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Патент USA US2411664

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Patented Now-26, 1946 .
Karl Miescher, Riehen, and Adrian Marxer, Basel,
Switzerland, assignors to Ciba Pharmaceutical
Products, Incorporated, Summit, N. J., a cor
poration of New Jersey
No Drawing. ' Application July 6, 1942, Serial No.
449,960. In Switzerland July 25,1941
8 Claims. (GI. 260-5703)
In the great ?eld of application which has been
found for the reactions with organo-metal com
pounds, it is surprising that the preparation of
organo-metal compounds of halogenalkylamines
and their reaction with reactive organic com
pounds have not yet been described. As experi
ments have shown, 2-chloroethyl-diethylamine,
ample, an ether (diethyl ether, dipropyl ether,
amyl ether, anisole, etc).
As reactive compounds which may generally
, be caused to react with organo-metal compounds,
mention may be made of aromatic, fatty aro
matic, hydroaromatic, aliphatic, and hetero
cyclic aldehydes, ketones, esters and nitriles, such
as benzaldehyde, cuminaldehyde, veratric alde
for example, does not react with magnesium un
hyde, anisaldehyde, piperonal, naphthaldehyde, _
der the usual conditions.
The subject of the present invention now Iorms 10 benzonitrile, benzoic acid ester, formaldehyde,
acetaldehyde, trichloro- and tribromacetalde
a process for the preparation of amines, com
isobutyl aldehyde, oenanthole, citralde
prising reacting halogenamines, in which the
hyde, pyridyl aldehyde, furfurole, benzophenone,
halogen group is connected with the amino group
acetophenone, desoxybenzoin, diphenyl ketene,
by at least 3 carbon atoms, with metals and,
if desired, allowing the resultant organo-metal 15 acetone, methylethyl ketone, diethyl ketone, cy
clohexanone, camphor 1etc.
compounds to react upon those reactive organic
The present reaction‘ is preferably carried out
compounds which usually react with organo
by adding the reactive compound in portions to
metal compounds.
the organo-metal compound according to the
As parent materials use may be made of .any
of the reaction. The reaction is preferably
desired halogenamines of the aliphatic, arali .20 state
carried out at about 40-50” C. in such a manner
phatic, cycloaliphatic or heterocyclic series, in
that the exothermic reaction iscontinually in
which an alkyl chain may be branched or inter
progress. In this manner,‘ the magnesium com
rupted, for example, by oxygen, sulphur or nitro
pound of the aminoalcohol formed remains in
gen atoms. As examples, mention may be made
solution practically up to the end of the reac
of chloropropyl-diethylamine, bromopropyl-di
tion, whereas, by too rapid addition‘ 01 the re
ethylamine, bromopropyl-dibutylamine, iodopro
active compound, it falls out of solution, bring
- pyl-piperidine, chlorobutyl-dimethylamine, chlo
ing the reaction to a standstill and naturally
robutyl-dipentylamine, chlorobutyl-methyl-cy
reducing the yield to a considerable extent.
clohexylamine, chlorobutyl - ethyl - cyclohexyla 30
The end products either have therapeutic prop
mine, halogen-octyl-dialkylamines, and also com
erties or can serve as intermediate products for
pounds having still longer or more branching
the manufacture of therapeutically active sub
chains, as well as, for example, m- or p-halo
gen-cyclohexyl-dialkylamines, dialkylamino-al
kyl-cyclohexyl-halides, N-methyl-v-halogen-pi
peridines, or even chloroethyl-diethylaminoethyl
ethers and other halogen-alkyl ethers or sul
phides, and, further, halogen-alkylamino-alkyl
The following examples illustrate the inven
35 tion:
Example 1
4.8 grams of magnesium turnings (0.2 mol)
are activated with a little iodine and are cov
amines. Especially suitable are those halogena
mines in which the halogen and the amino group 40 ered with 20 cos. of absolute ether. The Grignard v_
‘reaction is started by addition of 0.7 cc. of ethyl '
are placed relatively distantly from one another.
bromide, and 30 grams (0.2 mol) of l-chloropro
Specially to be recommended are those halogen
pyl-(3) -diethylamine in 50 cos. of' absolute ether
amines which are disubstituted at the nitrogen
are allowed to run in over a period of 3-5 min
atom and in which the substituents are of high
molecular weight, such as chloropropyldibutyla 45 utes. 0.5 cc. of ethyl bromide is then added, and
the ?ask is gently warmed for 5 minutes. Only
mine and -diamylamine, etc. For the reaction
a very small portion of the magnesium is dis
with these halogenamines, metals such as mag=
solved, and a white precipitate of diethylamino
nesium, zinc, potassium, lithium, sodium, and
propyl-magnesium chloride is formed.
