1. Process for the preparation of 2-methoxy-4-(N-t-butylaminocarbonyl) beinzenesulfonyl chloride by sulfonating m-hydroxybenzoic acid, methylating the hydroxy group of the resulting sulfonic acid or its salt, transforming the carboxylic acid group and the sulfonic acid group to acid chloride groups and reacting the 4-chlorosulfonyl-3-methoxy-benzoyl chloride with t-butylamine, which comprises carrying out the sulfonation of the 3-hydroxy-benzoic acid of the formula II II With 96% sulfuric acid, separating the resulting 3-hydroxy-4-sulfobenzoic acid of the formula III in the form of its salt of the general formula IV, - wherein Z stands for alkali metal or ammonium group-, methylating the compound of the general formula IV IV. 9 in the presence of a phase transfer catalyst at a pH value of about 11.5, transforming the 3-methoxy-4-sulfobenzoic acid mono salt of the general formula V. v. and reacting the compound of the formula VI - wherein the meaning of Z is as defined above - to the acid chloride of the formula VI, with t-butylamine used in equimolar amount or in a small excess, in the presence of an acid binding agent, in aprotic solvent, at low temperature.

2. Process as claimed in claim 1 wherein the sulfonation reaction is carried out with excess amount of 96% sulfuric acid, using the sulfuric acid also as the solvent of the reaction.

3. Process as claimed in claim 2 wherein the reaction is carried out at a temperature between 60°C and 120°C, preferably at 90°C. 10

4. Process as claimed in claim 1, wherein the compound of the formula IV IV. is separated in the form of its sodium, potassium or ammonium salt, preferably in the form of its potassium salt.

5. Process as claimed in claim 1 the phase transfer catalyst is tetrabutylammonium hydroxide or trimethylben2ylammonium hydroxide or the salts thereof, preferably tetrabutylammonium chloride or trimethylbenzylammonium chloride.

6. Process as claimed in claim 1 comprises carrying out the methylation of the compound of the general formula IV IV. wherein the meaning of Z is as defined in claim 1 in water or in the mixture of water and a water-immiscible solvent.

7. Process as claimed in claim 6 comprises using as water immiscible solvent toluene, xylene or dichloromethane. 11

8. Process as claimed in claim 1 wherein the compound of the general formula V is separated in the form of its sodium, potassium or ammonium salt, preferably in the form of its potassium salt.

9. Process as claimed in claim 1, wherein acid binding agent is trialkylamines, dialkylanilines, terciary-alkylamines, preferably tercbutylamine.

10. Process as claimed in claim 1, wherein the aprotic solvent is chlorinated hydrocarbons, such as dichloromethane, dichloroethane, chloroform; acetonitrile or acetone, preferably dichloromethane or acetone.

11. Process as claimed in claim 1, wherein the reaction of 3-methoxy- 4-chlorosulfonyl-benzoyl chloride with t-butylamine is carried at a temperature between (-40)°C and room temperature, preferably between (-5)°C and (-10)°C. 12 Dated this 20th day of December, 2001.

SANOFI-SYNTHELABO, of 174, Avenue de France, F-75013 Paris, France,

The following specification particularly describes the nature of the invention and the manner in which it is to be performed:-


The present invention relates to a process for the preparation of 2-methoxy-4-(N-t-butylaminocarbonyl) - benzenesulfonyl chloride.
2-memoxy-4-(N-t-butylaminocarbonyl)benzenesulfonyl chloride is an important building block to the angiotensine antagonistic compound SR. 121463. Its preparation is described in patent application WO 9715556; Because of the applied materials and reactions, the process described in the above patent application is appropriate to prepare the material only in laboratory scale, in low yield, and by involving several purification steps. The proce&s'ls the following: it starts from 3-methoxy-4-nitrobenzoic acid, this is transformed via the acid chloride into the acylamide, the nitro group is then reduced and the amine group is exchanged in a Sandmeyer-type reaction, performed in acetic acidic medium using great excess of sulfur dioxide. The weakest part of the synthesis is the exchange of the amino group for chlorosulfonyl group. The reaction is difficult to control, the main reaction is accompanied by a series of side-reactions, thus a severely contaminated product is obtained in only about 50% yield.
Preparation of 2-methoxy-(4-aminocarbonyl)benzenesulfonamide and of 4-chlorosulfonyl-3-methoxybenzoyl chloride is known from the literature from the work of SHAH (J. Chem. Soc. 1930: 1293). .
Our new process uses the basic elements of the above scientific work of 1930, but modifies it into a process, which can be technically realized and wich widely satisfies the environmental, economical and technological requirements of the late 20th century.
Our process contains the following findings, compared to the method of SHAH: Sulfonation of the m-hydroxybenzoic acid, is performed - instead of oleum, which is dangerous and difficult to treat - with 96% sulfuric acid, which also serves as the solvent of the reaction. After pouring the reaction mixture, onto ice, the product is obtained as a precipitate which can be filtered off, which is pure, free of isomers.
AMENDED SHEET


