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Патент USA US2135521

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Patented Nov. 8, 1938
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UNITED STATES PATENT OFFICE
2,135,521
HOMOLOGUES OF BETA-METHYLCHOLINE
HALIDE AND THEIR ACYL DERIVATIVES,
AND PROCESSES FOR THEIR PROD-UC
TION
Randolph T. Major, Plain?eld, and Howard T‘.
Bonnett, Rahway, N. J., assignors to Merck &
Co. Inc., Rahway, N. J., a‘ corporation of New
Jersey
No Drawing. Application December 4, 1935,
Serial No. 52,872
13 Claims. (Cl. 260-584)
This invention relates to higher homologues of the necessary puri?cation may be more readily
B-methylcholine halide and their acyl derivatives,
and to processes for their production.
The co-pending application of one of us, Ran“515 dolph T. Major, in association with Joseph K.
Cline, Serial No. 733,604, ?led July 13, 1934, relates
to the preparation of acetyl-B-methylcholine
chloride. We have now succeeded in producing,
as Well, its hitherto unknown higher homologues.
10‘ The general series of the ,B-n-alkyl choline halides which are the subject of the present inven-
e?ected.
The appropriate chlorhydrins used as starting
materials in each instance were prepared by the
reaction of chloroacetaldehyde with the selected 5
Grignard reagent. The hitherto unreported 1
chlorononanol-Z, was also prepared in this way.
During the working out of our process a num
ber of intermediate compounds were prepared
which had not previously been described; these in- 10
clude l-dimethylamino-butanol-2, l-dimethyl
tion have been tested pharmacologically with in-
amino-pentanol-Z,
teresting results. It has been found that, while
1-dimethylamino-octanol-2, and l-dimethylam
l—dimethylamino-hexanol-Z,
‘the acyl derivatives of these new compounds ex-
ino-nonanol-Z.
-
l5‘ hibit generally a “muscarine” action similar to
The following description of the more detailed 15
that of acetyl-c-methylcholine chloride, the nonacylated higher homologues exhibit rather unexpected and important di?erences in their therapeutic action. Thus, for instance, while the B20 hexylcholine and the B-heptylcholine chlorides
steps of the process exempli?es speci?c adapta
tions of the general method set forth above to the
ultimate production of various speci?c acetyl-?
alkylcholine halides, which are embraced within
the scope of our invention.
20
exhibit a “muscarine” action, the p-proplycholine and the 5-butylcholine chlorides exhibit the
typical, so-called “nicotinic” action which is a
matter of considerable practical therapeutic in25 terest.
Broadly, the process of the present invention is
directed to the production of beta alkylcholine
halides by the condensation of given chlorhydrins
with methyl amines.
30- One preferred modi?cation of our process for
producing‘these s-alkylcholine salts consists in
reacting upon an appropriate chlorhydrin with‘
dimethylamine and converting the resulting dimethylamino-alkanol into its methiodide, from
35 which the ?-n-alkylcholine chloride may be readily obtained, and which latter may then be readily acylated by appropriate means. The process
outlined above is preferably directed to the production of the higher of the homologues of ,3-
Preparation of 1-dimethyZamino-Ialkanol-2.
The appropriate chlorohydrin is heated with a
solution of two mols. of dimethylamine in benzene
at 1l5-120° C. for about 15 hours, and isolated
from the resulting mixture by the usual meth- 25
ods. The compounds obtained are mobile, color
less liquids possessing a strong amine-like odor.
1-dimethylamino-butanol-2 and 1—dimethylam
ino-pentanol-2 are very soluble in water, but the
higher homologues are insoluble in water. All 30
of the compounds are soluble in the usual or
ganic solvents.
Preparation of ,o-n-allcylchOline z'odz'de.—The
methiodides of the l-dimethylamino-alkanol-Z
compounds are prepared by treating the latter 35
with methyl iodide at room temperature. They
are recrystallized from warm acetone to which
ether is added, and occur in the form of non-hy
groscopic white, n1icro~crystalline solids.
4o methylcholines which constitute the subject-matPreparation of ,B-n-allcylcholine chlorz'da- 40
ter of our invention, but some of the relatively The fi-n-alkylcholine iodides are Converted to
lower homologues in question, as for instance, p’- their corresponding chlorides by reacting upon
ethylcholine chloride, ,B-n-propylcholine chlo- them with AgCl in alcoholic solution by the
ride, etc. may be prepared directly by treating methods of Jones and Major (Jour. Am. Chem.
45» the appropriately selected chlorhydrin with tri- Soc, 52, 309-1930). The silver salts formed in 45
methylamine, thus avoiding the intermediate step the reaction are remOVed by filtration, and the [3
of forming the methiodide.
n-alkylcholine chloride is precipitated by the ad
While either modi?cation of the above de- dition of anhydrous ether to the ?ltrate. The last
scribed method may be employed, for the prepa- traces of silver chloride are removed by adding the
50; ration of all of the homologues herein contem- precipitate to a Saturated Solution of hydrogen 50’
plated, it has been found more convenient, be- sul?de in absolute alcohol. Activated charcoal
cause of the rapid increase in hygroscopicity with is added and the mixture ?ltered.
increase in size of the alkyl group, to prepare the
B-ethylcholine chloride may be recrystallized
higher homologues by means of the reaction of from butyl alcohol, s-propylcholine chloride may
55 methyl iodide on dimethyl-amino-alkanol, so that be recrystallized from a mixture of butyl alcohol 55
2,135,521
2
5. ,B-n-butylcholine chloride occurring in the
and isopropyl ether, and p-butylcholine chloride
may be recrystallized with di?iculty from a mix
ture of butyl alcohol and benzene. The remain
ing compounds are obtained in the form of gums
which crystallize on standing in a dessicator.
