis-(2,3-dihydroxypropyl)amine (16.5 g., 0.1 mole) 18 and acrylonitrile (6.4 g., 0.12 mole) was mixed in an ice 19 bath and then warmed to room temperature. After standing for 2 hour~, the mixture was then heated at 45C.-55C. for 21 3 hours. The excess acrylonitrile was removed by gentle 22 warming under reduced pressure. The residue was taken up 23 in ethyl alcohol, mixed with sponge nickel catalyst and 24 hydrogenated under 200 psi hydrogen using good agitation.
After filtration of catalyst the solvent and excess acrylo-26 nitrile was removed by stripping under reduced pressure to 27 leave the product as an oil.

~ 157 .
1~836~)7 1 PREPAR~TION M
2 N,N!NLTri-(2,3-dihydroxy~ropyl)trimethylenediamine 3 N,N-di-(2,3-dihydroxypropyl)trimethylenediamine 4 ~11.1 g., 0.05 mole) was dissolved in 125 ml. of methanol and heated under reflux with agitation. Gly~idol (3.7 ~., 6 0.05 mole) was added dropwise over a period of 1.5 hour ~ .
7 and the solution mixed an additional hour at 60C.-80C.
8 The methyl alcohol and other volatiles were removed by 9 stripping under reduced pressure to leave the product `~ 10 suitable for use in the next steps.

12 5,9,9-Tri-(2,3-dihydxoxypropyl)-1,5,9-triazanonane .. j ~ .
`~ 13 An aliquot of the residual oil from Preparation 14 M (5.9 g., 0.02 mole) was mixed with acrylonitrile ~2.75 q., ~j 15 0.05 mole) at room temperature and then warmed at 50C.-60C.
16 for 10-15 hours. The excess acrylonitrile was removed by 17 stripping under reduced pressure and the residual oil taken 18 up in 50 ml. of ethanol, mixed with 2 g. of sponge nickel 19 catalyst and shaken under a hydrogen atmosphere of 200 psi 'or 6 hours. The mixture was filtered free of catalyst and 21 the solvent removed by disti~lation. The product could be 22 brought to analytical purity by chromatography on a silica 23 qel column and is an oil. -~8~6(37 Preparation of 1- ~,5-Di-(4-isopropylcyclohexyl)-3-penty 1,5,9-triazanone 1,5-Di-(4-isopropylcyclohexyl)-3-pentanone (6.70 g., 0.02 mole) and 3,3'-iminobispropylamine (13.1 g., 0.10 mole) in 150 ml. toluene is heated at reflux overnight with a Dean-Stark water separator. The cooled solution is concen-trated under reduced pressure-. The residue is dissolved in ethanol and hydrogenated with PtO2 at room temperature and 40 psi hydrogen pressure. The platinum catalyst is filtered off and the ethanol removed under vacuum. The residual oil is ; dissolved in ether and the ether solution washed several times with water to remove the excess 3,3'-iminobispropylamine. The ether extracts are dried over anhydrous sodium sulfate and concentrated under vacuum to leave the polyamine as a color-less oil.
The oil is dissolved in ether and hydrogen chloride gas is bubbled into the solution until no further precipi-tation occurs. The ether is evaporated under reduced pressure to leave the product as a solid which is digested with hot isopropyl alcohol. The solids are collected by filtration and dried under vacuum at 70C. to give a colorless product, 1-~,5-di-(4-isopropylcyclohexyl)-3-penty ~-1,5,9-triazanone trihydrochloride.
In an analogous manner, from the ketones and the amines set forth below, there are prepared the following compounds of this invention:

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,~ 15 7 1~836~7 ~ 1 EXAMPLE 2 .
~ 2 Preparation of l-tl,5-Di-(4-isopropylcyclohexen-1-yl)-3-- 3 pentyl]-l,S,9-triazanonane _ _ 4 1~5-(4-isopropylcyclohexen-yl)-3-pentanone, ~ 5 (6.60 g., 0.02 mole) and 3,3'-iminobispropylamine (13.1 g., ; 6 0.10 mole) in 150 ml. of toluene is heated at reflux over-7 night with a Dean-Staxk water separator. The toluene is ` 8 then removed under vacuum. The residual oil dissolved in 9 25 ml. isopropanol is added dropwise to sodium borohydride (1.90 g., 0.05 mole, excess) suspended in 50 ml. isopropanol.
- 11 After complete addition, the reaction mixture is heated at 12 reflux for one hour. The isopropanol is evaporated under 13 xeduced pressure, the residue treated with water and the 14 aqueous mixture extracted well with ether. The combined ether extracts are back-washed with water, a saturated 16 sodium chloride solution, dried over anhydrous sodium 17 sulfate and concentrated under vacuum to leave the polyamine 18 product as a clear oil 7.4 g. (90~).
19 The oil is dissolved in ether and the solution cooled in an ice-water bath. Hydrogen chloride gas is 21 bubbled into the solution until no further precipitate is 22 formed. The solid is collected by iltration, washed with 23 a small amount of ether, and dried under vacuum to leave 24 the polyamine trihydrochloride as a colorless product (96%), m.p. 256-257C.
26 In an analogous manner using the ketones and 27 the am~nes set forth below the following compounds of this 28 invention axe prepared.

