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Патент USA US2404691

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Patented July 23, 1946
2,404,691
UNITED STATES PATENT OFF-‘ICE
2,404,691
CHEMICAL ooMPonNns
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
No Drawing. Continuation of application "Serial
No. 163,034, September 9, 1937. This applica;
tion August 30, 1944, Serial No. 552,013 "
6 Claims. (Cl. 260-473)
1
2
This application is a continuation of Chris
The following examples are illustrative of the
invention.
tiansen and Harris application Serial No. 163,034,
?led September 9, 1937.
_
EXMIIPLE .1
p-diethylamina-ethyl ester of p-ethcryebcneoic
This invention relates to, and has for its object
the provision of, certain amino-alcohol esters of
oxy-benzoic acids, acid-addition salts thereof, and
methods of preparing them. The esters of this
invention are comprehended by the general for
acid
10 g. .of p-ethcxy-benzeyl chloride ?iswlve? in
5.0 cc. of dry benzene is treated with 6-8 .g- of
?=diethylamino-e$han¢1; a precipitate fqrma and
‘10
the reaction is com steel by heating on the wa
ter bath. After CQQllIlg the Bellamy ?ltering Off
the precipitate, and treating it with a slight ex
cess of 2N p?tassium hydroxide solution, the ester
is extracted with ether and dried with anhydrous
sodium sulfate. On passing dry hydrogen chlo
ride through the ether solution, a crystalline pre
cipitate of the nycrpehlgride 9f the ester forms;
wherein R represents a divalent aliphatic, cyclo
aliphatic, or aromatic radical providing a con»
tinuous carbon bridge, B.’ and R" represent alkyl,
it is ?ltered 01f, washed with dry ether, and then
aralkyl, hydroXY-alkyl, or hydroxy-aralkyl, or
meltsat 717255-1735? _C. (corrected).
‘
jointly represent an alkylene group, R’” repre»
20
EXAMPLE
2
sents an aliphatic, aromatic, or araliphatic radical,
R"" represents hydrogen, alkyl, or an alkoxy
p-[N-ethyl-N- (n-amyU-dminol :ethyl ester .of p,
radical, and Y represents hydrogen or alkyl.
ethoscyrbenzoic .acid
The compounds of this invention are valuable
therapeutic agents, being particularly effective 25 41 g- pf peethqxyrhenzorl ‘chloride .qisselveq in
15 cc. of dry benzene rammed $91" 3.0 minutes
for inducing local anethesia.
with a solution comprising 3.5 g. of p.- [ii-ethyl
‘In the practice of this invention, an aracyl
-.<n-amyl>.-.aminol?llanel in 19 (‘42- of dry ben
halide comprehended by the general formula '
zene; distilling oil‘ the ‘benzene in .vacuq, dissolv-'
o
30
l
Ru/CHO
ins the residue (crude hydrochloride pf the de
sired ester) in alcohol, .decohrizing with earbon»
and neprecipitating with dry ether. follpwed by
reclvsiallization from an meme-(Petroleum
ether) mixture. yields the ‘hydrochloride of the
desired product, having a melting point of 108
wherein X is a halogen, and Y, R'”, and R""
have the above-noted signi?cation, is reacted with
110" C, (corrected).
an alcohol comprehended by ‘the ‘general formula
3
p-[di- (n-but-yl) -amz'n0]-ethyl ester of p-ethomy
HO-eR-e-N
/RI
RI!
“
'
benzoic acid
40
4.6 'g. of p-ethoxyebenaoyl chloridedissolved in
12 cc. .of ‘dry ‘benzene is admixed with a solution
comprising 4.35 g. .of ?-[di-(n-butyD-aminol
wherein R, R’, and R'f have the above-desig
nated meaning, to produce the desired ester,
ethanol in 5 cc. of dry benzene, the reaction pro
However, other methods hereinafter described
ceeding to completion at room temperature; the
may be employed to produce the compounds of 45 “benzene
’ is distilled off under reduced pressure;
the present invention.
then recrystallizing the crude hydrochloride of
The amino-esters of this invention are gen
the desired ester .irQm
wane-(petroleum
erally recovered in ‘the form of their addition
ether) mixture yields ‘a product having'avmelting
salts with hydrochloric acid. However, other
point of 1445-1455“ C‘. (corrected).
acids forming addition-salts with amines may
be used in place of hydrochloric; such acids are
EXAMPLE 4
boric, nitric, lactic, tartaric, citric, phosphoric,
Gamma-[di- (n-butyl) gaminol-propyl ester of p
sulfuric, picric, and picrolonic. The addition
ethomy-belnzoic acid
salts may be converted into the free bases in the
A solution c0mprising>4.6‘g. of p-ethoxy-benzoyl
usual manner.
55 chloride in 12 cc. of dry benzene is added to 4.7 g.
24,404,691‘
3.
in benzene, the hydrochloride of the ester s‘ép
of gamma- [di- (n-butyl) -aminol -propanol dis
arating out; then ?ltering, and purifying the
?lter cake by reprecipitation from its alcoholic
solution with dry ether, yields a product having
a melting point of 139—139.5° C. (corrected).
solved in 5 cc. of dry benzene; after the reaction
is complete, the benzene is distilled off in vacuo;
and recrystallizing the hydrochloride of the crude
ester from an acetoneeether mixture, one obtains
a product melting at about 85.6-86.6o C, (cor
EXAMPLE 9
p-dz‘ethylamino-ethyl ester of p-(p-diethylammo
rected) .
EXAMPLE 5
,
c-diethylamino-ethyl ester of p-n-butozty-beneoic
acid
"
I
-
'
_
ethowy) -benzoic acid‘
5 g. of p-diethylaminoethoXy-benzoyl chloride
.
