Note: Descriptions are shown in the official language in which they were submitted.
i3~ii
PROCESS FOR PREPARING BENZOHETEROCYCLIC CO~IPOUNDS
This invention relates to a process for
preparing ben~oheterocyclic compounds of general formula f
R -N N ~ tl)
/ I '
(CH2 ~ 1
. S wherein Rl represents a hydrogen atom or a lower alkyl
group;
R2 represents a hydrogen atom, a lo--~er alkyl
group which ma.y be substituted with a halogen atom or a
hydroxy group, or a lower alkanoyl group which may be
substituted with a halogen atom;
X represents a hydrogen atom or a halogen atom,
n is an integer of 1 or 2;
with the proviso that when n is 1~ R should not be a ~ -
lower alkyl group substituted with a halogen atom.
Some o~ the benzoheterocyclic compounds o~
general ~ormula (I) are novel compounds and others are ~-
known compoullcls. They have an excellent ant;bacterial
activi.ty and are use~ul as an antibacterial agent.
~33535
An object of this invention is to provide a
novel process for preparing benzohe~erocyclic compounds
of general formula (I) which permits one to obtain the
objective compound in a high purity and good yield.
This invention provides a process for preparing
a compound of general formula (I)
X
R -N N ~ COOH (I3
.' \`-- ' ~H I
( 2~\Rl
wherein Rl represents a hydrogen atom or a lower alkyl
group;
R2 represents a hydrogen atom~ a lower alkyl
group which may be substituted with a halogen atom or a
hydroxy group, or a lower alkanoyl group which may be
substituted with a halogen atom;
X ~epresents a hydrogen atom or a halogen atom;
and
n is an integer of 1 or 2;
with the proviso that when n is 1, R2 should not be a
lower alkyl group substituted with a halogen atom, which
comprises cyclizing a benzoheterocyclic compound of
general formula (II)
35~
N
N 1 Rl (II) -
- h-~o
R3 ~ R4
wherein Rl, R2, X and n have the same meanings as defined
above; and R3 and R4, which may be the same or dif-ferent,
each represents a lower alkyl group; with the proviso
that when n is 1, R2 should not be a lower alkyl group
substituted with a halogen atom. t
In another aspect, this invention provides a - ~
process for preparing a benzoheterocyclic compound of the
formula ~
O
R2 N A ,~
~8~i3~
wherei3l Rl represents a hydrogen atom or a lower alkyl
group; .
R2 represents a hydrogen atom, a lower alkyl
group which may be substi-~uted with a halogen atom or a
hydroxy group, or a lower alkanoyl group which may be
substituted with a halogen atom;
X represents a hydrogen atom or a halogen atom;
and
n is an integer of 1 or 2;
with the proviso that when n is 1, R2 should not be a
lower alkyl group substituted with a h~logen atom, which
comprises cyclizin~ a quinoline compound of general
formula ~III)
.
~2
~ N
X ~ H 2 ) n
CH=ctcooR )2
wherein Rl, R2, X and n have the same meanings as de~ined
above and R5 represents a lower alkyI group to form a
benzoheterocyclic colnpound of ~eneral formula (IV)
.
~:83535;
o
,CooR 5
R2 N N~ ~ \ N ~ (IV)
( 2}~Rl , -.
wherein Rl, R2, R5, X and n have the same meanings as
deined a~ove, and then hydrolyzing this compound.
The position to which ~he substituent repre-
sented by X in general formulae (II~ and ~III) is
attached preferably is the S-position ~when n is 1) and
the 6-position (when n is 2) of the benzoheterocyclic
ring.
Preferably X is chlorine or fluorine. -~
The term "lower alkyl group" used herein
refers to a straight or branched chain alkyl group
having 1 to 6 carbon akoms such as methyl, ethyl,
propyl, butyl, tert-butyl, pentyl, hexyl, etc.S groups.
s
The t~rm "lower alkyl group which may be };
15 substituted with a halogen atom or a hydroxy group" as g
used herein refers to a straight or branchecl chain alkyl
~roup having 1 to 6 carbon aloms which may be substi-
tuted with 1 to 3 c~f a halogen atom or a hydroxy group
such as methyl, ethyl, propyl, butyl, tert-butyl, pentyl~
20 hexyl~ trifluoromethyl, trichloromethyl, dichloromethyl,
tribromomethyl, 2,2~2-trifluoroethyl, 2,2~2-trichloro- -
, .
:
~353~
ethyl, 2-chloroethyl, 1,2-d;chl~roethyl~ 3~353-trichloro-
propyla 3-:Eluoropropyl, 4-chlorobutyl~ 3-chlorobutyl,
hydroxymethyl, 2-hydroxyethyl, 3-hydroxyprop~l~ 2,3- :-
dihydro~ypropyl, 4-hydroxybutyl, 2-hydroxypropyl~ etc.,
groups.
The term "lower alkanoyl group which may be
substituted with a halogen atom" as used herein refers
to a straight or branched chain alkanoyl group having 1
to 6 carbon atoms which may be substituted with 1 to 7 ~-
halogen atoms such as formyl, acetyl, propionyl~ butyryl,
isobutyryl~ valeryl, isovaleryl, hexanoyl, trifluoro-
acetyl, trichloroacetyl, tribromoacetyl, 2,2-dichloro-
propionyl, monochloroacetyl, 2-chlorobutyryl, penta-
fluoropropionyl, heptafluorobutyryl, etc., groups.
The term "halogen" as used herein refers to 5
iodine, chlorine, bromine, fluorine, etc. {
Of the compounds of general formulae ~II) and
~III), some are novel and can be prepared by processes
shown in Reaction Schemes-l and -2 below. J
3~
Reaction Scheme-l
_ _
X~ X N0 2
a Nitration
N
(V) (VI)
'
Reduct;on of
Nitro Group
,~J~Rl
~VII) -
R2
2 ~ CH2C~I20H N
CH2CH20H ~N~
(VI I I ) X_~1R1
(IX)
- 7 -
.. . . . . . .. . . . .. . . . .. . . . . .. . .. .. . . . . .. .
3~i~S
R~ d u c t i o r~
/- CN; 1 Rl
~R70CH=C(CooRS)
(X I ) (XI I )
R 2 ~ 2
~N~ ~N~
R ~"~1Rl
C~l C~l=C (CooR5 ~ 2
0?~ ( I I I a )
Xo .
~ I I a)
...... . .. .. . . , .. ... . _ ~ .. , .. = .
53~
In the above formulae 9 R6 and R7~ which may be
the same or different~ each represents a lo~er alkyl
group, and Rl, R2, R3, R4, R5 and X have the same mean-
ings as defined aboveO
The nitration reaction of the compound of
general formula ~V) can be carried out under conditions
conventionally used for the nitration of nitro group of
aromatic compounds, for example, in the- absence of
solvents or in the presence of an inert solvent uslng a ;
nitration agent. As for the inert solvent there can be
illustrated, or example, acetic acid, acetic anhydride9
concentrated sulfuric acid~ etc. Suitable examples of
the nitration agent include fuming nitric acid, concen-
trated nitric acid, mixed acids (a mixture o~ nitric ~
acid ~Yith su:lfuric acid, fwning sulfuric acid, phosphoric
acid or acetic anhydride), a combination of alkali metal
nitrate, e.g., potassium nitrate, sodium nitrate, etc.,
` and sulfuric acid and the like. The amount of the nitra-
tion agent to be used is at least 1 mole per mole of the
starting compound. Usually, a large excess amount of
the nitration agent is used. The reaction can be carried
out aclvantagcously at 0 to 15C for 1 to 4 hours.
The reduction reaction of the nitro group of
the compound of the formula ~VI) obtained by the above
procedure can be carried out, for example, in a suitable
g
..... , , ~
51353~
inert solvent using a reducing agent SUC}I as a mixture
of iron, zinc, tin or stannous chloride and an acid
~e.g., hydrochloric acid, sulEuric acid, etc.) or a
mixture of iron, ferrous sulfa~e~ zinc or tin and an
alkali metal hydro~ide, sulfate, sulfite, etc. J and the
like. Alternatively, the reaction can be carried out
catalytically using a catalyst for catalytic reduction
such as palladium-carbon, etc. As for the inert solvent,
there can be illustrated, for example, water, acetic
acid, methanol~ ethanol~ dioxane, etc. Reaction condi-
tions can be selected appropriately depending on the
kind of the reducing agent ~o be used. For exam~le, the
reaction can be carried out advantageously at 70 to 100C
for about 0.5 to 1 hour when using a mixture of stannous -~
chloride and hydrochloric acid as a reducing agent. The
reducing agent can be used in an amount of at least 1 ;::
mole, preferably 1 to 2 moles, per mole of the starting ; 5
compound.
The reaction between the compound o~ general ~;-
formula (VII) and the compound of general formula ~VIII)
can be carriea out in the presence of a dehydrocondensing ~.-
agent without solvents or in a su;table solvent. !:
Examples of the dehydrocondensing agent which can be
~.
used include condensed phosphoric acids such as poly-
25 phosphoric acid, etc., phosphoric acids such as ortho- ~.
r
- 1 0 - ,-,
, .
