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Patented Nov. 5, 1946
2,416,431
UNITED STATES PATENT OFFICE
,
2,410,431
ALKYL MERCAPTO SUBSTITUTED AMINO
BENZOICACID ALKAMINE AMIDES, SALTS,
‘INTERMEDIATES; AND PROCESS OF PRE
' PARING SAME
John J. Donleavy, Montclair, N. J., assignor to
Allied Laboratories, Inc., Kansas City, M0.
N0 Drawing. ‘Application April 24, 1943,
Serial No. 484,472
5 Claims.
(01. 260—558)'
1
2
This invention relates to a newly discovered
group of organic compounds which have a local
anesthetic action similar to :.cocaine or procaine
and‘ the like.
This'application is a continuation-in-part'of
to a certain point produce intermediates but
thereafter the processes are changed herein and
there are produced amides having the advantages
before mentioned over the esters produced by the
process of that co-pending disclosure.
By way of explanation only it is stated that
common to the Patent No. 2,173,827, and the co
the co-pending application Serial‘ No. 282,352
?led January 1, 1939‘(now Patent No. 2,321,468),
and ‘entitled Alkyl thio substitutedv amino ben‘zoic
acid alkamine esters, salts,‘ intermediate and‘
pending application disclosure, now Patent No.
2,321,468, and the instant application all the
process of preparing same, in turn a continua
products include the introduction of an alkyl
tion-in-partof Patent No. 2,173,827, dated Sep
meroapto group into molecules previously known
tember 26, 1939.
'
to have some anesthetic power, but such intro
duction in the products of the co-pending appli
The chief object of this invention is to prepare
_a compound which has local anesthetic proper
cation disclosure, now'Patent No. 2,321,468, were
ties equal or greater than that of cocaine, etc, 15 more desirable for reasons stated therein over the
products of the earlier patent and in comparable
and which has a toxicity equal to or less than
that of the last mentionedproducts, the anes
manner the products of the instant disclosure
thetic property of the present newly discovered
(the amides, etc.) are more desirable than the
organic compounds being of local character.
esters, eta, set forth in the copending application,
Speci?cally the products are amides and com 20 now Patent No. 2,321,468.
parable to the esters of the application herein
The formula of this subsequent speci?c. dis
before referred 'to and now allowed.
closure is set forth as follows for one compound
of one series of compounds:
An amide of the examples’ hereinafter men
tioned was found to have approximately four
times the anesthetic power of cocaine although 25
only having a toxicity equal to that of cocaine
and to that extent this amide is more suitable
for anesthetic purposes-than the esters of the
co-pending application, which included an ex
ample that showed only twice the anesthetic 30
power of cocaine for the best comparable ester
, ,In the series of compounds, the CONI-ICHzCI-IzN'
product. The products herein of amide char-,
(C2H5)2 may vary in position and the SC2H5 may
acter have the general, form expressed algebrai
vary in position relative to each other and, the
cally as follows:
position of NI-Ia. Also in place of (CzHs), wher
RfSCsI-Ia (NI-I2) CONH(CH2) INR' 'R’”, wherein 35 ever the same appears, other alkyl groups may
R’ is an alkyl radical, R," is an alkyl radical and
be substituted therefor. One example of the
R’” is an alkyl radical and r is an integer greater
species group represented by the preceding dia
than the unity and less than 4. In certain in
gram is:
stances R," and R'” may be combined in the form
of a polymethylene chain, for examplethe group 40 Dialkylaminoealkyl amides of 3-dmino-4-dlkyl
mercaptol-benzoic acids
NR"R”' may be the piperidyl radical.
‘
Broadly speaking, the product is an amide of
As representatives of this type there have been
an aromatic acid and a dialkyl amino alkyl
prepared the beta-diethylaminoalkyl amide of 3
amine, or is a salt thereof.
,
Inasmuch as the aforementioned allowed ap
amino - .4 - methylmercaptobenzoic,
45
plication, now. Patent. No. 2,321,468, dated Sep
tember 26, 1939; fully and accurately sets forth in
considerable detail the highly desirable charac
3 - amino-4
ethylmercaptobenzoic andv 3-amino-4-propylmer
captobenzoic acids.
,
A convenient method of preparing compounds
of this type depends on they discovery that the
teristics of the general class of products to which
that disclosure and the instant disclosure is di
rected, no further description or explanation is
believed necessary.