the like have proved suitable. In preparing the
The ?ask is now heated on a water bath to
organo-metal compounds, it is advisable to ac 50
45—50° C., and a total quantity of 18 grams (0.1
tivate the metal (magnesium, for example, with
mol) of benzophenone in 80 cos. of absolute ether
the help of small quantities of iodine and/or an,
alkyl-halide) and then quickly allow it to react
with the corresponding halogenamine, work be-.
is allowed to run in in portions. With each addi- "
tion a lively action commences, the solution is
ing carried out in presence of a solvent, for ex 55 temporarily colouredred and the magnesium is
ately. The methyl-phenyl-3-diethylaminopropyl
gradually used up. The reaction mixture is maim
tained for a further 12 hours at 45° C. and is
worked up by decomposing the Grlgnard com
plex with ice and ammonium chloride. On shak
ing the ethereal solution with dilute hydrochloric
carbinol, which is isolated in the usual manner.
has a boiling point of 110° C. (0.07 mm.).
From the base, a hydrochloride of M. Pt. 133
134° C. which crystallizes in needles can be ob
Example 6
acid, the hydrochloride of diphenyl-3-diethyl- .
aminopropyl carbinol is obtained, which melts at
179-1795“ C. after recrystallization.
In a similar manner to that described above,
20.4 grams of anisaldehyde (0.15 mol) are brought
Phenyl - benzyl-3-diethylaminopropyl carbinol
can be obtained from desoxybenzoin in a similar
to reaction.
The p-methoxyphenyl - 3 - diethylaminopropyl
Example 2
carbinol thus obtained boils at 142° C. (0.15
mm.) after being twice distilled. The yield is
With 4.8 grams of magnesium in 20 ccs. of
absolute ether and 30 gms. of chloropropyl-di
ethylamine in 50 cos. of absolute ether, the mag
nesium compound is obtained in the manner de
scribed in Example 1, and to this is added con
tinuously, in portions, 16 grams benzaldehyde in
Example 7
From piperonal a practically theoretical yield
of 3'z4'
- methylenedioxyphenyl - 3 - diethyl
aminopropyl carbinol is obtained. B. Pt. 136-142”
50 cos. of absolute ether. After boiling on the 20 C. (0.07 mm.).
water bath at 50° C. for 12 hours, ice and hydro
The base yields a crystalline hydrochloride
chloric acid are added. The aminoalcohol is ex
which, however, is very hygroscopic.
tracted from the ethereal solution by means of
Example 8
hydrochloric acid; the free base is liberated from
the united hydrochloric acid extracts and is then 25 From 4.8 grams of magnesium (0.2 mol), 30
isolated by extraction with ether in the usual
grams of diethylaminopropyl chloride (0.2 mol)
and 25 grams of veratric aldehyde (0.15 mol),
The phenyl-3-diethylaminopropyl~carbinol, ob
tained in a yield of 67%, boils at 108-111” C.
(0.03 mm.) . The hydrochloride is crystalline but
is very hygroscopic.
3':4' - dimethoxyphenyl - 3 - diethylaminopropyl
carbinol is obtained in an analogous manner.
The base, a viscous oil, boils at 155-1610 C.
(0.07 mm.). From it, a hydrochloride (M. Pt.
128—132° C.) which crystallizes magni?cently can
In place of magnesium, zinc, for example, may
be used.
be obtained; this may be puri?ed by recrystal- -
Phenyl-p-dimethylaminocyclohexy1 carbino1 is
lization from chloroform-ethyl acetate.
obtained if p-dimethylaminocyclohexyl chloride
be used in place of chloropropyldiethylamine.
Example 9
2.6 grams magnesium, activated by means of
Example 3
iodine, is introduced into 20 cos. of absolute ether
The magnesium compound of the desired furyl
and is caused to react with'0.6 cc. of ethyl bro
3-diethylaminopropylcarbinol is obtained in the
40 mide. Whilst warming gently, 16.2 grams (0.1
manner described above from 4.8 grams mag
mol) of N-[l-chloropropyl-(3) ]—piperidine in 40
nesium (0.2 mol), 30 grams chloropropyldiethyl
cos. of absolute ether are added and, after add
amine (0.2 mol) and 14.4 grams furfurole (0.15
mol). On extraction with dilute hydrochloric
ing a further 0.5 cc. of ethyl bromide, 14.5 grams
(0.08 mol) of benzophenone in 50 cos. of anhy
acid the solution is quickly coloured dark blue, 45 drous ether are added in portions. The mage
the base is liberated immediately, when» it is treat
ed in ether with dehydrated active charcoal and
then distilled several times. B. ‘Pt. 88° C. (0.07
sium is used up fairly quickly and, after 10 hours,
only traces are left.