~3~S
~hosphoric acid, pyrophosphoric acid, metaphosphoric
acid, etc., phosphorous acids SUC]I as or~hophosphorous
acid, etc., phosphoric anhydrides such as phosphorus
pentox;de, etc., acids such as hydrochloric acid,
5 sulfuric acid, boric acid, etc., metal ~hospha~es such
as sodium phosphate, boron phosphate, ferric phosphate,
aluminu~ phosphate, etc., activated alumina, sodium
hydrogen carbonate, Raney nicXel, and the like. Of these,
polyphosp}loric acid, phosphoric acids and phosphorus -.
10 pentoxide are pre~erred.
The amount of the dehydrocondensing agent to be
used is not limited particularly and can be varied
broadly. Usually, the dehydrocondensing agent is used
in a catalytic amount relative to the compound of general
15 formula (VII). Preferably, it is used in an amount of
about 0.5 to 1.5 moles per mole of the compound of
general formula ~VII). --
~s for the solvent there can be illustrated a ~
high boiling point solvent such as dimethylformamide, -
20 tetralin, ctc.
The proportion of the compound of genel-al
formula (VIII) to the compound of general form~la tVII) f
is not limited particularly and can be varied broadly.
Usually, at least about 1 mole, ~referably 1 to 2 molesS
25 of the compound of general formula (VIII) per mole of
the compound of general formula (VII) is used.
~ 5 ~ ~
The above reaction can be carried out in an
atmosphere of an inert gas in order to prevent oxidation
reaction l~hich affects the reaction adversel~ from occur-
ring. The reaction can be carried out either at atmo- -
spheric pressure or under pressure. It is preferred
that the reaction be carried out a~ atmospheric pressure
in view of working effic~ency.
The reaction can ~roceed at about 100 to 350C,
preferably 125 to 300C and be completed generally in
about 3 to 10 hours.
The reduction reaction of the pyridine ring in
the compound of ~eneral formula ~IX) thus obtained can be
carried out by catalytically reducing the compound of
general formula (IX) -in a suitable inert solvent under
acidic conditions. Any acids that can form a salt with
quinoline can be used in the reduction react:ion. For
example, acetic acid, hydrochloric acid, sulfuric acid,
etc., can be used. As for the iner~ solven~, there cari
be illustrated dioxane, tetrahydrofuran, acetic acid,
water, etc. ~amples o~ the catalyst WhiC}l can be used
in the catalytic roduction ;nclude platinum-carbon,
palladium-carbon 9 radium-carbon, rutheniwn-carbon, etc.
The reduction reaction can proceed advantageously at room
tempcrature to 50C for about 1 to 10 hours.
- 12 -
5i3~
The reaction between the compound of general
formula ~X) and the compound of general foTmula (XI) can
be carried out in the absence of solvents or in the
presence of a suitable solvent. Examples of the solvent
include alcohols such as methanol, ethanol, isopropanol~
etc., aromatic hydrocarbons such as benzene, toluene9
etc., acetonitrile, dimethylformamide? dimethyl sulfoxide~
hexamethylphosphoric triamide, and the like. It is
preferred that the reaction be carried out without
solvents. The proportion of the compound of general
formula (XI) to the compound of general formula ~X) is
usually at least 1 mole, preferably 1 to 1.5 moles, of
the compound o general formula tXI~ per mole of the
compound of general formula (X). The reaction can be
carried out usually at about room ke~perature to 150C,
preerably at 60 to 120C and completed generally in
about 0.5 to 6 hours~ thus yielding the compound of _
, , . ,. : i
general foTmula ~IIa) with ease.
The reaction bet~reen the compound of general
formula (X) and the compound of generc~ formula ~XII) can
be carried out under conditions analogous to those used
in the reaction between the compounds o general formula
~X) and the compound of general ormula (XI), thus yield-
ing -the compound o-f general formula (IIXa) with ease~
- 13 -
~L8~53~
Further, in Reaction Scheme-l above, of the
compounds of general formula ~IX), a compound in which
R2 represents a hydrogen atom can be converted to a
compound of general formula (IX) in which R2 represents
a lower alkyl group which may be substltuted with a -
halogen atom or a hydroxy group or a lower alkanoyl
group which may be substituted with a halogen a-tom by -~
reacting the above compound of general formula (IX) in
which R2 represents a hydrogen atom with a lower alkyl
halide which may be substituted with a halogen atom or
.. ..
a hydroxy group, or a lower alkanoyl halide which Jnay
be substituted with a halogen atom.
-
- 13a - -
~133~3~;
Reaction Scheme-2
xl xl
X~`N > X--~3` 8 Nitration
~XI I I ) (XIV)
xl R2 ',
X~ 8 HN N-Ri!~N~
N02 (XVI) ,1~ Reduction
(XV) X~N~ 9 .
NOz
~XVI I ) ':.
R2 R2 '-
~N~
~R9 ~N~R
(XIX)
(X~TI I I )
'' ' ''
- 14 -
3~3~
(."VI I I ) (X I X)
~¦ Halogenation /ogenation
R2 L/ R2
) Hydrolysis ~ ~ ~tllrl~ ~
[~ N\ 9 ~ ;
(XX) ~XXI)
~j~X2 RlCOC}125R N2~ i:
, NH-X (XXIII) ~N~ 5R10 ~ ~ b
(XXII)
~XX~V)
,, 1
~3~3~
(XX I V)
Desulfuriza- / \
~ion k/ \~
R2 R2
t,N`~ Dehalogena- ~N~ Reduc-
tion l tion
N J ~ N ~ .
~ ~ ~Rl
x2 H H
(XXV) ~XXVI )
~R6 ~2
~N~ CH
~ J 0~"0
X~ 1 R3XR~ 1R1
H CXI ) ,,.,_~ ~1
~XVII) . (~
R70CH=C (COORS) ~ R3>< 4
~XII)
(IIIb) ~lIb) `
- 16 -
~3~
R
X~ `, -
~I=C(COORS) 2
- ~ tIIIb) . - -- -~
- 16a -
. .
, ~
.. .. . . . . .. ... ..
.. .... , ... ... . .. ... . . . . .. . .. .. . . . . . .. .... . .. . .. . ~
1353~i
In the above formulae, Xl, x2 and X3, which
may be the same or different, each represents a halogen
atom; R8 represents a hydrogen atom; R9 represents a
lower alkanoy]. group 3 R8 and R9 may combine together
with the nitrogen atom to which they are attached to
form a group of the formula
Il . . ~ . . .
~1 ' ~ ,-.
O
R10 represents a lower alkyl group; and Rl, R2, R3, R4,
R6, R7 and X have the same meanings as defined above.
In Reac~ion Scheme-2, the aniline compound of.
general ormula (XIII~ can be converted to the aniline.
compound o general formula (XI~ by reacting the compound :;.
of general formula (XIII) with an acid anhydride or acid
halide in a suitable solvent. Examples of the solvent
which can be used include lower alcohols such as
methanol, ethanol, isopropanol, ~tc., ethers such as
dioxane, tetrahydrofuran, etc., acetic acid, pyridine,
dimethylformamide, dimethyl sulfoxide, etc. As for the
acid anhydride, there can be illustrated acçtic
anhydride; phthalic anhydride, etc. As for the acid
. - - .
17 -
~8353S
halide, there can be exemplified acetyl chloride,
propionyl chloride, bu~yryl bromide, etc. The amount
of ~he acid anhydride or acid halide to be used is
usually at least about 1 mole, preferably 1 to 3 moles,
per mole of the aniline compound of general formula
(XIII). The reaction can be carried out usually at
about room temperature to 200C, preferably room temper-
ature to 160C and completed generally in about 0.5 to .
5 hours.
The nitration reaction of the compound of
general formula (XIV) can be carried out using conYen-
tional nitration agents such as fuming nitric acid,
.concentrated nitric acid, mixed acids (sulfuric acid,
fuming sulfuric acid, phosphoric acod or acetic
anhydride and ni1:ric acid), a mixture of an alkali
- metal nitrate such as potassium nitrate, sodium nitrate,. . ;;
etc., and suluric acid, and the like. The amount of . ~.
,. . . . ~ - :.;
the nitration agent to be used is at least about 1 mcle, : .;
pre~erably 1 to 1.5 moles~ per mole of the compound of .
general.formula ~XIV). The reaction can be carried out
at about -20 to 50C, preferably -10C to room tempera-
tllle and completed generally in about 1 to 7 hours.
The rezction between the compound of general ~.
form~lla (XV) and the piperazine compound o~ general
formula (XVI) can be carried out in the presence of a
18
- ' '' ' t,
~3353~i;
solvent. Examples of the solvent ~hich can be used
include aromatic h~drocarbons SUC}l as benzene, toluene,
xylene, etc., lo~er alcohols such as methanol, e-thanol,
isopropanol, etc., ethers such as dioxane, tetrahydro-
furan, ethylene glycol dimethyl ether, diethyl ether,etc., polar solvents such as N-methylpyrrolidone,
dimethylformamide, dimethyl sulfoxide, hexamethyl-
phosphoric triamide, etc., and the like.
