Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~s~
The present invention relates to a process for producing
chlorosulfonylbenzoylchlorides. Chlorosulfonylbenzoylchlorides
produced by the process of the invention are useful as
intermediates in the preparation of medicines, food additives
and agricultural chemicals.
The following conventional processes for producing
chlorosulfonylbenzoylchlorides are known.
(1) An alkali metal salt or the ammonium salt of an aromatic
sulfocarboxylic acid is chlorinated with phosphorous penta~ -
chloride or a mixture of phosphorus pentachloride and phosphorus
oxychloride to produce a chlorosulfonylbenzoylchloride.
(Berihite Vol. 31, page 1649; ibid. Vol. 31, page 1654; ibid
Vol. 55, page 1506; American Chemical ~ournal Vol. 13, page 261;
ibid Vol. 30, page ~87; ibid Vol. 23, page 235; ibid ~ol. 23,
page 239; ibid Vol. 25, page 204 and ibid Vol. 50, page 196)
(2) Benzotrichloride is chlorosulfonated with chlorosulfonic
acid to obtain m-chlorosulfonylbenzo-trichloride, which is heated
to obtain m-chlorosulfonylbenzoylchloride (USP 3,290,370)
(3) Benzoic acid is chlorosulfonated to obtain m-chlorosul-
fonyl benzoic acid, which is chlorinated with thionylchloride
to obtain m-chlorosulfonylbenzoyl chloride. (B.P. 9~1,520).
However, the above described conventional processes
have various disadvantages and are not suitable for industrial
operation.
In the conventional process (1), the phosphorus penta-
chloride or the mixture of phosphorous pentachloride and
phosphorus oxychloride used as a chlorinating agent is expensive.
Also phosphorus oxychloride or metaphosphoric acid are produced
as by-products thereby making it necessary to purify the
produced chlorosulfonylbenzoylchloride by distillation.
Furthermore the phosphorus oxychloride or metaphosphoric acid
produced as by-products may cause pollution. Further disadvan-
-1- ~ .,
~ ' . ' : ' . . : ,
tages o~ the conventional process (1) are that the chlorosulfonyl-
benzoylchloride is produced in a low yield and a marked colour
is imparted thereto.
In the conventional process (2), it is difficult to
produce the chlorosulfonylbenzoylchloride in high yield and
it is difficult to prevent hydrolysis of the chlorosulfonylbenzoyl-
chloride produced.
In the conventional process (3), sulfur dioxide gas is
generated and causes a serious pollution problem.
In the conventional processes (2) and (3), it is not
possible to produce o- or p-chlorosulfonylbenzoylchlorides,
i.e. benzoylchlorides having chlorosulfonyl group in an o- or
p- position relative to the chloroformyl group. In accordance
with the present invention, there is provided a process for
producing chlorosulfonylbenzoylchloride having the formula
COCl
X ~ S2Cl (II)
wherein X represents a hydrogen atom, a halogen atom or a nitro
group, comprising reacting phosgene with an aromatic sulfocarboxylic
acid having ~he general formula
COOH
I (I) -
X ~ SO3H
wherein X is as stated above or an alkali metal salt or alkaline
earth metal salt of an aromatic sulfocarboxylic acid of the
general formula (I) in the presence of dimethylformamide. The
present inven~ion enables chlorosulfonylbenzoylchloride to be
produced economically and on industrial scale~ The present
invention also enables chlorosulfonylbenzoylchloride to be
produced in high purity and high yield. In the process of the ~-~
invention, both the carboxyl group and the sulfonic acid group -~
-2-
' ` :'
'
~5~
of the aromatic sulfocarboxylic acid or the salt thereof are
simultaneously chlorinated. In the process of the invention,
as shown by the following equations, dimethylformamide reacts
with phosgene by reaction (I) to form a reaction product (III).
The reaction product (III) serves as a chlorinating agent for
the aromatic sulfocarboxylic acid (a) or the alkali metal salt
of the aromatic sulfocarboxylic acid (b)(c) or (d) or the
alkaline earth metal salt of the aromatic sulfocarbo~ylic acid
(e)(f) and (g). The chlorination proceeds according to
reaction (2 ), (3 ) or (4) to produce the chlorosulfonylbenzoyl-
chloride (II) and to recover dimethylformamide.
Reaction (1):
-
(CH3 ) 2NCOH -~ COC12 ~~CH3 ) 2NCHC12 + C2 '~
( I I I )
Reaction (2):
COOH ~COCl
A/ + 2 (III) ~ A -~ 2 (CH3) 2NCOH + 2HCl
\ S03H \ S02Cl :
(a)
Reaction (3):
~ .
