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Патент USA US3060203

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ite grates
a
EQQ
1
3,05,]:92
Patented Get. 23, 1962
2
which only one isomer is soluble, separating the insoluble
3,060,192
isomer, separately recovering the soluble isomer, and hy
PRODUCTION OF ENANTIOMERS 0F ALPHA
METHYL-PHENETHYL HYDRAZINE
drolyzing each isomer to yield the corresponding dextro
and levo enantiomers of a~methyl-phenethylhydrazine.
Among the N-acylhydrazines of Formula III of this in
vention are the following compounds:
>~ IN
TERMEDIATE
Jack Bernstein and Kathryn A. Losee, New Brunswick,
NJ., assignors to Oiin Mathieson Chemical Corpora
tion, New York, N.Y., "a corporation of Virginia
( l ) N’-(ix-methyl-phenethyl) ~N-acetylhydrazine
No Drawing. Filed Apr. 29, 1959, Ser. No. 809,607
7
2 Claims.
(Cl. 260-3263)
10
This invention relates to new and useful organic hydra
zine derivatives.
An object of this invention is the provision of new and
( 2) N'-a~methyl-phenethyl) -N-propionylhydrazine
(3) N’-( u-methyl-phenethyl) -N-benzoylhydrazine
(4) N'-( a-methyl-phenethyl) -N-p-tolylhydrazine
( 5 ) N’- (a-methyl-phenethyl) -N-1-naphthoylhydrazine
(6 ) N'- ( a-methyl-phenethyl) -N-phenacetylhydrazine
(7) N'~( cx-methyl-phenethyl) -N-cinnan1oylhydrazine
useful optically active isomers of u-methyl-phenethylhy
(8) N'-(a—methyl-phenethyl) ~N-acryloylhydrazine
15
drazine and non~toxic acid addition salts thereof.
(9 ) N’-( u-methyl-phenethyl) -N-acetylhydrazine mono
Another object of this invention is the provision of new
hydrochloride
and useful N'-acyl derivatives of a-methyl-phenethylhy
( 10) N'- ( a-methyl-phenethyl) -N-phenacetylhydrazine
drazine and acid addition salts thereof.
mononitrate
Yet another object of this invention is the provision of
(
1
1 ) N’-( a-methyl-phenethyl) -N-isonicotinoylhydrazine
an improved process for preparing a-methyl-phenethyl 20 ( 12)
N'-( a-methyl-phenethyl) -N-isonicotinoylhydrazine
hydrazine and optically active forms thereof.
dihydrochloride
A further object of this invention is the provision of a
( l3 ) N’-(o¢~methy1-phenethyl) -N-picolinoylhydrazine
method for preparing the hydrazides and salts of this in
( 14) N’- ( a-methyl-phenethyl) -N-nicotinoylhydrazine
vention.
) N'-(a-methyl-phenethyl)-N-6-oxo-piperidy1-2-car
The method of this invention essentially comprises: 25 ( l5bonylhydrazine
(A) reacting phenyl-Z-propanone with a primary acyl
( 16) N'- (a-methyl-phenethyl) ~N-pip eridyI-Z-carbonyl
hydrazine of the Formula I: RCO-NHNH2, wherein R
hydrazine
is an organic radical (formed by the reaction of a mono
( 17) N'- (oc-methyl-phenethyl) -N-pyroglutamoylhydra
basic carboxylic acid, which may, or may not, be opti
z1ne
cally active, with hydrazine) to yield an N'-acylhydra 30 ( 18 ) N'- ( a-methyl-phenethyl) -N-pyro glutamoylhydra
zone having the following Formula II:
zine dihydrochloride
( 19 ) N'-( oc-methyl-phenethyl) -N-pyrroly1-2-carbony1
hydrazine
35
wherein the term acyl indicates the acyl radical of a
(20) N'- ( a~methyl—phenethyl) -N-1actoylhydrazine
( 21 ) N’- ( a-methyl-phenethyl) -N-mandeloylhydrazine
In order to prepare the compounds of this invention by
the process of this invention phenyl-Z-propanone is re
acted with a hydrazide of a monobasic carboxylic acid of
monobasic carboxylic acid, and (B) reacting the hydra
zone with a reducing agent to yield the new N’-acyl de~
rivatives of a-methyl-phenethylhydrazine of this inven
the Formula I, to. yield the N'-acylhydrazone of phenyl
tion having the following Formula III:
Hr
2-propanone as represented by Formula II above. The
reaction is preferably conducted with equimolar amounts
of ketone and hydrazide, although excess of either may
be present. For optimal yields it is desirable to conduct
HI
45 the reaction in the presence of an organic solvent such as
a lower alkanol (e.g., ethyl alcohol), under anhydrous
wherein acyl is as hereinbefore de?ned.