In working up, both with
hydrochloric acid and with ammonium chloride,
the hydrochloride of diphenyl-3-piperidinopropyl
In an analogous manner, starting with Dyridyl
(3)-aldehyde, for example, pyridyl-(3')-3-di
50 carbinol is precipitated as a dense precipitate. It
is puri?ed by recrystallization from chloroform
ethyl acetate. M. Pt. 212~214° C.
ethylaminopropyl carbinol is obtained.
Example 4
Example 10
Working according to the method described in 55
described in Example 9, 4.8
Example 1, 0.2 mol of chloropropyldiethylamine
grams (0.2 mol) of magnesium in 20 cos. of abso
is caused to react with 0.1 mol (15.6 grams) of
lute ether, 32 grams (0.2 mol) of chloropropyl
piperidine in 50 cos. of absolute ether and 16
The base isolated from the hydrochloric acid
grams of benzaldehyde (0.15 mol) in 50 cos. of
absolute ether are caused to react. In a reaction
carbinol, boils in a high vacuum (0.07 mm.) at
extracts, naphthyl - (1’) - 3 - diethylaminopropyl
158-164° C. On standing, the highly Viscous oil
solidi?es, forming lea?ets which, when recrys- '
which proceeds smoothly, 22 grams of phenyl-B
piperidinopropyl carbinol of B. Pt. 131—133° C.
(0.06 mm.) are obtained. The base gives a beau
tallized from petroleum ether, melt at 59-62° C.
crystallizing hydrochloride of M. Pt.
In an analogous manner, 1-chloro-2-dimethy1 65
109-111° C., which can be puri?ed by recrystal
aminomethylcyclohexane, for example, or its de
lization from chloroform-ethyl acetate.
rivatives further substituted in the nucleus, can
be caused to react with a cycloaliphatic substi
Example 11
tuted aldehyde.
In the same manner as in Example 10, 20.4
Example 5
70 grams of anisaldehyde (0.15 mol) are converted
As is described in detail in Example 1, the di
into p-methoxyphenyl-3-piperidinopropyl car
ethylaminopropyl.magnesium compound is pre
binol. B. Pt. 153—158‘’ C. (0.08 -mm.); yield 74%.
pared and is caused to react with 12 grams of
After distilling twice, the viscous oil solidi?es to
acetophenone. The sparingly soluble magnesium
white crystals of M. Pt. 53-56“ C. The hydro
compound of the alcohol is precipitated immedi 75 chloride is crystalline but deliquescent.
benzaldehyde are added in portions. The base
which is isolated at the end 01 the reaction,
Example 12
In the same manner, 0.15 mol oi piperonal can
be caused to react with chloropropyl-piperidine.
The 3' :4'-methylenedioxyphenyl - 3 - piperidlno
3.. Pt.
124-127“ C. (0.05 mm), is a mobile oil.
Example 20
4.8 grams of magnesium in 20 cos. of absolute
ether are thoroughly activated with iodine and
ethyl bromide, after which 30 grams (0.2 mol) of
propyl carbinol which is isolated boils at 168-170°
C. (0.08 mm.). On standing, the base solidi?es
and may be recrystallized from benzene-petro
leum ether. M. Pt. ‘ll-71,5” C. The hydrochlo
ride melts at 132-134" C.
10 chloropropyl-diethylamine in 50 cos. of ether are
added. Whilst warming at 45-50° C., a suspen
Example 13
sion of 9 grams (0.3 mol) of well-dried paraform~
By the method described in previous examples,
aldehyde in 50 cos. of ether is allowed to ?ow into
phenyl-3-dimethyl-aminopropyl carbinol is pre
pared from 5 grams of magnesium in 20 cos. of
the reaction mixture.