~ COOH
A ¦ COCl
(b) S03M ~ + 2 (III) ~A + 2 (CH3) 2NCOH + HCl -~ MCl
COOM ~ S2
\ S03H )
(c)
COOM ~ COCl
A/ + 2 (III) 7~ A + 2 (CH3) 2NCOH + 2MCl
\ S03M S2
(d)
,,, ,. , ,, ~, . ,, . ,,,, :
Reaction (4):
COOH COCl
¦ A/SO3 - 2 M ~ 4 (III)--i`2A + 4 (CH3) 2NCOH + 2HCl ~ M'C12
(e) \ SO2Cl
~ coo t M' / COCl
\ SO - + 1 (III) ~ 2A + 4 (CH3) 2NCOH + 2 M C12
3 2 M' S2
(f)
COO~ COCl
"Ml + 2 (III) ~A + 2 (CH3)2NCOH + M'C12
10 (g) SO3 S02Cl
In the above equations, A represents a benzene ring which may
be substituted with a halogen atom or a nitro group, M represents
an alkali metal atom and M' represents an alkaline earth metal
atom.
When the o-sulfocarboxylic acid or the metal salt
thereof wherein the sulfonic ac.id group is in the ortho position
relative to the carboxylic group is u~ed as a reactant in the
process of the invention, a mixture of o-chlorosulfonylbenzoyl-
chloride and a dichlorotolylsul~one i9 produced as shown in the
20following equation:
COCl
~3/S2Cl ': ., .
C IOOH .-
~ / (CH3)2NCOH
X~ I , ~,
~ COC12
C \ / Cl
X~ \o
It may not be necessary to separate and purify the
o-chlorosulfonylbenzoylchloride and the dichlorotolylsultone
in the mixture produced.
.. . .
s~
For example, in accordance with one aspect of the
process of the invention, phosgene reacts with the o-sulfobenzoic
acid or the alkali metal salt or alkaline earth metal salt of o-
sulfobenzoic acid in the presence of dimethylformamide. The
resulting reaction mixture of o-chlorosulfonylbenzoylchloride
and dichlorotolylsultone is mixed with an alcohol to esterify
the o-chlorosulfonylbenzoylchloride. The mixture of the ester of
o-chlorosulfonylbenzoylchloride and dichlorotolylsultone is
mixed with ammonia to produce the ammonium slat of o-sulfobenzimide.
The o-sulfobenzimide is useful as an intermediate in
producing medicines, (sweet for diabetics), food additives (sweet)
and agricultural chemicals and can be produced by treating the
ammonium salt of o-sulfobenzimide with a mineral acid.
The reaction sequence in the production of o-sulfoben-
zimide by the above described method is shown below.
Cl
~, ~SO/
ROH 2
Cl Cl
COOR ~ C
SO2Cl 1 /
1 NH3 2
~ C \
1 Mineral acid
O
11
~ ~ N - H
~ SO/
,. ,:
'
~5~
In the process of the invention, an aromatic sulfo-
carboxylic acid of the formula (I) or an alkali metal salt or
alkaline earth metal salt of such an aromatic sulfocarboxylic
acid is used as a reactant.
The sulfo~ic acid group and X in the formula (I) may each
be attached to the benzene ring at a desired position. X may
be a hydrogen atom, a nitro group or a halogen atom such as a
chlorine, bromine, iodine or fluorine atom.
The aromatic sulfocarboxylic acid (I) may be produced
by o~idation of toluenesulfonic acid or by sulfonation of an ~-
aromatic carboxylic acid. The alkali metal salts or alkaline
earth metal salts of aromatic sulfocarboxylic acid may be the
alkali metal salts (b) (c) and (d) in Reaction (3) or the
alkaline earth metal salts (e) (f) and (g) in Reaction (4) -
or a mixture thereof.
The alkali metal may be sodium or potassium. The alkaline
earth metal may be magnesium, calcium or barium.
The mono-metal salts (b) and (e) in the Reaction (3) and
(~) may be produced by salifying the aromatic sulfocarboxylic acid
(I)-
The dimetal salts (d) (f) and (g~ in the Reactions (3)
and (4) may be produced by neutralizing the aromatic sulfo-
carboxylic acid (I) with an alkali metal hydroxide or an alkaline
earth metal hydroxide.
The reaction of the aromatic sulfocarboxylic acid (I)
or the alkali metal salt or alkaline earth metal salt thereof
with phosgene in the presence of dimethylformamide is conveniently
conducted in an inert organic solvent. - -
The amount of dimethyl formamide used in the reaction `
is in preferably less than 1 mole, conveniently 0.01 - 0O3 mole,
and preferably 0.03 - 0.1 mole per 1 mole of the aromatic
sulfocarboxylic acid (I) or the salt thereof. It is possible,
-6-
`"~
31L~5~
though uneconomical, to use excess dimethyl formamide. The
amount of phosgene used i5 preferably more than the equivalent
(i.e. the stoichiometric amount). More preferably, the phosgene
is used in 5 - 20% excess. The phosgene can be directly
introduced in the reaction system or may be used dissolved in
an inert solvent such as carbon tetrachloride or toluene.
