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Патент USA US2409664

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Patented Oct. 22,1946
2,409,663
UNITED“ STATES l PATENT . OFFICE
2,409,663
AMINO ALCOHOL ESTERS OF ALKYL-SUB- ‘
STITUTED ALKOXY BENZOIC ACIDS
Walter G. Christiansen, Glen Ridge, and Sidney
E. Harris, Nutley, N. J., assignors to E. R.
Squibb & Sons, New York, N. Y., a corporation
of New York
7 7
No Drawing. Original application September ,9‘,
'
1
1937, Serial No. 163,034. Divided and this ap
plication June 28, 1944,'Serial No. 542,622
4 Claims. (Cl. 2605473)
This application is a division of our applica
2
cooling the reaction mixture causes a white
tion Serial No. 163,034,, ?led September 6, 1937.
This invention relates to, and has for its ‘ob
ject the provision of, certain amino alcohol esters
crystalline precipitate of p-diethylamino-ethanol
hydrochloride to separate out completely; ‘then
?ltering, treating the ?ltrate with alcoholic hy
of oxy-benzoic acids, and acid-addition salts CR drochloric acid, and distilling off the benzene and
thereof. These esters have the general formula
alcohol, leaves a white solid residue which upon
recrystallization from a mixture of absolute alco
(alkyl)
hol and dry ether, yields the hydrochloride of
—O-—R—N
the desired product as a white crystalline precipi
tate having a melting point of 142=.5-l45° 0.
(alkyl)
wherein R represents a divalent radical providing
EXAMPLE 2
a continuous carbon bridge, preferably an alkyl- ‘
p-diethylammo-ethyl ester of 2-methyl-4-ethoxy
ene radical.
‘
benzoic acid
The compounds of this invention are valuable
therapeutic agents, being particularly eifective
for inducing local anesthesia.
In the practice of this invention, an aracyl
halide of the general formula
(lower alkyl)——CHg-O
("J-(halogen)
(alkyl)
is reacted with an alcohol of the formula
(alkyl)
HO-R-N
.
7.5 g. ,of 2-methyl-4-ethoxy-benzoic acid is
warmed with 8.6 g. of phosphorus pentachloride
until the reaction ceases; fractional distillation
of the reactants under reduced pressure yields 2
methyl-li-ethoxy-benzoyl chloride as a colorless
20 liquid boiling at Bil-140° C./3 mm. A solution of
6 g. of this fraction in 20 cc. of dry benzene is
treated with 7.6 g. of ?-diethylamino-ethanol
dissolved in 10 cc. of dry benzene, and crystals
of 'diethylamino-ethanol hydrochloride separate
25 out; ?ltering off the precipitate, treating the
?ltrate with alcoholic hydrochloric acid and di
luting it with dry ether, yields the hydrochloride
of the desired ester as a white crystalline solid
(alkyl)
melting at 101-103° 0.
to produce the desired ester.
30
The amino-esters of the invention are gener
EXAMPLE 3
ally recovered in the form of their addition salts
Gamma-dimethyZamino-prom/Z
ester of B-methyl
with hydrochloric acid. However, other acids
4-butomy-benzoic acid
forming addition-salts with amines may be used
in place of hydrochloric; such acids are boric,
1.53 g. gamma-dimethylamino-propanol and
3.17 g. 3-methyl-4-n-butoxy-benzoyl chloride are
nitric, lactic, tartaric, citric, phosphoric, sulfuric,
picric, and picrolonic. ‘The addition salts may
dissolved in 10 cc. of dry alcohol-free chloroform.
The solution is warmed on a steam bath for half
be converted into the free bases in the usual
an hour and the product precipitated as the hy
manner.
The following examples are illustrative of the
drochloride by adding dry ether; it may be puri
invention:
?ed by redissolving in chloroform or absolute
alcohol and reprecipitating. The product is a
EXAMPLE 1
White crystalline powder melting at 1255-1265”
- p-diethylamino-ethyl ester of 3-methyl-4-ethory
C. (corrected).
benzoic acid
45
EXAMPLE 4.