The N-acylhydrazine derivatives of Formula III are
new pharmacologically active compounds as hereinafter
conditions and at elevated temperatures up to and includ
ing re?ux temperatures. Any monobasic carboxylic acid
primary hydrazide may be used in the reaction. Among
described. In addition, these acylhydrazine derivatives
are useful intermediates in the preparation of u-methyl
the useful compounds of the Formula I there may be
phenethylhydrazine, formed by hydrolyzing 01f the acyl
named inter alia hydrazides of the following acids: lower
group. By the practice of the process of this invention,
utilizing the new acylhydrazine derivatives of this inven
tion, an improved process for preparing u-methyl
phenethylhydrazine is thus afforded. In contrast to the 55
alkanoic acids (e.g., acetic, propionic, butyric, isobutyric,
valeric and caproic acids); hydroxyloweralkanoic acids
straight forward method for obtaining a-methyl-phen
ethylhydrazine by reacting unsubstituted hydrazine with
phenyl-Z-propanone, a process which gives only low yields
of a-methyl-phenethylhydrazine in admixture with the
undesired N,N’-bis(phenylisopropyl) hydrazine deriva
tive, through the practice of this invention and ?nal hy
drolysis of the new acylhydrazine intermediates, a-methyl
phenethylhydrazine is obtained to the exclusion of the
60
(e.g., dextro, levo and racemic lactic acid); mono- and
bicyclic aryl acids (e.g., benzoic, p-toluic and naphthoic
acids); monocyclicaryloweralkanoic and loweralkenoic
acids (e.g., phenylactetic and cinnamic acids); lower
alkenoic acids (e.g., acrylic and methacrylic acids);
monocyclic aryl-hydroxyloweralkanoic acids (e.g., man
delic acid); and 5 and 6 membered-N-monoheterocyclic
carboxylic acids (e.g., picolinic, isonicotinic, nicotinic,
pyrrole-Z-carboxylic, 6-oxo-piperidyl-2-carboxylic, piper
idyl-Z-carboxylic and pyroglutamic acids).
undesired N,N’-disubstituted hydrazine by-product.
Compounds of Formula II are then reduced by con
' Moreover, if an optically active acid is, employed in 65 ventional means to yield the acylhydrazines of Formula
preparing the N-acylhydrazine reactant, the resulting di
astereoisomers of Formula II are further useful as inter
III.- A suitable procedure consists in contacting the start
ing material, in a solution of alcohol, with platinum oxide
mediates’for the separation of oc-methyl-phenethylhydra
in the presence of palladium on charcoal. The reduction
zine into its dextro and levo optical isomers, the former
may be carried out at room temperature and at pressures
having signi?cantly higher activity than either its antipode 70 of from 15 to 200 p.s.i. and is completed when a theo
or its racemate. This separation can be accomplished by
contacting the mixture of Formula III with a solvent in
retical amount of hydrogen has been absorbed. Alter
natively, compounds of Formula II may be reduced by
'
8,060,192
3
4
contact with an aqueous alkanolic mixture of an alkali
nicotinic acid. Substituting the latter hydrazides into
I(B) for the N-isonicotinoyl-N'-(a-methyl-phenethyl)
metal borohydride. The compounds of Formula I are
separated from the borohydride mixture by standard pro
cedures.
To prepare the pure dextroand levo a-methyl-phenethyl
hydrazines of this invention, an optically active mixture
of hydrazines of Formula III is prepared by reacting an
acylhydrazine of the Formula I, wherein the acyl group
is the radical of an optically active acid with phenyl-2
hydrazine, there are obtained the corresponding N'-(oc
methyl-phenethyl)hydrazides of picolinic acid and nico
tinic acid.
