Note: Descriptions are shown in the official language in which they were submitted.
15759Y
:; ~
,
~ 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
R5
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.
R3
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)-
. ~
- 6 -
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.
- 8 -
~ 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
-- 10 --
~ 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
- 12 -
~_~ 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.
- 14 -
15759Y
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.
- 16 -
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
- - 18 -
.~ 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-
-- 19 -
~ 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
- 20 -
~ 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.
15759Y
~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.
- 23 -
~ 15~
~3607
1 PREPARATION D
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.
- 25 -
1 5 7 5
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.
26 PREPARATI3N G
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 _
~`
15759Y
~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.
- 27 -
15759Y
~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
- 28 -
15759Y
~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
- 29 -
~ 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.
- 30 -
~ 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.
11 PREPARATION N
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. -
- 31 -
15759Y
~8~6(37
EXAMPLE 1
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:
- 32 -
- - `'` . 15
.,
0~ 3316()7
.~ . ~ . .
o ,~ o~ ~ o
o 1~ 3 1` ~
~1 r ~o ~ co
., o ~o ~ . ,
.~ ~4 ~I I ' ~ N I
I o ~ ~ o ~ ,) O I o
o n o o o o o
~~ Ln ~ ~ O h
~0 ~ u~ n
~a
a). ~ o o~ :: o o O . D.
C.~ ri Ln O O t~
. ~ ~ Ln ~
I I I I I I I I
;~ --I o ~ ~ a~ ~ ~ ~ o ~ ~ o ~ o
h ~ ~ ~ X ~ S~ ~ h JJ
O :~ a) I a) ~ h O au :~ S O a
S P~ O P~ O ~ S~ ~ S O ~ ~ .C D. S ~ a)
I NI C~ O I ~ I J~ I O
x ~ x ~ X ~X .-a X ~ N
O O O C O a~ -,l o I ~ o ,l `~ ~ o o o o o ~d
U ~ n O C~ U ~
C)31 N ~ 1 0 ~ 1 0 ~-1 N ~ N
~U i U r~U ~1 ~ U I ~1 U ~ U ~ U ~ U
oa ~ ~ a ~ ~a_~ o Q X V 0. ~ I ,1 U Q ~ ~ a h ~ ao
~I ~ rd I ~ I O O I s ~a o ~ o I ~ ~a I L) ~ I ~1
P~o~ u~ s ~h m ~-rl ~: ~ h r~ Ln I ~1 Ln
~ o ~ ~ o~1 a~ s ~1 ~ ~ --I ~ o ~ o ~1 ~ o ,~
_ In ~ F3 r~ ,--S S ~ ,~ S ab S _ Ln -t --Ln
~ S I ~ SI I ~ I I rl I h S I I ,1 1 ~ S I ` S~ I
_I _I U z ~ I Ln ~I Z ~I ~ z; IJ U ~ I 5) ~1 ~1 V ~ ~1
~'
~ ~ :
~ ~ o b -~
O
_.~, Q C ~ O I O I --I
cJ~n rl 0 5
C ~; ~ C4 ~ ~ ~ Q. G
,1R ta G I ~ O ~ O O
O rl O ~ I ~ C
C ~; C
,~ 1 ~ x ~ x u~
e ~ o ~ ~ O ~
H O ~S ~I s:: ~ C ,~ 1~ C Q R S
,~ a ~ ~ o o
S --~ ~O ~ :~: O
t`~ w Z ~ H
~U C C ~ C C 5: ~
1~ 0 0 0 0 0 0 0
O ~ C ~ ~ C ~ ~
C C P~ ~ C
O ~ ~ O
C ~ Q~ ~ S ~ Q~
Q~ I I I I I
n ~ ~ U
~x x x x x x x x x
oa) a) a) ~ ~ a\ a) ~ c)
rc ~ ~ ~ ~c
a~o o o o o o o o o
u ~ u u u u v v u
u u u u u o u v ~
. a a a a Q a a a a
t
cn Ln Ln ~ U ~ n 1` Ln Ln
~ ~p Ln ~ o ~l ~ ~ ~r Ln ~ CO o. o r t ~ ~ ~ n ~
,~ 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.
- 34 -
~ fF~ 1575'
6~)7
~r1
O
..,
,~ ~ ~
~ C~
1: O o o
~r~ ~ r~ C~
~ N 1
r-~
a~
:E: o o o
N ~ ~ r~l q) ~,
r~
~- I o ~ U
~ I I O' X O
" ~ r~
I o I e
_ ~ x ,1 o ~ ox ~ r~ -1 1 eo ~
1: .C OU ~ ~a ~ O r-l ~1 'h I rl I I U N
O O ~ 10
r~ U r~ S r~l r~ I ~4 0 1
u ,~, ~ u e ~ x I
~) N ~ O ~ S r1 ~L) r~
I t~ UU h ~) U I I I ` e x
x rl ~ ~ ~ o ~ o ~ o l
~:~ ~ I s ~s I ~ __a) ~ o ~u ~C) D~
o ~ o ~ 0 r~ r~ c --r~
U ` rl E3 ~ ~ rl I l~i ~ r O ~ I N r-l ~ h -- S-l ~ rl
t) ~ I ~ UI r-l ~O t~ 1 U R. I ~ rl I ~r
u ` o ~ o a) ~ I ~ rl~
~0 _ ~ N~ ~ a~ O I O ~a O a) --
o ~ I s I I ~I o (ao a~ P- "
51 rl r-- U r1 U~ t:rl ~ N rl ~ X ~1 'a rl 1` ~rl ~1 ~1 ~ a,~ o a I o a ~ ` e ~ a,~
--~ rl ~ ~ r~ ~ X I r~ ~ '1 0 E3 1 ~-- Cl. O _ Q,
._ I _
~ a)
~ a~ o ~ ~
,¢ ~ O ~ `
e o o D.
O r1 E~
e ~
~ ~ ~ 0 0 ~ r~
a~ 0~
~ ~ ~ ~ e
r1
E3 ~ 0 ~
"S ~rl r~ ~ ~ Ul N I ~ r1 O
o o ~ a ~ I
H H E 1 E~ I D. ~-1 ~ X ~ I
er O
r 1 1 ~ ~
-- X U X I I O
O --O O
U ~ d~
I I ~ O
x --I o ~ I I o tl~
I C X X
Q) ~ .C ~ O I ~ O
~ O ~ ~ .C ~
O r1 Il) 0 r~ 0 U~
~J U E3 ~
a~ I I I ~ I O u u
I o I ~ ~ o `~ o ~ ~1
~: ~ r~ r~ ~ r~ I r~ ~ r~
a ~ Q ~ a,~ a-- a ~
X a~ R. I` ~ X
S ~ ~ r~ ~ r~ S .~ ~
r~ o ,~ o ,~ n ~D
- 35 -
!' ~ 1575
.:
~3836~7
., .
1 EXAMPLE 3
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 -
15759Y
~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.
- 38 -
~ 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
- 39 -
? 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 _