The reaction can proceed advantageously in the
10 presence of a basic compound as an acid acceptor. .
Examples of the basic compound include potassium
carbonate, sodium carbonate, sodium hydroxide, sodium
hydrogencarbonate, sodium amide, sodium hydride,
tertiary amines such as triethylamine, tripropylamine~
etc., pyridine, quinoline, etc. The amount of the
piperazine compound of general formula (XVI) is usually - ~:
about 1 to 10 moles, preferably 3 to 7 moles, per mole - .-
of the compound of general formula (XV). The reaction -
can be carried out usually at about 50 -to 150C3 prefer-
ably 50 ~o 100C and completed generally in about 1.5 to `,
10 hours. .
In tile reduct:ion of the compound of gener~
form~lla (XVII), conventional reduction reactions for
nitro ~roups can be used. ~or example~ l) a process can
be used in which catalytic reduction is carried out
19 - .
~ .
~353~
using a reducing catalyst such as platinum oxide,
palladium blac~, palladiu]n-carbon, etc., in a solvent
such as water, methanol, ethanol, isopropano'l, tetra-
hydrouran, diethyl ether, etc., usually at a hydrogen
gas pressure of l to 10 atm~ preferably 1 ~o 3 atm,
usually at a temperature o~ -30C to the boiling point
of the solvent, preferably 0C to room temperature,
- 2) a process in which reduction is carri'ed out in an
anhydrous solvent such as diethyl ether, tetrahydrofuran,
10 etc., using lithium aluminum hydride as a reducin~ --
agent~ and 3) a process in which reduction is carried ~ ~
out in a solvent such as water, ethanol, methanol,
acetic acid, etc., using a mixture of a metal compound
such as iron, zinc, tin, stannous chloride, etc., and an
acid such as hydrochloric acid, acetic acid, etc., and
the like processes can be used. Of these processes, the
above process 3) is preerred. ;
The reaction can be carried out usually at
about 0 to l00C~'preferably 10 to 50C and completed
in about lO minutes to 3 hours. The amount of the metal
compound to be used is at least about 1 mole, preferably '
2 to 5 mol'es, per mole of the compound o general formula
'' t~'VII),
The halogenation reaction of the compound of
general formula (XVIII) can be carried out by conrerting
'the compound of general formula ~XVIII) to a correspond- -
- 20 -
3S3~
ing diazonium salt in a solvent such as ~ater using an
acid such as sulfuric acid, hydrochloric acid3 hydro-
bromic acid, :Eluoroboric acid, etc., and sodium nitrite
and then either reacting the resulting diazonium salt
5 ~ith copper pol~der or a copper halide (e.g., cuprous .
bromide, cuprous chloride, cupric chloride, etc.) in the
presence of a hydrohalogenic acid ~e.g., hydrobromic
acid, hyclrochloric acid, etc.), or reacting the diazonium
salt with potassium iodide in the presence or absence of
10 copper po~der~ It is preferred that the reaction be -;
carried out by reacting the compound of the formula (XVIII)
with copper pol~der in the presence of a hydrohalogenic
acid.
The amount of sodium nitrite to be used is
usually 1 to 2 m~les, preferably 1 to 1.5 moles, per
mole of the compound of general formula (XVIII). On the r'
other hand, the amount of the copper pol~der to be used
- . r
is usually 1 to 3 moles, preferably 1 to 2 moles, per
mole of the compound of general formula ~XVIII). The
reaction can be carried out at a t.emperature of usually
about 20C to room temperature, preferably -S to 5C
and completed generally in about 10 minutes to 5 hours.
The deamination reaction of the compound of the
ormula ~XVIII) can be carried out in a solvent such as
water and the like by converting the compound of the
- 21 -
~83~
formula (XVIII) ~o a corresponding diazonium salt using
an acid sueh as sulfuric acid, hydroch]oric acid, hydro-
bromic acid, fluoroboric acid and the like arld sodium
nitrite and then reacting the diazonium salt with a
hydrogenation agent such as alcohols, e.g., ethanol,
etc., aldehydes, e.g., alkaline formaldehyde, etc.,
metals, e.g., zinc, copper, etc., or hypophosphorous
acid, etc. The amount of sodium nitrite to be used is
usually 1 to 2 moles, preferably 1 to 1.5 moles, per
mole o~ the compound of the formula (X~III). On the
other hand, the amount of the hydrogenation agent to be
used is usually large e~cess amount, preferably 5 to 15
moles per mole o~E the compound of the formula ~XVIII).
The reaction can be carried out at a temperature of
lS usually about -20C to room temperature, preferably -5 ,~
to 5C and completed generally in about 5 to 24 hours.
Further, the compound o-f general formula ~XX) --~
can be prepared by reacting the compound of general
formula (XIX) with a halide such as chlor;des, bromides,
etG. The reaction can be carried out in a solvent such
as halogenated hydrocarbons, e.g.~ dichloromethane,
chloroform, carbon tetrachloride, etc., acetic acid,
concentrated suluric acid, and the like in the presence
o~ a Lewis acid such as aluminum chloride, zinc chloride,
iron chloride, tin chloride~ boron tribromide, boron
- 22 -
~3~
trifluoride, concentrated sulfuric acid, etc., or a
catalyst such as silver sulfate, iodine, etc., at a
temperature of usually about room temperature to 100C
and completed generally in abou~ 0.5 to 5 hours. The
amount of halide to be used is usually at least about
1 mole, preferably 1 to 3 moles, per mole of the compound
of general formula (XIX).
The hydrolysis reaction of the compounds o
the formula ~XX) can be carried out in a suitable solvent
in the presence of a basic compound. Examples of
suitable solvent which can be used include water,
methanol, ethanol, isopropanol and the like. Examples
of suitable basic compound include potassium hydroxide~
sodium hydroxide, potassium carbonate, sodium carbonate,
sodium hydrogencarbonate and the like. The amount o~
the basic compound to be used is usually large excessive
amount, preferably 4 to 8 moles per mole of the compound
of the formula (XX). The reaction can be carried out at
a temperature of usually about room temperature to 150~C,
preferably 50 to 100C and com~leted generally in about
lO minutes to 5 hours.
The reaction between the aniline derivative of
general formula (XXI) and a halogenating agent can be
carried out in a suitable solvent. Any conventional
solvents that give no adverse effect on the reaction
- 23 -
353~
can be used. Examples of suitable solvent include
halogenated hydrocarbons such as chloroform, methylene
chloride and the like, ethers such as dio~ane, diethyl
ether, tetrahydrofuran, aromatic hydrocarbons such as c
5 benzene, toluene, xylene and the like, lower alcohols
such as methanol, ethanol, isopropanol and-the like~
polar solvents such as dimethyl sulfoxide, hexamethyl-
phosphoric triamide, acetonitrile and the likeO As the
halogenating agent can be used various compounds which
10 can be used in conventional halogenation reaction.
Representative examples thereof include N-bromo-
succinimide, N-chlorosuccinimide, sodium hypobromite,
sodium hypochlorite, bleaching powder, thionyl chloride,
tert-butyl hypochloride and the like. The amount of the
15 hydrogenating agent to be used is usually at least 1
mole, preferably 1 to 1.5 moles, per mole of the starting
compound. The reaction can be carried out at a tempera- -
ture of generally about -78 to 0C, preferably -60 to
-10C and can be completed usually in several minutes.
Thus, an intermediate compound o~ the formula
(XXII) can bc obtained. The compound of general ~ormula
(XXII) can be iso]ated from the reaction system and
subjected to subsequent reaction steps. Alternatively,
it can be subjected to suhsequent reaction with the thio
compound of general ~ormula (XXIII) without isolation
from the reaction system.
- 24 -
~3~35~
The reaction between the intermedia~e compound
of the formula ~XXII) and the thio compound of the
formula (XXIII) can be carried out usually in the
presence of a basic compound in the same solvent as
described above under the same temperature conditions
as described above. Examples of suitable basic compound
which can be used include inorganic basic compounds such
as potassium carbonate, sodium carbonate, sodium
hydroxide, sodium hydrogencarbonate, sodium amide,
sodium hydride and the like and inor~anic basic compounds
such as tertiary amines, e.g.~ triethylamine~ tripropyl-
amine, pyridine, quinoline and the like~ The proportion
of the compound of ~eneral formula ~XXIII) to the
compound of ~eneral formula (XXI~ is ~enerally at least
1 mole, preferably 1 to 1.5 moles, of the former per
mole of the latter. The reaction can be completed
usually in about l to 5 hours. Thus, the indole deriva-
tive of the formula ~XXIV) of this invention can be
obtained.
The desulfurization reaction of the compound
of general formula ~XXIV) can be carried out in a
solvent in the presence of a suitable catalyst.