The yield of the reaction is around 90%The sulfonic acid is isolated in the form of its potassium salt.
In the method described in the literature the methylation step was carried out using 18-fold excess of dimethyl sulfate, which was added in small portions subsequently with high amount of 25 % potassium hydroxide. We have, however, found that even a small excess of dimethyl sulfate is sufficient if higher temperature is applied, the pH is maintained above 11.5 and a phase transfer catalyst (PTC) is used in aqueous medium or in a two-phase mixture. After isolating the product in the form of its salt, without further purification, a product of analytical purity (96-99%) can be obtained, in a yield as much as 90%.
Reacting the 3-methoxy-4-fobenzoic acid mono-potassium salt with an inorganic acid halogenide the 4-chlorosulfonyl-3-methoxybenz'6yl chloride is obtained. To our surprise we have found that at lower temperature, in an appropriate solvent the -butylamine reacts selectively with the aromatic acid chloride. Thus, the desired 2-methoxy-4-(N-t-butylaminocarbonyl)benzenesulfonyl chloride is obtained in 92% yield, with a purity of 96%, so it can be used without further purification for the synthesis of drug substances.
In accordance with the above, the subject of our invention is a process for the preparation of 2-methoxy-4-(N-t-butylaminocarbonyl)benzenesulfonyI chloride by sulfonating m-hydroxybenzoic acid, methylating the hydroxy group of the resulting sulfonic acid or of its salt, transforming the carboxylic acid group and the sulfonic acid group into acid chloride groups and reacting the 4-chIorosulfonyI-3-methoxybenzoyl chloride with 7-butylamine, which comprises carrying out the sulfonation of the 3-hydroxy-benzoic acid of the formula II

3 AMENDED SHEET


with 96% sulfuric acid, separating the 3-hydroxy-4-sulfobenzoic acid of the
formula III, .


in.

thus obtained in the form of its salt of the general formula IV


IV.

- wherein Z stands for alkali metal or ammonium group -, methylating the compound of the general formula IV


IV.

in the presence of a phase transfer catalyst at a pH above 11.5, Transforming the 3-
i ■
methoxy-4-sulfobenzoic acid mono salt of the general formula V

- wherein the meaning of Z is as defined above - to the acid chloride of the formula VI
-4-
AMENDED SHEET



C0C1
VI.

and reacting the compound of the formula VI thus obtained with r-butylamine, used in equimolar amount or in a small excess, in the presence of an acid binding agent, in aprotic solvent,^! low,temperature. (See^"Figures 1 and 2").
According to a preferred embodiment of the invention the sulfonation is carried out with excess amount of 96% sulfuric acid, using the sulfuric acid also as the solvent of the reaction. The reaction is carried out at a temperature between 60°C and 120°C, preferably at 90°C. The compound of the formula IV


IV.

is separated in the form of its sodium, potassium or ammonium salt, preferably in the form of its potassium salt. As for phase transfer catalyst tetrabutylammonium hydroxide (TEBA) or trirnethylbenzylammonium hydroxide or their salts, preferably tetrabutylammonium chloride or trirnethylbenzylammonium chloride are used. Methylation of the compound of the general formula IV

- wherein the meaning of Z is the same as defined above - is carried out in water or in the mixture of water and a water-immiscible solvent. As for water-immiscible solvents toluene, xylene, or dichloromethane can be used. The compound of the general formula V
5
AMENDED SHEET


