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Патент USA US3064062

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3,064,052
Patented Nov. 13, 1962
2
alkyl group and acid anion, e.g. an alkyl halide such as
3,064,052
SYMMETRECAL ALICYCLIC AMM
methyl chloride.
The novel secondary and tertiary amines and their acid
addition salts, formed from inorganic or organic acids,
DERWATH‘VES
Moses Wolf Goldberg, Upper Montclair, and Sidney
Teitel, Nutley, N.J.,'assignors to Hohmann-La Roche
Inc., Nntley, NJ., a corporation of New Jersey
No Drawing. Filed Apr. 17, 19,58, Ser. No. 729,077
l1 Claims. (Cl. 260-563)
5
particularly the mineral acids, which are used as inter
mediates are also part of this invention.
he compounds of this invention are useful as anti
microbial agents, for example, in combatting infections
due to bacteria, such as Streptococci and Staphylococci
This invention relates to symmetrical alicyclic amine 10 (including Staphylococcus strains resistant to antibiotics)
derivatives. More particularly, the invention relates to
and protozoa such as Trichomonas vaginalis. These sub
amine derivatives which can be represented by the fol
stances may be applied topically, for example in the
lowing structural formula:
form of creams, lotions, ointments, etc., or may be ad
ont
wherein m represents 0 or l, _rr represents an integer from
2 to l2 and X represents an acid anion.
ministered parenterally, for example, in a sterile medium
such as water, by incorporating therapeutic dosages _in
The lower alkyl groups in the above formula include
such groups as methyl, ethyl, proyl, isopropyl, etc. The
acid anions in Formula 1_ are anions of medicinally ac
ceptable inorganic or organic acids such as the anions of
carriers, excipients, etc. according to accepted practice.
The following examples are illustrative of the inven
tion. All temperatures are stated in degrees centigrade.
Example I
the mineral acids, e.g. Sulfate, phosphate, nitrate, the
Ahalides, for example, chloride, bromide, iodide, etc., or
Five tsp. of Raney nickel catalyst were added to a
solution of 250 g. of ß-ionone and 200 g. of anhydrous
methylamine in 400 ml. of methanol. The mixture was
toluenesulfonate, citrate, tartrate, etc. The halides, and
especially the chloride, are preferred. In the compounds
hydrogenated at 150° and at a pressure of 1500 p.s.i.
represented by the above structural formula, the lower
The catalyst was iiltered off, the excess methylamine and
alkyl groups are the same, the two acid anion groups are 35 methanol were distilled oíf and lthe residual oil was frac
the same and m has the same value in each part of the
tionated in vacuo to give [l-methyl-3-(2,6,6-trimethyl~lmolecule, so that in each instance the compound is struc
cyclohexenfl-yDpropyl]methylamine, B.P. 117-119er at
the anions of organic acids such as benzenesulfonate,
turally symmetrical.
It is understood, however, that
5 mm.
compounds of Formula I can exist in different spatial
To 62 g. of [l-methyl~3-(2,6,6-trimethyl-l-cyclohexen
configurati-ons, which are also within the scope of this 40 l-yl)propyl]methylamine, dissolved in 38 m1. of 90%
invention.
When m=0 in Formula l, the compounds may be
The solution was stirred on a steam bath for 3 hours,
synthesized from ß-ionone; when m=l, the compounds
and the excess formaldehyde and formic acid were dis
forímc acid, were added 28.5 ml. of 35% formaldehyde.
may be synthesized from 4-(2,6,6-trimethyl-l-cyclohexen 45 tilled off. The residual oil was made strongly alkaline
l-yl)-2-methyl - 2 - ‘outen-l-al, [IS-CM-aldehydel Two
with 50% potassium hydroxide and then extracted with
alternate routes may be followed. For example, ß
ether. The ether extract was washed with water, dried
ionone is reductively condensed >with methylamine in the
and the ether was distilled oil'. The residual oil was
presence of a reducing catalyst such as Raney nickel to
fractionated in vacuo to give [l-methyl-3-(2,6,6-trimeth-
obtain the corresponding secondary amine, [l~methyl-3-
yl-l-cyclohexen-’l-yl)propyl]dimethylamine, B.P. 97-99°
(2,6,6-trimethyl-l-cyclohexen « l-yl)propyl]methylamine.
at 2 mm.