Examples of suitable catalyst include aluminum amal~am,
lithium lower alkylamines, Raney nickel~ Raney cobalt~
triethyl phosphite, triphenylphosphine and the likeg
- 25 -
~ ~353~
~ith Raney nickcl being preferred. Examples of the
solvent include alcohols such as methanol, ethanol,
iso~ro~anol and the like~ ethers such as dioxane,
tetrahydro~uran, diethyl e~her and the like. The reac-
tion can be carried out at a temperature of about 0 to
200C, preferably about room temperature and completed
in about I to 5 hours. The amount of the catalyst to be
used is usually about l to 10 parts by weight per part
by ~eight of the indole derivative of the formula (XXIV).
The dehalogenation reaction of the compound of
the formula (XXV) thus obtained can be carried out in a
manner analogous to conventional dehalogenation. For
exampl~, a process ;n which zinc powder is used in
acetic acid or catalytic reduction process can be used.
The former process can be carried out usuaIly at a
temperature o-f about 50 to 150C for about 2 to 5 hours~
The amount of thle ~inc powder to be used is usually about
2 to 5 moles per mole of the compound of the formula
~XXV). On the other hand, the catalytic reduction
process can advanta~eously be carried out in a suitable
solvent such as alcohols, e.~., metllanol~ ethanol,
isopropanol alld the like, ethers, e.g., diethyl ether,
dioxane, tetrahydrofuran and the like, acetic acid, etc.,
using a catalyst such as palladium-carbon, palladium
black and the like. The reaction can be carried out at
,
- 26 -
~3~35
a temperature of about 0~C to room t~m~erature under a
pressure of about 1 to 3 atms for about 0.5 to 3 hours.
The amount of the catalyst to be used is as that used
conventionally, for example, about 1/10 to 1/20 part by
weight per part by ~eight of the compound of the formula
(XXV). Ic is also possible to add sodium acetylate and
the like during the above catalytic reductionO
Further, the compound of the formula (XXVI)
can also be prepared directly from the indole derivative
10 of the formula (XXIV). This reaction can be carried out -
usually in a sultable solvent using a catalyst. Any
solvents that are exemplified for the above desulfuriza-
t;on reaction can be used. As the catalyst can be used
triethyl phosphite, triphenylphosphine~ Raney nickel and
the like, with Raney nickel being preferred. The reac-
tion temperature is usually 0 to 200C, pre:Eerably 50 to
100C. Other conditions are the same as the above
desulfurization reaction.
The reduction of the compound of the formula
~XVI) thus obkained can be carried out catalyt;ally in
a suitable inert solvent. Examples of suitable inert
solvent include alcohols such as methanol, ethanol,
isopropanol and the like, ethers such as dioxane, tetra-
hydrofuran, diethyl ether and the like, acetic acid,
~ater, etc. Examples of reduction catalyst include
27 -
11~3~3~
platinum, Raney nickel, palladium black, copper chromate,
platinum-carbon, palladium-carbon, radium-carbon,
ruthenium-carbon and the like. The reduction reaction
can advantageously be carried out at 0 to 200~C under a
pressure of 1 to 250 atms for about 0.5 to 10 hours.
The amount of the catalyst is usually about 1/10 ~o 1/20
part by ~cight per part by weight of the compound of the
formula ~XXVI).
Alterna-tively, the reduction reaction of the
compound of ~eneral formula ~XXVI) obtained by the above
- procedure can be carr;ed out, for example, in a sui~able -
inert solvent using a reducing agent such as a mixture
of iron, ZillC, tin or stannous chloride and an acid
~e.~.~ hydrochloric acld, sul-furic acid, etc.) or a
lS mixture of iron, ferrous sulfate, zinc or tin and an
alkali metal hydroxide, sulfate, sulfite~ etc., and the !,
like. As Eor the inert solvent there can be illustrated,
for example, water, acetic acid, methanol, ethanol,
dioxane, etc. Reaction conditions can be selected
appropriately depending on the Xind of the reducing
agent to be used. Por example, the reaction can be
carried out advanta~eouslY at 0 to 50C for about 0.5 to ~.
1 hour when using a mixture of-stannous chloride and
hydrochloric acid as a reducing agent. The reducing
agent can be used in an amount of at least 1 mole,
- ~8 -
3~
preferably 1 ~o 2 moles, per mole of ~he starting
compound..
The reaction between the compound of general
formula (XXVII) and ~he compound of general formula ~XI~
and that between the compound of general formula ~XXVII)
and the compound of gencral formula (XII) can be carried
out under conditions analogous to those used in the
reaction between.the compound of general formula ~X) and ~. --
the compound of general formula (XI) or ~XII).
Further, in Reaction-Scheme-2 above, of the
.: ,
compounds of general formula (XXVI), a compound in which
R2 represents a hydrogen atom can be converted to a
compound of general formula ~XXVI) in which R2 represents
a lower alkyl group which may be substituted with a
hydroxy group or a lower alkanoyl group which may be
substituted with a halogen atom by reacting the above
compound of general formula ~XXVI) in which R2 represents
a hydrogen atom with a lowe~. a~kyl halide which may be
. substituted with a hydroxy group, or a lower alkanoyl
halide which may be substituted with a halogen atom.
Cyclization reaction of the compound of the
ormula tII) or (III) can be carried out us;.ng various
conventional cyclization reactions such as cyclization
by heating 9 cyclization with an acidic substance such as
.
- 29 ~
535
phosphorus o~ychlor;de, phosphorus pentachloride,
phosphorus trichloride, th;onyl chloride, concentrated
sulfuric acid, polyphosphoric acid and the like. I~hen
cyclization is effected by hea~ing the reaction can
proceed in a solvent such as hydrocarbons and ethers
both having a high boiling point, e.g., tetralin~
diphenyl ether, diethylene glycol dlmethyl ether and
the like at a temperature oi usuaily lOO~to 250C, ' -'
preEerably 150 to 200C. lYhen cyclization is effected
with an acidic substance the reaction can be carried'out ' --
'in the presence of 1 mole to a large excess amount,'preferably
10 to 20 moles'of the acidic substance per mole of the
compound of the formula ~II) or ~III) at a temperature
of usually 100 to 150C for about 0.5 to 6 hours.
lS l~en a compound of general ~ormula ~II) is
used as a starting compound the objective compound of
general formula ~I) can be obtained according to the
above cyclization reaction. ' ''
Fur-ther, when a compound of the formula ~III)
is used as a starting compound, a cornpound of the
~ormula ~IV) above can be obtained according to the
above cyclization reaction, and the compound of general
formula ~IV) can be subjected, with or without isolation,
to the subsequent hydrolysis reaction.
.
- 30 - '
~.~83~
The hydrolysis reaction of the compound of
general formula (IV) can be carried out by conventional
methods, for example, in the presence o-f a conventional
catalyst such as a basic compound, e.g., sodium
hydroxide, potassium hydroxide, barium hydroxide and
the like, a mineral acid, e.g., sulfuric acid, hydro- -
chloric acid, nitric acid, or an organic acid, e.g.,
- acetic acid, aromatic sulonic acid and the like.
The reaction can be carried out generally ln
a conventional solvent such as water, methanol, ethanol9
isopropanol, dioxane, e~hylene glycol~ acetone, methyl
ethyl ketone, acetic acid and -the like. The reaction
temperature is usually room temperature to 200~C, pre-fer-
ably 50 to 150C. Thus, the compound of general formula
(I) can be prepared.
The benzoheterocyclic compounds of the formula
~I) thus obtained can be isolated rom the respective .;
react;on mixtures upon completion and purified by conven- ~
tional ~rocedures, e.g., by -flltration, sol~ent extraction, dilution, pre-
Z0 cipitation, recrystailization, coll~n c~lroma-tography, preparative I~C~ etc.
~ ccording to the processes of this invention
the compounds of general ormula (I) above can be
obtained in a high purity and good yield with simple
operations.
.
~ ~ ~ 3 ~ ~ ~
Further, in ~he processes of this invention,
the compound of general formula (II) or (III) can be
supplied ~o subsequent steps directly t~ithout isolation
and by so doing the compound o-f general formula (I) can
be obtained in a much more improved yield.
This invention ~ill be described in greater
detail with reference to Reference Examples and Examples
but this invention is not limited thereto.
RefeTence Example l
6-Chloroquinaldine ~11 g) l~as dissolved in
concentrated sulfuric acid (15 mQ) and the solution was
ice-cooled. A solution o-f potassium nitrate ~7.1 g) in
concentrated sulfuric acid (20 mQ) was added thereto
dropwise with keeping the reaction temperature to a
temperature not higher than 10C. After completion of
addition, the mixture was stirred for 1 hour at the same
temperature as above~ and the reaction mixture was poured
onto 200 g of ice. I'hen, the reaction mixture was
rendered alkalina by the addition of an aqueous 10%
sodium hydroxide solution taking care that the internal
temperature would not exceed 20C. ~s a result, pale
yello~ precipitations ~ere formed. The precipitations
were collected by filtration, washed with water and
recrystallized from ethanol to give 12.3 g of 5-nitro-6-
chloro~uinaldine. Pale yellow rhombic crystals, m.p.123-124C.