The reaction proceeds very slowly. After de
absolute ether, 24.3 grams (0.2 mol) of l-chloro
propyl-(3) -dimethylamine in 50 cos. of absolute
ether and 15 grams (0.15 mol) of benzaldehyde in’
composition with ice and hydrochloric acid, the
base is extracted with further hydrochloric acid
Example 14
Using ‘the same quantities of magnesium and
chloropropyl-diethylamine as in Example 15, 17.1
additions‘ and is then liberated by means of po
50 cos. of absolute ether. The base is a mobile
tassium hydroxide. The 4-‘diethylamino-butanol~
oil, B. Pt. 106.5° C. (0.05 mm.) which, however, 20 (1) obtained boils at 92-97° C. (11 mm.)
readily crystallizes to yield crystals of‘ M. Pt.
Example 21
45-48” C. Yield 70%.
In the same way as in Example 13, 3' :4'-meth
grams (0.15 mol) of oenanthole are caused to re
25 act to yield IO-diethylaminodecanol-(7). The
reaction proceeds very violently, and the mag
' binol, B. P. 162.5-164" C. (0.6 mm.), is obtained
.ylene-dioxyphenyl-3-dimethylaminopropyl car
from 0.2 .mol of chloropropyldhnethylamine and
nesium is completely used up. The decanol base
shows the foaming‘ and emulsifying properties
0.15 mol of piperonal.
Example 15
30 characteristic of such bodies.
Example 22
3.8 grams of magnesium in 20 cos. of absolute
The quantities of magnesium and chloropropyl
ether, 30 grams (0.15 mol) of 1-ch1oropropyl-3
diethylamine used in Examples 20 and 21 may
di-n-butylamine and 10.6 grams (0.1 mol) of
benzaldehyde are allowed to react in the manner 35 also be caused to react with 10 grams (0.1 mol) of
benzonitrile. The w-diethylamino-n-butyrophe
described in Example 9. Several hours after ad
none isolated boils at 105—106° C. (0.07 mm.) and
dition of the aldehyde (during which timev the
yields a hydrochloric melting at 127-130“ C,
reaction mixture is maintained at 50° C. in a
water bath) the mixture is worked up.
Example 23
On extracting the ethereal solution with 2-n '40
grams of chloropropyl-di
hydrochloric acid, the hydrochloride of phenyl-3
ethylamine (0.1 mol) and 18.2 grams of benzo~
di-n-butylamino-propyl carbinol- is precipitated ,
phenone (0.1 mol) in 100 cos. of benzene are al
as an oily intermediate layer. The base isolated
lowed to drop into 7.8 grams (0.2 mol) of pow
'_ therefrom boils at 136° c. (0.1 mm).
45 dered potassium in 50 cos. of absolute benzene
Example 16
during 50 minutes. After addition of the ?rst
Using the same quantities of magnesium and
drops, the solution is coloured dark blue, and to
wards the end of the addition a strong reaction
chloropropyl-di-n-butylamine as given in Exam
_ develops, which is moderated by cooling. The
ple 15, together with 10 grams (0.1 mol) of cyclo
hexanone, 1'- (3-di-n-butylamino-propyl) -cyclo 50 reaction mixture is allowed to stand for a further
2 hours with stirring, after which 2 cos. of alcohol
hexanol-(l') of B. Pt. 118° C. (0.1 mm.) is ob
tained in an almost stormy reaction. The hydro
chloride melts at 134-136° C.
Example 17
Using the quantities of magnesium and chloro
are added, followed by 150 cos. of water. The
crude base which separates, after removal of hen
zene, is converted into the hydrochloride and
melts at 177-178“ C. after recrystallization from
55 chloroform and ethyl acetate. It shows no de
pression of the melting point when mixed with
the diphenyl-3-diethy1aminopr0pY1 carbinol hy
drochloride prepared according to Example 1.
propyl-di-n-butylamine given in Example 15, 15
grams (0.1 mol) of cuminaldehyde are brought
to reaction. The 4'-isopropy1-phenyl-3-di-n
butylamino-propyl carbinol obtained boils at 154°
C. (0.06 mm.).
Yield 17 grams.
The reaction can also be carried outin a sim
60 ilar manner in ether at 0° C.
In a similar manner to Examples 15-17, 15.2
grams (0.1 mol) of camphor is worked up into
Example 24
10.6' grams of benzaldehyde and 15 grams of
chloropropyl-diethylamine in 50 cos. of absolute
2’-[3-di-n-butylamino-pr0pyll-borneol, B. Pt.
65 ether are dropped over a period of 1% hours into
Example 18
11'7—121° C. (0.09 mm.) .
Example 19
22.4 grams of freshly distilled l-chloropentyl
(5) -diethylamine (B. Pt. 52-54“ C. (0.1 mm.)) in 70
50 cos. of anhydrous ether are allowed to run into
3.6 grams of magnesium, activated with 0.5 cc. of
ethyl bromide in 20 cos. of absolute ether.
