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Патент USA US3022314

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enamel
ire Sttes
Patented Feb. 20, 1962
at
‘an
hydrogen, by reacting the latter either with formic acid
formaldehyde or an appropriate alkyl halide.
The compounds of Formula I may, in addition, be de
1
3,022,201
AMIDO-DIAMINES AND TRIAMINES
Moses Wolf Goldberg, Upper Montclair, and Sidney
Teitel, Nutley, N.J., assignors to Hotlmann-La Roche
rived by reducing, for example with lithium aluminum
hydride, a corresponding amido-diamine of the formula
Ind, Nutley, N.J., a corporation of New Jersey
No Drawing. Filed Oct. 24), 1959, Ser. No. 847,463
13 Claims. (Cl. 260-2472)
(II)
'
>
a.
R-alkylene-N [YD-O O-—lower alkylene-III-lower alkylene~N
R1
R2
This invention relates to amido-diamines and triamines.
More particularly, the invention concerns triamines rep-‘
The
symobls
R,
R1
and‘
R2
and
the
alkyl
and
alkylene
10
resented by the structural formula
groups have the same meaning as in Formula I.
, The amido-diamines corresponding to Formula II are
(I)
R;
novel
compounds which are produced by reacting a di
R—alkylene—N-lowcr alkylene--N—lower alkylene—N/
alkylaminoalkylamine with the appropriate haloacylam
ide.
For example, 3-dimethylaminopropylamine, Z-dieth
15
ylaminoethylamine, N-aminopropylmorpholine and the
as well as acid addition salts and quaternary salts of said
like will react with N-[1-methyl-3-(2,6,6-trimethyl-1-cy
triamines.
clohexen-l-yl)propyl] -a-chloroacetamide, N-[4-methyl-6J
R in the above formula represents the cyclic part of the
I‘h
llii
R2
saturated or unsaturated ionone, isoionone or irone struc
ture, that is, a group such as 2,6,6-trimethyl-l-cyclohexen
l-yl, 2,5,6,6-tetramethyl-Z-cyclohexen-1-yl, 2,6,6-trimeth
yl-2-cyclohexen-1-yl, 2,2,6-trimethylcyclohexyl, 2,2,3,6
(2,6,6-trimethyl-l-cyclohexen-LyDhaxyl] - 0c - chloroacet
20
l-yl)octyl]-a-chloroacetamide, N - [1-methyl-3-(2,2,6-tri
methyl-cyclohexyl)propyl]-a.-chloroacetamide or N-[l
methyl - 3 - (2,6,6-trimethyl-2-cyclohexen-l-yl)propyl]-ot
tetramethylcyclohexyl, 2 - methyl-S-isopropyl-I-cyclopen
chloroacetamide. The haloacylamides, used as interme
ten-1~yl and 2-methyl-5-isopropyl-l-cyclopentanyl. R1
represents hydrogen or lower alkyl. The group
amide, N-[2,6-dimethyl-8 - (2,6,6-trimethyl-l-cyclohexen
diates, are prepared by the reductive condensation of the
appropriate ketone or aldehyde,-e.g. a-ionone, ?-ionone,
25
isoionone, tetrahydroionone, tetrahydroisoionone, ,B-Cm
aldehyde, B-Cm-aldehyde [6-(2,6,6—trimethyl-l-cyclohex
en-l-yl)4-methyl-2,4-hexadien-l-al] or ?-Cm-aldehyde [8
in Formula I represents a tertiary amino group wherein 30 (2,6,6-trimethyl-l-cyclohexen-l-yl) - 2,6-dimethyl-2,4,6
octatrien-l-al], with ammonia, using Rauey nickel cata
each R2 represents a lower alkyl radical to form a dilower
alkylamino group or the two symbols R2 together join
lyst, and reacting the resulting amine with a haloacyl
in a polymethylene or polymethyleneoxy structure which,
with the tertiary nitrogen, form a saturated 5 or 6 mem
bered nitrogen heterocyclic radical such as morpholinyl,
chloride.
piperidyl, pyrrolidyl and the like.
structural formula
‘
A preferred group of compounds within the class de
?ned by Formula I are those triamines represented by the
'
lower alkyl
(III)
R4
'.
' lit;
lower alkyl
In the above formula, the lower alkyl, lower alkylene
wherein R3 represents a radical selected from the group
saturated aliphatic hydrocarbon radicals of the alkane
trimethyl-cyclohexyl, and R4 represents a member of the
group consisting of hydrogen and lower alkyl, as well as
acid addition salts and quaternary salts of these com
and alkylene groups are straight chain or branched chain 45 consisting of 2,6,6-trimethyl-cyclohexen-l-yl and 2,2,6
series. The lower alkyl and lower alkylene groups may.
have up to about 7 carbon atoms in the chain, whereas
the alkylene groups may have longer chains, e.g. up to
pounds.‘ The corresponding amido-diamines also consti
about 12 carbon atoms.
tute a preferred group.
The triamines of Formula I may be produced by re
'ductive condensation of an aminoalkylaminoalkanol
such as 3-(2-hydroxyethylamino)propylamine, Z-hydroxy
ethylethylenediamine or the like with IS-ionone or with
lit-C14 aldehyde [4-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2
methyl-Z-buten-l-al] to form the corresponding di-sec
ondary-diamino alcohol, followed by alkylation with
formic acid-formaldehyde. The resulting di-tertiary-di
amino alcohol is then halogenated, e.g. with thionyl chlo
ride, and the halo-di-tertiary-dian'iine dihydrohalide is re
acted with a dialkylamine to give the tri-tertiary amine.
As an alternative, a primary-secondary-tertiary tria
The amido-diamines and triamines form acid addition
salts by reaction with inorganic or organic acids and qua
ternary salts by reaction with conventional quaternizing
agents. Mono-acid addition salts and mono-quaternary
salts as well as poly-acid addition salts and poly-quater
nary salts may be produced. Illustrative of the acid addi
tion salts are those formed from hydrohalic acids, e.g. hy
drochloride, hydrobromide, etc., other mineral acid salts
such as sulfate, nitrate, phosphate, etc., arylsulfonates
such as benzenesulfonate, tolu'enesulfonate, etc., other or
ganic acid salts such as tartrate, citrate,'ascorbate, malate,
oxalate and the like. The acid addition salts, whose for
mation frequently provides a ready means of puri?cation,
may be converted to the free base by neutralization, e_.g.'
mine or the like, may be reductively condensed with a
ionone, ?-ionone, isoionone, a-irone, tetrahydroionone or 65 with sodium hydroxide. Quaternary salts may be pro
duced by reacting the base with quaternizing agents such
tetrahydroisoionone, or with ?-Cw, li-Cls- or ?-cm-alde
as alkyl halides, alkyl sulfates, alkyl nitrates and the like,
hyde to give the di-secondary-tertiary amines which may
e.g. methyl chloride, methyl bromide, ethyl chloride, eth
in turn be alkylated, e.g. with formic acid-formaldehyde,
yl iodide, propyl bromide, butyl chloride, etc., methyl
to produce the tri-tertiary amine.
mine, e.g. N-(3-dirnethylaminopropyl)-1,3-propanedia
When R1 in Formula I represents a lower alkyl group, 70 sulfate, ethyl sulfate, ethyl nitrate, etc., aralkyl halides,
aralkyl sulfates and the like, e.g. benzyl chloride, benzyl
the compound of that structure is best obtained from the
corresponding compound of Formula I, wherein R1 is
bromide, phenethyl sulfate, etc. _
v
_
,
'
3,022,801
4
3
ing to the procedure described in Example 1 to obtain
The compounds of this invention have a variety of bio
logical activities useful for therapeutic purposes. They are
oz - [3 — diethylaminopropylamino] - N - [1 - methyl - 3
active against organisms such as T. vaginalis, C. albiczzns
and E. histolytica and ‘are therefore useful as antifungal,
amide. Addition of an excess of oxalic acid dissolved in
anti-protozoan and antiamebic agents.