7
hydrochloride
suspended in a solution comprising
2 g. of p-diethylamino-ethanol in 20 cc. of dry
benzene is re?uxed for several hours; the precipi
ride in 25 cc. of dry benzene is re?uxed for two
tate (mono-hydrochloride of the ester), after
hours with a solution comprising 6.191 g. of ,B-di
ethylamino-ethanol in 10 cc. of, dry benzene; the 15 ?ltration and puri?cation by reprecipitating the
A solution of 10.5 g. of p-n-butok‘ybenzoyl chlo
solution is allowed to cool, and 'the’hydrochloride .* ?lter cake from a mixture of alcohol and ether,
of the desired ester separates as a heavy‘crystal
yields the desired product as a very hygroscopic
line deposit; after ?ltering and washing the pre
cipitate with benzene and dry ether, a compound
having a melting pointof 146° C. (corrected) is
substance,
‘ _
The p-(B-diethylamino-ethoxy) ~benzoic chlo
ride may be prepared as follows: 13 g. methyl
ester of p-hydroxy benzoic acid is, dissolved in
obtained.
‘EXAMPLE
'
6
"
35 cc. acetone, and 15 g. anhydrous potassium
carbonate is suspended therein. The mixture is
i
,c-dimethylamino-ethyly _' ‘ester 30f»? 'p-n'—biLto?cy—
re?uxed andxstirred, and 13 g. ,B-diethylamino:
ethyl chloride is added, the reaction mixture be
benzoic acid
10 cc. of dry benzene is treated withv a solution
ing heated andstirred for 15 hours. The in
organic salts precipitated are ?ltered off, andthe
comprising 10.5 g. of p-n-‘but'oXy-‘benzo'yl ‘chloride
in 20 cc. of dry benzene;v ?ltering off the precipi
is treated with an excess of aqueous sodium hy
{1.5 "g. of ,cédim'ethylamino-ethanol dissolved‘in
?ltrate concentrated by distillation; the residue
tate and washing it with benzene and petroleum 30 droxide, and boiled until saponi?cation is com
plete. Any alkali-insoluble material is removed
ether yields the hydrochloride of the'desired ester,
by extracting with a solvent such as. ether or
having a melting point of 132-133": C.
benzene; the clear alkaline solution is acidi?ed
EXAMPLE 7
with HCl, evaporated to dryness in vacuo, and the
residue extracted with absolute alcohol. The ex
e-diejthylamino - ethyl ester of 2- ethoaéy g 3
'
‘
methyl-beneoic
acid
'
tract is ?ltered, evaporated to dryness, and the
residue recrystallized from methyl alcohol and
'
11.5 g. 'of 2_-_ethoxy-3-methyl-benzoyl chloride
ether. The hydrochloride of p-(p-diethylamino
dissolved in 50 cc. ofrdry benzene is treated with
ethoxy) -benzoic acid obtained is in the form of
a solution comprising 13 g. of ,B-diethylamino 40 white needles, melting at 160-161° C. (corrected).
ethanol in 25 cc. of. dry benzene; as the reaction
19.5 g. p-(,B-diethylamino-ethoxy) -benzoic acid
proceeds, a crystalline deposit separates out;
and 15 g. phosphorus pentachloride are heated
?ltering and washing the precipitate, evaporat
together on the steam bath until reaction ceases.
ing the ?ltrate and ‘washings to dryness, redis
The P0013 which forms is distilled off in vacuo,
solving the residue in alcoholic hydrochloric acid, “
and the residue is allowed to crystallize; crystal
followed by reprecipitation therefrom with dry ‘ lization may be hastened by triturating with
,ether,‘ yields the desired product, havinga melt
ing point of 97-97.5° C.
acetone and ?ltering.
The
'
The‘, 2-ethoxy-3-methyl-benzoy1 chloride may
'be prepared by treating 3.5 g. of sodium dissolved
in 100 cc. of absolute alcohol with 25 g. of ethyl 50
o-cresotinate, after which 20 g. of ethyl bromide
V
hydrochloride
of
“
l
p-(c-diethylamino
ethoxy) -benzoy1 chloride formed melts at 143° C.
(corrected) .
,
EXAMPLE 10
V
p-diethylamino-ethyl ester of 2-methyl-4-ethoxy
,is added and the solution is boiled‘until neutral
benzoic acid‘
to moist litmus; then‘ after ?ltering, and dis
tilling the alcohol from the ?ltrate, the ethyl 55. 7.5 g. of 2-rnethyl-4-ethoxy-benzoi'c acid is
ether of ethyl o-cresotinate, having a boiling
warmed with 8.16 g. of phosphorus pentachloride
point'of 116-118o 'C./6 mm., is fractionated in
until the reaction ceases; fractional distillation
vacuo from the residue; dissolving 21 g. of this
of the reactants under reduced pressure yields
fraction in alcoholic sodium hydroxide, cooling,
2-methyl-4=-eth0xy-benzoyl chloride as a color
and ‘acidifying the solution with hydrochloric
less liquid boiling at 138-140° C./3 mm. A solu
“acid, yields 2-ethoxy-B-methyl-benzoic ‘acid as
60
an oily precipitate, which may be extracted with
tion of 6 g. of this fraction in 20 cc. of dry benzene
is treated with ‘7.6 g. of ,B-diethyl-amino-ethanol
dissolved in 10 cc. of dry benzene, and crystals of
vether and subsequently dried; this extract, after
distilling off the ether, is boiled for two hours
‘with 20 g. of thionyl chloride, whereupon frac
diethylamino - ethanol
hydrochloride
separate
2-ethoxy-3-methyl-benzoyl chloride, which passes
'over at 102—1Q5° C./2.5 mm.