Whilst. gently warming to 45° 0., and after a
7.8 grams of pulverised potassium in 100 cos. of
anhydrous ether at 0° C. After adding alcohol
and water as in Example 23 the isolated base is
distilled. It is identical with that obtained in
Example 2.
Example 25
8.48 grams of magnesium powder are activated
with iodine and are covered with 25 cos. of dry
further addition or ethyl bromide, 10.6 ‘grams of 75 ether. The reaction is started with 0.7 cc. of
' 2,411,664
ethyl bromide, 26.5 grams of chloropropyl-di
3. A process for the manufacture of an amino
ethylami'ne are immediately added and the whole ,
compound, which comprises reacting a halogen
is heated for about 1 hour. It is poured off from
the magnesium in excess, better yields are how
ever obtained if the reaction is effected without
pouring o? directly with 18.75 grams of meta
benzyloxy-benzaldehyde in '70 cos. of dry ether.
After working up as described in Example 2, there
amine of the formula
wherein hal stands for a halogen, and X stands
for an unsubstituted alkyl chain of 3 to 5 carbon
is obtained the meta7benzyloxy-penyl-3-diethyl~
aminopropyl carbinol of boiling point l91-194° C. 10 atoms interconnecting the halogen with the
under 0.05 mm. pressure.
amino group, with magnesium, and reacting the
In analogous manner the compounds listed in
the following table were also obtained.
P aren t ma t ens
' 1,
Free base
Reactive component
Reaction product
B. P., ° 0.
° 0.
a-(3-dietl1ylamino propyD-geraniol __________________ __
Styryl-3-diethylaminopropyl carbinol _______________ -_
122—124°/0.1 min _____________ ..
l40—142°/0.07 mm____ ________ __
Cl(CHz):N(C2Hs):'_-_- D ilBdenzyloxy - benzalde-
p - Beinzyloxy - phenyl-3 - diethylaminopropyl
l94°/0.05 mm ...... __
y e.
p - Dimcthylaminobcnzal-
car mo .
p - Dimethylamino - phenyl ~3 - dlethylamino-
Citraldehyde ............ “
Cmnamic aldehyde _____ __
or e
M_ P" '
ropyl carbinol.
______ _.
Cl(CHg):N(C1H9)1._-. Benzophenone .......... __
D phenyl;3-dibutyl_aminopropyl carbinol __________________________________ ._
Hexyl-3-dibutylam1nopropyl carbinol _______________ __
Oenanthole ............. _.
What we claim is:
1. A process forthe manufacture of an amino
l50—l52°/0.08 mint... ________ __
l30-l31°/0.07 mm'____ ____;___..
4. A process for the manufacture of an amino
compound, which comprises reacting a halogen
amine of the formula
compound, which comprises reacting a halogen
amine of the formula
wherein hal stands for a halogen, Y stands for
a substituted amino group selected from the
wherein hal stands for a halogen, and X stands
85 for an unsubstituted alkyl chain of 3 to 5 carbon
class consisting of
atoms interconnecting the halogen with the
amino group, with magnesium, and reacting the
resultant organo-metal compound with a ketone.
5. A process according to claim 3, wherein the
R representing the atoms necessary to complete 40 magnesium is magnesium activated by treatment
a six-membered heterocyclic nitrogenous ring
with a small quantity of a member of the group
system containing only carbon and nitrogen
consisting of iodine, alkyl halide and a mixture
atoms, and X stands for a saturated non-aro
matic hydrocarbon chain of 3 to 5 carbon atoms
6. A process according to claim 4, wherein the
interconnecting the halogen with the amino 46 magnesium is magnesium activated by treatment
group, with a metal selected from the group con
} with a small quantity of a, member of the group
sisting of magnesium, zinc and potassium, and
reacting the resultant organo-metal compound
consisting of iodine, alkyl halide and a mixture
7. An amino ‘carbinol of the formula
with a member of the group consisting of alde
hydes and ketones. >
2. A process for the manufacture of an amino
compound, which comprises reacting a halogen
amine of the formula.
55 wherein R1 and R2 each stands for a phenyl
wherein hal stands for a halogen, and X stands
8. The amino carbinol of the formula
for an alkyl chain of 3 to 5 carbon atoms inter
connecting, the halogen with the amino group, 60
a with magnesium, and reacting the resultant or
gano-metal compound with a member of the
group consisting of aldehydes and ketones.
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