Compounds of
ether gave the m-[3-diethylaminopropylamino] -N-[1-meth
this series are also ganglionic blocking agents and are use
ful as hypotensive agents. They furthermore act on the
yl - 3 - (2,6,6 - trimethyl - 1 - cyclohexeu - 1 - yl)propyl]
(2,6,6 - trimethyl - 1 - cyclohexen - 1 - yl)propyl] - acet
acetamide dioxalate which was crystallized from 760%
central nervous system. They may be administered orally
or parenterally in conventional solid or liquid forms such
1 ethanol, M.P. 196—197° (with dec.).
Example 5
as tablets, capsules, elixirs, ointments, injectables and the 10
like by incorporating therapeutic dosages of the free base
To 116 g. (0.5 mol) of ?-Cle-aldehyde-suspended in
or medicinally acceptable salt thereof in appropriate ve
300 ml. of ice cold methanol were added 6 teaspoons of
hicles according to accepted pharmaceutical practice.
Raney nickel and 70 ml. of liquid ammonia. The mix
The following examples are illustrative of the inven~
ture was hydrogenated at 100° under a pressure of 1,000
tion but not limitative thereof. All temperatures are ex— 15 psi. The catalyst was ?ltered off and the solution was
pressed on the centigrade scale. All melting points are
concentrated. The residual oil was fractionated in vacuo
corrected.
to obtain 4-met-hyl-6-(2,6,6-trimethyl-l-cyclohexen-l-yl)~
Example 1
To 54.4 g. (0.2 mol) of N-[l-methyl-3-(2,6,6-tri
methyl-1-cyclohexen-1-yl)propyl] ~a-chloroacetamide dis
hexylamine, B.P.0_2 106-110". An aliquot, when treated
with a solution of oxalic acid in ether, gave the crystalline
20
solved in 100 ml. of dry toluene were added 30.6 g. (0.3
mol) of 3-dimethylaminopropylamine and 42.4 g. (0.4
mol) of sodium carbonate (anhydrous powder). The
mixture was stirred and re?uxed for 26 hours, cooled, ren
dered strongly‘ alkaline with dilute sodium hydroxide,
oxalate hemihydrate, M.P. 158-160°, with sintering at
120° (crystallized from 95% ethanol).
35.2 g. (0.31 mol) of chloroacetyl chloride were added
slowly over a period of one hour at a temperature of 4°
to a well stirred suspension containing 73 g. (0.31 mol)
25
of
4-methyl-6-(2,6,6-trimethyl-l-cyclohexen-1-yl)hexyl
then extracted with ether. The organic layer was sep
arated, washed thoroughly with Water, dried over anhy
amine in 280 ml. of ether and 180 ml. of water. The re
action mixture was maintained alkaline to phenolphthal
adding ethanolic hydrogen chloride and concentrated at
dilute hydrochloric acid and Water, then dried over anhy
drous sodium sulfate. It was then concentrated and the
ein with periodic additions of 15% potassium hydroxide.
drous sodium sulfate and concentrated at steam tempera
ture under water vacuum. The residual oil was dissolved 30 The mixture was stirred at 4° for an additional two hours.
The ether layer was then separated, washed with water,
in ethanol, the solution was made acidic to Congo red by
steam temperature under water vacuum.
The residual
gum was crystallized from ethanol-acetouitrile-ether. The
a - [3 - dimethylaminopropylamino] - N - [1 - methyl - 3
(2,6,6-trimethyl-l-cyclohexen-l-yl)propyl]-acetamide di
hydrochloride melted at 170-172° (with dec.).
The dihydrochloride obtained above was neutralized
with aqueous sodium hydroxide and extracted with ether.
The ether extract was evaporated to dryness to give the
residual oil was fractionated in vacuo to obtain N-[4
methyl - 6 - (2,6,6 - trimethyl - 1 ~ cyclohexen - 1 - yl)
hexyl]-ot-chloroacetamide, B.P.o_01 156-157°.
22 g. (0.07 mol) of N[4-methyl-6-(2,6,6-trimethyi-l
cyclohexen-1-yl)hexyl] -a-chloroacetamide, 10.7 g. (0.11
mol) of 3-dimethylaminopropylamine and 14.8 g. (0.14
mol) of anhydrous sodium carbonate were reacted accord
free base, a-[3-dimethylaminopropylamino] -N—[ l-methyl
ing to the procedure described in Example 4 to obtain .
3 - (2,6,6 - trimethyl - 1 - cyclohexen - 1 - yl)propyl]
a - [3 - dimethylaminopropylamino] - N - [4 - methyl - 6
acetamide, as a pale yellow oil.
(2,6,6-trimethyl-1-cyclohexen-l-yl)hexyl] -acetamide diox
alate, M.P.161-163°, with dec. (crystallized from water
Example 2
ethanol).
Example 6
To 13.5 g. (0.04 mol) of ot-[3-dimethylaminopropyl 45
amino] - N - [1 - methyl - 3 - (2,6,6 - trimethyl - 1 - cy
54 g. (0.2 mol) of [SCH-aldehyde were reduced in the
clohexen-1-yl)propyl]-acetamide were added 25 ml. (0.4
mol) of formic acid (90% ). The resulting solution was
cooled, then 3.9 ml. (0.044 mol) of formaldehyde (37%)
presence of excess liquid ammonia according to the pro
cedure of Example 5 to obtain 2,6-dimethyl-8-(2,6,6-tri
methyl-l-cyclohexen-l-yl)octylamine, 13.13.05 141-145 °.
were added. The solution was heated at steam tempera
ture with occasional shaking for three hours and then re
?uxed for four hours. The volatiles were distilled off at
steam temperature under water vacuum. The residual
An aliquot, when treated with a solution of oxalic acid in
oil, comprising the crude free base, was dissolved in ex
cess ethanolic hydrogen chloride and the solution was
sintering at 110°
evaporated to dryness. The ‘residual gum was crystal—
lized from ethanol-acetonitrile-ether to obtain a-[N-meth
yl - 3 - dimethylaminopropylamino] - N - [1 - methyl - 3
(2,6,6-trimethyl- l-cyclohexen- 1 -yl ) propyl] -acetamide di
hydrochloride 'hemihydrate, M.P. 173-174° (with dec.).
Example 3
54.4 g. (0.2 mol) of N-[1-methyl-3-(2,6,6-trimethyl-1
cyc1ohexen-1-y1)propyl]-a-chloroacetamide and 35 g. (0.3
mol) of 2-diethylaminoethylamine were reacted accord
ing to the procedure of Example 1 to obtain a-[Z-diethyl
aminoethylamino] - N- [1 - methyl - 3 - (2,6,6 - trimethyl
l - cyclohexen - 1 - yl)propyl] - acetamide dihydrochlo
ride monohydrate, M.P. 96-98“ (crystallized from ace
tonitrile ether).