- 32 -
.,
~353~
Reference Example 2
Stannous chloride (25 g) was dissolved in
concentrated hydrochloric acid (50 mQ) and S-nitro-6-chloro-
quinaldine (6.7 g) was added to the solution. The
mixture was reac~ed on a water bath kept at 80 to 90C
or 30 minutes. The reaction mixture was ice-cooled and
rendered alkaline (pH 10) with an aqueous 30~ sodium
hydroxide solution and then filtered an~-extracted using - ~-
chloroform ~500 mQ) and celite. The chloroform layer
10 was dried over anhydrous sodium sulfate, concentrated -
and recrystallized from benzene-hexane to give 4.5~g of - -~---
5-amino-6-chloroquinaldine. Colorless plates, m.p.
196-197C.
Reference Example 3
A m:ixture of 5-amino-6-1uoroquinaldine ~22 g)
and polyphosphoric acid (100 g) was heated -to 150C with
stirring. N-methyldiethanolamine (lO0 g) was added ~
dropwise to the mixture in 30 minutes and the mixture
was kept at an internal temperature of 180C. The reac-
~ion was continued for 8 hours at the above ternperature
.Tith removing moisture formed out of the react;on system.
After confirmin~ disappearance of a spot corresponding
to the starting compound by thin layer chromatography,
the reaction mixture was cooled slowly. A-fter lowering
the internal temperature to 80C~ water (100 mQ) was
- 33 -
~3~3~
added to ~he reaction mi~ture to form a homogeneous
solution, ~hich was t}len taken out, neutralized with an
aqueous sodium hydroxide solution and extracted with
hexane (200 mQ) three times. The hexane layers were
put together, washed with water (250 mQ), dehydrated
over anhydrous magnesium sulfate and filtered. Then~
the t}lus-treated hexane layer was concentrated until the
total amount thereo~ was reduced to lOO~m.~. After add-
ing activated carbon (2 g), the concentrate was refluxed
10 for 30 minutes. ~ile hot the activated carbon was --
filtered out. After cooling, crystals which precipitated ~ -
~ere collected by filtration to give 23 g of 5-(4-methyl-
l-piperazinyl)-6 -fluoroquinaldine. Pale yellow crystals,
m.p. 87-89.5C.
Reference Example~4
5-(4-Methyl-l-piperazinyl)-~fluoroquinaldine
(3.7 g) was dLissolved in a mixed solvent consisting o-E
acetic acid (100 mQ) and ethyl acetate ~10 mQ). After
adding 5% platinum -carbon ~l g), the solution was
placed in a vitrified autoclave and stirred at room
temperature for 3 hours under a hydrogen gas pressure oE
5 kg/cm2~ AEter removing hydrogen gas the content was
taken out, the catalyst was removed and the content was
concentrated to dryness. Then, chloroform (100 mQj was
added to the residue. After dissolution, the solution
3~
,
3535
was neutralized with an aqueous 5% sodium hydroxide
solution (50 mQ). After separation, the chloroform
layer l.ras ~ashed l~ith water (100 mQ) twice. After dry-
ing, the chloroform layer ~as concentrated to dryness
and hexane (Z0 mQ) and activated carbon (0.5 g) ~ere
added to ~he residue followed by heating the mixture to .
dissolve the residue. A~ter removing the actlvated
carbon by filtration~ the hexane layer was~cooled and
. .
crystals formed were collected by filtration to give
- .:
- lO 3.5 g of 5-(4-methyl-1-piperazinyl)-6-fluoro-1,2,3,4-
tetrahydroquinaldine. Pale yellow crystals, m.p. 64.5
65.5C.
Reference Example 5
3-Chloro-4-fluoroaniline ~50 g) was dissolved
15 in 15Q mQ of acetic acid and acetic anhydride ~.
(70.2 g) was added dropwise to the solution. After
stirring for 30 minutes at room temperature, the reaction
mixture was poured into water and solids which precipi-
tated were collected by filtration. After washing with
water, the solids were dissolved in ethyl acetate. The
ethyl acetate layer was was}lecl ~.ith a dilute acllleous
solution of potassium carbonate and dried over magnesium
sulfate followed by evaporating the solvent. Thus, 62 g
of 3-c]lloro-4-fluoroacetanilide was o~tained. m.p. 116-
117~.
- 35 -
~iL835~5
Reference Example 6
3-Chloro-4-fluoroaniline ~10 g) and phthalic
anhydride (10.2 g) were dissolved in dimethylformamide
~30 mQ) and the solution was refluxed for 2 hours.
Water was added to ~he reaction mixture and crystals
which formed were collected by filtration. The crystals
were dissolved in ethyl acetate. After washing with an
,
aqueous sodium hydrogencarbonate solution~'the solution~
was dried over magnesium sulfate to give 14.4 g of N-~3- -
10 chloro-~-fluoro-l-phenyl)phthallmide. m.p. 192-193C. - ;.
. ~ ~
Re-ference Example 7 , ~ -,~-'',~ ,' ,' - ~
3-Chloro-4-fluoroacetanilide ~lO g) was
dissolved in concentrated sulfuric acid ~35 mQ)'and a r
solution of potassium nitrate ~6.5 g) in concentrated 5
15 sulfuric acid ~25 mQ) was added dropwise to the solution ,;
in 30 minutes af, 0C. After completion o addition, the
mixture was stirred at 0C for 1.5 hours. The reaction _,'
mixture was poured into ice water ~400C) and crystals
which formed were collected by filtration, washed with ,~
20 water and dried to give 12.3 g of 2-nitro-4-fluoro-5-
chloroacetanilide. m.p. lll-112c.
Re~erence Exam~le 8
Ke~ping the temperature at lS to 20C, N-~3-
, chloro-4-fluoro-1-phenyl)phthalimide ~14 g) was dissolved
in concentrated sul~,uric acid {75 mQ), and a solution of
36
.
. , . , , ., . , , - - - ~ ' ' ' ;' ': ' ' ' ' ' ''` ~ " " ' ~' ` ; "'
335i3~3i
potassium nitrate (5.6 g) in concentrated sulfuric acid
(20 m~ as added dropwise to ~he solution in 30 minutes
at -5C. After stirring at -5 to 0C for 1 hour, the
reaction mixture was poured in ice water (1.5 Q) and
crystals which formed t~ere collected by filtration.
After washing with water, the crystals were dissolved
in dichloromethane and the solution was dried over ;-
magnesium sulfate. Evaporation oE the sotvent gave ~-
15.4 g of N-~2-ni-tro-4-fluoro-5-chloro-1-phenyl)- -
phthalimide. m.p. 222-224C.-
- - Reference Example 9 ~ ~
..
2-Ni~ro-4-fluoro-5-chloroacetanilide ~12 g) and r',
methylpiperazine (25.8 g) ~ere dissolved in 120 mQ of
dimethylformamide and the solution was stirred at 70C - ,r~
15 ;Eor 2 hours. Excessive methylpiperazine and dimethyl- ,
ormamide ~Yere evaporated under reduced pressure. l~ater
(50 mQ) was added to khe residue and crystals which
Eormed ~tere collected by filtration. AEter washing wikh
water, the crystals were recrystallized from methanol-
20 water and then ;Erom isopropanol to give 14.3 g o 2-
ni~ro-4-Eluoro-5-(4-methyl-1-~iperazinyl)acetanilide.
m.p. 133-135C.
Re:Eerence Example 10 r
2-Nitro-4-Eluoro-5-(4-methyl-1-piperazinyl)-
25 acet~nilide (10 g) and a solution oE potassium hydro~ide `
~9.5 g~ in water ~8 mQ) were dissolved in methanol (100 mQ)
- 37 -
335i3~;i
and the solution was refluxed for 30 minutes. After
cooling, water (50 mQ) was added to the reaction mixtureO
Solids which precipitated were collected by filtration,
washed with water and recrystallized from isopropanol to
give 8.0 g of 2-nitro-4-fluoro-5-~4-methyl-1-piperazinyl~-
aniline. m.p. 151-153~C.
Reference_Example 11
2-Nitro-4-fluoro-5-(4-methyl-1-piperazinyl)-
acetanilide (25 g~ was dissolved in hydrochloric acid
(250 mQ) and a solu~ion of stannous chloride dihydrate
(57.2 g) in concentrated hydrochloric acid (250 mQ) was
added to the solution at a time. During this operation,
the tempcrature of the reaction mixture increased to 40C.
After allowîng to cool for 1 hour with stirring, solids
which pIecipitclted were collected by filtration and
dissolved in a small amount of water. The aqueous
solutioll wa5 rendered alkaline with aqueous sodium
hydroxide solution under ice cooling and extracted with
dichloromethane. After drying over potassium ca~bonate,
the solvent was evaporated. To the residue was added n-
hexane and crystals which formed were collected by
filtration and dried to give 15.7 g of Z-amino-4-fluoro-
5-t4-methyl-1-piperazinyl)acetanilide. m.p. 168-169C.