The organic inert solvent used in the reaction may be
an aliphatic hydrocarbon such as cyclohexane or n-hexane, a
halohydrocarbon such as chloroform, carbon tetrachloride, tri-
lO chloroethylene or tetrachloroethylene, an aromatic hydrocarbon
such as benzene, toluene, xylene or chlorobenzene, an ether
such as diethyl ether, dibutyl ether or dioxane, a ketone such
as acetone, methylethyl ketone or methylisopropyl ketone, a
nitrile such as acetonitrile or propionitrile, or an ester
such as ethyl acetate or butyl acetate.
The preferred reaction temperature and the reaction
time depend upon the aromatic sulfocarboxylic acid, the alkali
metal salt or alkaline earth metal salt thereof used as one
reactant and the rate at which phosgene is fed to the reaction
20 system. The reaction temperature is conveniently in the range
of 20 - 150C, preferably 40 - 100C.
The reaction time may be less than 8 hours and is
conveniently in the range of 5 - 7 hours.
In the process of the invention as shown in the
equations above, hydrogen chloride, an alkali metal chloride
or an alkaline earth metal chloride is produced as a by-product.
The hydrogen chloride can be easily recovered by using
an absorption tower. The metal chloride can be easily separated
by a conventional process.
Characteristics and advantages of the process of the
invention are described below.
(l) Both the carboxyl group and the sulfonic acid group
-7-
- . . , : ., . . : . , . - ., , , ~. . . .:
. ,. : . - ., : .
.. . . .. . . .
~ 5~tg~
of the aromatic sulfocarboxylic acid or the salt thereof are
simultaneously chlorinated under mild conditions. Accordingly,
it is unnecessary to remove and purify an intermediate reaction
mixture. The chlorosulfonylbenzoylchloride can be produced in high
yield in a single step without decomposition thereof.
(2) Chlorosulfonylbenzoylchloride wherein the chlorosulfonyl
group is bonded at any desired,(whether o-, m- or p-) position
relative to the chloroformyl group can be produced by suitably
selecting the sulfocarboxylic acid or salt thereof used as a
reactant
(3) The chlorosulfonylbenzoylchloride produced by the process
of the invention has high purity, and accordingly it is unnecessary
to purify it and it may be directly used as a starting material
in a subsequent step.
(4) Phosgene, which is economica:Lly and easily available,
is used as the chlorinating agent. Accordingly, the process
is industrially advantageous in comparison with conventional
processes using expensive chlorinating agents such as phosphorus
pentachloride, phosphorus oxychloride and thionylchloride.
The invention will be further illustrated by the following
examples.
EXAMPLE 1:
,
Into a four necked flask equipped with a stirrer, a
thermometer, a condenser and a dropping funnel, 20.2 g of o-
sulfobenzoic acid, 75 ml of carbon tetrachloride, and 0.22 g of
dimethylformamide were charged. The resulting mixture was ~ ~ -
stirred at 70 - 75C and 75 ml of a carbon tetrachloride solution
of phosgene (phosgene content of 30~ W/V) was added dropwise
thereto. The reactants were allowed to react for 7 hours. After -~
the reaction, nitrogen gas was injected into the flask to remove
excess phosgene therefrom. The reaction solution was concentrated
to remove the solvent and was distilled under a reduced pressure
-8-
,~' .
5~
to obtain 21.8 g of a distilled product having a boiling point
of 142 - 146C/4mmHg (yield 9102~).
Gas chromatography analysis confirmed that the distilled
product was a mixture of o-chlorosulfonylbenzoylchloride and
dichlorotolylsultone.
Pre~aration of o-sulfobenzimide
A 20 g of the mixture of o-chlorosulfonylbenzoylchloride
and dichlorotolylsultone was added dropwise to 40 ml of methanol
with stirring at 15 - 20C and the mixture was stirred for 1 hour
to cause the reactants to react. After the reaction, the
reaction mixture was added dropwise to 35 g of an 8% aqueous
ammonia solution with stirring at 25 - 25C, and the reaction
mixture was kept for one night. Then, methanol was distilled
off from the reaction mixture under reduced pressure and hydro-
chloric acid was added to the residual proudct to adjust its
pH to 1 - 2. Crystals were precipitated and the precipitated
crystals were filtered and washed with water and dried. The
dried crystals consisted of 14.3 g of white crystals of o-sulfo-
benzimide having a melting point of 227-228C (yield o~ 93%).
EXAMPLE 2:
In accordance with the process of Example 1, p-sulfobenzoic
acid was reacted with phosgene by mixing 20.2 ~ of p-sulfobenzoic
acid in 75 ml of carbon tetrachloride and 0.22 g of dimethyl-
formamide with 75 ml of a carbon tetrachloride ~olution of
phosgene (phosgene content of 30~ W/V).