Example 4
54.4 g. (0.2 mol) of N-[1-methyl-3-(2,6,6-trimethyl~1
cyclohexen-1-yl)propyl] -ot-chloroacetamide and 39 g. (0.3
ether and crystallized from 90% acetone, gave crystalline
2,6 - dimethyl - 8 - (2,6,6 - trimethyl - 1 - cyclohexen - 1
yl)octylamine oxalate hemihydrate, M.P 138—140°,_with
33 g. (0.12 mol) of 2,6-dimethyl-8-(2,6,6,-trimethyl-1
cyclohexen-l-yl)octylamine and 13.6 g. (0.12 mol) of
chloroacetyl chloride were reacted according to the pro
cedure described in Example 5 to obtain N-[2,6-dimethyl
8 - (2,6,6 - trimethyl - 1 cyclohexen - 1 - yl)octyl] - u
chloroacetann'de, B.P.D_25 192°.
26.6 g. (0.076 mol) of the chloroacetarnide obtained
above and 11.6 g. (0.114 mol) of B-dimethylaminopro
pylamine were reacted according to the procedure de
scribed in Example 4 to obtain a-[3-dimethylaminopropylamino] - N - [2,6 - dimethyl - 8 - (2,6,6 - trimethyl -
1-cyclohexen-l-yl)octyl]-aeetamide dioxalate, M.P. 177-v
179°, with dec. (crystallized from methanol).
'
Example 7
44 g. (0.13 mol) of a-[3-dimethylaminopropylaminol-_
N - [1 - methyl-3-(2,6,6~trimethyl-l-cyclohexen~1-yl)pro
pyl]-acetamide, obtained as described in Example 1, were
dissolved in 240 ml. of absolute ether and added over a
mol) of 3-diethylaminopropylamine were reacted accord 75 period of one hour to a stirred suspension of 16.6 g.
3,092,301
absolute ether.
6
warm to room temperature and then re?uxed for six
hours. The volatiles were distilled off at steam bath
temperature under water vacuum. To the residue were
(0.44 mol) of lithium aluminum hydride in 1 liter of
The reaction mixture was stirred and re
?uxed for four hours and then cooled. 100 mL'of ethyl
added 28 g. (0.6 mol) of dimethylamine dissolved in
acetate were slowly added, followed by the addition of
350 ml. of water-wet ether and then 150 g. of sodium 5 100 ml. of ethanol. The resulting. solution was heated
in a sealed tube at 100° under 500 p.s.i. of nitrogen for
chloride and 90 ml. of water. The solid which formed
18 hours.v The volatiles were distilled off, the residue
was ?ltered off and washed with ether. The ?ltrate and
was made strongly alkaline with aqueous potassium hy
ether washings were combined, washed with water, dried
droxide andv extracted with ether. The. ether extract
over anhydrous sodium sulfate and the ether was dis
tilled oil. 40 g. of residual oil comprising crude N-(3 10 was Washed with water, dried over anhydrous sodium
dimethylaminopropyl) - N’ - [1 - methyl - 3 - (2,6,6 -
sulfate and the ether was distilled off.
trimethyl - l - cyclohexen - l “ yl)propyl] - ethylenedi
(2 - dimethylaminoethyl) ~ N’ - [.1 - methyl - 3 - (2,6,
6 - trimethyl - 1 - cyclohexen - l - yl) propyl1- N,N' - di
amine were dissolved in ethanol, alcoholic hydrogen chlo
The residue, N
methyl-1,3-propanediarnine, was dissolved in ethanolic ’
ride was added until the solution was acid to Congo red
and the volatiles were distilled oil. The residue was 15 hydrogen chloride. The volatiles were removed and the
crystallized from ethanol-acetonitrile-ether. The N-(3
_ resulting gum was crystallized from ethanol-hexane to
obtain N - (Z-dimethylaminoethyl)-N’-[l-methyl-3-(2,6,
dimethylaminopropyl) ~ N’ - [1 - methyl - 3 - (2,6,6 -
trimethyl - 1 - cyclohexen - 1 - y1)propyl] - ethylenedi
6 - trimethyl -’1 - cyclohexen - 1 ~ yl)propyl] - N,N' -
amine trihydrochloride hemihydrate melted at 194—l95°,
dimethyl-1,3-propanediamine' trihydrochloride sesquihy
with sintering at 180°.
drate, M.P. 227-239°, with dec.
Example 8
To 16 g. (0.036 mol) of N-(3-dimethylaminopropyl)
Example’IO
. 212 g. (4 mols) of acrylonitrile were added, with stir
N’ - [1 - methyl ~ 3 - (2,6,6 - trimethyl - 1 - cyclohexen -
ring, to 612 g. (6 mols) of 37dimethylaminopropylamine
1-yl)propyl]-ethylenediamine were added 29 ml. (0.48
mol) of formic acid (90%). The resulting solution was
cooled, then 14.5 ml. (0.165 mol) of formaldehyde
(37%) were added.
The solution was heated at steam
over a two hour period so that the reaction temperature
remained below 30°.
days. It was then fractionally distilled giving, 3-(3-di
temperature ‘with occasional shaking ‘for: 3 hours and
then re?uxed for 4 hours.
The volatiles were distilled
OK at steam temperature under water vacuum.
The re
sidual oil was dissolved in excess ethanolic hydrogen
chloride and the solution was evaporated to dryness. The
residual gum was crystallized from methanol-acetone to
obtain N - (3 - dimethylaminopropyl)-N’-[1-rnethyl-3—(2,
6,6 - trimethyl - l - cyclohexen- 1 - yl)propyl]-N,N’ -
dimethylethylenediamine trihydrochloride hemihydrate,
M.P. 204—206°, with dec.
The solution, at room tempera
' ture, was stirred for ?ve hours and then stored for four
methylaminopropylamino ) propionitrile, B.P.17 130 ° .
30
To 193.5 (1.24 mols) of 3-(dimethylaminopropyl
amino)-propionitrile dissolved in 500 ml. of‘ 10% am
monia in ethanol, were added 6 teaspoons of Raney
nickel. The mixture was hydrogenated at 100° and
1,000 p.s.i. The catalyst was ?ltered off andlthe vol
35 atiles were removed from the ?ltrate ‘by distillation. The
residual oil was fractionated in vacuo to obtain N-(3-di
\ methylaminopropyl) -l,3-propanediamine, B.P.U,1 67".
An aliquot,_when treated with ethanolic hydrogen chlo
ride and crystallized from methanol-ether, gave the crys
Example 9
talline trihydrochloride, M.P. 219—220°.