13 g. of 3-methyl-4-ethoxy-benzoic acid and 15
g. of phosphorus pentachloride are heated on a
cam-Di (dimethylamtnomethyl) -gamma-phenyl-n
propyl ester of 3-methyl-4-n-butomy—benzoic
steam bath for 30 minutes, and then fractionally
acid (hydrochloride)
distilled in vacuo, the fraction 3-methyl-4
ethoXy-benzoyl chloride being obtained as a color 50
36 g. of the ethyl ester of 3-methyl-4-hydroxy
less liquid boiling at 147-152” C./6 mm. A solu
benzoic acid and 27.4 g. of n-butyl bromide dis
tion comprising 6.5 g. of this fraction dissolved in
solved in 200 cc. acetone are treated with 84 g.
16 cc. of dry benzene is mixed with 7.5 g. of di
anhydrous potassium carbonate, and the reac
ethylamino-ethanol dissolved in 18 cc. of dry
tion mixture is then re?uxed, with stirring, for
benzene, and the mixture boiled for 60 minutes; 55 15 hours. The potassium carbonate and potas~
2,409,663
sium bromide precipitated are ?ltered o?, the
4
6. a-methyl-u-dimethylaminomethyl - gamma
phenyl-n-propyl ester of 3-methyl-4-n-butoxy
acetone distilled from the ?ltrate, and the resi
due boiled with dilute sodium hydroxide solu
benzoic acid.
tion until dissolved. The product, 3-methyl-4
7. qua-Di-dimethylaminomethyl-n-amy1 ester
n-butoxyibenzoic acid, is precipitate'dwith hy
of 3-methyl-4en-butoxy-benzioc acid.
60% alcohol, is obtained in the form of white
yl-4-propoXy-benz0ic acid.
9. Gamma-oliethylamino-n-propyl ester of 3
ethyl-‘i-n-propoxy-benzoic acid.
drogen chloride; and after ?ltering, washing and
drying the precipitate, and recrystallizing from
‘ 8. p-Dimethylamino-n-propyl ester of B-meth
plates melting at 144-1‘16" C. (corrected).
15 g. of this acid is treated with 15 g. phos
10.
phorus pentachloride to about 70° C. until hy-,
’ 1'0. Délta-diethylamino-n-buty1
ester
of
3
methyl-{l-n-butoxy-benzoic acid.
"The invention may be variously otherwise em
bodied'within'the scope of the appended claims.
drogen chloride is no longer evolved, ‘and the
reaction mixture is fractionally distilled vacuo.
The product, 3-methyl-4-n-butoxy-benzoyl chlo
We claim:
ride boils at 144-154” C. at 1.5 mm.
15 1,. A compound of the group consisting of:
1.05 g. of 3-methyl-4-n-butoxy-benzoyl chlo
aminoeesters of the formula
ride and 1.25 g of m,a-di(dimethylamiiiomethyl)-\
gamma-phenyl-propanol are dissolved in 10 cc.
0
of chloroform and the solution is re?uxed for a
few minutes. Dry ether is added until a faint 20
precipitate appears, and the whole is allowed to
stand for sometime. The crystalline precipitate
formed is ?ltered off and washed with dry ether;
it melts at 161-162° C. (corrected).
' ’
EXAMPLE 5
a-Methyl+a-dimethylaminomethylm-amyl ester
'
RH
wherein R_ represents a divalent alkyl residue
with 2 to 4 carbon atoms R’ represents an alkyl
residue with 2 to 4 carbon atoms, R" represents
25 an alkyl residue with 1 to 2 carbon atoms, and
3”’ represents an alkyl residue with 1 to 2 car
bon atoms; and acid-addition salts thereof.
of v3-17;ethyleé-n-butozy-benzoic acid (hydro
chloride)
RHFQL
2. The hydrochloride of ?-diethylamino-ethyl
3-methyl-4-eth0Xy-benzoic acid.
'
4.4 g. of 3-methyl-4-n-butoxy-benzoyl chloride 30 3. The hydrochloride of p-diethylamino-ethyl
Z-methyl-Ll-ethoxy-benzoic acid.
and 3.0 g. of a-methyl-a-dimethylaminomethyl
n-amyl alcohol are reacted together in 10 cc. of
4- 'I‘he hydrochloride of gamma-methyl
amino-propyl 3-methyl-ll-n-butoxy-benzoate.
chloroform as directed in Example 4. The prod
uct melts at 126-131° C. (corrected).
‘
The following are among the many other com
pounds embraced by the present invention, and
may be prepared according to the directions given
above:
35
WALTER G. CH‘RIYSTIANSEN.
SIDNEY E. HARRIS.
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