When ß-Cl., aldchyde is used, [2-methyl-4-(2,6,6ftrimeth
yl-l-cyclohexen- l-yl) butyl] methylarnine is obtained. The
treated with hydrogen chloride, gave the crystalline hydro
chloride, M.P. 69-71" (crystallized from acetonitrile
secondary amine is converted to a tertiary alkyl amine by
ether).
treatment, for example, with formic acid-formaldehyde.
rl`he double bond of the cyclohexene ring is then cata
lytically reduced, eg. with a platinum catalyst. The
To 4.0 g. yof platinum oxide in 100 ml. of glacial acetic
acid were added 62 g. (0.24 mol) of [l-rnethyl-3-(2,6,6-
An alcoholic solution of the latter, when
trimethyl#l-eyclohexen-1-yl)propyl]dimethylamine hydro
appropriate a,w-dihaloalkane is then reacted with two
chloride and the volume was adiusted to 300 ml. with
equivalents of the saturated tertiary amine to give the
glacial acetic acid. The mixture was hydrogenated at
desired symmetrical compound of Formula I.
60 100° and at pressure of 1000 p.s.i. The catalyst was
Alternatively, the saturated ketone, e.g. cis-tetrahydro
filtered olf and the colorless ñltrate was concentrated, at
ionone, is reductively condensed in the presence of Raney
steam temperature and water vacuum, until a syrup re
nickel or a noble metal catalyst with one-half equivalent
mained. rl`he latter was triturated with ether and crystal
of the appropriate «,w-diaminoalkane to obtain a satu
lized from ethanol-ether. The [l-methyl-3-(2,2,6-tri-
rated diamine. For example, when cis-tetrahydroionone 65 methylcyclohexyl ) propyl] dimethylamine hydrochloride
is reductively condensed with one-half equivalent of 1,6
melted at 12S-127°. lt is hygroscopic.
y
hexanediamine, N,N’-bis[l - methyl - 3-(2,2,6-trimethylThe hydrochloride obtained above Was dissolved in
cyclohexyD-propyl]-l,6-hexanediarnine is obtained. Re
water, neutralized with aqueous sodium hydroxide and
acting the lsaturated diamine, for example with formic
the mixture Was extracted with ether. The ether was dis
acid`formaldehyde, converts it to the di-tertiary amine. 70 tilled off to obtain the free base, [l-methyl-3-(2,2,6-tri-
The latter is then quaternized by treatment with an ex
-cess of a quaternizing agent containing the appropriate
- methylcyclohexyl ) propyl] dimethylamine.
3,064,052
3
4
methylcyclohexyDpropyl]dimethylamine were added 1.79
g. (8.9 m mols) of 1,3-dibrornopropane, dissolved in 30
ml. of acetonitrile, and the mixture was reiluxed. The
'Il-le reductive condensation described in the first para
graph of this example Was repeated using instead of
Raney nickel catalyst (l) 1.5 g. of platinum oxide and
in a separate experiment (2) 1.5 g. of 10% palladium
mixture became homogeneous- at reflux temperature.
After 18 hours, the solution was cooled, and the result
ing straw yellow solution was concentrated, at steam
on-calcium carbonate to obtain the same product, N,N’bis[1-methyl-3-(2,2,6 - trimethylcyclohexyl)propyl] - 1,6
hexanediamine.
temperature and water vacuum, until a syrup Was ob
Example 5
tained. The latter was crystallized from acetonitrile-ether
to
obtain
N,N’-bis[1-rnethyl - 3 - (2,2,6-trimethylcyclo
hexyl)propyl]-N,N'-dimethyl - 1,3-propanediamine
bis
Upon recrystallization from aceto
nitrile-ether, the compound melted at 214-216", with de
To 5 g. of N,N'-bis[1-methy1-3-(2,2,6-trimethylcyclo
10 hexyl)propyl] - N,N' - dimethyl- 1,6 - hexanediamine dis
solved in 100 ml. of methanol, at 4°, were added 100 ml.
.(methobromide) .
methanol containing 10 g. of methyl chloride. The solu
composition.
tion was heated in a closed vessel at 60° for 15 hours.