Reference Examp~e 12
2-Amino-4-fluoro-5-(4-methyl l-piperazinyl)-
acetanilide ~3.0 g) was dissolved in a mixture of water
- 38 -
53~ -
~lO mQ) and concentrated hydroch]oric acid ~30 mQ3 and
an aqueous sodium nitrite solution (a solution of 0.77 g
of sodium nitrite in 5 mQ of water) was added dropl~ise
to the resulting solution follol~ed by s~irring for Z
minutes. After adding 2 drops of n-octanol, copper
.
powder ~0.96 g) was added to the solution at a time.
After stirring for 30 minutes, the reactlon mlxture was~ -
- poured into l~ater, rendered alkaline with' an aqueous
sodium hydroxide solution and extracted with dichloro-
methane. After'drying over magnesium sulfate, the ~ -
solvent was evaporated and the resi'due was purified ' '-~
through silica gel column chromatography ~eluent:
chloroorm-methanol = 4:1) to give 0.90 g of 3-(4-
methyl-l-piperazinyl)-4-fluoroacetanilide. m.p. 17S- ~ '
176~C.
Reference Exam~
Silver sulfate (0.60 g) was dissolved in --;
concentrated suluric acid (lO mQ) and 3-(4-methyl-1-
~i~erazinyl)-4-fluoroacetanilide (0.80 g) was added to
the solution with stirring. ~fter adding bromine
(0.61 g), the solution was stirred for 1 hour at an
internal temperature of 30 to 40~C. The reaction
mixture was poured into water and insoluble substances
,were filtered out. The filtrate was rendered alkaline
by the addition of aqueous sodium hydroxide solution
- ' :
- 39 -
~83~i3~
and extracted with dichloromethane. After concentration,
the extract was purified through silica gel column
chromatograllhy ~eluent: chloroform-methanol = 8:1) to
give 0.21 g of 2-bromo-4-fluoro-5-(4-me~hyl-1-
S piperazinyl~acetanilide. m.p. 126-127C.
Re~erence_Example_14
2-Bromo-4-fluoro-5-(4-methyl-1-plperazinyl)-
acetanilide ~0.10 g) was added to 47% hydrobromic acid
( 5 mQ) and the mixture was refluxed for 1 hour. After
evaporating 47% hydrobromic acid, the residue was
rendered alkaline by the addition of an aqueous sodium - ~
hydroxide solution. l~ite insoluble solids which
precipitated were collected by filtration and dried to
give 0.08 g of 2-bromo-4-fluoro-5-(4-methyl-1-
p~perazinyl)aniline. m.p. 122-124C.
Reference Example 15
2-Bromo-4-fluoro-5-~4-methyl-1-piperazinyl)-
aniline tl45 g) was dissolved in methylene chloride ~1 Q)
and the solution was cooled to a temperature below -50C
on dry ice-acetone bath. At the same temperature as
above, tert-butyl hypochlorite (60 g? was added dropwise ~.
to the solution, during which operation the reaction
mixture was changed -~rom heterogeneous mixture to a
homogeneous solution. Then, methylthio-2-propanone
~67 g) was added dropwise to the solution and the mixture
-'- . : ' ' ::-
- 40 -
~L~8353~ii
was reactcd for 2 hours at the same tem~erature as above.
Subsequently, triethylamine ~80 mR) -ras added dro~l~ise
to the reaction mi~ture. After completion of additioll,
the tempera~ure of the m;xture was elevated to room
temperature slowly. After room temperature was reached,
water (1 Q) was added to the reaction mixture to separate
a methylene chloride layer. After drying over sodlum
sul~ate, the methylene chloride layer was concentTated - -~
under reduced pressure -followed by resrystallization
10 from ethanol-water to give 150 g of 2-methyl-3-methylthlo- -
5-fluoro-4-(4-me$hyl-1-piperazinyl)-7-bromolndole~
Elemental Analysis for C15HlgN3SBrF
C H N
Calc'd~%): 4S.39 5.14 11.29
i5 Found (~): 48.25 5.03 11.38
Reference Example 16
2-Bromo-4-fluoro-5-~4-methyl-1-piperazinyl)- ;
aniline (800 g) was dissolved in dry methylene chloride
~4 Q) and the solution ~as cooied to -60C. Then, a
solution o-f tert-butyl hypochlorite (350 g) ;n methylene
chloride (500 mQ) was added dropwise to the solution at
~he same tempcrature as above. Subsequently, a solution
of ethylthio-2-propanone (6S0 g) in dichloromethane (1 Q)
was added dropwise to the mixture. After completion oE
addition, the resulting mixture was rcacted for 2 hours
-
- 41 -
.. . .. . . , , . ,. . ~ . ., . .. ., .. . , . .. ,,~
~35~
at thc same ~empera~urc as above and a solu~;on of triethyl-
amine (325 g) in methylene chloride (1 ~) was added
drop~ise to the reaction mixture. ~fter completion of
addition, the tcmperature of the mixture was elevated
slo~ily to room tempera~ure. After adding water ~5 Q) and
stirring, methylene chloride layer was separated, drled
over magnesium sulfate and concentrated under reduced
... . , ;. - . . .
pressure to give 0.95 kg of 2-methyl-3-ethylthio-4-~4- r~
methyl-l-piperazinyl~-5-fluoro-7-bromoindole.
Reference Example 17 ~ -
2-Methyl-5-fluoro-4-C4-methyl-l-piperazinyl)- - .
. .
indole (138 g) was dissolved in acetic acid (1.5 Q).
To this solution was added tin metal ~200 g~ and the
mixture was refluxed. Concentrated hydrochloric acid
(1.5 Q) was added dropwise thereto in 1 hour under
refluxO A~ter completion of addition, the mixture.was
reacted ~or 2 hours at the same temperature as above.
After completion of reaction, the solvent was evaporated
under reduced pressure. l~ater (1 Q) was added to the
residue and the solution was adjusted to pH 13 with an
aqueous 20% sodium hydroxi(le solut;on. ~ftcr adding
diethyl ether (1 Q) and stirring, insoluble substances
~ere removed by filtration. A diethyl ether layer was
separated from the iltrate and dried over anhydrous
potassium carbonate. Evaporatiorl of diethyl ether gave
,: - . - -
- 42 - -
.
~33~3~
75 g o 2-methyl-4-(4-methyl-1-piperazinyl)-5-fluoro-
indolîne.
Reference Example 18
2-~lethyl-3-methylthio-4-(4-methyl-1-piperazinyl)-
5 5-fluoro-7-bromoindole (214 g) was disso~ved in ethanol --
(3 Q). Raney nic~el (1.5 kg) was added to the solution
and the mixture was reacted for 3 hours;with refluxing. ',':
- ~
After cooling, Raney nickel was removed by'f'îltration
and ~he filtrate was concentrated to give 101 g of 2-
10 methyl-4-~4-methyl-1-piperazinyl)-5-fluoroindole. --
~ Reference Example 19
2-Methyl-3-methylthio-4-(4-methyl-1-piperazinyl~-
5-fluoro-7-bromoindole (5~ g) was dissolved in dioxane
tl Q). Raney nickel (400 g) was added to the solution
15 and the mixture ~was reacted for 4 hours at room tempera-
ture. After completion of reaction, Raney nickel ~as r
removed by filtration and the filtrate was concentrated ; ~'
under reduced pressure. The residue was recrystallized - -~.
from ethanol~ ater to give 33 g of 2-methyl-4-(4-methyl-
20 1-piperazinyl)-S-fluoro-7-bromoindole.
ElemeTItal Analysis for Cl~H17N3FBr
C ~I N
Cald'd~ 51.55 5.25 12.88
~ound (~): 51.42 5.37 12.74
.
.
- ~3 -
'
353~;
Reference ExamPle 20
.
2-~lethyl-4-~4-me~hyl-1-pipera~inyl)-5-1uoro-
7-bromoindole (24 g) was dissolved in ethanol ~200 mQ).
5~ Palladium-carbon (1 g) and then an aqueous 20% sodium
hydroxide solution (15 mQ) ~ere added to the solution.
The mixture was subjected to catalytic reductlon at room
temperature under atmospheric pressure. The reaction
was continued till theoretlcal amount ~about 1.7 Q~ of
hydrogell gas was absorbed, and then the catalyst was
removed by filtrat;on. The filtrate ~as concentrated
and the residue was purified through silica gel column - - .
chromatography tl~Jako gel C-200; eluent: chloroform :n- - -
hexane = 5:1) -to give 11.8 g o 2-methyl-4-(4-methyl-1-
piperazinyl)-5-~luoro;ndole. ;
Elemental Analysis for C14H18N3F L
C - H N
Cald'd(%): 67.99 7.34 16.99
Found ~%): 67.84 7~20 17.13
Reference Example 21
2-Amino-4-fluoro-5-~4-methyl-1-piperazinyl)-
acetanilide ~1.94 g) l~as dissolved in a mixture o~ ~ater
~7 mQ) and hydrobromic acid (20 mQ). A solution o
sodium nitrite ~0.53 g) in ~ater (3 mQ) was added drop-
wise to the resulting solution at 0C. After 5 minutes J
one drop of n-octanol (defoaming agent~ and then copper
. . ,:
- 44 -
~L~L83~ii3~ii
powder (0.46 g) ~ere added at a time. Foaming occurred
immediately. A~er foaming ~as over, ~he mixture was
stirred at 0 to SC for additional 3 minutes. The reac-
tion mixture was diluted ~ith tia-ter and rendered alkaline.