'
To 290 g. (1.52 mols) of ?t-ionone suspended in ice 40
4teaspoons of Raney nickel were added to 76 g. (0.4
cold methanol were added 6 tsps. of Raney nickel and
mol) of ?-ionone and 67 g. (0.42 mol) of N-(3-di
197 g.v (1.68 mols) of 3-(Z-hydroxyethylamino)propyl
methylaminopropyl)-1,3-propanediamine. The mixture
amine. The mixture was hydrogenated at 100° under
was diluted with ethanol to 300 ml. and hydrogenated
pressure of'l,000 psi. The catalyst was ?ltered off and
at 100° and 1,000 p.s.i. The catalyst was ?ltered off
the solution was concentrated. The residual oil was frac
tionated in vacuo to obtain N'-(2-hydroxyethyl)-l\l-[l
45
methyl - 3 - (2,6,6, - trimethyl - 1 - cyclohexen - 1 - yl) -
and the volatiles were removed from the ?ltrate by dis
tillation. The residual oil was fractionatedin vacuo to
obtain
'propyl]-l,3-propanediamine, B.P.0_5 178—l83°. All Elli
N - (3 - di-rnethylaminopropyl) - N’ - [l - methyl
3 - (2,6,6 - trimethyl - 1 - cyclohexen - 1 - yl)propyll
quot, when treated with alcoholic hydrogen chloride and
1,3-propanediamine in the form of an oil, B'.P.o,3 155
crystallized from ‘ethanol, gave the crystalline dihydro 50 168°. The oil was dissolved in ethanol, ethanolic hy
chloride, M.P. 235~237°.
drogen chloride was added until acid to ‘Congo red and
To 116 g. (0.4 mol) of N’-(2-hydroxyethyl)-I~l-[l
the solution was then evaporated to dryness. The re
methyl - 3 - (2,6,6 - trimethyl - 1 - cyclohexen - l - yl) -
sidual
solid,
N - (3 - dimethylaminopropyl) - N’ - [1
propyl] -1,3-'propanediarnine were added 160 ml. (2.67
mols) of formic acid (90%). The resulting solution
was cooled, then 80 ml. (0.91 mol) of formaldehyde
_propyl] ~ 1,3 - propanediamine trihydrochloride
(37%) were added.
with dec.
methyl - 3 -‘(2,6,6 - trimethyl - 1 - cyclohexen - 1 - yl)
hemi
hydrate, was crystallized from ethanol, M.P. 262-264°,
The solution was heated at steam
temperature with occasional shaking for 3 hours and then
Example 11
re?uxed for 4 hours. The volatiles were distilled oit‘ at
33.7 g. (0.1 mol) of N—(3-dime'thylaminopropyl)-N’
steam temperature under water vacuum. The residual 60
[l - methyl - 3 - (2,6,6 - trimethyl _ 1 - cyclohexen - 1
oil was dissolved in excess ethanolic hydrogen chloride
yl)propyl]-1,3-propanediamine, 40 ml. (0.67 mol) of
and the solution was evaporated to dryness. The resid
formic acid (90%) and 20 ml. (0.23 mol) of formal
ual gum was crystallized from ethanol-ether to obtain
N’ - (2 - hydroxyethyl) - N '- [1 - methyl - 3- (2,6,6 , trimethyl - 1 - cyclohexen - l - yl)propyl1 - N,N' - di
65
dehyde (37%) were reacted according to the procedure
described in Example 9 to obtain N-(3-dimethylamino
methyl-1,3-propanediamine dihydrochloride hemihydrate,
propyl) - N’ - [1 - methyl - 3 - (2,6,6 - trimethyl - 1~
M.P. 116-118°.
To a solution of 40.7 g. (0.1 mol) of l ’-‘(2-hydroxy
panediamine trihydrochloride hemihydrate, M.P. 259
ethyl) - N - [1 - methyl - 3 - (2,6,6 - trimethyl - 1 - cyclo
261°, with dec.
hexen - 1 - yl)propyl] - N,N’ - dimethyl - 1,3 ~ propane
-dia1nine dihydrochloride heruihydrate in 500ml. of chlo—
roform which had been saturated with hydrogen chlo
ride at 4° were slowly added 22 ml. (0.32 mol) of thionyl
cyclohexen - 1 ~ yl)propyl] - \T,N' ~ dimethyl - 1,3 - pro
~
An aqueous solution containing 16.1 g.. (0.03 mol) ‘
of the hydrochloride obtained above was made alkaline
with sodium carbonate and extracted with ether. The
ether extract was washed with water, dried over anhy
drous sodium sulfate and the ether was distilled off.
chloride over a half-hour period. The solution was
stirred for an additional 1% hours at 4°, allowed to 75 The residual oil comprising N-(3-dimethylaminopropyl)
2,922,301
»
7
6
Example 14
An aqueous solution containing 9.2 g. (0.02 mol) of
N’ - [1 - methyl - 3 - (2,6,6 - trimethyl - 1 - cyclohexen
1 - yl)propyl] - N,N' - dirnethyl - 1,3 - propanediamine
was dissolved in dry benzene and the benzene was dis
tilled 011;
1 - [2 - methyl - 4 - (2,6,6 - trimethyl - 1 - cyclohexen
1 - yl)butyl] - 1,4,7,7 - tetramethyldiethylenetriamine‘
Example 12
The residual oil comprising N- (3 -dimethylamino
Ur
trihydrochloride was rendered alkaline with sodium car-I
bonate and extracted with ether. The ether extract was
washed with water, dried over anhydrous sodium sulfate‘
and concentrated. The residual oil was dissolved in dry
propyl) - N’ - [1 - methyl - 3 - (2,6,6 - trimethyl - 1 - cy
cyohexen - 1 - y1)propyl_] - N,N’ - dimethyl - 1,3 - pro
benzene and then the benzene was distilled ed. The‘
panediamine obtained in Example 11 was dissolved in
250 ml. of acetone containing 80 got methyl bromide. 10 oil was then dissolved in 50 ml. of methanol and 15
The solution was stored in a tightly stoppered flask at
ml. of methyl iodide were added.
room temperature for 15 hours.
standing at room temperature for 48 hours, was evapo~~
The crystals‘ which
The solution, after
formed were ?ltered o?, washed with acetone and re
rated to dryness.
crystallized from isopropanol-acetone.
(2,6,6 - trirnethyl - 1 - cyclohexen - 1 - yl)butyl] - 1,4,7,7-~
The N - (3 - di
methylaminopropyl) - N’ - [‘ - methyl - 3 - (2,6,6 - tri~
The residual solid, 1-[2-methyl-4-
tetramethyldiethylenetriamine tri(methiodide) monohy
_
drate, was crystallized from ethanol, MP. 190-192",
with dec.
methyl - 1 - cyclohexen ‘- 1 - yl)propyl] - N,N' - dimethyl
1,3-propanedia-mine tri(methyl bromide) monohydrate
Example 15
melted vat 210-213“, with dec.
To
58
9.