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- 35 -!' ~ 1575 .:
~3836~7 ., .

2 1-[1,7-Di-~4-methylcyclohexyl~-4-heptyl]-1,4~,8-triazaoctane A mixture of 1,7-di-(4-me~hylcyclohex-3-enyl)-4-4 heptanone (0.03 mole) and 1,2-diaminoethane ~12.0 g., 0.20 mole) in 250 ml. ethanol is heated at reflux overnight.
6 The cooled reaction mixture is hydrogenated with PtO2 at 7 room temperature and 40 psi hydrogen pressure. The g platinum cataly~t is filtered off and the ethanol removed g under reduced pressure. The residual oil is dissolved in ether and the ether solution washed several times with 11 water to remove the excess diaminoethane. The ether extracts,;
12 are dried over anhydrous sodium sulfate and concentrated 13 under vacuum to leave a colorle~s oil, 11.2 g. (100~).
14 The oil i8 dissolved in 20 ml. tert-butanol and chilled to 0C.-5C. in an ice-water bath. Acrylonitrile 16 (1.75 g., 2.2 ml., 0.033 mole) is added dropwise over a 17 5-minute period. The reaction mixture is allowed to warm 18 up to room temperature and is then heated at 60C. overnight.
19 The t-butanol was removed under reduced pressure. The residual oil was dissolved in lS0 ml. glacial acetic acid 21 and hydrogenated with PtO2 at room temperature and 40 psi 22 hydrogen pressure. The platinum catalyst i~ filtered off 23 and the acetic acid removed under vacuum. The residue is 24 dissolved in ether and made basi~ with 10~ sodium hydroxide.
The ether solution is washed with water, dried over anhydrous 26 sodium sulfate and concentrated under reduced pressure 27 to leave the product.

28 In addition, the ~ompound3 of this invention set 29 Corth below are prepared by the reactions set forth in the previous examples.
.~
.

- 36 ~`~ 157 1~1336{~7 [1,9-Dicyclohexyl-5-nonyl]l-1,5,8,12-tetr~zado-2 decane from N,N'-bis-(3-aminopropyl)-1,2-ethahediamine and 3 1,9~dicyclohexyl-S-nonanone~
; 4 1-[1,5-Dicyclohexyl-3-penty]Ll-10-(2-hydroxyethyl~-5 1,4,7,10-tetrazadecane from 1-t2-hydroxyethyl)-1,4,7,10-6 tetrazadecane and 1,S-dicyclohexyl-3-pentanone;
7 1-~1,5-Dicyclohexyl-3-pentyl]-4-(2-!aminoethyl)-8 1,4,7-triazaheptane from tris-~2-aminoethyl)amine and 1,5-g dicyclohexyl-3-pentanone;
10 1-[1,5-Dicyclohexyl-3-pentyl]-5-(2-hydroxypropyl)-" , 11 9-hydroxymethyl-1,5,9-triazanonane from 1-hydroxymethyl-5-12 (2-hydroxypropyl)~1,5,9-triazanonane and 1,5-dicyclohexyl-13 3-pentanone;
14 ExAMpLE 4 Preparation of 1-~1,5-Di-(4-isopropylcyclohexyl)-3-pentyl]-16 5-(2,3-dihydroxxpropyl)-1,5,9-triazanonane 17 1,5-Di-(4-isopropylcyclohexyl)-3-pentanone (6.7 g., 18 0.02 mole) and 3,3'-(2,3-dihydroxypropylimino)bispropylam~ne 19 (20.5 g., 0.10 mole3, (obtained by the catalytic hydrogenation of dicyanoethylated glycerylamined in 150 ml. of toluene is 21 heated at reflux overnight with a Dean-Stark water separator.
22 The cooled solution is concentrated under reduced pressure.
23 The residue is dissolved in ethanol and hydrogenated with 24 PtO2 at room temperature and 40 psi hydrogen pressure. The 25 platinum catalyst is filtered off and the ethanol removed 26 under vacuum. The residual oil is dissolved in ether and 27 the ether solution washed several times with water to remove 28 the excess 3,3~-(2,3-dihydroxypropylimino)bispropylamine.
29 The ether extract~ are dried over anhydrous sodi~um sulfate and concentrated to leave the polyamine product as an oil.