Solids which precipitated were collected by flltration
and clissolved in a mixed solvent of methanol-chloroform
ollol~ed by removing insoluble substances. After concen-
- tration, the residue was purified through column -
chromatography to give 1.6 g of 2-bromo-4-fluoro-5-(4-
10methyl-i-plperazinyl)acetanilide. m.p. 126-127C.
- Example I ~ -
(a) 5- (4-methyl-1-piperazinyl)-6-fluoro-
1,2,3,4-tetrahydroquinaldine (10 g) and isopropylidenyl
methoxymethylenemalonate (8 g) were mixed with each other
15at room temperature and heated for 30 minutes at 100C
with stirring to form solids. The solids were ~ecrystal-
lized from chloroform-n-hexane to give 14.6 g ~92%) of _ :
cyclic isopropylidenyl N- L5- (4-methyl-1-piperazinyl)-6-
fluoro-1,2,3j4-tetrahydro-1-quinaldinyl]aminomethylene-
malonate. l~ite crystals.
Elemental Analysis for C2~H2~04N3F
` C H N
Calc'd(~): 63.2g 6.76 10.07
Found (%): 63.42 6.59 10.05
-''
- 45 -
l:~B3535
(b) Polyphosphoric acid (50 g) prepared from
phosphorus pentoxide (25 g) and phosphoric acid ~25 g)
and cyclic isopropylidenyl N [5-~4-methyl-1-piperazinyl)-
6-fluoro-1,2,3,4-tetrahydro-l-quinaldinyl~aminomethylene- ;
S malonate (14.0 g) obtained in stey (a) above were heated
at 100C for 1 hour with stirring. After cooling to
;..
80C, water (60 mQ) was added to the mixture to form a
solution, which was then neutralized with an aqueous 20%
sodium hydroxide solution and extracted with chloroform
~200 mQ) twice. After dehydrating and drying over
..
anhydrous magnesium sulfate the chloroform layer was
concentrated to dryness. To the crystals thus-obtained
were added methanol ~40 mQ) and activated carbon (O.S g)
and the mixture was heated. After removina the acti~ated
carbon from the ^resulting solution and cooling, crystals
which fvrmed were collected by filt~ation to give 10.2 g ',
(84.6%) of 8-(4-methyl-1-piperazinyl)-9-fluoro-5-methyl-
6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-caTboxylic ' ' 5
acid. White rhombic crystals, m.p. 262-263C.
Example 2
~n an analo~ous manner as in Example :L,
compounds shown in Table 1 beLow were prepared ~rom
appropriate starting materials.
In ~able 1, each compound was expressed in
terms of combination of Rl9 R2 and X in ~ormula (Ia),
- - .
- 46 -
. . .
53~
and the melting point of the compound and yield thereof
in step (b) are also shown. --
R~-N \I/~COO}I tIa)
Rl . j
., -
i.
- ~ .
.
- ~7 -
35~
~1 .
Q.) i~! C`l ~1 ~ O a~ ~ o d` ~ ~ ~ ~_1 ,r~i
U~
~ ~ O 1~ L~ I~ ~ U) ~ C~l
C ~
~_ Oc~l ~ ~ O O ~ ~ ~ O C~l C`~ ~ ''
~1 0 I I I ~ I O
C) P~ ~-- A ~i~ CO A
~ 1 0~ 1 1 1 1 1 o ~ ,
~: . ' , ,s,,
r-i ~ ~i i I I i ~ I I ! I I I ~i . ,.-.
a~ . .-
r-l O O r.
~ ~rl O a~
rl JJ ~1 ;:
, ,_,
''. ~
~ ~ ~ r~
L
O o l ~ c~i ~ ~ u~ ~D ~ CO a~ o ~1
C, , , - ,
- - ~ - - -
- 48 -
~3353S
,~ ~
U~ o ,~ ~ o $
n
~o ~ n o cru~ ;~ o o
oC~ J oC~ l ~ ~ o
~ ~ ~, o , , , o , I , , I I o
,~ o o ~,~ ~ ~ ~ ooCO ~ ~CO U~
c) ~4 ~~/\ ~r~Il~ Ao :) o~ oo C1~C~ . A
C`l C`~
a
I I I I OI ~ O I I 0
.
O . '-.
~1 .,1 JJ
,1 ~ ~
1 ~ Cd
r~ ' '
Ql ~ '
rl ~: ~C :,'
~ ~ O O~ . '.
E-l ~ r :
~,1 ~ ~ F~ I y
Uo~.Q ..
~4 ~ ..
. '-,
O ' ' ' '
.
O O ~ t~ O C~lF4 0 ~;
O C~
. ~ ~ ~ r~
c~ ~ ~ ,rr~ ~) r~
tC ~ 4 r~
.
~ ¦ tq ~rr~ ~ qrL~
5 1 ' ' .
O z ~U) ~ ~CO ~O r~
C~
, -
- 4g -
3~ii
Example 3
(a) Diethyl cthoxymethylenemalonate (9 g) was
added to 5-(4-formyl-1-piperazinyl)-6-chloro-1,2~3,4-
tetrahydroquinaldine (8.5 g) and the mixture was heated
at 150C -for 30 minutes to form solids, which were then
recrystallized from chloroform-n-hexane to give 12O7 g
(92%) of ~iethyl N-[5-(4-formyl-1-piperazinyl)-6-chloro- a'~~
1,2,3,4 tetrahydro-l-quinaldinyl~aminomethylenemalonate.
White rhombic crystals.
Elemental Analysis for C23H30O5N3CQ
C H N - - - - - - ?i
Calc'd(~): 59.54 6.52 9.06 - ~f;
Found C%): 59.~9 6.53 9.07
(b) Polyphosphoric acid ~70 g) prepared :Erom ~-~
phosphorus pentoxide (35 g) and phosphoric acid ~35 g)
and diethyl N-[5-(4-for~l-1-piperazinyl~-6-chloro
1j2,3,~-tetrahydro-1-quinaldinyl]aminomethylenemalonate
~12.5 g) obtained in step ~a) above were heated at 140
to 150C for 1 hour. After completion of reaction~ the
reaction mixture was poured into ice water (200 g) and
,
the mixture was adjusted to pH 6 to 7 with an aque~ous
10 N sodium hydroxide solution. precipitates which
formed were co~lected by iltration and added to concen-
trated hydrochloric acid ~60 mQ). The mixture was
refluxed for 1 hour. Thereafter, water (100 mQ) was
,
- 50 -
53~ -
added to the reaction mixture and crystals which formed ~-:
were collected by filtra~ion, washed with water and
dried. Recrystallization from methanol gave 8.9 g
(S2.5~) of 8~ formyl-1-piperazinyl)-9-chloro-5-methyl-
6,7-dihydro-1-oxo-lH,5H-benzo[ij]quinolizine-2-carboxylic
acid. ~hi~e rhombic crystals, m.p. 262-265C. -~
Example 4 `
:
In an analogous manner as in Example 3,
- . .
compounds shown in Table 2 belo~ ere prepared from
appropriate starting materials. In Table 2, each
compound is expressed in terms of combination of Rl, R~ -
and X in formula (Ia) and the melting point of the
compound and yield in step (b) are also shown. r-:
r:
00~1 , .;,
R2 N N/~\N . lIa) ~,;
~R~
~e
.
' i
,
~3~i3~
1~ ~ ~ r~ r,~l O O ~ r~~ I~ ~ r.~J r,r~ ~ ,
,
bO r~O r~ ~r~ ~ ~r,~l
~ o ,~ , o o ,~ , o ,~ , o
r~ O ~ i I O O I I I O I I O
~1 0 U~ r,~ ~ ~ ~ O r.~ r,~J ~ rr
r~ ~~ A~D r~r.~o A A ~ D Acr~ r~ A
X r.~ C`l r,~l r.~l r.~J C`l ' :
,, ~ I I I O O I 1.'~ O ~
'
' ~ ' ',
m O 0 5 0 ~ O I I i I m O
,.~,~c '"~'1 ' ~ m . ,1 ~
,~ . ...
,~ ~''
E~ ~ v ~ td ~
~rl O a~ ~ cr ra~ o~ rJ~
. .,
n r
rJ~ ,
: r.
r~l~ m m ~ mr~ ~ m ~ m ~ `' m~,
,~, i
~ r,r) ~ ~,) ~ r,~ r,~ ~
~C Pi ~ m ~ ,m~ m
o zO ~ ,~ O,~ I r~
, ,~, . - .
.
- 52 -
~8~53~i
a~ ~ ~ ~ ~ o u~
~ c~ r) o cs~ o o
lJ rl r~ t~ l g ~ ~ O
,~ O O r. e~l ~ ~ o~ co ~ ~ 00 ~n -
~ ~ _~ ~ 1~ 11~ A 00 ~ 0~ l . A
~J . -
V
~, I'III~`'II11i
r-l ' ' , , ' -.
.