(0.5
mol)
of
4-dimethylaminobuty-lamine were
Example 13
20
added 21.2 g. (0.4 mol) of acrylonitrile over a two
123.6 g. (0.6 mol) of ;5’-C14-aldehyde and 61.2 g. (0.6
hour period at a temperature below 30° with stirring.
mol) of 2-hydroxyethylethylenediamine were reductiveiy
condensed according to the procedure described in Ex
ample 9 to obtain N’-(2-hydroxyethyl)-N§[2-methyl-4
(2,6,6 - trimethyl - 1 - cyclohexen - 1 - yl)butyl] - ethyl
The reaction mixture was stirred for ?ve hours at room
temperature, then one hour at 100°, and ?nally traction
ally distilled. 56 g. of the distillate boiling at 103-105 °
25 at 0.7 mm. were dissolved in 100 ml. of 10% ammonia
enediamine, B.P.0,1 165". An aliquot, when treated with
in ethanol and reduced in the presence of Raney nickel
ethanolic hydrogen chloride and crystallized from meth
catalyst at 800 -p-.s.-i. of hydrogen and 70°. The catalyst
anol-ether, gave the crystalline dihydrochloride mono
was ?ltered oil, the‘ solution was concentrated and the
hydrate, M.P. 229—231°, with sintering at 175 °.
residual oil was fractionally distilled to obtain N-(4-di
143 g. (0.5 11101) of N’-(2-hydroxyethyl)-N-[2-methyl 30 methylaminobutyl)-1,3-propanediamine, 3.13.02 75-76".
4 - (2,6,6 - trimethyl - 1 - cyclohexen- l -yl)butyl]
3 teaspoons of Raney nickel were added to 30.5 g.
ethylenediamine, 200 ml. (3.35 mols) of formic acid
(90%) and 100 ml. (1.15 mols) formaldehyde (37%)
were reacted according to the procedure described in
Example 9 to obtain N'-(2-hydroxyethyl)-N-[2-methyl
4 - (2,6,6 - trimethyl - 1 - cyclohexen - l - y1)butyl]
N,N'-dimethylethylenediamine dihydrochloride monolay
drate, M.P. 195-197° (crystallized from ethanol-ether .
(0.16 :mol) of ?-iononeand 30.0 g. of N-(4-dimethyl
aminobutyl)-1,3-propane diamine. Ethanol was added to
a volume of 300 ml. The mixture was hydrogenated at
35
100° and a pressure of 1,000 p.s.i. The catalyst was
?ltered off, the ?ltrate was concentrated and the residual
oil was fractionated in vacuo to obtain N-(4-dimethyl
aminobutyl) - N’ - [1-rnethyl-3-(2,6,6-trimethyl-l-cyclo
To 50 g. (0.12 mol) of N’—(2~hydroxyethyl)~N-[2
methyl - 4 - (2,6,6 - trimethyl - 1 - cyclohexen - 1 - yl)»
butyl] - N,N' - dimethylethylenediamine dihydrochloride
monohydrate dissolved in 700 ml. of chloroform which
had been saturated with hydrogen chloride at 4° was
slowly added 34- ml. (0.49 mol) of thionyl chloride
40
hexen-1-yl)propyl] — 1,3 - propanediamine, B.P.0_05 170
182°.
An aliquot, when treated with an excess of hy
rogen chloride in ethanol and crystallized from ethanol,
gave the crystalline tri~hydrochloride, Ml’. 274-276",
with dec.
’
over a period of one hour. The solution was stirred
for an additional two hours at 4°, allowed to warm to
xample 16
T030 g. (0.08 mol) of N-(4-dimethylarninobutyl)-N’
room temperature and then re?uxed and stirred for six
hours. The mixture was then cooled and the precipitate
[l-methyl - 3 - (2,6,6-trimet‘nyl-l-cyclohexen-l-yDpro
acetone-ether
with occasional shaking for one hour and then refluxed
for eight hours. The volatiles were distilled off at steam
temperature under water vacuum. The residual oil, com
pyl]-,3-propanediamine were added 40 ml. (0.67 mol)
which formed was ?ltered off. The ?ltrate was evapo
of formic acid (90% ). The resulting solution was cooled,
rated to dryness, the residue was combined with the 50 then 20 ml. (0.23 mol) of formaldehyde (37%) were
precipitated material and crystallized from methanol
added. The solution was heated at steam temperature
to
obtain N’ - (2 - chloroethyl) - N - [2
methyl - 4 - (2,6,6 — trimethyl - 1 - cyclohexen - 1 - yl)
butyl] - N,N’ - dimethylethylenediamine dihydrochloride
monhydrate, Ml’. 179-181".
To 44.3 g. (0.1 mol) of N'-(2-chloroethyl)-N-[2
prising crudc N-(4-dimcthylaminobutyl)-N'~[l-methyl-3
methyl ~ 4 ~ (2,6,6 - trimethyl - 1 - cyclohexen - 1 - yl)
methyl-1,3—propanediamine, was dissolved in excess eth
(2,6,6-trimethyl » 1 - cycloh-exen-l-yUpropyll-N,N'-di
butyl] - N,N' - dimethylethylenediamine dihydrochloride
anolic hydrogen chloride and the solution was evaporated
monohydrate were added 33.4 g. (0.58 mol) of dimethyl—
to dryness. The resulting gum was crystaiiized from eth
amine in 200 ml. of methanol. The mixture was‘ heated 60 anol-ethyl acetate to obtain N-(4-dimethylaminobutyl)
in a sealed tube under 500 p.s.i. of nitrogen at 100°
N’-[1-methyl — 3 - (2,6,6-trimethyl-l-cyclohexen-l-yl)
for 18 hours. The volatiles were distilled off, the resi
propyl]-N,N’-dimethyl-1,3-propanediamine
trihydrochlo
due was ‘made strongly alkaline with aqueous sodium
ride monohydrate, MP. 236-238”, with dec.
hydroxide and extracted with ether. The ether extract
was washed with water, dried over anhydrous sodium
sulfate and the ether was distilled oil. The residue,
,
comprising crude 1 - [2 - methyl - 4 - (2,6,6 - trim-ethyl
1 - cyclohexen - 1- yl)butyl] - 1,4,7,7 - tetramethyl di
ethylenetriamine, was dissolved in ethanol, ethanolic hy
Example 17
To 300 mg. of rhodium-on-carbon were added 10 g.
(0.02 mol) of N-(S-dimethylaminopropyl)-N’-[1-methyl
3-(2,6,6-trimethyl - 1 - cyclohexen-1~y )propyl'j-1,3-pro—
panediamine trihydrochloride hemihydrate dissolved in
drogen chloride was added until acid to Congo red and 70 100 ml. of ethanol. The mixture was hydrogenated at
then the solution was concentrated. The resulting gum
was crystallized from methanol-ether to obtain 1- [2
methyl - 4 - (2,6,6- trimethyl - 1 - cyclohexen - 1 - yl)
butyl] - 1,4,7,7 - tetramethyldiethylenetriamine
drochloride, Ml’. 252-254’.
trihy
100° and a pressure of 1,000 psi. The catalyst was ?l
tered cit and the ?ltrate was concentrated. The residual
solid, N-( 3~dimethylaminopropyl) -N’- [1-methyl-3-(2,6,6
75 trimethyleyclohexyl)propyl] - 1,3 - propanediamine trihy
3,022,301
10
Q
(2,6,6 - trimethyl - 2 - cyclohexen-l-yl)-propyl]-1,3-pro
drochloride, Was'crystallized from methanol-acetonitrile,
panediamine, B.P.(,_3 171°. The latter, when treated with
ethanolic hydrogen chloride and crystallized from ethanol,
gave the crystalline trihydrochloride sesquihydrate, M.P.
M.P. 262-264°, with dec.
Example 18
41.2 g. (0.2 mol) of cis-tetrahydroionone and 35.1 g.
250—252°, with vdee.