Example 2
4.5 g. (0.02 mol) of El-methyl-3-(2,2,6-trimethylcyclo
hexyl)-propyl]dimethylamine and 2.3 g. (0.01 mol) of
The colorless solution was concentrated and the resulting
15 White solid crystallized from ethanol-acetonitrile-ether to
obtain N,N'-bis[1 - methyl-3-(2,2,6-trimethylcyclohexyl)-
propyl]-N,N'-dimethy1-1,6-hexanediamine bis(methochlo-
1,5-dibromopentane were reacted according to the proce
ride) hemihydrate.
dure in the last paragraph of Example 1 to obtain N,N’-
Example 6
bis[1-methyl-3-(2,2,6-trirnethylcyclohexyl) - propyl] .- N, 20
N' - dimethyl - 1,5 - pentanediamine
To 5 g. of N,N’-bis[l-methyl-3-(2,2,6-trimethylcyclo
bis(methobromide),
hexyl)propyl] - N,N' - dimethyl - 1,6 - hexanediamine,
M.P. 253-155 ° with decomposition (crystallized from
hexyl)-propyl]dimethylamine and 12.2 g. (0.05 mol) of
dissolved in 100 ml. of methanol, were added 10 g. of
methyl p-toluenesulfonate, dissolved in 100 ml. of ace
tone. The resulting solution was reñuxed for 18 hours,
concentrated, and the syrup crystallized from acetonitrile
acetone-ether to obtain N,N’-bis[1-rnethyl-3-(2,2,6-tri
1,6-dibromohexane in 100 ml. of acetonitrile were reacted
methylcyclohexyl)propyl]-N,N’-dimethyl - 1,6 -- hexane
methanol-acetonitrile) .
Example 3
22.5 g. (0.1 mol) of [l-methyl-S-(2,2,6-trimethylcyclo-
diamine bis(methyl p-toluenesulfonate), M.P. 191-193°.
according to the procedure described in the last paragraph
of Example 1 to obtain N,N’-bis[l-methyl-3-(2,2,6-tri- 30
Example 7
methylcyclohexyl)propyl] - N,N' - dimethyl-1,6-hexane
diamine bis(methobromide), M.P. 26S-266° (crystallized
from methanol-acetonitrile-ether).
Example 4
To a solution of 49 g. (0.25 mol) of cis-tetrahydro
To 0.5 g. of N,N'-bis[1-methyl-3-(2,2,6-trimethylcyc1o
hexyl) propyl] - N,N' - dimethyl- 1,6 - hexanediamine bis
(methobromide), dissolved in 100 ml. of water, was add
A white precipitate
formed. It Was filtered off, washed with Water and re
35 ed an excess of dilute nitric acid.
ionone and 14.1 g. (0.12 mol) of 1,6-hexanediamiue in
150 ml. of ethanol was added l teaspoon of Raney nickel.
yl-3-(2,2,6-trimethylcyclohexyl)propyl] - N,N’ - dimethyl
'The volume was adjusted to 300 ml. with ethanol and the
1,6-hexanediamine bis(metl1yl nitrate), M.P. 287-288",
crystallized from 25% ethanol to obtain N,N'-bis[1-meth-
mixture was hydrogenated at 50° and a pressure of 200 40 With decomposition.
Example 8
4.0 g. (17.8 mmols) of [1~methyl-3-(2,2,6-trimethyl
cyclohexyDpropyl] dimethylamine and 2.4 g. (8.9 mmols)
p.s.i. The catalyst was filtered off, the ñltrate was con
centrated and the residual oil fractionated in vacuo to
obtain N,N'-bis[1 - methyl-3-(2,2,6-trirnethylcyclohexyl)
propyl]-l,6-hexanediarnine; B.P. l92-202° at 0.02 mm.
An aliquot, when treated with alcoholic hydrogen
l chloride, gave N,N’-bis[l-rnethyl-S-(2,2,6-trimethylcyclo
of 1,8-dibromooctane were reacted according to the proce
‘ dure described in the last paragraph of Example 1 to ob
hexyl)propyl]-1,6-hexanediamine dihydrochloride; M.P.
197-199" (crystallized from ethanol-ether).
tain N,N’-bis[ 1 - methyl- 3 - (2,2,6-trimethylcyclohexyl)
propyl]-N,N’-dimethyl-1,8 - octanediamine bis(methobro
ed 182 ml. (3.04 mols) of formic acid (90%). The
resulting colorless solution was cooled, then 91.3 ml.
