Note: Descriptions are shown in the official language in which they were submitted.
This is a divisional o Patent Application No.
278,574, ~iled May 17, 1977.
This inventi~n relate~ to novel hydrazine deriva-
tives w~i~h are useful intermediates for the preparation of
quin~xaline-1,4-dioxid~s, particularly 3-substituted-(2-
quinoxalinylmethylene~ carbazate-Nl,N4-di~xides, whi~h com-
pounds have antibac~erial and veterinary properties. The
preparation of suck 3-~ubstituted ~quinoxalinylmethyl~ne)
carbazate-Nl,N4-dioxides is desoribed and claimed in Appli-
cation No~ 278,574.
Continuing ynthetic ef~ort~ t~ discover new com-
pounds that are active a~ainst bacteria and protozoa and act
as growth promo~ants in swine and poultry have led, over the
yea~, to the development of a variety ~f prototype organic
compounds including numerou~ analog~ of quinoxaline-1,4-
dioxldes: J. Chem~ Soc., 2052 ~1956); Helv. Chim. Acka.,
29, 95 ~13~6~; Tetrahydron Letters, 3253 ~1965); JO Oxg.
Chem., 31~ 4~67 ~1966); Agnew. Chem. Internat~ Edit~, 8~
S96 (196g); U~S. 3,~7~,67~, 3,728,34S, 3,753,987; 3,75~,162;
3,767,657; 3,803,145; 3,81B,0~7, 3,422,871; 3,371,09~; and
Belgia~ Pa~ent 721,728.
A pxoae~s ~or pxeparing 3-substi~uted-~2--~uinox-
alinylmethy}ene)carbaza~e, Nl,N4-di~xid~ descri~ed in
U.S. 3,389,326 wherein a 2-bi~hal~geno~methylquinoxaline
deriv~ti~e is rea~ted with hydr~xylamin~ ~r an appr~priate
hy~raxinoaaxbonic acid ester in the pre~ence of a primary
Gr sec~ndaxy amine and ~ater~
Our Patent ~ppli¢atio~ No O~ 278,574 pro~ide~ a pr~-
ces~ for preparing a ~uin~xaline-carha~ate~ dioxide of ~he
677
--2
formula:
o
N ~ CH=NNHCOOCH3
O
wherein R is hydrogan, alkyl of 1 to 6 carbon atoms, hydroxy-
alkyl of 1 to 6 carbon atoms, alkanoyl of 2 to 7 carbon atoms,
ben~oyl or CON ~ 1 wherein each of Rl and ~2 is hydrogen,
alkyl ~f 1 to 6 carbon atoms, hydroxyalkyl of 1 to 6 carbon
atoms or aminoalkyl of 1 to 5 carbon atoms, which compriqes
reacting a 2-halomethylquinoxaline-Nl,N4-dioxide of the
formula:
o
~ N ~
~ ~ ~ CH2X oo~II
wherein R is as defined above and X is chlorine or br~mine,
with from one to t~o equivalent3 of an alkali metal carbon-
ate and from one to two equivalent~ of a hy~raz~ne of the
formula:
R"NHN~COOC~3 ............... ,III'
wherein R" i~ CF3SO2, CF3~2SO~ CH3SO2 3 6 4 2
reaation-iner~ solvent at a ~empera~ure o~ ~rom 75 to ~5C.
: and subae~uently recoverin~ the said carbazateO
Tho~e compound~ of Fo~mula I wherein R i other
~han hyd~ogen, alkyl having 1 to 6 carbon at~ms and CONHCH3
are novel,
AccordingIyt our Patent Applicatlon No. 278,574
also disclo~es a aarbazate o~ th~ formula:
,'' . - ' ~ ,,
.. . ', . ' ' ', :
. . . ~ . .
:
~9~
--3--
o
~CN=NNHCOOCH 3
O . O .I '
wherein R' is hydroxyalkyl having 1 to 6 carbon atoms,
~ R~
alkanoyl having 2 to 7 carbon atoms, benzoyl or CON~
wherein each of Rl and R~ is hydrogen, alkyl having 1 to 6
carbon a~oms, hydroxyalkyl ha~ing 1 to ~ carbon atoms or
aminoalkyl having 1 to 6 aarbon atom~, with the proviso that
when one of Rl or R2 i6 methyl the other is not hydrogen.
The proaess descxibed and claimed in Application
No. 278,578 comprises reacting a 2-halomethylquinoxaline,
Nl~N4-dioxide in a reaction-inert solvent in the presence of
an alkali metai carbonate, e.g., anhydrous potassium carbon-
ate, with an alkyl or aryl-sulfonyl-subskituted hyd~azine,
e.g., N-methoxycarbonyl-N'~trifylhydrazine, and may b0
represented by the following xeaction ~chemeo
O CF O
1 3
15 ~ + IIN ~ ~CN=NNNC02CN3 +
O COOC~H3 CF3SO2K
IX III
q~he 2-halomethyl~;Euinoxaline intermediates used. in
the ab~e pro~e~s may ~e prepared by ~he general me~ho~s de-
: scribed in U.S. 3,753,987, ~. Chem. Soc., 2352 ~1956~ and
: Chemistry of ~eterocyolic Compounds, ~40 ~1967~. ~he halogen
: 20 may be chlorine or br~mineO ~he ~re~erred intermedlates are
the 2-bromomethylquin~xaline compounds~ These compound~ are
prspared from the 2-methylquin~x line-1,4-d1oxides by the
methods d~scribed in J. Çhem. Soo., 322 ~1943~, U.So3,474,097;
' ''', - ~ .