(0.22 mol) of N-(3-dimethylaminopropyl)-1,3-propane
dramlne were hydrogenated in the presence of R'aney
nickel catalyst according to the procedure described in
Example 17 to obtain N-(3-dimethylaminopropyl)-N'-[1
methyl ~ 3 - (2,2,6-trirnethylcyclohexyl)propyl]-1,3-pro
panediamine trihydrochloride, M.P. 262-264", with dec.
(crystallized from methanol-acetonitrile).
Example 19
Example 25
44.7 'g. (0.1 mol) of N-(3-dimethylaminopropyl)-N'
[1 - methyl - 3 - (2,6,6 - trimethyl - 2 - cyclohexen - 1
y1)propyl]-1,3-propanediamine, 40 ml. of formic acid
10 (90%) and 20 ml. of formaldehyde (37%) were reacted
according to the procedure described in Example 16 to
obtain N-(3-dimethylaminopropy1)-N’-[1-methyl—3-(2,6,
6 - trimethyl - 2 -. cyclohexen - 1 - y1)propy1] - N,N'
dimethyl ~ 1,3 - propanediamine trihydrochloride hemi
82.5 g. (0.4 mol) of ?-Cm-aldehyde and 67 g. (0.42 15 hydrate, M.P. 259~260°, with dec. (crystallized from
mol) of N-(3-dimethylaminopropyl)-1,3-propanediamine
ethanol).
were hydrogenated in the presence of Raney nickel cat
alyst according to the procedure described in Example 15
to
obtain
20
diamine, B.P.0,3 174“. An aliquot, when treated with
ethanolic hydrogen chloride and crystallized from ethanol,
gave the crystalline trihydrochloride dihydrate, M.P. 227
229°, with dec.
Example 26
To 17 g. (0.038 mol) of.N-(3-dimethylaminopropyl)~
N- ( 3-dirnethylaminopropyl) -N'- [2-methyl-4
(2,6,6-trimethyl - 1 - cyclohexen-l-yl)butyl]-1,3-propane
.
'
N’ - [1 - methyl - 3 - (2,2,6 - trimethylcyclohexyl)pro
pyl]-1,3-propanediamine, 20 ml. of formic acid (90%)
and 14 ml. of formaldehyde (37%) were reacted accord
‘ing'to the procedure in Example 16 to obtain N-(3-di
methylaminopropyl) - N' - [1 - methyl - 3 - (2,2,6 - tri
~
Example 20
35.1 g. (0.1 mol) of N-(3-dirnethylaminopropyl)-N'
25 methylcyclohexyhpropyl] - N,N’ - dimethyl - 1,3 - pro
panediamine trihydrochloride, M.P. 262-264°, with dec.
(crystallized from methanol-ether) .
[Z-methyl - 4 - (2,6,6-trimethy1-l-cyclohexen-l-yl)butyl]
Example 27
1,3-propanediamine, 40 ml. of formic acid (90%) and
19 ml. of formaldehyde (37%) were reacted according
54.4
g.
(0.2
mol)
of
N-[l-methyl-3-(2,6,6-trimethy1-1
to the procedure described in Example 16 to obtain N~(3 30 cyclohexen-l-yl)propyl]-u-chloroacetamide and 42.5 g.
dimethylaminopro-pyl)-N'-[2-methyl - 4 - (2,6,6-trimeth
(0.3 mol) of N-aminopropylmorpholine were reacted
yl - 1 - cyclohexen - 1 - yl)butyl]-N,N'-dimethyl-l,3-pro
according to the procedure described in Example 1 to
pandiamine trihydrochloride monohydrate, M.P. 278~
279°, with dec. (crystallized from ethanol).
Example 21
67.2 g. (0.29 mol) of 6-(2,6,6-trirnethyl-l-cyclohexen
1-yl)-4-methyl-2,4-hexadien-l-al and 49 g. (0.31 mol)
of N-(3-dimethylaminopropyl)-1,3- propanediamine were
reacted according to the procedure described in Example
obtain ' a- [3-(4-morpholinyl ) propylamino] -N- [ l-methyL
3-(2,6,6-trimethyl f 1 - cyclohexen-1-yl)propyl] -acetamide
‘dihydrochloride monohydrate, M.P. 193-195", with dec.
Example 28
.
.
. 96 g. (0.5 mol) of isoionone [4-(5-isopropenyl-2-meth
40 ‘yl-l-cycl0penten-1-yl)-2-butanone] were reductively con
densed with excess ammonia according to the procedure
15 to obtain N-(3-dimethylaminopropyl)-N’-[4-methyl~6
described in Example 5 to obtain 1-methyl-3-(2-methyl
(2,6,6 - trimethyl-l¢cyclohexen-1-yl)hexyl]-l,3~propane
5-isopropyl-l-cyclopenten-l-yl)propylamine, B.P.0_o1 61°.
diamine, B.P.Q_1 176-181". The latter was treated with
ethanolic hydrogen chloride and crystallized from Water~ ‘
ethanol to obtain the crystalline trihydrochloride rhemihy
drate, M.P. 260~262°, with 'dec.
Example 22
80 g. (0.29 mol) of [Him-aldehyde and 49 g. (0.31
mol) of N-(3-dimethylaminopropyl)-l,3-propanediarnine
were reacted according to the procedure described in 'Ex
ample 15 to obtain N-(3-dimethylaminopropyl)-N'-[2,6~
dimethyl - 8 - (2,6,6-trimethyl-l-cyclohexen-1-yl)octyl]~
45
68 g. (0.35 mol) of 1-rnethyl-3-(2-methyl-5-isopropy1
l-cyclopenten-1-yl)propylamine and 40 g. (0.35 mol) of
tchloroacetyl chloride were reacted according to the pro
cedure described in Example 5 to obtain N—/[1-methyl-3
(2 - methyl - 5- isopropyl - 1 ~ cyclopenten - 1 - yl)pro
pyll-a-chloroacetamide, B.P.0_06 135°.
'
23 g. (0.084 mol) of N-[1-methyl-3-(2-methyl-5-iso
propyl - 1 - cyclopenten — 1 - yl)propyl] - a --chloroacet_
‘amide and 12.8 g. (0.13 mol) of 3-dimethylaminopropyl
amine were reacted according to the procedure described
in Example 4 to obtain a-[3-dirnethylaminopropylamino]
1,3-propandiamine, B1101 180—185°. The latter, when
N - [l - methyl - 3 - (2 - methyl - 5 - isopropyl - 1 - cyclo
treated with ethanolic hydrogen chloride and crystallized 55 penten-l-yl)propyl] ~ acetamide dioxalate monohydrate,
from Water-ethanol, gave the crystalline trihydrochloride
.M.P. 173—175'° (crystallized from methanol).
sesquihydrate, M.P. 259~261°, with dec. '
.