^ - 37 -~836~
;:
In a like manner and using analogous quantities, but employing N,N-di-(2,3-dihydroxypropyl)trimethylenediamine and 5,9,9-tri-(2,3-dihydroxypropyl)-1,5,9-triazanonane instead of 3,3'-(2,3-dihydroxypropylimino)bispropylamine there are prepared respectively N- ~,5-di-(4-isopropylcyclohexyl)-3-penty ~-N'-di-(2l3-dihydroxypropyl)trimethylenediamine, and 1- ~,5-di-(4-isopropylcyclohexyl)-3-penty ~-5-(2,3-dihydroxy-propyl)-9-di-(2,3-dihydroxypropyl)-1,5,9-triazanonane.
ÆXAMPLE 5 10 Preparation of 1- ~,5-Di-(4-isopropylcyclohexyl)-3-penty ~-5-(2,3-dihydroxypropyl)-9-(1,3-dihydroxyl-2-propyl)-1,5,9-triazanonane ~-1- ~,5-Di-(4-isopropylcyclohexyl)-3-penty ~-5-(2,3-dihydroxypropyl)-1,5,9-triazanonane (5.2 g., 0.01 mole) and 1,3-dihydroxyacetone (9 g., 0.1 mole) in 100 ml. of chloroform was heated at reflux with a water separator connected until 1.8 ml. of water was collected (8-12 hours). The chloroform and excess 1,3-dihydroxyacetone were removed by distillation under reduced pressure. The residual oil was taken up in 75 ml. of ethanol, mixed with 1 gm. of platinum oxide and hydrogenated at 40 p9i hydrogen pressure with shaking at room temperature. The catalyst was removed by filtration and ethyl alcohol by distillation to leave an oil. The product could be purified by column chromatography using silica gel and development with methyl alcohol containing ammonium hydroxide.
In an analogous manner but starting with 1,7-di-(2,3-dimethylcyclohexyl-4-heptyl)ethylenediamine, instead of 1- ~,5-di-(4-isopropylcyclohexyl)-3-penty ~-1,5,9-triazanonane there is obtained N- ~ ,7-di-(2,3-dimethylcyclohexyl)-4-hepty ~-N'-(1,3-dihydroxy-2-propyl)ethylenediamine.

~ 157'~
3~;07 . 1 EXAMPLE 6 : 2 1-[1,7-Di-(4-methylcyclohexyl)-4-hepl:yl]-4~8f8-tri-(2,3-3 dihydroxyproRyl)-1,4,8-triazaoctane 4 1-[1,7-Di-(4-methylcyolohe~1)-4-h~ptyl]-1,4,8-triazaoctane ~4~1 g., 0.01 m~le) was dissolv~d in 50 ml.
6 o methanol and heated under reflux with agi~ation.
7 Glycidol tl5 g., 0.2 mole) wa~ added dropw1s~ over a 8 period of 1.5 - 2 hours. After complete add~.tion, the 9 reaction mixture was stirred an additional 2 hours at 90C.-100C. The methyl alcohol was removed by stripping 11 under reduced pressure and excess glycidol by distillation 12 at 1 mm pre~sure. The residue could be further purified 13 by conversion to the trihydrochloride salt in ethyl 14 alcohol with dry hydrogen chloride and fractional crystal-. 15 lization. The free base may then be liberated from its ; 16 salt by resin ~on exchange or neutralization with aqueous 17 sodium hydroxide.
18 In an analogous manner using the follcwing di-19 cyclohexyl polyamines, there are obtained ~he following product~.
21 Dicyclohexyl Polyamine Produ~t 22 1-¦1,5-Di-(4-isopropylcyclo~ 1,5-Di-(4-isopropylcyclo-23 hexyl-3-pentyl]-2,7-di- hexyl)-3-pentyl]-2,7-di-24 hydroxy-1,5,9-triazanonane hydroxy-5-(2,3-dihydroxy- ~:
propyl)-9,9-di-(2,3-di-26 hydroxypropyl)-1,5,9-tri-27 azanonane 28 1-[1,5-Di-(4-isopropylcyclo- 1-[1,5-Di-(4-isopropylcyclo-29, hexyl)-3-pentyl~-1,4,7- hexyl~-3-pentyl3-4-(2,3-di-30 triazaheptane hydroxypropyl)-7,7-di-(2,3-31 dihydroxypropyl)-1,4,7-32 triazaheptane 33 1-~1,5-Di-(4 i~opropylcyclo- N-[1,5-Di-(4-isopropylcyclo 34 hexyl)-3-pentyl]ethylene- hexyl)-3-pentyl3-N',N'-di-35 diamine (2,3-dihydroxypropyl)- :
36 ethylenediamine ? 1575 ~36~7 1 Also each of the respective ketone~ IV set forth 2 in Preparations C and D when reacted with each of the 3 individual amines set forth at page 12, lines 24-30 and 4 page 13, lines 1-11, firstly, according to the method set forth in Example 1, and then second according to Example 2 fi produce the entire range of compounds described according 7 to this invention as embodied in Formula I.