EXAMPLE 8
diluting it with dry ether, yields the hydrochlo
out; ?ltering off the precipitate, treating the
65 ?ltrate with alcoholic hydrochloric acid, and
tional distillation yields the desired intermediate,
lis-dz'ethylamino-ethyl .ester of o-ethoxy-benzoic
acid
ride of the desired ester as a white crystalline
solid melting at 101-103" C.
EXAMPLE 11
70
v,6-diethylamina-ethyl ester of 3-methyZ-4-eth
,
_ 10 g. of o-ethoxy-benzoyl chloride dissolved in
,50 cc. of dry benzene is treated with a‘ solution
>
'
omy-beneoic acid
-
13 g. of 3-methyl-4-ethoxy-benzoiciacidandjlfa
comprising 6.5 g. of p-diethylamino-ethyl alcohol 75 g, of phosphorus pentachloride are heated on a
5
ether, yields the desiredproduct, which is a mix
ture of two isomers, and has a melting-point
steam ‘.bath .f or . 30 minutes, and then ,hactionally
distilled in vacuo, the ?raction.3,=-;methyl-4-eth
range of 120-1260 C.
oxy~benzoyl chloride being _:_0btained as acolorless
liquid .boiling at 14fl—'152° (EL/6‘ mm. Asolution
comprising 6.5 g. of this fraction dissolved in ,16
Exelvmtyn v15
16- [lNeethyleNl- (p-hydroxyéthyl) .-.aminol eethyl
cc. of ,dry benzene, is mixed with 7,5 g. .ofdi
ester of p-ethozryebeneoiciaetd
ethylamino-ethanol dissolvedin ‘18 0.0..of ,dry ben
zene, and the mixture boiled for 60minutes; cool
ins the reaction mixture causes a white crystal
line precipitate of ?-diethylarnino-ethanol hydro
'
‘
‘ 6.73. .of 18,19’adihydroxyetriethylamine‘is dis
10
chloride to separate out completely; then ?lter
ing, treating the ?ltrate with alcoholic hydro
chloric .acid, and distillinao? the benzene and
alcohol, leaves a white. solid residue which upon
recrystallization .irom amixture of absolute alco
hol anddry ether, yields the hydrochloride cf the
desired product as ,a white crystalline ;-preei.pitate
solved in 100 cc, oidrybenzene; L4 g, ofkpotassium
carbonate is suspended therein, and ‘after adding
9.2 g. of p-.ethoxy-benz0yl chloride, ‘the reactants
are re?uxed, Iwith stirring, for two'hours. viFilter
ingfthe reactants, evaporating thehenzene, and
15
distilling the residue in vacuo yields ‘the desired
product as a thick, colorless ,oil, soluble ‘in dilute
acids, and having a boiling point of 2I8+f225° ‘C.'/8_
mm, Its hydrochloride is very hygroscopic.
having a melting inointeof "142;,5—~14_5°1C.
EXAMPLE l2
G'amma-diethylamino-propyl ester of p-ethoaty
20
EXAMPLE 16
¢,a-di- (N -dimethylaminomethyl:) -n-propyl ester
, of p-ethoay be'nzoic acid
1.5.
..g.,
of
il;3-.di-dimethylamino-Zsethylepmpa
5.5 g. of gamma-diethylamino-propanol, 9.3 g.
nol-‘Zand 1.6 .g. ,ofjp-ethoxy-loenzoic,acid areqeach
of p-ethoxy-benzoyl chloride,>and 25cc. ofsodium
hydroxide ‘(10% solution) are vigorously stirred 25 dissolved :in ‘5 cc. :of 1chloroform,,and :the mixture
of ‘the :solutionsis- heated on a ‘steam. bath for
for-30 minutes; the mixture is cooled, the oily
benzoicacid
5 minutes. 4 Adding .drytether, ?ltering :the :pre
layer extracted with benzene, ‘and the resultant
cipitate formed, washing, and drying the ?lter
solution is washed with dilute sodium hydroxide
cake, yields ,thehydrochloride __of the desired
and water; distilling off the benzene, dissolving
the residual oil in absolute alcoholic hydrochloric 30 product rasua ‘whitecrystalline powder having a
melting :poi-nt\o_f 121421.5“ C.
,
acid solution, and diluting ‘the latter’ with ‘ether,
causes the hydrochloride of the desired ester to
. ExAMRLn l7
separate out as a crystalline precipitate, "which,
e-‘dz'ethylamino-z'sohexyl ester of lp-ethocwben
after ?ltering and recrystallizing from an alcohol
ether mixture, yields the desired product, having
a melting point of 148.5-1495" C.‘ i
‘
‘
s
i
-
eoic acid
=1
g. of pjdiethylamino-isohexanol, ‘6,1 g. of
p-ethoxy-benzoyl chloride, 10 got potassium car
EXAMPLE 13
Z-(diethylamz'no)ecyclohezcyl ester of memory-
.bonataand 50 cc. of dry benzene are reacted in
‘benzoic acid
A solution comprising 6.8 g. of 2-_diethylamino~
cyclohexanol-‘l dissolved in 75 cc. of dry benzene
is treated With 10 g. of ?nelypowdered anhydrous
c./5 mm.
potassium carbonate suspended therein; 7.3 E‘ .of
p-ethoxy-benzoyl ‘chloride is added to the mixture
the manner described in Example .15. ‘The ester
formed boils at 1757-185" C./2.5 mm. and 193-1‘95°
‘ Ex-AMPnE 18
45
solution is shaken vigorously; and. the‘ benzene
layer containing ‘the desired tester separates out.