. ' . ' - - ' , ' ,
-,: .
- ~
77
~ 4--
U.S. 3,S53,208; U.SO 3,660~398 and British Paten~ 1,215,815.
Two of the intermediate hydrazine compounds of
Formula III above, i.e., N methoxycarbonyl-N'-trifylhydrazin~
and N-methoxycarbonyl-N'-tresylhydra~ine, are novel compounds
and may be prepared by the general procedure described in
J, Oxg. Chem., 40, 3450 ~1975).
In accordance with the present invention there is
provided a process for preparing a hydrazine of the formula:
~"NHNHCOOC~3 ,..III
wherein R" i5 CF3SO2 or CF3CH2SO2, which comprises reacting
methyl carbazate with the appropriate anhydride or sulfonyl
halide.
For example, in accordance with the present inven-
tion, N-methoxycarbonyl-N'-trifylhydra~ine is prepared by
adding a solution of triflic anhydride in methylene chloride
dropwise to a methylene chloride solution containing an equi-
molar amount of methyl carbazate and a slight molar excess
of triethylamine at -78~C. The re~ultlng mixture is allowed
to warm to room temperature and stirred for about 16 hours.
The mixture is concentrated under vacuum at room temperature
and the residue i5 then extracted with several portions of
ether. The ether extract is concentrated under vacuum at
room temperature to a waxy ~olid that is used directly in
the subsequent reaction without furth2r purification, Al-
ternatively, the deletion of triethylamine and the u~e oftwo equivalents of me~hyl carbazate yield the crystalline
product.
The following Examples illu~trate the preparation
of the novel intermediates o thi~ invention~
E _ I
Triflic anhydride ~35.4 mmoles) in methylena
chloride ~40 ml.) was added dropwise to a solu~ion of me~hyl
carbaæate ~35.5 mmole6) and trie~hylamine ~38.9 mmoles) in
methylene chloride ~200 ml.) at -78C. with stirrin~O The
re~ulting mixture was allowed to warm to room t~mperature
and ~tirred ~or 16 hours. The mixture was con~entrated at
,: ' .' ' ~
::
,:
,
~7~;7~
--5--
room temperature under vacuum and the residue was extracted
with three 100 ml. portions of refLuxing ether. The combin-
ed ether extract was concentrated under vacuum at room temp-
erature to yield a waxy solid ¢5.26 g., ca 67%). The nmr
spectrum of the crude product was consistent ~ith the expect-
ed product contaminated with the triethylamine salt of triflic
acid. The crude material was used directly without further
purification for subsequent reactions.
Methyl carbazate ¢336 mmoles~ was added over a 20
minute period with stirring to a solution of triflic anhydride
(178 mmoles) in methylene chlorlde ~2000 ml.) under a nitro-
gen atmosphere at -78C. The resulting solution was allowed
to warm to room temperakure and stirred for 20 hours. The
resulting ~hick white su~pension was concentrated undex
vacuum at room temperature to give a white solid. This mate-
rial was trituxated with diethyl ether ~450 ml.) and collect-
ed to give the methyl carbazate salt of kriflic acid. The
diethyl ether filtrate was concentrated under vacuum at room
temperature to give a white solid which was triturated ~ith
hexane, collected, ~ashed with hexane and dried to give the
product as a white crystalline solid ~yield 84%), m.p~ 107-
109C
Anal~sis:
Calc~d for C3H5O~N2F3S: C, 16.21; ~, 2.25; N, 12.61
Foun~: C, 16.24; H, 2.20; N, 12.68
EXANPLE II
N-Met bonvl-N'-TresYlhYdrazine
The method o~ Example I is repeated employing tresyl
chloride i~ place of triflic anhydride to p~oduce the title
compound~
The following Example illustrates the use of an
intermediate prepared by the process of this invention in
the prepara~ion o~ a preferred product as disclosed in Appli-
cation No. 27~,574.
EXAMPLE III
A suspension of 2~bromomethylquinoxaline, Nl,N -
,
,,.. ,' ' ' " .
7~i77
--6--
dioxide (6 mmoles) in acetonitrile (70 ml.) was heated to
reflux with stirring Powdar anhydrous potassium car~onate
(6.52 mmoles) and N-methoxycarbonyl-N'-trifylhydrazine t6.6
mmoles) were added to the suspension in one portion. A solid
separated from the resulting incipient solution wi-~hin a few
minutes. The mixture was heated at reflux for a total of
1.5 hours. The solid was collected, washed successively
with two 20 ml. portions each of acetonitrile and ether, and
dried to constant weight to give a dark yellow solid (1.89
g., ca. 100%~. The crude product was suspended in 5% sodium
bicarbonate ~50 ml.~ for 30 minutes, collected, washed with
water, and then recrystallized from acetic acid t30 ml.) The
recrystallized product was washed with kwo 20 ml. portions of
acetic acid/ether ~1;1) and then with two 20 ml portion of
ether to yield the product aa a yellow crystalline powder,
m.p. 243C~ ~U.S. 3,371,090~.