".."

,._..~

- 40 _

Claims (32)

The embodiments of the invention in which an exclu-sive property or privilege is claimed are defined as follows:

1. A method of preparing a compound of the formula:

where A is cyclohexyl or cyclohexenyl of the formula:

or or where each R is either hydrogen or C1 to C6 alkyl, and the dashed line indicates a double bond;
each R1 is alike or different and is C1 to C4 alkylene;

Z is - (CH2)3NH(CH2)3NH2;
- (CH2)2NH(CH2)2NH(CH2)2NH2;
- (CH2)3NCH3(CH2)3NH2;
- CH2CHOHCH2NH2;
- (CH2)3NH2;
- (CH2)2NH2, comprising reducing a Schiff base of the formula:

where A, R and Z are as above defined.

2. The process of Claim 1, wherein the reduction is carried by hydrogenation in the presence of a metal catalyst.

3. The process of Claim 2, wherein the reaction product of 1,5-di-(4-isopropylcyclohexyl)-3-pentanone and 3,3'-iminobispropylamine is reduced to form the 1-[1,5-di-(4-isopropylcyclohexyl)-3-pentyl]-1,5,9-triazanonane.

4. The process of Claim 2, wherein the reaction product of 1,9-dicyclohexyl-5-nonanone and 3,3'-iminobis-propylamine is reduced to form the 1-(1,9-dicyclohexyl-5-nonyl)-1,5,9-triazanonane.

5. The process of Claim 2, wherein the reaction product of 1,5-dicyclohexyl-3-pentanone and ethylenediamine is reduced to the N-(1,5-dicyclohexyl-3-pentyl)ethylenediamine.

6. The process of Claim 2, wherein the reaction product of 1,5-dicyclohexyl-3-pentanone and N-(3-aminopropyl)-N-methyl-1,3-propane is reduced to the 1-(1,5-dicyclohexyl-3-pentyl)-5-methyl-1,5,9-triazanonane.

7. The process of Claim 2, wherein the reaction product of 1,3-dicyclohexylacetone and 2-hydroxy-1,3-diamino-propane is reduced to form the N-(1,3-dicyclohexyl-2-propyl)-2-hydroxy-1,3-diaminopropane.

8. The process of Claim 2, wherein the reaction product of 1,5-dicyclohexyl-3-pentanone and 1,3-diaminopropane is reduced to form the N-(1,5-dicyclohexyl-3-pentyl)trimethyl-enediamine.

9. The process of Claim 2, wherein the reaction product of 1,5-dicyclohexyl-3-pentanone and 2-hydroxy-1,3-diaminopropane is reduced to form the 1-amino-3-[(1,5-dicyclo-hexyl)-3-pentylamino]-2-propanol.

10. The process of Claim 2, wherein the reaction product of 1,7-dicyclohexyl-4-heptanone and iminobispropyl-amine is reduced to form the 1-(1,7-dicyclohexyl-4-heptyl)-1,5,9-triazanonane.

11. The process of Claim 2, wherein the reaction product of 1,5-dicyclohexyl-3-pentanone and iminobispropyl-amine is reduced to form the 1-(1,5-dicyclohexyl-3-pentyl)-1,5,9-triazanonane.

12. The process of Claim 2, wherein the reaction product of 1,5-dicyclohexyl-3-pentanone and triethylene-tetramine is reduced to form the 1-(1,5-dicyclohexyl-3-pentyl)-1,4,7,10-tetraazadecane.