Gcmmawdietiwlamico- (debt/dressy) errors/1 ester
of ,‘p-n-butoay benzoic ‘acid I‘
and the latter is re?uxed, With stirring, for sev
eral hours, whereupon 100 cc, of water and 100
cc. of benzene are added thereto and the diluted
‘
A solution vof 5 g. ‘of I-diethylamino-ZB-pro
panediol, 6.2 vg. of p-n-butoxy-benzoyl chloride,
50 and 10 (g. of potassium carbonate, in 50cc. of
benzene, is re?uxed for 90 minutes and treated
in accordance with Example 14. The desired
product, being a mixturepf two isomers, has no
Decanting offthe benzene solution, washing it
with dilutesodium hydroxide and Water, distilling
off the benzene, and adding an alcoholic solution
of hydrochlorioacid to'the residue, followed ‘by
dilution with dry ether, yields the crude hydro‘
chleride of the desired Lesteras'an .qily’precipitate
sharp melting point (79-96" 0.).
EXAMPLE 19
which rapidly crystallizes_;.11ltfering ‘and purifying .
the ?lter cake by recrystallizingjrom an alcohol
ether mixture, yields‘the desired‘product, melting
This ‘com'pound‘is obtained .in‘the same manner
60
at ‘184-185" c.
‘ EXAMPLE 1&1
c-hydrory-gamma-diethyZamién0-propyl ‘ester 07‘
p-ethoacy-benzoic acid'
as that of Example '15, except‘ that ip-n-butoxy
benzoyl chloride is used instead of the p-ethoxy
benzoyl chloride, and the amount ‘of the ethyl
diethanolamine used is 7 g. ‘Thedesired‘product
‘has’, 9a boiling point of 216-220‘? .C./3 mm.‘ Its
hydrochloride is hygroscopic.
A‘ solution of 5 g. of 1.-diethy1amino-,2,3-pro¢
panediol dissolved in .50 cc. of benzene wherein 8
ring, for '90, minutes. , On cooling‘pvérnig-ht, the
“
i . ‘
EXAMPLE .20 , >
g. of potassium carbonate is previously suspend
ed, is treated with 5.4 g, .of .p-ethoxymenzoyl
chloride, and ‘the mixture is re?uxed, with stir
:
0;,0t-tli- (N -dz‘methylaminomethyl-) ~n-propyl ester
70
of p-nebutozcy-be'nzoic acid
‘
' This compound is prepared in the same manner
as ‘that of. Example 16, except that p-n-butoxy
precipitate formed is ?ltered oil, and alcoholic
benzoic acid is used instead of the p-ethoxy ben
hydrochloric acid is added to the filtrate, the re
zoic acid. , The desired substance has a melting
,sultant, solution being evaporated to dryness, :Re
crystallizing, the residue trom , alcohol andldry 75
point of lllf’C; ‘
‘
l
"
.
a
“
' 1
2,404,691.
7
;‘~
.
_-Ex_AMrLE 21.
..
B-‘diethyldmi‘no‘ethgl ester of m-ethoxy-benzoic
acid
‘
'
'
8
anol, each in 25 cc. of dry benzene, are mixed and
warmed on a steam bath for 60 minutes. Filter
ing off the precipitated‘diethylamino-ethanol hy
'
drochloride, and evaporating the benzene from
the. residue, the'latter is treated with ether and
alcoholic hydrochloric acid to yield vthe'desired
11.5 g. of m-ethoxy-benzoyl chloride dissolved
in 50 cc. of dry benzeneis mixed with 14.5 g. of di
ethylamino-ethanol dissolved in 50 cc. of benzene,
and. the mixture is heated on a steam bath for 60
ester as thehydrochloride in the form of a white
crystalline solid meltin'gat 125.5” C.
1
minutes, ‘whereupon the precipitate formed (di
ethylamino-ethanol hydrochloride) ‘is ?ltered off 10
and 'the benzene is distilled from the ?ltrate,
p-dicthylcmirtoeethyl ester of p-allyloivy-berlzo'ic
'
yielding a residue which after puri?cation by vac
.,
uum distillation has“ a boiling point of 163-175°
C./ 2
Diss'olving this product in alcoholic hy
1
.
'
EXAMPLE
'
25
add
_
I
-
‘
'
' This compound is'prepared in the same man
neras that of Example 24, except that 8 g. of
drochloric acid. and reprecipitating with ether, 15 p-alloxy-benzoyl
chloride (instead of‘ the p-n
yields the hydrochloride of the ester melting at
propoxy derivative) and 9.5 g. of diethyl-amino
ethanol are'used. The‘boiling point of the ester
EXAMPLE 22
is 165-175° C./4 mm. The hydrochloride melts at
;
,
; ‘
e-diethylamz'no-ethyl 'ester' ‘of p- (,B-ethowy-eth 20 130° 0.