O
~ rl V 1 1 l l I H l l l l l
al ~
~ ~C
~ _~ O O
~ O ~ ~ m ~ c~ u'
.u ~,1 ~ ~ o~
~rl V
P~ ~
U~ .
g -:
o o ~ c~ o ~ ~ o
~1 ~~ ~N ~ ~
c~l $ ,r~ 5 1:~ N ~ ~ ~ N ~ ~1
~ o~ ~
~ ¦ - ~ ~ ~ $ 8 ~ ~ 8
~0 0 ~ U~ o ,I c~
O r I r-l r l r-l r-l r-l C`l N C~J N C~l
C~ _
. . . ' .
- 53 -
353~
Examplc 5
Die~hyl etho~ymethylcnemalona~e (6.0 g) was
added to 5-(4-methyl-1-piperazinyl)-6-fluoro-1,2,3,4-
tetrahydroquinaldine (6.G g) and the mixture was heated
at 160C for 30 minu-tes. Then, polyphosphoric acid
~48 g~ prepared from phosphorus pentoxide (24 g) and
phosphoric acid ~24 g) was added thereto and the result-
ing mixture was heated at 150 to 160C for l hour. After
completion of reaction, the reaction mixture was poured
into ice water ~150 g) and precipitates which formed
were collected by ~iltration, washed with water and - -
dried. To the crystals thus-obtained was added an
aqueous 10% sodium hydroxide solution (70 mQ) and the mixture
was reacted at 100 to 110C for 1 hour. A~ter cooling,
the reaction mixture was rendered acidic with concen-
trated hydrochloric acid to form crystals. The.crystals
were collectecl by filtration, washed with water and
recrystallizecl from methanol to gi~e 7.6 g ~84%~ of 8-(4-
methyl-l-piperazinyl)-9-fluoro-5-methyl-697-dihydro-l-
oxo-lH95H-benzo[ij~quinolizine-2-carboxylic acid. ~ite
rhombic crystals J m.p. 262-263C. ,
E~ 6
(a~ 4-(4-Methyl-l-piperazinyl)-5-fluoro-2-
methylindoline (9.6 g) and isopropylidenyl methoxy-
methy~enemalonate (8 g) were mixed ~ith each other at
- 54 -
11f33535
room temperature and the mixture was heated at 100C for
30 minutes Wit}l stirring to form solids, which were then
recrystallized from chloroform-n-hexane to give 14.0 g
of cyclic isopropylidenyl N-[4-(4-methyl-1-piperazinyl)-
5-fluoro-2-methyl-1-indolinyl]aminomethylenemalonate.
Elemental Analysis for C21H26N3O4F
C H
- Calc'd(%). 59.18 6.33 9.99 -- ; - -
Found (%): 59.31 6.16 9.88
(b) Polyphosphoric acid (50 g) prepared from
phosphorus pentoxide C25 g) and pho-sphoric acid (25 g?
and cyclic isopropylidenyl N-[4-(4-methyl-1-piperazinyl)-
5-fluoro-2-methylindolinyl]aminomethylenemalonate ~13.5g)
obtained in step ~a) above were heated at 100C for l
hour with stirring. After cooling to 80C, water (60 mQ)
was added to the mixture and the resulting solution was
neutralized with an aqueous 20% sodium hydroxide solution ;
follo~ed by extraction with chloroform ~200 mQ~ twice.
The chloroform layer was dehydrated and dried over
anhydrous magnesium sulfate and concentrated to dryness.
To the crystals thus obtained ~Yere added methanol (40 mQ)
and activated carbon (0.5 g) and the mi~ture ~ras heated
to form a solution. A~ter removing the act;vated carbon
by filtration and cooling, crystals which formed were
collected to give 9.8 g of 9-(4-methyl-1-piperazinyl)-8-
.. . .
11~3535
fluoro-2-methyl-1,2-dihydro-6-oxo-pyrrolo~3,2,1-ij]-
quinoline-5-carboxylic acid. l~hite rhombic crystals,
m.p. 242-244C.
Example 7
,
In an analogous manner as in Example 6,
compounds sho~n in Table 3 were prepared rom appropri-
ate star~ing materials.
In Table 3, each compound is expressed in
terms of combination of Rl, R2 and X in formula tIb)
and the melting point o the compound and yield in step
~b) are also shown. ~
O r:
N/---\N ~ COOH ~Ib)
R~
'.
- 56 -
35~;
Table 3
Compound ~ 2 ~lelting
N'o. R- R X Point HX Yield
~ C) ( % )
l CH H F Above HCQ 85.5
3 300C
(30~-306
decomp.3 -
2 H H H Above HCQ 83.4
300 C
3 CH3 H H 269-273 HCQ 86.5
(decomp.) -
4 CH3 H CQ 258-260 ~~ 82.5
3 CH3 CQ 273-276 -- 84.1
Example 8 .^
(a) Diethyl ethoxymethylenemalonate (9 g) was
added to 4-~l-pipera~inyl)-5-chloro-2-methylindoline
(6.8 g) and the mixture was heated at 160C for 30
minutes to orm solids, which were then recrystallized
from chloroform-n-hexane to give 10.2 g (92%) of diethyl -~
N-[4-(l-piperazinyl)-5-chloro-2-methylindol;nyl]amino-
methylenemalonate.
Elemental A~alysis for C2lH26M3O~CQ
C H M
Calc'd~%~: 60.22 6.12 10.l4
Found (%); 60.07 6.24 lO.Ol
- 57 -
~L~L8~
(b) Polyphosphoric acid (65 ~) prepared from
phosphorus pento~ide (32~5 g) and phosphoric acid (32.5 g)
and diethyl N-[4-(1-piperazinyl)-5-chloro-2-methyl-
indolinyl]aminomethylenemalonate (10.0 g) obtained in
step ~a) above ~ere heated at 140 to 150C for l hour.
After completion of reaction, the reaction mixture was ;-
poured into ice ~ater CZ00 g) and the mixture was
adjusted to pH 6 to 7 with an aqueous 10 N sodium
hydroxidc solution. Precipita-tes which formed were
- 10 collected by filtration and added to concentrated hydro- -
chloric acid C60 m~). The mixture was refluxed for 1-
hour~ Thereafter, water CloO mQ) was added to the
reaction mixture and crystals which formed were collected 1,
by filtration, ~ashed with water and dried. RecTystal-
lization from methanol gave 7.1 g ~82.5%) of 9~
piperazinyl)-8-chloro-2-methyl-1,2-dihydro-6-oxo-
pyrrolo[3,2,1-ij]quinolille-5-carboxylic acid. Pale
yello~ rhombic crystals~ m.p. 258-260C.
Example 9
In an analogous manner as in Example 8,
compounds shown in Table 4 belo~ ere prepared from
appropriat~ starting matellals. In Table ~ each
compound is expressed in terms of combination of Rl, R2
and X in formula ~Ib) and the melting point o~ the
compound and yield in step (b) are also sho~n.
- 5~ -
353~
X~ ~ COOH
R2 N N ~ ~ N ~ (Ib)
\ J
, ,
Table 4
Compoulld 1 2 Melting ~ ~
No. R R X Point HX.Yield ..
-- (" C) ' ~ ~
1 CH3 . CH3 F 242-244 -- 83.6
2 H H H Above 300 HCQ81.4
3 CH3 H ~l 269-273 HCQ8~.3
~decomp . )
. 4 CH3 H CQ 258-260 -- 82.5
CH .CH3 CQ 273-276 -- 83.1 --~
. Example 10 ' .~ .
Diethyl ethoxymethylenemalonate (6.0 g) was ..
:, , , . , , - :
added to 4-(4-methyl-1-piperazlnyl)-5-1uoro-2-methyl- : :
indollne ~6.2 g) and the mixture was heated at 160C for
30:.minutes. Then, po.lyphosphoric acid (48 g) prepared
~rom phosphorus pentoxide (24 g) and phosphoric acid
:1.5 (2~ g) was added thereto and the resulting mixture was
heated a-t 150 to 160C for 1 hour. ~ter completion of
reaction, the reaction mi~ture was poured into ice water
~150 ~) and precipitates which formed were collected by
- , .
- 5g - .
.
~3353~
filtration, washed with water and dried. To the crystals
thus-obtained ~.as added an aqueous 10% sodiwn hydroxide
solution(70 m~ and the mi~t~lre~as reacted a-t 100 to 110C-for
1 hour. After cooling, the reaction mixture was rendered
acidic with concentrated hydrochloric acid to form
crystals. The crystals were collected by filtration,
washed with water and recrystallized from methanol to
give 7.1 g (84%~ of 9-C4-methyl-1 piperazinyl)-8-fluoro-
2-methyl-1,2-dihydro-6-oxo-pyrrolo[392 3 1- ij ]quinoline-5-
carboxylic acid. ~Yhite rhombic crystals, m.p. 242-244C.
~ Yhile the invention has been described in
detail and with reference to specific embodiments
thereo, it will be apparent to one skilled in the art
that various changes and modifications can be made
therein without departing from the spirit and scope
thereof .
- ~0 -