Example 9
4.0 g. (17.8 mmols) of [1-methyl-3-(2,2,6-dimethylcyclohexyDpropyl]dimethylamine and 2.7 g. (8.9 mmols)
mide), M.P. 21S-217°, with decomposition (crystallized
To 217 g. (0.456 mol) of N,N’-bis[1-metl1yl-3-(2,2,6trimethylcyclohexyl)propyl]-1,6-hexanediamine were add 50 from acetonitrile-ether).
(1.043 mols) of formaldehyde (37%) were added. The
solution was heated at steam temperature with occasional
shaking for 2 hours and then reñuxed for 8 hours. The
volatiles were distilled oiï at steam temperature under
Water vacuum and the residual oil was made strongly alka
_ of 1,10-dibromodecane were reacted according to the
line with 50% potassium hydroxide. The reaction prod
uct was extracted with ether.
The ether extract was
Washed with Water, dried and concentrated in vacuo. The 60
residual oil Was fractionated in vacuo to obtain N,N'bis[1 - methyl-3-(2,2,6 - trimethylcyclohexyl)propyl]-N,
N’-dimethyl-1,6-hexanediamine, B.0_4 230-240°, 111326
1.4833. An aliquot, when treated with an ethanolic hy
procedure described in the last paragraph of Example 1
to obtain N,N' - bisIl-methyl-B-(2,2,6-trirnethylcyclohex
yl ) propyl] N,N'-dimethyl-l, IO-decanediamine bis (metho
bromide), M.P. 197-199° (crystallized from ethanolace
tone-ether).
Example 10
To a solution of 200 g. of 4-(2,6,6-trimethyl-l-cyclo
hexen-l-yl)-Z-methyl-Z-buteu-l-al and 115 g. of anhy
drous methylamine in 300 ml. of methanol were added
drogen chloride, gave the crystalline dihydrochloríde, 65 three teaspoons of Raney nickel catalyst. The mixture
M.P. 183-185° (recrystallized from ethanolacetonitrile).
was hydrogenated at 150° and a pressure of 1500 p.s.i.
To 5 g. of N,N'-bis[l-methyl-3-(2,2,6-trimethylcyclo
The catalyst was filtered off, and the excess methylamine
and methanol were distilled otï. To the residual oil,
solved in 150 ml. of acetone, were added 50 ml. of a
dissolved in 114 ml. of 90% formic acid, were added
40% solution of methyl bromide in acetone. The solu 70 85.5 rnl. of 35% formaldehyde. The solution was stirred
_tion was stored overnight at room temperature. The
on a steam bath for 3 hours, and the excess formaldehyde
crystals which had formed Were filtered ofr”, Washed with
and formic acid were distilled off. The residual oil was
acetone and dried to obtain N.N'-bis[methyl-3-(2,2,6-trimade strongly alkaline with 30% sodium hydroxide and
methylcyclohexyl)propyl] - N,N’ - dimethyl-1,6-hexanedi
the mixture was extracted with ether. The ether extract
amine bis(methobromide), M.P. 26S-266°.
75 was Washed with water, dried with potassium carbonate
hexyl)propyl] - N,N’ - dimethyl - 1,6-hexanediamine,
dis
3,064,052
5
and the ether was distilled oiî. The residual oil was frac
tîonated in vacuo to give N-[2-methy1-4-(2,6,6-trimethyl
is
We claim:
1. A compound represented by the formula
CH3\ /CHa
CH:4\ /CHs
/C\ /
(lower alkyDg
(llower alkyDg
H\ /C\
112C
o-oHr-CHT-0H~<oH2>m-rîr-<oHz> „- l *(oHnVoH-CHT-CHZ-IIJ
ou;
H2C\ /C\-\H
CH3
X
X
CH3
H--C\ /CHz
C
CH3
Hz
CH3
1-cyclohexen-1-yl)-butyl] dimethylamine, B.P. 100° at 0.4
mm.
wherein:
When treated with alcoholic hydrogen chloride,
-
the crystalline hydrochloride was obtained, M.P. 150151°
C
H2
ìlnîëî’lìëîäììsaîlniäì¿Èîîrfîänzotêolà’ and
(crystallized for acetonitrile-ether).