EXAMPLE 26'
-- ~ oxw-Denzoic acid
15 g. of methyl p-hydroxy-benzoate and 18 g. of , ?-diethyldmino-ethylj ester 0]‘ p-(p-phenyaethé
cry) -benzoic acid
?-bromo-ethyl ether dissolved in50 cc. of. dry
acetone, are treated with a suspension therein of
The aracyl halide for the preparation of this
20 g. of powdered .anhydrous potassium carbonate, 25 compound is‘ obtained as follows: To 15.2 g. of
and the mixture is then re?uxed, with stirring,
methyl :p-hydroxy-benzoate dissolved in a solu
for .15 hours. The potassium carbonate and po
tion of 2.5 g. of metallic sodium in- 90 cc. of abso-.
tassium bromide precipitated are ?ltered oh‘, the
lute alcohoL-isadded 20.5 g. of B-phenyl-ethyl
acetone is distilled from the ?ltrate, and the resi
bromide, andthe mixture is re?uxed? hours.
due boiled with dilute. sodium hydroxide solution 30 Filtering off the inorganic salts, distilling o? the
until dissolved; p-(p-ethoxyethoxy)-benzoic acid
is precipitated with hydrogenchloride, and after
?ltering, washing, drying the precipitate, and re
crystallizing from benzene, yields a product melt
alcohol fromthe ?ltrate, hydrolyzing the residue
by boiling it with aqueous alkali, precipitating
the free'acid with hydrogen chloride, ?ltering,
washing, and drying, .yields the intermediate, p
ing at 131-132° C. Heating a mixture comprising
6 g. of this benzoic acid derivative and 6 g. of
(18-phenyl-eth0xy)—benz0ic acid, in the form of a
white powder, melting at 163-164" C. Dissolving
phosphorus pentachloride to'about 70° C. until hy
10 g. of this intermediate compound in 40 cc. of
drogen chloride is no longer evolved, and frac
phosphorus oxychloride, adding 8.6 g. of phos
tionally distilling in vacuo, yields p-(?-ethoxy
phorus pentachloride, warming themixture on a
ethoxy) -benz'oyl chloride as a colorless oil having 40 steam bath, evaporating off the excess phosphorus
a boiling point of 150_160° C./5 mm. Refluxing a
oxychloride, adding 8.6 g. of phosphorus penta
mixture comprising 5 g. of this benzoyl chloride
chloride, warming the mixture on a steam bath,
evaporating'off the excess phosphorus oxychlo
derivative, 5.1 g. of diethylamino-ethanol, and 50
cc. of dry benzene, for 30 minutes, ?ltering off the
ride, andvacuum-distilling the residue, yields the
precipitate
(diethylamino — ethanol hydrochlo
ride), evaporating o? the benzene and alcohol,
treating the residue with ether, and adding alco
holic hydrogen chloride, yields the desired ester
as .a vwhite'crystalline hydrochloride melting at
102-10350
~
''
>
C.
'
,
EXAMPLE
45
C./5 mm.,
f
'
'
‘
'
EXAMPLE 27
50
p-diethyZamino-cthyl ester of p-(?-brornallyl
' ‘
23
?-dz'ethylamino-ethyl ester of p-n-propoa'y-ben
zoic acid
acid chloride of the intermediate, having a boiling
point (with slight decomposition) of 215-230°
,
oxy) -benzoic acid
'
solution comprising 17 g. methyl p-hydroxy- '
benzoate and 25 g. 2,3-dibromopropene and a
suspension of 20 g. potassium carbonate in 50 cc.
After mixing and re?uxing solutions compris 55
of acetonais'reflux‘ed, with stirring, for 10 hours;
ing 9.5g. of p-n-propoxy-benzoyl chloride and
?ltering
the ‘mixture, evaporating the acetone
11.2 g. of diethylamino-ethanol, each dissolved in
from the ?ltrate, hydrolyzing. the residue by heat
25 cc. of benzene, for 30 minutes, the reaction
mixture is cooled, and 100 cc. of dilute sodium hy
ing-with aqueous sodium hydroxide, precipitat
ing the free acid .with hydrogen chloride, and
droxide solution‘is added; then after vigorously 60 after ?ltering, washing, and drying the precipi
shaking the mixture, the benzene layer, contain"
tate, recrystallizing it from benzene, yields the
ing the desired ester, separates and is decanted
desired intermediate, 11- (p-bromallyloxy) —benzoic
off. Then Washing the benzene solution with
acid, melting at 200°C. (with decomposition). '
‘water, distilling off the benzene, and vacuum
Warming 9.5 g. of this benzoic acid derivative
‘distilling the residue, yields the desired ester, hav 65 with 7.7 g. of phosphorus pentachloride, and frac
ing a boiling point of 160-165" C.‘/4 mm.
tionating the mixture in vacuo, yields the- de
The hydrochloride "is obtained, in accordance
sired‘ acid chloride intermediate, boiling at 160
with Example 21, in the form of a white crystal
170°c./5 mm.
,
'
‘
line solid, melting ‘at 135-l36° C.
Re?uxing a mixture comprising 6 g. of this
p-(p-bromalloxy)-benzoy1 chloride and5.1 g. of
EXAMPLE 24
_
.
'diethylamino-ethanol, each dissolved in 25 cc. of
~e-dietiiylamino-ethyl1 ester ofp-isopropoxy-ben
_
201-0 acid;
summons ‘comprising 6.5 g. of .p-isopropoxy
' benzoyl chloride and 7.7 g. 01 diethylaminoée'th- 0' 75
dry benzene, for half an hour, ?ltering off the
precipitate and ‘treating the ?ltrate with alcoholic
hydrochloric acid, yieldsaiter evaporating the’
benzene and hydrogen chloride and recrystalliz
2,404,691
9‘.
10
tremely hygroscopic substance formed is N
ing the residue from alcohol and ether, the de
sired compound, melting at 81.5-83.5° C.
phenacy-N-ethyhamino-ethanol hydrochloride.