13. The process of Claim 1, wherein the reduction step is a chemical reduction step.

14. The process of Claim 13, wherein the reaction product of 1,5-(4-isopropylcyclohexen-1-yl)-3-pentanone and 3,3'-iminobispropylamine to form the 1-[1,5-di-(4-isopropyl-cyclohexen-1-yl)-3-pentyl]-1,5,9-triazanonane.

15. The process of Claim 13, wherein the reaction product of 1,7-di-(cyclohex-3-enyl)-4-heptanone and iminobis-propylamine is reduced to form the 1-[1,7-di-(cyclohex-3-enyl)-4-heptyl]-1,5,9-triazanonane.

16. The process of Claim 13, wherein the reaction product of 2,8-di-(4-methylcyclohex-3-enyl)-5-nonanone and iminobispropylamine is reduced to form the 1-[2,8-di-(4-methylcyclohex-3-enyl)-5-nonyl]-1,5,9-triazanonane.

17. The process of Claim 13, wherein the reaction product of 1,5-di-[4-(isopropyl)cyclohex-1-enyl]-3-pentanone and triethylenetetramine is reduced to form the 1-[1,5-di-(4-isopropylcyclohex-1-enyl)-3-pentyl]-1,4,7,10-tetrazadecane.

18. A compound having the formula:

where A is alike or different cyclohexyl or cyclohexenyl of the formula:

or where each R is either hydrogen or C1 to C6 alkyl, and the dashed line indicates a double bond;
each R1 is alike or different and is C1 to C4 alkylene;

z is - (CH2)3NH(CH2)3NH2;
- (CH2)2NH(CH2)2NH(CH2)2NH2;
- (CH2)3NCH3(CH2)3NH2;
- CH2CHOHCH2NH2;
- (CH2)3NH2;
- (CH2)2NH2, and acid addition salts thereof, when prepared by the process defined in Claim 1, 2 or 13 or by an obvious chemical equiva-lent.

19. The 1-[1,5-di-(4-isopropylcyclohexyl)-3-pentyl]-1,5,9-triazanonane, when prepared by the process defined in Claim 3 or by an obvious chemical equivalent.

20. The 1-(1,9-dicyclohexyl-5-nonyl)-1,5,9-triaza-nonane, when prepared by the process defined in Claim 4 or by an obvious chemical equivalent.

21. The N-(1,5-dicyclohexyl-3-pentyl)ethylenediamine, when prepared by the process defined in Claim 5 or by an obvious chemical equivalent.

22. The 1-(1,5-dicyclohexyl-3-pentyl)-5-methyl-1,5,9-triazanonane, when prepared by the process defined in Claim 6 or by an obvious chemical equivalent.

23. The N-(1,3-dicyclohexyl-2-propyl)-2-hydroxy-1,3-diaminopropane, when prepared by the process deflned in Claim 7 or by an obvious chemical equivalent.

24. The N-(1,5-dicyclohexyl-3-pentyl)trimethylene-diamine, when prepared by the process defined in Claim 8 or by an obvious chemical equivalent.

25. The 1-amino-3-[1,5-dicyclohexyl)-3-pentylamino]-2-propanol, when prepared by the process defined in Claim 9 or by an obvious chemical equivalent.

26. The 1-(1,7-dicyclohexyl-4-heptyl)-1,5,9-triaza-nonane, when prepared by the process defined in Claim 10 or by an obvious chemical equivalent.

27. The 1-(1,5-dicyclohexyl-3-pentyl)-1,5,9-triaza-nonane, when prepared by the process defined in Claim 11 or by an obvious chemical equivalent.

28. The 1-(1,5-dicyclohexyl-3-pentyl)-1,4,7,10-tetraazadecane, when prepared by the process defined in Claim 12 or by an obvious chemical equivalent.

29. The 1-[1,5-di-(4-isopropylcyclohexen-1-yl)-3-pentyl]-1,5,9-triazanonane, when prepared by the process defined in Claim 14 or by an obvious chemical equivalent.

30. The 1-[1,7-di-(cyclohex-3-enyl)-4-heptyl]-1,5,9-triazanonane, when prepared by the process defined in Claim 15 or by an obvious chemical equivalent.

31. The 1-[2,8-di-(4-methylcyclohex-3-enyl)-5-nonyl]-1,5,9-triazanonane, when prepared by the process defined in Claim 16 or by an obvious chemical equivalent.

32. The 1-[1,5-di-(4-isopropylcyclohex-1-enyl)-3-pentyl]-1,4,7,10-tetrazadecane, when prepared by the process defined in Claim 17 or by an obvious chemical equivalent.