EXAMPLEII
N-Is0nic0tinoyl-N’-(et-Methyl-Phenethyl) Hydrazine,
Oxalic Acid Salt
To a solution of N-isonicotinoyl-N'-(a-methyl-phen
propauone and reducing the resulting hydrazones. The 10
ethyl)hydrazine (9.0 g.) in 75 ml. of absolute ethyl al
resulting mixture is then separated into its optically active
cohol is added a solution of oxalic acid (5 g.) in 50 ml.
components by treating the mixture with a liquid which
of absolute ethyl alcohol. On cooling about 7 g. of the
is a solvent for only one of the diastereoisomers. The in
di-oxalate of MP. l0l—l03° C. (with decomposition)
soluble isomer precipitates While the other remains dis
solved in the liquid medium. Suitable solvents for sep 15 crystallizes out. After recrystallization from acetonitrile
the pure compound has a constant melting point at about
arating the isomers in this manner are the conventional
103~105° C. (with decomposition);
inorganic solvents, such as Water; and organic solvents
In a similar manner the- dioxalic acid salts of N’-(ot
such as autonitrile. The precipitated isomer is separated
methyl~phenyl) hydrazides of picolinic and nicotinic acid
by ?ltration from the mother liquid which retains the
soluble isomer. Each isomer is puri?ed and then- sep 20 are readily obtained.
arately subjected to hydrolysis to yield a hydrolysis prod
EXAMPLE III
.
uct which contains only one enantiomer of a-methyl
(A) N-Acetyl-N'-(u-Methyl-Phenethylidene) Hydrazine
phenethylhydrazine.
The acid addition salts of the enantiometers of wmethyl
A solution of acetic acid hydrazide (74 g.) and phenyl
phenethylhydrazine, as well as of the acylhydrazines of 25 Z-propanone (134 g.) in 500 ml. of absolute ethyl al
Formula III, can be prepared in the conventional manner
cohol is re?uxed for 5 hours. The alcohol is removed
by treating the base with the desired acid. Suitable acids
under reduced pressure and the viscous residue triturated
include non-toxic mineral acids, such as the hydrohalic
with Water to yield about 144 g. of the crystalline product
melting at about 103-1050 C. After recrystallization
andv non-toxic organic acids such as acetic, propionic, 30 from hexane the product has a constant melting point at
tartaric, citric, oxalic and benzoic acid.
about 104-105" C.
The compounds of this invention i.e., the acyl deriva
(e.g., hydrochloric), sulfuric, nitric and phosphoric acid,
(B) N-Acetyl-N'-(a-Methyl-Phenezhyl) Hydmzine
tives of Formula III, dextro-u-methyl-phenethylhydrazine,
levo-a-methyl-phenethylhydrazine and the non-toxic addi~
A suspension of ,N-acetyl-N?(a-methyl-phenethyl
tion salts thereof, are pharmacologically active substances 35 idene)hydrazine (57- g.) in 200 ml. of absolute ethyl alco
of low toxicity which may be used in both human and
hol is shaken for 24‘ hours at 60-70“ C. and S0 p.s.i. in
veterinary medicine as anti-depressants, i.e., resurgitives.
the presence of 200 mg. of PtO2 and 1 g. of 5% Pd on
The compounds are useful for example, in the treatment
charcoal. The catalyst is ?ltered off and the alcohol re
of case of, neurosis characterized by states of depression
moved under reduced pressure. To the residue is added
and for this purpose they may be administered in dosages 40 750 ml. of hexane (crystallization occurs and a solid is
and’ by routes (e.g., perorally) prescribed for amphet
formed Weighing about 49 g. and melting at about 75—'77°
C.) After recrystallization from hexane the pure product
amine per se.
' The following examples'are presented to more fully il
lustrate the invention.
EXAMPLE I
(A) N-Is0nic0tin0yZ-N'-(a-Methyl-Phenethylidene)
Hydrazine
melting at about 76-77D C. is obtained.
-
Following the procedure of III(A), except for‘ the sub
45 stitution of equimolar amounts of the hydrazides of
propionic acid, benzoic acid and phenylacetic acid for
the acetic acid hydrazide there are obtained the corre
sponding N’-(a-methyl-phenethylidene) hydrazides of
propionic benzoic and phenylacetic acids. Substituting
A solution of phenyl-Z-propanone (40.2 g.) and isonico
tinic acid hydrazide (41.1 g.) in 1 liter of absolute ethyl 50 these hydrazides into the procedure of :III(B), the corre
alcohol is re?uxtd for 8 hours. The alcohol is removed
under reduced pressure and the very viscous residue tri
turated with 500 ml. of toluene to yield about 64 g. of a
product melting at about IDS-110° C. Recrystallization
from toluene yields the pure product melting at about 55
110-111“ C.
(B) N-Is0nic0tin0yl-N'-(a-Methyl-Phenethyl) Hydrazz'ne
sponding N'-(u-methyl-phenethyl)hydrazides of propi
onic, benzoic and phenylacetic acids ‘are obtained.