_
„
.
.
_ ’
.
.
50 g. of N_[2_methy1_ 4_ (2, 6’ 6_trimethy1_I_cyclohexeml* l5 X represents a medlcinally acceptable acid anlon.
y1)-butyl]dimethylamine hydrochloride and 3.5 g. of
CH3
2. A Compound represented by the formula
CH3
\C
CH3
H
(loweralkylh
HzC/ \C£CHz-CHz-CH-N
H2O
C-H
(lower alkyl»
CH2 -Iïl
CH3 halogen
ñ
CH-CHz-CHz-C
halogen CH3
\C/
\CH3
H2
platinum oxide in 100 ml. of glacial acetic acid were hy
drogenated according to the procedure described in the
third paragraph of Example 1 to give N-[2-methyl-4-(2,2,
6 - trimethylcyclohexyl)butyl]dimethylamine
CH3
\ / \
(IÉH:
H-C
CH2
CH3 \C/
H2
wherein .halogen represents a member selected from the
group consisting of chlorine, bromine, and iodine.
hydrochlo
ride, M.P. 159-160°. The latter, when neutralized with 30 kylhalide), said halide being selected from the group con
aqueous sodium hydroxide, gave the free base, N-[2
sisting of chloride, bromide, and iodide.
methyl - 4 - (2,2,6 - trimethylcyclohexyl)butyl]dimethy1amine.
8.1 g. (0.034 mol) of N-[2-methyl-4-(2,2,6-trimethyl
cyclohexyl)butyl]dimethylamine and 4.1 g. (0.018 mol)
5. A compound selected from the group consisting of
bases represented by the formula
of 1,6-dibr0mohexane were reacted according to the pro
cedure described in the last paragraph of Example 1 to 45 wherein:
obtain N,N’ - bis[2 - methyl-4-(2,2,ó-trimethylcyclohexyl)
m represents an integer from 0 to 1 and
n represents an integer from 2 to 12.
butyl] - N,N’- dimethyl-1,6-hexanediamine bis(methobro-
mide), M.P. 23S-237° with decomposition (crystallized
from ethanol-ether).
50 propyl]-1,6-hexanediamine.
Example 11
To 20 g. of N,N’-bis[1«methyl-3-(2,2,6-trimethylcyclo
8. A compound selected from the group consisting of
bases represented by the formula.
hexyl)propyl]-N,N’-dimethyl ~ 1,6 - hexanediamine, dis
solved in 250 ml. of ethanol, were added 21.8 g. of ethyl
CH3 CH3
C
H
CH3
lower alkyl
CH3
lower alkyl
H26/ \C£CHr-CH2-CH-(CH2)m-- l-(CH2)u-dI-œHnm-CH-CHZCHÈC/ \CH„
Hzo
c-H
CH3 `
ons
H-d
(IJHZ
\C/ `\CH3
CH3 \C/
H2
2
bromide. The solution was heated at 80° Vfor 15 hours.
The volatiles were distilled oiî and the residue was crys
wherein:
(2,2,6-trimethylcyclohexyl)propyl] - N,N’- dimethyl-1,6~
m represents an integer from Oto 1 and
n represents an integer from 2 to 12.
hexanediamine bis(ethobromide), M.P. 19o-198°.
9. A compound represented by the formula
CH3
C
CHS
H
/ \ /
CH3
lower alkyl
lower alkyl
H
CH3
C
\ / \
Hz-C Cll-CHg-CHz-CH-N-(CHzh-N-CH-CHg-CHß-C (13H2
H2-C\ C /CîHCH3
CH3
CH3
H;C\
/CHI
CH3 C
Hr
Hs
3,064,052
8
Y.
References Cited in the file of this patentV
UNITED STATES PATENTS
2,736,746
propy1]-N,N’-dimethy1 - 1,6 ~ hexanediamine dihydrochlo- 5
ride.
2,736,747
2,767,168
2,795 ,612
2,933,530
Goldberg et al _________ __ Feb. 28, 1956
Goldberg et a1 _________ __ Feb. 28, 1956
Cheney ______________ __ Oct. 16, 1956
Luduena _____________ __ June 11, 1957
Kralt et al. ___________ __ Apr. 19, 1960
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