Example 29
xample 2:7
60 i 76 g. (0.4 mol) of isoionone and 67 g. (0.42 mol) of
31 g. (0.07 mol) of N-(3~dimethylaminopropyl)-N'
N-(3-dimethylaminopropyl)-l,3-propanediamine were re
[2,6 - dimethyl - 8 - (2,6,6-trimethyl-l-cyclohexen-l-yl)
acted inthe presence of Raney nickel and hydrogen
octyl]-1,3-propanediamine, 30 ml. of formic acid (90%)
according to the procedure described in the second para
and 15 ml. of formaldehyde (37%) were reacted accord
graph of Example 15 to obtain N-(3-dimethylaminopro
ing to the procedure described in Example 16 to obtain
pyl) - N’ -. [1 -v methyl - 3 - (2 - methyl -,5 - isopropyl
N - (3-dimethylaminopropyl)-N’-[2,6~dimethyl-8-(2,6,6
trimethyl - 1 - cyclohexen-l-yl)octyl]-N,N’~dimethyl-l,3
propanediamine tri-hydrochloride' monohydrate, M.P.
227-229", with dec. (crystallized from acetonitrile
ethanol).
'
'
Example 24
56 g. (0.29 mol) of a-ionone and 49 g. (0.31 mol) of
N-(3-dimethylaminopropyl)-1,3-propanediamine were re
- acted according to the procedure described in Example 15
1 - cyclop'enten - 1 - -yl)propyl] - 1,3 - propanediamine,
B.P.g_15 182°.
_
‘
I
v
34.1 g. (0.1 mol) of N-(3~dimethylaminopropyl)-N‘
[1 _- methyl -'3 - (2 - methyl - 5 - isopropyl - 1 - cyclo
70 vpenten-1-yl)propyl]—1,3-propanediamine, 40 ml. of formic
acid (90%) and 20 ml. of formaldehyde (37%) were
reacted according to the procedure described in Example
16 to obtain N-(3-dimethylaminopropyl)-N’-[1-methyl—
3 - -.(2 - methyl - 5 - isopropyl - 1 - cyclopenten- 1 - yl)
tov obtain N-(3-dimethylarninopropyl)7N’-[l-methyl-3 75 propyl]p-N,N'-dimethyl-1,3-propanediarnine trihydrochlo
3,022,801
it
12
mine trihydrochloride sesquihydrate, M.P. 27 0-272°, with
sintering at 235° (crystallized from water-ethanol).
Example 33
ride sesquihydrate, M.P. 263-265", with dec. (crystal
lized from ethanol-acetonitrile) .
'
Example 30
103 g. (0.5 mol) of ot-irone and excess ammonia were
6 teaspoons of Raney nickel (ethanol washed) were
added to 78.6 g. (0.39 mol) of 3-[3-(4~morpholinyl)
propylamino]—propylarnine and 68.5 g. (0.35 mol) of
cis-tetrahydroionone in 200 ml. of ethanol. The mixture
methyl-Z-cyclohexen-i-yl)propylamine, HP.“ 74°, 11D"
to obtain N-[3-(4-morpholinyl)propyl]-N'-[1~methyl-3—
ethanol-ether) .
reductively condensed according to the procedure de
scribed in Example 5 to obtain 1-methyl-3-(2,5,6,6-tetra
1.4785. An aliquot, when treated with an excess of phos
was hydrogenated at 100° and at a pressure of 1,000
p.s.i. The catalyst was ?ltered off and the solution was 10 phoric acid in ethanol, gave the crystalline diphosphate,
M.P. 280-2.82°, with sintering at 135° (crystallized from
concentrated. The residual oil was fractionated in vacuo
36.4 g. (0.174 mol) of 1-methyl-3-(2,5,6,6-tetramethyl
2-cyclohexen-1-yl)propylamine and 19.7 g. (0.174 mol)
( 2,2,6 - trimethylcyclohexyl)propyl]-1,3-propanediamine,
B.P.o_05 171-186", nD23 1.14901. An aliquot when
treated with an excess of hydrogen chloride in ethanol, 15 of chloro-acetyl chloride were reacted according to the
procedure described in Example 5 to obtain N-[l-methyl
gave the crystalline trihydrochloride. After crystalliza
tion from 95% ethanol-ether, it decomposed at 288°.
3 - (2,5,6,6 - tetramethyl - 2 - cyclohexen - 1 - yl)propyl]
a-chloroacetamide, B11002 130°, nD25 1.5015.
7 To 36 g.- (0.097 mol) of N-_[3-(4-morpholinyl)propyl]~
20 g. (0.07 mol) of N-[1-rnethyl-3,—(2,5,6,6-tetrarneth
pyl]-1,3-propanediarriine were slowly added 65 ml. (1.27 20 yl~2-cyclohexen-1-yl)propyl] -a-chloroacetamide, and 10.7
g. (0.105 mol) of 3-dimethylaminopropylamine were re
mole) of. formic acid (90%). The resulting solution
acted according to the procedure described in Example 1
was cooled and 45‘ ml. (0.52 mol) of formaldehyde
N’ - [1 - methyl g 3 - (2,2,6 - trimethylcyclohexyDpro
(37%),were then added.
to ‘ produce oc- [3-dimethy1amino-propylamino] -N— [ l-meth
The mixture was heated at
yl - 3 - (2,5,6,6 - tetrarnethyl - 2 - cyclohexen - 1 - yl)
steam bath temperature with occasional shaking for 2
hours and then re?uxed for 8 hours. The volatiles were
distilled off, the residual oil was dissolved in excess eth
anolic hydrogen chloride and the solution was then
evaporated to dryness. The resulting gum was crystal
lized from ethanol to obtain N-[3-(4-morpholinyl)pro
propyll-acetamide dihydrochloride monohydrate, M.P.
'
pyl] - N’ - [1 - methyl - 3 - (2,2,6 - trimethylcyclohexyl)
156-458“, with sintering at 135° (crystallized from
ethanol-acetonitrile-ether) .
Example 34
82.5 g. (0.4 mol) of m-irone and '67 g. (0.42 mol) of
30
N-(3-dimethylaminopropyl)-1,3-propanediamine were re
propyl]-N,N’-dimethyl-1,3-propanediamine trihydrochlo
acted according to the procedure described in Example 15
to obtain N-(3-dimethylarninopropyl)-N’-[1-methyl-3
ride, M.P. 281~283°, with dec.
Example 31
(2,5,6,6 - tetrarnethyl - 2 ? cyclohexen - l - yl)propyl]
1,3-propanediarnine, B.P.9.1 175°, 111326 1.4845. An ali
quot, when treated with ethanolic hydrogen chloride,
73.4 g. (0.37 mol) of 3-[3-(1-piperidyl)propylamino]
propylarnine and 68.5 g. (0.35 mol) of cis-tetrahydro
gave the crystalline trihydrochloride monohydrate, M.P.
243—244°, with dec. (crystallized from ethanol).
Example 35
35.2 g. (0.1 mol) of N-(3-dimethylaminopropyl)~N'
ionone were reductively condensed according to the pro
cedure described in Example 30 to obtain N-[3-(1-pi
peridyl)propyl] - N’ - [1 - methyl - 3 - (2,2,6 - trimethyl
cyclohexyl)propyl] ~ 1,3 - propanediamine, B.P.0_05 195
205°, n;;26 1.4889. An aliquot, when treated with an
excess of hydrogen chloride in ethanol, gave the crystal
line trihydrochloride, M.P. 286-288", with dec. (crystal
[1 - methyl - 3- (2,5,6,6 - .tctrarnethyl - 2 - cyclohexen
1-yl)propyl]-1,3-propane-diamine, 40 ml. of formic acid
, (90%) and 20 ml. of formaldehyde (37%) were re
lized from water-acetone) .