It may be here brie?y stated that the ?rst two
products being the corresponding derivatives of
processes set forth in the copending application, -
3-nitro~4-alkylmercaptobenzoic
chlorine atom of derivatives of 3-nitrochloro
'benzoic acid such as its salts, esters’ and amides
can readily be replaced by an alkylmercapto
group by treatment with a metal mercaptide, the
acids. > Subse
as originally ?led, are processes which followed 55 quently the nitro group'may be converted to an
2,410,431 '
5
acid, B. P. 180° C. at 4 mm.; the methyl ester of
3-amino-4-n-propylmercaptobenzoic acid, B. P.
182° at 5 mm.; the corresponding beta-diethyl
aminoetliyl amide dihydrochlorides M. P. 149
151° C. and 145-149" C. respectively: in both cases
the free amides were again oils, which did not
crystallize.
Method II
6
While the invention has been described in
great detail in the foregoing speci?cations the
same is to be considered as illustrative only of
the general claims and not restrictive in char
acter. Modi?cations here-of comparable to those
disclosed in the earlier Patent No. 2,173,827, as
well as in the co-pending application, now Pat
ent No. 2,321,468, as well as others which will
readily suggest themselves to persons skilled in
A solution of 2.1 grams of the methyl ester of 10
this art, are to be considered as within the scope
3-nitro-¢l-ch1oro-benzoic acid in 30 cc. of 95% a1
of this invention, reference being had to the ap
cohol was heated to boiling and added to a boil
ing solution of sodium methyl mercaptide, pre
pared by bubbling one gram of methyl mercaptan
pended claims ior the de?nition thereof.
The present disclosure is intended as a basic
disclosure of basic compounds previously de
slowly into a solution of 0.4 gram of sodium hy
. scribed and the related compounds which differ
droxide in a mixture of 3 cc. of water and 30 cc.
in the position of the groups in the benzene ring.
of 95% alcohol. The total mixture was boiled
Herein the general disclosure 'is directed to
under re?ux for thirty minutes. The solvent was
compounds comprising as a Markush group the
then removed by distillation under diminished
pressure and the solid residue was washed with 2-0 amides and the acid addition compounds of said
amides and wherein said amides have the gen
15 cc. of water containing a drop of hydrochloric
eral
formula, R’S (NI-I2) CeI-Is CONH (CI-12M NR"
acid. The product, the methyl ester of 3-m'troJl
R" where x is an integer greater than unity
methylmercaptobenzoic acid, was purified by re
and less than four and R’, R” and R’” represent
crystallization from methyl alcohol.
Further procedure following this method is
identical with that applied to the same compound
alkyl radicals of like or unlike character.
The invention claimed is:
1. An organic compound having the formula
in Method I. Method II, therefore, is an alter
para-R’S-meta-NI-IzCeHaCONH(CH2) eNR' 'R' ' ’
native method of preparing the intermediate.
In connection with the beta-diethylaminoethyl
where a: is an integer greater than one and less
amide of 3-amino~4-ethylmercaptobenzoic acid
than four and R’, R" and R’” represent alkyl
used for the production of the dihydrochloride in 30 radicals containing not more than six carbon
a similar manner as before mentioned, same pro
atoms.
duced the corresponding dihydrochloride wherein
2. IS-Diethylaminoethyl amide of 3-amino-4
the actual nitrogen yield was 11.36% compared
(n-propylmercapto) benzoic acid.
with the theoretical nitrogen yield of 11.44% and
3. p-Diethylaminoethyl amide of 3-amino-4
the ionizable chlorine found was 18.80% as com
pared to the calculated amount of 19.07%.
The beta~diethylaminoethyl amide of 3-amino
li-N-propylmercaptobenzoic acid when used to
prepare the dihydrochloride thereof in a compa
rable manner produced a product which upon
analysis was found to contain nitrogen in the
amount of 11.09%, whereas the theoretical nitro
gen content was 11.02%.
(ethylmercapto) benzoic acid.
4. p-Diethylaminoethyl amide of 3-amino-4
(methylmercapto) benzoic acid.
5. The method of preparing a 3-nitro-4-(alkyl
mercaptolbenzoic acid by heating a sodium mer
captide and the sodium salt of a 3-nitro-4
chlorobenzoic acid in aqueous alcohol solution.
JOHN J.v DONLEAVY.
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