EXAMPLE IV
a-Methyl-Phenezhy[hydrazine Hydrochloride
A solution of N-acetyl-N'-(a-methyl-phenethyl) hy
drazine (5 g.) in 50 ml. of 10% HCl is re?uxed for 4
hours.
The aqueous HCl is removed under reduced
A solution of N-isonicotinoyl-N'-(a-methyl-phenethyl
pressure and the viscous residue is triturated with 30 ml.
idene)-hydrazine (12.8 g.) in 100 ml. of ethyl alcohol, 60 of absolute ethyl alcohol and the alcohol then removed.
in the. presence ofvPtOz (100 mg.) and 5% Pd (1; g.) on
The remaining white crystalline solid is washed With dry
charcoal is shaken at room temperature and 50 p.s.i. until
ether and the ether removed by ?ltration to yield about
the theoretical amount of hydrogen is absorbed. The
4 g. of a crystalline product melting at about 115—l17°
catalyst is ?ltered and the alcohol removed under reduced
C. After recrystallization from> an alcohol-ether mix
pressure. The viscous residue is dissolved in 30 ml. of 55 ture the product melting at about 1l7—118° C is obtained.
toluene and to this solution is added 70 ml. of hexane.
Similarly, by substituting the N"-(a-methyl-phenethyl)
Upon trituration a White crystalline solid, melting at about
hydrazides of. propionic, benzoic and phenylacetic acids
84—86° C., is- formed. After recrystallization from
for‘ N-acetyl-N’-(ix-methyl-phenethyl)hydrazine in Ex~
toluene-hexane (116) the pure product melting at about
ample IV, the corresponding hydrochloridesare obtained.
84—86‘’ C. is obtained.
70
EXAMPLE V
Following ‘the procedure of HA) except for the sub
stitutionof equiinolar amounts of the hydrazides of pico
linic acid and nicotinic acid'for the hydrazidexof isonico
(A) ~L-Pyroglutamic Acid, N'-( oc-Methyl
Phenethylidene)Hydrazide"
A solution of L-pyroglutamic acid hydrazide (39g)
methyl-phenethylidene) hydrazides of picolinic acid and 75 and phenyl-Z-propauone (36.2 g.) inv 500 m1. of- absolute
tinic acid there are obtained the corresponding N'-(a
3,060,192
6
ethyl alcohol is re?uxed for seven hours. The alcohol
is removed under reduced pressure and upon cooling
mitted to evaporate at room temperature and the result
crystallization begins. The crystals are separated by
?ltration, recrystallized from ethyl alcohol and ?nally
recrystallized from ether. The crystalline product melt
extract is dried over MgSO4, ?ltered and allowed to
evaporate to yield a solid (M.P. about 65-670 C.) which
ing residue is extracted with hot ethyl acetate. The
is recrystallized from ethyl acetate to yield crystalline
ing at about 152-154" C. weighs about 49 g. and repre
sents a yield of about 70%.
L(—) -pyro\glutamic acid, N’-(a-methyl-phenethyl)hydra
zide melting at about 80-83° C.
Analysis.—Calcd. for C14H17N302: C, 64.84; H, 6.61.
Found: C, 64.26; H, 6.67.
10
(B) L-( :) Pyroglutamic Acid, N'-(a-Methyl
Phenethyl ) Hydrazide
H, AnaIysis.—Calcd.
7.32. Found: N,for16.01;
C14H19N3O2;
C, 64.39;N,H, 7.20. C,
[a]D=—14.6° (in water).
The L(—) -pyroglutamic acid, N'—(a-methyl-?-phen
ethyl)hydrazide (16 g.) thus obtained, is dissolved in
160 ml. of 10% HCl and re?uxed for three hours, after
To a suspension of L-pyroglutamic acid, N'-(a-methyl
which, the aqueous HCl is removed under reduced pres
phenethylidene)-hydrazide (56 g.) in 300 ml. of meth 15 sure leaving a viscous residue which is dissolved in water
anol, is added sodium borohydride (15.9 g.) suspended
and made strongly alkaline with 50% NaOH. (d)~u
in 100 ml. of water. The borohydride is added slowly
and with constant stirring. The temperature rises to
40° C upon starting the addition, and the solution be
methyl-phenethylhydrazine precipitates as an oil and is
twice extracted with 250 ml. ether. The ethereal ex
tracts are dried over K2003, ?ltered and the ?ltrate made
strongly acid to Congo with 1.5 N ethereal HCl. A
comes clear. At the end of the addition the temperature
of the mixture rises to 60° C and there is a gentle re
?uxing action with a mild evolution of gas. The reaction
crystalline precipitate forms and is ?ltered to yield about
10 g. (90%) of a solid melting at about 119-124° C.