A mixture‘ comprisingg'k28-g. of N-phenacyl
EXAMPLE 28
N-ethyl-amino-ethanol; 7.5 ‘g. ‘ p-ethoxy-‘benzoyl
‘?-dz'ethylamino-ethyl ester of 3-methomy-4
chloride, 30 ‘cc. benzene,~and 8‘ g. potassium‘ car
bonate ‘is "stirred and re?uxed for ?ve hours,
?ltered, and the ?ltrate is treated with a-solu
‘
ethoxy-benzoic acid
9.3 g. of» 3-methoxy-4~ethoxy-benzoic acid're
tion of hydrogen chloride in ether. The impure
acted with 10.5 g. of phosphorus pentachloride,
material is then puri?edby crystallization from a
yields the acid chloride, boiling at 147-150" .C./5 10 chloroiorm- (petroleum ‘7 ether) ‘ mixture.“ ‘ The
mm. and having a melting point of 72" C. ‘ Treat
white‘ crystalline substance obtained is" the N
ing 9 g. of this 3-methoxy-4-ethoxy-benzoy1
phenacyl-N-ethylamino ethyl‘? ester of‘ p-ethoxy
chloride and 9.8. g. of. diethylamino-ethanol in
benzoic acid (hydrochloride). 1.
0.9 g. of- this hydrochlorideis dissolved_‘ in 60
accordance-with» Example ‘27, yields the desired
compound as. a white crystalline powder having 15 cc. ‘alcohol containing 0.3.gsplatinumloxide. The
a‘; melting-point v0i 1715-1725‘ C.
mixture is shaken .r’or eight. hours.‘ under. a. pres
sure-‘oi- 35 pounds .of‘ hydrogen; . it. is‘ then ?ltered,
EXAMPLE 29
and-the?ltrate is-concentrated to. a smallvolume
and diluted’ with ether. .The brownish-white .
Delta-dicthylamino-deltazJmtenyl ester of‘ p
ethory-benzoic acid
20
‘2.5 g‘. of p-ethoxy-benz'oate of‘brombutenol
ride. » The substance. is . l3- [N-ethyl-N- (p-phenyl
‘ is mixed with 5.5‘ g‘. of‘di‘ethylamine and 15 cc.
lB-hydroxy-ethyl) 1-- amino \- ethyl
of‘ benzene; the mixture is‘heated' in a sealed
tube‘rat 125-135’ C; for about 8 hours; after
cooling, the contents of the tube‘ is treated with 25
of
D
‘
“Ex-steers 31‘ ‘
propoxy-bensoie acid (hydrochloride)
after washin’gwith water, isv driediover‘“ anhy
drous sodium‘ sulphate‘; the ether,‘fr'ee diethyl
2 > g. ppl-di- (dimethylamine)uisopropanol and
3.2 g. p-n-propoxyfbenzoylchloride are each dis
Solved‘ in 5'00; chloroform; and the solutions are
amine,- and benzene ‘are removed‘ by distillation
of the extract; the oily residue is ‘subjected to
further heating on a steam‘ bath under dimin
mixed.‘ As precipitate forms», which-is dissolved
by adding dry acetoneyand-thereaction‘iscom
ished pressure‘, thereby‘removi‘ngthe solvent by
pleted by warming for a short time on the water
bath. The solvents are then‘ distilled oh, and the
distillation; the product is ‘dissolved in" a small
amount of alcoholic‘ hydrochloric‘ acid, and pre
residue recrystallized‘ from" al-imixture ‘ of alcohol
cipitated as‘ an oily hydrochloride by the‘ addition
and‘ ether-.1 The product», which. melts at ‘203° C.
witlrdecomposition, is a mixture of the mono
of ether; the supernatant: alcohol-ether mixture
is‘ decanted off, leaving ‘an‘ oily ‘residue which,
after extraction‘ with dry ether, yields the desired
product‘a’sa yellowish white crystalline substance
,
ester
ethoxy-benzoio- acid- (hydrochloride). 1 -
‘as'-di'(dimethyldmino)éisopropyl ester of 15-”
water; the water-insoluble product is then‘ sep
arated or extracted with‘ ether; the ether extract,
melting at 146-147° C.
crystalline substance is ?ltered. off,~washed-with
ether, and dried in a ‘vacuumover calcium chlo
and di-hydrochlorides. ‘I
‘
"
EXAMPIZE‘ 32'
'
‘
.
s-diethylamino-e‘thyl' ester of p-(p'-am-ino-ben
zyloxy) benzoic acid (mono-hydrochloride)
l '
The intermediate p-ethoxy-benzoat‘e‘ of brom
butenol may be‘preparedias‘ fOllOWS‘Z' 51-5‘ g.‘of
dry sodium‘ p-ethoxy benz‘oat'e‘ is‘ mixed With 8
g. of a-gamma-dibrombuteii‘el ‘and 10' ‘g. of‘ dry
45
5 g. B-diethylamino-ethyl. ester of p- (pi-nitro
ben‘zyloxy) -benzoic‘_‘,.aci‘d , ‘hydrochloride is dis
solved‘in absolute‘ alcohol‘ and shakenwith hy
xylene; the mixture is-heated in a sealed tube
at. 165-17.0° C. for about. 6 hours, the, contents
drogen gas in the presence of Adams platinum
oxide“ catalyst (Org! Sync, Col‘. Vol“. page ‘452),
offthe tube'is then extracted with dilute alcohol
and‘ ether; theether extract, after washing with 60 until no morerhydro‘gen is absorbed; The cata
lyst is“ then removed ‘by filtration", and? dry ether
water; is dried over anhydrous sodium sulphate;
is/added'to precipitate the hydrochloride; on re
the ether and xylene; are removed by distillation
crystallizing by-dissolv-ing in ‘absolute alcohol and
of the extract on a steambath under diminished
adding dry ether, a product melting at 185-1870
‘pressure; the oily, ‘residue is fractionated in. a
high vacuum; the ?rst fraction coming over at :55 C. (corrected) is obtained.