After the reaction, excess phosgene was removed and the
reaction mixture was concentrated and the precipitated crystals
were filtered. The filtered crystals consisted of 22.0 g of
white crystals of p-chlorosulfonylbenzoylchloride having a
melting point of 56 - 58C (yield of 92%).
EXAMPLE 3:
Into a flask (four necked) equipped with a stirrer, a
"
_g_ ~"
thermometer, a condenser and a phosgene inlet, 24.0 g of the
monopotassium salt of m-sulfobenzoic acid.
COOH
~ 503K
150 ml of toluene, and 0.22 g of dimethylformamide were charged.
The mi~ture was stirred at 80C and 23 g of phosgene was
introduced during 4 hours to cause a reaction to occur. The
reaction was further continued under a reflux at 80 - 90C for -
3 hours with stirringO After the reaction, nitrogen gas was
injected into the flask to remove excess phosgene.
The reaction mixture was filtered to remove potassium ~ -
chloride, and the filtrate was condensed and distilled under
reduced pressure to obtain 22.8 g of a colorless liquid consisting
; of m-chlorosulfonylbenzoylchloride and having a boiling point
of 146 - 148C/5 mmHg. (yield of 95.2%)
EXAMPLE 4:
In accordance with the process of Example 3, the calcium
salt of p-sulfobenzoic acid ~
((~IOOC ~ - S3)2 Ca)
was reacted with phosgene by mixing 24.1 g of the calclum salt
of p-sulfobenzoic acid, 150 ml of toluene, 0.35 g of dimethyl-
formamide and 23 g of phosgene. After the reaction, nitrogen
gas was injected into the falsk to remove excess phosgene. The
reaction mixture was filtered to remove potassium chloride and
the filtrate was condensed and the precipitated crystals were
filtered and recrystallized from petroleum ether to obtain 21.3 g
of whike crystals of p-chlorosulfonylbenzoylchloride having a
melting point of 57 - 58C (yield of 89.0~).
Com~arative Test:
Into the four necked flask equipped with a stirrer, a ~-
' ~:
-10
' :
'" ''
: , . . ; . . , ~ , . , . .:
~0~35:~
thermometer and a condenser, 24.0 g of the monopotassium salt of
m-sulfobenzoic acid, and 20.8 g of phosphorus pentachloride were
charged and the mixture was s-tirred to cause reaction to occur,
at 100 - 110C for 5 hours. After the reaction, phosphorus
oxychloride was distilled off and the product was extracted with
ether and washed with water and dried. The ether solution was
condensed and dried to obtain 18~6 g of m-chlorosulfonylbenzoyl-
chloride. (yield of 78.0%).
EXAMPLE 5:
In accordance with the process of Example 4, the reaction
of aromatic sulfocarboxylic acids, alkali metal salt and alkaline
earth metal salts thereof with phosgene was conducted in inert
solvents in the presence of dimethylformamide as shown in Table 1,
to obtain various chlorosulfonylbenzoylchlorides. The results
are shown in Table 1.
.. . ... , ,,.. , ,... ,, ,.. ,. - . . . . .. ... ..
:. : ,, . , :: . . , , . : . ~ ............ . . . : : .
' ' ' ~
:
Table 1
Z Starting Material Amount Solvent Amount React. React.
. of & of Temp. Hour
Compound Amount Phosgene Amount DMF (C) (hr.)
X (g) (g) (ml) (g)
..
COOH
~ Chloro-
1 ~ SO3Na25.923.0benzene 0O3 80 6
_ ~1 . ~ __ .. _ .
2 j \ 30.4 23.5 Xylene 0-3 go 7
_ COOK - _ _ _ _
SO3K
Propio-
3 ~ 35.7 22.0 n:itrile 0.25 80 7
Br
_ ....... _ . . , .. : '
COOK
SO3K Meetthhyll~
~ ~ ~N ~ J _ ~ ~ 0 4 1 1~ L~ :~
Note: DMF = Dimethylformamide
'
' :
.
. ' ':
- ~2 ~:
. . .. . . .. . .
,
:, . `, , .- , . :. ~
Tabl e 1 Con t ' d
-
~?rc~duct
~t ¦ ~ c~ (S) ~ Amounc Yield i m p;
11 ~3~ 125.4 93.0140-42
__--rOCI ~ . _
~ 2 ~ ~ 24.0` ~ 88.0 40-42
-COCI -Cl~ cl r ~-
¦ 3 [ ~ + ~ ~/ /O
__ _ _ ___ ~ _ _ : '
COCl N2 \ ~
~S02Cl ~C ~
4 ~W W\3 2 2 5 . 3 8 9, O 51- 5 7
L
: . ' .
:~ 3 ~:
,.