mixture is allowed to stand vfor two hours, prior to
The solid, after three crystallizations {from 500 ml. of
being used in sections C and D below.
acetonitrile each time, and a ?nal recrystallization from
25 550 ml. of ethyl acetate-ethyl alcohol (10:1) yields the
(C) (d) -u-Methyl-Phenethylhydrazine and
crystalline hydrochloride of (1)-u~methyl-phenethylhy
Hydrochloride
drazine (M.P. about 148-4l49° C.).
The methanolic reaction mixture prepared in section
Analysis.-Calcd. for C9H14N2.HCl: N, 15.00; Cl,
B is subjected to reduced pressure ‘to remove the meth
18.99.
anol. The residue is treated with 500 ml. of water and 30
Found: N, 15.09; Cl, 19.01.
the crystalline solid which precipitates is ?ltered off.
The invention may be variously otherwise embodied
It Weighs about 30 g. and has a melting point about
within the scope of the appended claims.
138-142“ C. The mother liquor is retained for further
What is claimed is:
treatment in section D. Recrystallization of the precipi
l. Pyroglutamic acid, N'-(u-methyl-phenethyDhydra
tate ‘from 300 ml. of water yields about 14 g. of crystal 35 zide.
line L(+)-pyroglutamic acid, N’-(m-methyl-phenethyl)
2. The method which comprises reacting phenyl-2-pro—
hydrazide (M.P. about 157-159” C.). The sample is
panone with L-pyroglutamic acid hydrazide, reducing
crystallized from water.
the resulting N-L-pyrog1utamoyl-N'-(a-methyl-phenethyl
Melting point about 163-4169‘° C.
idene)hydrazine to obtain a mixture of the diastereoiso
Analysis.—Calcd. for C14H19N3O2: N, 16.08; C, 64.34; 40 mers of N-L-pyroglutamoyl-N’-=(a-methyl-phenethyl)-hy
H, 7.32. Found: N, 16.01; C, 64.39; H, 7.20.
drazine, separating the mixture into its diastereoisomeric
[aD]:==+24.4° (in water).
The L(+)-pyroglutamic acid, N'-(a-methyl-phenethyl)
components and hydrolyzing each component to obtain
the corresponding enantiomer of a-methyl-phenethyl
hydrazide (14 g.) is dissolved in 140 ml. of 10% HCl
hydrazine.
and re?uxed for three hours, after which time the major 45
portion of the aqueous HCl is removed under reduced
References Cited in the ?le of this patent
pressure. The residue is dissolved in 100 ml. of water
UNITED STATES PATENTS
and made strongly alkaline with 50% NaOH (saturated
With potassium carbonate).
(d)-a-methyl-phenethylhy
drazine precipitates as an oil and is twice extracted with 50
200 ml. of ether each time. The extracts are dried over
MgSO4, ?ltered and the ?ltrate acidi?ed with 1.5 N
ethereal HCl until acid to Congo. The white crystalline
precipitate which forms is ?ltered, dried and recrystallized
from 800 ml. of acetonitrile to yield about 5.5 g. of 55
2,701,815
2,743,276
2,744,935
2,763,662
2,894,972
2,923,713
the crystalline hydrochloride of (d)-a-methyl-phenethyl
hydrazine melting point about 148-149° C.;
[a]D'=+13.8°; (in water)
Analysis.—Calcd. for C9'H14H2JHCl; N, 15.00; Cl,
18.99. Found: N, 14.81; Cl, 18.70.
(D) (1)-a-Methyl-Phenethylhydrazine and
Boker et al. __________ _.. Feb. 8,
Anderson ____________ __ Apr. 24,
Johner ______________ __ May 8,
Archer ______________ __ Sept. 18,
Bloom et al ___________ __ July 14,
Fox ________________ __ Feb. 2,
1955
1956
1956
1956
1959
1960
FOREIGN PATENTS
722,679
203,499
Great Britain ________ __ Ian. 26, 1955
Austria ____________ __ May 25, 1959
60
OTHER REFERENCES
Karrer: ‘Organic Chemistry, Elsevier, N.Y., pp. 87 to
96; 120, 438 and 455-456 (1938).
The retained mother liquor from section C is per 65 Sah: I. Am. Pharm. Assoc., vol. 43, pp. 513—24 (1954).
Hydrochloride
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