95‘-97°"C./;3'-4' mm.; the second‘ at‘ 165-1750 C./3
,mml; the third‘ at 200° C./3 mm.; thesecond
fraction being the desired intermediate, p
EXAMPLE 33.
M;_.dimethyZ-gamma-diethyZamino-propyl ester
of peethory benaoicucid (hydrochloride)
ethoxy-benzoate of brombutenol, 7‘
'EXAMPLE 30S
‘ "
4.1» g. 5,3-dimethyl-gamma-diethylamino-pro
‘160 panolis“ dissolved ‘in 4 cc. ‘dry acetone, and a
:amino-ethyl. ‘ester of ,p-ethory-benzoic acid
. :Avlmixture: comprising 9.95 g: 'of' phena‘cyl
bromide, 4.4 g. ethylaminoethanoL. and ‘100 cc.‘
benzene is: re?uxed for three hours“; On adding
10 g. of potassium» carbonate. a vigorous evolution
of carbon dioxide ensues. The suspension is then
further refluxed, for four hours, the, mixture of
potassium bromide and potassium carbonate ?l-i
tered oh, and the ?ltrate treated with a solution
of hydrogen chloride in. ether. The reddish
;brown‘ semi-solid‘ which . separates out ‘crystallizes,
and. is ?ltered off, washed-with ether, and. dried
in a vacuum over; calcium. chloride; The‘ ex-~ '
solution of'4.7 g. p-ethox-y‘benzoy-rchloride-in 5
cc. dry acetoneiis added thereto.‘ Heatisevolved
and a white crystalline ‘mass: forms.‘ The- crude
prcductris-dissolvedin absolute "alcohol and pre
cipitated- by addingdryether. The hydrochloride
is thus obtained» as-al White‘ crystalline solid melt
ing-at 122-124’ C. (corrected). 1
_
‘
EXAMPLE
34
.
I
.
Gammc-dimethylamino-pr0pyl esterlofat’onethyl
4—n-but0ry.-benzoic- acid .
1.53 g. gamma-dimethylamino-propanol and
3117 g. 3-methylL4'-n-butoxy-benzoyl chloride‘ are
dissolved in 10'cci of’ dry alcoholefre'e‘ chloroform. >
2,404,691
1I
12
The ‘solution is warmed on a steam bath for half
40. p-(N-piperidino)‘-ethyl ester of p-ethoxye
an'hour and the product precipitated as the hy
benzoic acid.
drochloride by adding dryvether; it may be puri
?ed by r'edissolving‘ in chloroform or absolute al
coh‘ol’ua'nd ‘reprecipitating. The product irs'a white
Q‘
,
"'
~
"
'
I‘
crystalline, powder melting" at 125.5-125.5°V._¢.
41. Delta-diamylamino-n-butyl ester of 2-pro
poxy-3-methy1-benzoic acid.
42. ‘or-methyl-a-dimethylaminomethyl-gamma
phenyl-n-propyl ester of p-(p-phenyl-ethoxw
(corrected).
benzoic acid.
r
-
I
-
‘
_
'
ExAMr-Ln35
'
>
_
‘
»
.
.
(Ld'sdi (dimethylaminomethyl) '- .gamma-phenyl-‘n 10
Zn‘ropyl ester‘ ‘of 3-methyl-4-n-butozry-benzoic
acid
(hydrochloride)
'
'
.
‘
,
43. aémethyl-a-dimethylaminomethyl-gamma
phenyl-n-propyl ester _of 3-methyl-4-nebutoxy
benzoic acid.
I
_
_
V
44. Gamma-diethylamino-n-propy1 esterof 3
'
ethyl-4-n-propoxy-benz'oic acid.,
36 g. of the ethyl ester of 3-methyl-4-hvdroxy
benzoic acid and’27.4 g. of n-butyl'bromide dis
_.
V j
H
_. .
45. Gamma-dimethylainino-n-propyl ester of
solvedjn 200 cc. acetone, are treated ‘with-V84 g. 15
3-methyl-4- (,B-phenyl-ethoxy) -benzoic, acid. v
46. a - methyl-a-dimethylaminomethyl-néamyl
anhydrous potassium carbonate in themanner
described in Example 22. ,The product, ,3-methyl7
acid.
4-nebutoxy-benzoic acid, is recrystallized from
60% alcohol in the form of'white plates melting
47. a-methyl-u-dimethylaminomethyl-gamma
phenyl-n-propyl ester of
at 144-146? C. (corrected).
1
a
ester of 3-methyl-4-(p-phenyl-ethoxy)-benzoic
20
:_
ethoxy) -benzoic acid.
15 g. of this acid is reacted with 15 g. phosphorus
22.
' '
.
48. a - methyl-u-dimethylaminomethyl-n-amyl
pentachloride in the manner described in Exé’
ample
,
ester of p-(p-phenyl-ethoxy) -benzoic acid. -1 5
The, product, 3-methyl-4-n-butoxy,
_>
V
a
__
49. “,4 - di(dimethylaminomethyl) - gamma
benzoyl chloride, boils at 144-154" C. at 1.5 mm.
phenyl-n-propyl: ester of 3-methyl-4-(p-pheny1
1.05 g. of 3-methyl-4-n-butoxy-benzoyl chlo 25
ethoxy)-benzoic
ride and 1.25 g. of u,a-di(dimethylaminomethyl) -
gamma-phenyl-propanol are dissolved in 10 cc. of
chloroform and the solution is re?uxed for a few
minutes. Dry ether is added until a faint precipi
tate appears, and the whole is allowed to stand 30
for some time. The crystalline precipitate formed
is ?ltered on and washed with dry ether; it melts
at 161-162“ C. (corrected).