. Treatment of 26.5 1g. (0.07 mol) of N-[3-(1-piperidyl)- '
acted according to the procedure described in Example
16 to produce N-(3-dirnethylaminopropyl)-N'-[l-methyl
propyl] - N’ - [1 - methyl - 3 - (2,2,6 - trimethylcyclo
3 - (2,5,6,6 - tetramethyl - 2 - cyclohexen - 1 -yl)-propyl]
hexyl)propyl] - 1,3 -propanediamine with 45 ml. (0.88
N,N'-dimethyl-1,3-propanediamine trihydrochloride herni
mol) of formic acid (90%) and 30 ml. (0.35 mol) of
formaldehyde (37%) according to the procedure de
scribed in Example 30 yielded N-[3-(1-piperidyl)propyl]
N’ — [1 - methyl - 3 - (2,2,6 - trimethylcyclohexyl)pro
pyl] -N,N'-dimethyl-1,3-propanediamine trihydrochloride,
M.P. 253-254“, with dec. (crystallized from methanol
hydrate, M.P. 252—253°, with dec. ‘(crystallized from
50
ethanol).
We claim:
1. A compound selected from the group consisting of
triamines represented by the formula
ether).
Example 32
78.6 g. (0.39 mol) of 3-[3-(4-morpholinyl)propyl
amino]-propylamine and 68.5‘ g. (0.35 mol) of 4-(2-meth
yl-5-isopropylcyclopentyl)-2-butanone were reductively
condensed according to the procedure. described in Ex
ample 30 to yield N-[3-(4-morpholinyl)propyl]-N'-[1
methyl - 3 - (2 — methyl - 5 s isopropylcyclopentyl)pro
I hit
1th
-
R2
wherein R represents the cyclic moiety of a member se
lected from the group consisting of saturated and unsatu
60 rated ionone, irone and isoionone, R1 represents a mem
ber of the group consisting of hydrogen and lower alkyl,
and the group
‘
pyl]-1,3-propanediamine, 13.13.9116 166-171", nnzs 1.4846.
An aliquot, when treated with an excess of hydrogen
chloride in ethanol, gave the crystalline trihydrochloride
hemihydrate, M.P. 285—288°, with dec. (crystallized from .
water-acetone) .
. Treatment of 23.5 g'. (0.063 mol) of N-[3-(4-rnorpho~
.
R2
‘
represents a tertiary amino radical selected from the group
consisting of di-lower alkylamino and, when taken to
gether, polymethylene and polymethyleneoxy groups
isopropylcyclopentyl)propyl]-1,3-propanediamine with 65 70 forming a saturated 5 to 6 membered monocyclic ring
containing one hetero-nitrogen atom and up to one hetero
(1.27 mols) of formic acid (90%) and 45 ml. (0.52
mol) of formaldehyde (37%) according to the procedure
oxygen atom, medicinally acceptable acid addition salts
described in Example 30 yielded N-[3-(4-morpholinyD
and medicinally acceptable quaternary salts of said tri
propyl] - N’ - [1 - methyl - 3 - (2 - methyl - 5 - isopropyl
amines, said quaternary salts being selected from the
cyclopentyhpropyl] - N,N’ - dimethyl - 1,3 - propanedia 75 group consisting of alkyl and aralkyl quaternary salts.v
linyl) Y~ propyl] ~ N’ - [1 - methyl - 3 - (2 - methyl - 5
3,022,301
2. A compound represented by the formula
CH:
14
wherein R represents the cyclic moiety of a member
CH;
\ /
/C\
lower alkyl
112C!) (‘JI-—alky1ene——NH——lower alky1ene—NH—-lower alkylene-N
H,O\ /C\
lower alkyl
C
H:
CH!
3. Acompound represented by the formula
CH3
selected from the group consisting of saturated and un
CH3
\ /
/ \
HzC
lower alkyl
(iJ-—-alkylene—N—lower alkylene-N-lower alkylene-N
Ha \ /C\
0
H2
lower alkyl
lower alkyl
lower alkyl
0H:
4. A compound represented by the formula
CH:
\ /
saturated ionone, irone and isoionone, R1 represents a
CH;
/C\
lower alkyl
H2O
(’3H—alkylene——NH-—lower alkylone-NH-lower alkylene-N
HgC\C/C\H\
lower alkyl
H:
CH:
.
5. Acompound represented by the formula
CH:
member of the group consisting of hydrogen and lower
CH;
lower alkyl
H20
/ \
Hz
/
(EH-alkylemr-N-lower alkylene—-N—-—lower alkylene-N\
Cg
C
H:
lower alkyl
lower alkyl
lower alkyl
OH:
6. N - (3 - dimethylaminopropyl) - N' - [1 - methyl- 35 alkyl, and the group
3 - (2,2,6 - trimethylcyclohexyl)propyl] - N,N' - dimeth-
R“
yl - 1,3 '- propancdiamine.
- \
7. N - (3 - dimethylaminopropyl) - N' - [1 - methyla 3 - (2,2,6 - trimethylcyclohexy1)propyl] - N,N' - dimeth—
R,
‘
represents a tertiary amino radical selected from the
40 group consisting of di-lower alkylamino and, when taken
yl - 1,3 - propanediamine hydrochloride.
together, polymethylene and polymethyleneoxy groups
8. N - (3 - dimethylaminopropyl) - N' - [2 - methyl
.
4 ' $2516 ' mmethyl " 1- " cyclf’hefien ' 1 " yl) ' Putyu'
forming a saturated 5 to 6 membered monocyclic ring
containing one hetero-nitrogen atom and up to one hetero
N,N -d11nethl/1-1,J 'pl'opalledlamme hydl'ochloflde-
oxygen atom, medicinally acceptable acid addition salts
9. N - (3 - dimethylarninopropyl) - N’ - [1 - methyl- 45 and medicinally acceptable quaternary salts of said tri
3 _ (2,6,6 _ trimethyl _ 1 _ cyclohexen _ 1 __ yl)pmpyn_
amines, said_quaternary salts being selected from the
N’N, _ dimethy1_ 1,3 _ propanediamine.
group consisting of alkyl and aralkyl quaternary salts.
2.71 -
’10- N " (3 ' dimethylaminopmpyl) ' N’ ‘ 1 ' methyl‘
3 - (2,6,6 - trimethyl - 1 - cyclohexen - 1 - yl)propyl]-
3 - dimeth lamino ro
lmino
- N -
1
melthyl - 3[- (2,6,6 - trimethylp- IPY eclyclohlexen - 1 351)
50
1,3 -propanediamine hydrochloride.
propyl] -acetamide.
13- a - [3 - (4 - morpholinynln'opylaml'nol - N - [1
methyl - 3 -(2,6,6 - trimethyl - 1 - cyclohexen - 1 - yl)
11. A compound selected from the group consisting of
amino-diamines represented by the formula
propyl] - acetamidc.
55
/R'
B-alkylene-NH-OO-lower alkylene—N—-lower alkylene-—N\
it,
B, 60
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,576,106
Cusic _____ ___________ __ Nov. 27, 1951
2,705,244
2,736,746
Goldberg et a], ________ __ Mar. 29’ 1955
Goldberg et a1. ___ ____ _,_ Feb. 28, 1956
‘
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