The ?nal products are obtained in the form of
form of a white, extremely hygroscopic, crystal
line solid having a melting point of about 100.5
white, extremely hygroscopic solids.
'7. The process for the production of [3-alkyl
choline chlorides wherein the alkyl radicals con
102° C.
white, extremely hygroscopic, crystalline solid
melting at about 72-74° C.
‘
Preparation of acetyl-p-n-alkylcholine chloride.
—Acetyl-5-n-alkylcholine chloride is prepared ac
cording to the method described by Major and .
Cline in their aforementioned co-pending appli
cation, Serial No. 733,604. In accordance with
this method, a mixture of p-n-alkylcholine'
.
tain from two to seven carbon atoms, inclusive, 10
which comprises reacting upon the correspond
ing chlorhydrin with dimethylamine to obtain the
corresponding amino-alkanol, converting the
amino-alkanol to its methiodide, and reacting
chloride with an excess of acetic anhydride is
15 heated for six hours at 100° C. Dry ether is then
upon the iodide with silver chloride to obtain the 15
corresponding chloride.
added to the cooled solution. The precipitate
which forms is washed several times with ether
and then dissolved in absolute charcoal, and then
8. The process for the production of ?-alkyl
choline chlorides wherein the alkyl radicals con
tain from two to four carbon atoms, inclusive,
the acetylated compound reprecipitated by the
which comprises condensing the selected chlorhy
20 addition of dry ether. The products are obtained
20
drin with trimethylamine to' obtain the corre
in the form of white, crystalline hygroscopic
sponding p-alkylcholine chloride.
solids.
9. In a process of producing a member 'of the
Examples for the production of other products
group consisting'of B-alkylcholines, homologues
of this series can be readily derived by reference
of c-methylcholine, their salts and acyl deriva 25'
tives, the steps which comprise the condensation
25 to the table given below, with the selection of
the appropriate chlorhydrin. Thus, the selection
of the corresponding homologues of .chlorhydrin
of any given chlorhydrin shown in the ?rst
column of the table, and its treatment involving
with methylamines.
I
.
10. In a process of producing a member of the
the reaction with dimethylamine by the modi?ed
30 _
r
,6. B-n-amylcholine chloride in the'form of a
group consisting of ,B-alkylcholines, homologues 30
of ,o-methylcholine, their saltsv and acyl deriva
tives, the step which comprises the condensation
of the corresponding homologue of chlorhydrin
with trimethylamine,
steps of the process outlined in detail above, will
‘produce, respectively, the corresponding di
methylamino-alkanols, p-n-alkylcholine iodides,
chlorides, etc., shown on the same line in the
other columns of the table.
35
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l-chloroheptauol1-ch1ol‘0-0ctan0l-2__
_____ __
l-chloro'nonanol-2 ___________________ __ nC1H1§______
According to the other modi?cation of our
process, as mentioned above, for the preparation
of the ,B-ethyl, B-p-ropyl and. p-butyl-choline
chlorides, trimethylamine is condensed with the
appropriate chlorhydrin in benzene solution at
116° C. for about 24 hours. The resulting choline
chlorides are precipitated by the addition of ether
and recrystallized from organic solvents asindi
'
We claim as our invention:
1. p-alkylcholine chlorides wherein the alkyl
65 radicals contain from two to seven carbon atoms,
'
‘2. [i-alkylcholine iodides wherein the alkyl rad
icals contain from two to four carbon atoms.
3. c-alkylcholine iodides wherein the akyl rad
70 icals contain from six to seven carbon atoms.
4. B-n-propylcholine chloride in the form of a
white, extremely hygroscopic, crystalline solid
having'a melting point of about 115-7° C.
'
U
.-i
' °C.
_'45
°C.
M. P. 162 —
M._P. 174 — 6
M. P. 144— 6
M. P. 198 --200
M. P. 115 — 7
M. P 168- 9
M. P. 90 —92
M. P. 100. 5—102
M. P. 186- 7
M. P. 98 —100
M; P. 109 -1_l0
M. P. 122. 5-123. 5
MI. P. '72 — 74 _. M. P. 182- 4
M. P. 69 — 71
M. P. 169-71
M. P. 97 - 99
P. 176- 7
50'
11. In a process of producing a member of the
group consisting of ,B-alkylcholines, homologues 55
of p-methylcholine, their salts and acyl deriva
tives, the steps which comprise the condensation
of the corresponding homologues of chlorhydrin
with dimethylamine and methyl iodide.
'
l2. c-alkylcholine halides wherein the alkyl 60
radicals contain from two to seven carbon atoms,
inclusive.
cated.
inclusive.
v
311
O
7°C.
.
eo
0
1
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13. The process for the production of salts of
,B-alkylcholine ‘wherein the alkyl. radicals contain
from two to seven carbon atoms, inclusive, which 65
comprises reacting upon the corresponding chlor
hydrin with dimethylamine to obtain the corre
sponding amino-alkanol, converting the amino
alkanol to its methiodide, and reacting upon the ,
iodide with a salt of silver which is more soluble 70
than silver iodide.
RANDOLPH T. MAJOR.
HOWARD T. BONNETT;
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