Gamma-dimethyZamino-n-propyl ester of p-(e
'
51. a,a-di¢dimethylaminomethyl-n-amyl ester
of 3-methyl-4-n-butoxy-benzoic acid. ‘
1
52. Delta - diethylamino - n - butyl ester'nof 3
methyl-4-n-butoxy-benzoic acid. ~
g
, .
Example 35. The product melts at 156.5-15'7.5° C.
(corrected).
ethyl ester of p-ethoxy-benzoic acid.
a
»
‘
- ~ ~
56. a-methyl - oz - diethylaminomethyl-n-butyl
ester of p-n-propoxy-benzoic acid. '
‘
~
‘
57. p-diethylamino-ethyl ester of 2-methyl-4propoxy-benzoic acid.
,
'
-
-
58. ,8 - dimethylamino - n - propyl I ester of 3
methyl-4-propoxy-benzoic. acid.
EXAMPLE 37
a-methyl-a-dimethyZaminOmethg/Z-n-amyl ester
*
»
59. B-(,e-diethylamino-ethoxy) -ethyl ester, of
45
p-ethoxy-benzoic acid.
of 3-methyZ-4-n-butory-benzoic acid (hydro
a‘
7'
>
-
i;
'
-
The
'
intermediate,
' EXAMPLE
3-methyl-4-(ls-phenyl-eth
60
,
,
4.4 g. of 3~methyl-4-n-butoxy-benzoyl chloride
and 3.0 g. of.a-methyl-a-dimethylaminomethyl 50 oxy)-ben,zoyl.chloride used in the preparation
,of the compounds of Examples 45, .46, 47, 49, ‘and
n-amyl alcohol are reacted together in 10 cc. of
chloroform as directed in Example 35. The prod
50 may be prepared as follows:
uct melts at 126-131° C. (corrected).
23 g. of the ethyl ester of 3-,methyl-4-hydroxy
benzoic acid, 3.2g. of sodium,‘ and 23 g. of #
EXAMPLE, '38
-
.
.
~
. .2
phenyl-ethyl bromide are reacted together in
e-diethylamz'no-ethyl ester of p-(p'mitro-benzyl
200 cc..absolute alcohol in the manner described
oxy)-benzoic acid (hydrochloride)
in Example 26. The product, >3-methyl-4(?
phenyl-ethoxw-benzoic acid, melts at 150-152’
5.5 g. p-nitro-benzyl bromide is added to a’
C.
(corrected).
1
,
.
.
i
solution or 6.4 g. p-diethylamino-ethyl ester of
‘ 13 g. of this acid, reacted with 10.5 g. phos
p-hydroxy-benzoic acid in 50 cc. dry’ acetone in 60 phorus
pentachloride in the manner described in
which 15 g. anhydrous potassium carbonate is
Example 26, gives the corresponding acid chloride
suspended. » The mixture is re?uxed for 12 hours,
boiling at 210-2150 0. at 1.0 mm. P
?ltered. and'the acetone distilled from the ?ltrate.
The residue is treated with a solution of hydrogen
chloride in alcohol, some acetone is added, then
ether; and the product precipitates as the hydro
chloride. It is puri?ed by recrystallization from
acetone and ether,‘ and melts at 145-146° C.
.1 .
The invention may be variously otherwise em
bodied, within the scope of the appended claims.
We claim:
'
"
r’
'
"
1. A compound of the group consisting of:
amino esters of the general ‘formula.’
‘
(corrected) .
The following are among the many other com
pounds embraced by the present invention, and
may be prepared according to the directions given
,
~
53. ,3 - [N - ethyl - N09 .- phenyl-ethyl) -amino]
reacted in chloroform in the manner indicated in
.
-
55. a - benzyl - oz - diethylaminomethyl -_ propyl
ester of p-n-butoxy-benzoic acid.’
‘
_
1.55 g. gamma-dimethylamino-propanol and
4.0 g. p-(p-phenylethoxy) -benzoyl chloride are 40
‘
r
35 amino-propyl ester of p-ethoxy-benzoic acid.
phenyZ-ethoxy) -benzoic acid (hydrochloride)
chloride)
‘
54. on - methyl - 13 - benzyl - gamma - dimethyl
' EXAMPLE 36
'
acid."
50. a,a-di (dimethylaminomethyl) -n-amylester
of 3-methyl-4-(p-phenyl-ethoxy) -benzoic acid.
70
.
I
\R.
..
...
wherein R represents a divalent alkyl residue
with
2 to 3 carbon atoms, and each of R’ ‘and R"
39. at - di(dimethylaminomethyl) -amy1 1ester
of p-(p-phenyl-ethoxy) -benzoic acid.
"
75 represents‘ an alkyl residue with 2 ‘to 4 ‘carbon
above:
atoms; and'acid-addition salts thereof.‘ -
I
2,404,691
13
14
2. An acid-addition salt of an amino ester of
‘ the general formula
4. An acid-addition salt of p-diethylamino
‘
h)
ethyl p-ethoxy-benzoate.
/R'
CHaGHrO‘<:>4J_0~CH'CHrN\
R"
5. The hydrochloride of p-diethylamino-ethyl
p-ethoxy-benzoate.
5
wherein each of R,’ and R." represents an alkyl
residue with 2 to 4 carbon atoms.
3. ,B-diethylamino-ethyl ester of p-ethoxybenzoic acid.
10
6. The hydrochloride of 5 - [di - (n - butyl) -
aminoJ-ethyl p-ethoxy-benzoate.
I
WALTER G. CHRISTIANSEN.
SIDNEY E. HARRIS.
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