is separated in the form of its sodium, potassium or ammonium salt, preferably in the form of its potassium salt.
As for acid binding agent trialkylamine, dialkylaniline, tertiary-alky 1 amine, preferably tert.-butylamine is used. As for an aprotic solvent chlorinated hydrocarbons, such as dichloromethane, dichloroethane, chloroform; or acetonitrile or acetone, preferably dichloromethane or acetone is. used. The reaction of the 3-methoxy-4-chlorosuIfonylbenzoyl chloride with r-butylamine is carried out at a temperature between -40°C and room temperature, preferably between (-5)°C and (-10)°C
The invention is further demonstrated by the following examples, without limiting the claims to the examples.
Examples
•Example 1.
Into 550 g (300 cm3) of 96% sulfuric acid 80 g (0.58 mol) of 3-hydroxybenzoic acid is added under stirring at room temperature. The resulting brown solution is heated to 90 °C and kept at that temperature. The thick, but treatable mass is poured onto crushed ice, the precipitate is filtered off, washed with ice-cold water. The wet product is dissolved in hot water, clarified with charcoal and its pH is adjusted to 3-3.5. After cooling the precipitated white crystals are filtered off, washed subsequently with water and acetone, and dried. 140g of 3-hydroxy-4-sulfobenzoic acid mono-potassium salt monohydrate is obtained. It can be used without purification for the next step. Mp.:>300°C. Yield: 87.9%.
AMENDED SHEET

Example 2.
To the solution of 11.2 g (0.2 mol) of potassium hydroxide in 50 cm3 of distilled water 2.7.5 g (0.1 mol) of 3-hydroxy-4-sulfobenzoic acid potassium salt monohydrate is added and in that solution 0.5 g of TEBA is dissolved. The solution is heated to 50 °C and dropwise, under vigorous stirring to it the solution made of 25 cm3 (33.25 g, 0.26 mol) of dimethyl sulfate, 17.4 g (0.31 mol) of potassium hydroxide and 60 cmJ of water is added, while the pH is maintained between 11.5-12,5. The reaction mixture is kept at 50 °C, and the pH is checked regularly. The solution is clarified with charcoal, filtered, the pH is adjusted to 2 with hydrochloric acid, then it is cooled in refrigerator overnight.
The precipitated crystals are filtered off, washed with distilled water and dried to ' constant weight: 26.7 g (92.7%).
Example 3a.
To 105 cm3 (172.7g5 1.128 mol) of phosphoryl chloride 57.6 g (0.2 mol) 3-methoxy-4-sulfobenzoic acid potassium salt monohydrate is added under stirring and the reaction mixture is heated to 110-120 °C from oil bath. Hydrogen chloride gas evolution ceases within 3 hours. The reaction is kept at that temperature for an additional 1 hour, then 500 g crushed ice is added to it. The precipitated white crystals are filtered off, washed with ice-cold water, dried in vacuum. 45-49 g of 3-methoxy-4-chlorosulfonylbenzoyl chloride is obtained. Mp.: 86-88 °C, yield: 84-91%.
Example 3b.
To 105 cm3 (172.7g, 1.128 mol) of phosphoryl chloride 57.6 g (0.2 mol) of 3-methoxy-4-sulfobenzoic acid potassium salt monohydrate is added under stirring and the reaction mixture is heated to 110-120 °C from oil bath. Hydrogen chloride gas evolution ceases within 3 hours. The reaction is kept at that temperature for an additional 1 hour, then 500 g crushed ice is added to it. The reaction mixture is
AMENDED SHEET

extracted several times with dichlorometttane. The united organic phase is dried. After assay determination the solution is directly used for the next step.
Example 3c. -
137 g of dimethylformamide is cooled to -5 °C, 235 g of phosphoryl chloride is added to it. The mixture is allowed to warm up then under stirring 125 g of 3-methoxy-4-suIfobenzoic acid is added to it in portions. It is then heated to 40-45 °C, kept at that temperature for 1 hour, then poured onto 550 g of crushed ice. The precipitate is filtered off, washed thoroughly with water, and dried. 110 g of product is obtained, its quality is similar to that of the product obtained in Example 3 a.
Example 4.
AMENDED SHEET
The dichloromethane solution of the 49 g (0.182 mol) 3-methoxy-4-chlorosulfonyl-benzoyl chloride - obtained as written in Example 3b - is cooled to -10 °C, and to it dropwise, under vigorous stirring, in a period of 50-60 minutes, the -10 °C solution of 26.7 g (0.364 mol) of t-butylamine in 260 cm of dichloromethane is added. The mixture is then poured onto 1000 cm3 ice-water containing 40 cm3 of 1M hydrochloric acid. The dichloromethane phase is separated, washed with 2x1000 cm3 ice-water, dried over sodium sulfate, clarified with charcoal, filtered, and evaporated. 51.0 g of 2-methoxy-4-(N-?-butylaminocarbonyl)benzenesulfonyl chloride is obtained. Yield: 92%. Mp.: 145-149 °C. Assay: 95-96% (by HPLC,


WE CLAIM:
1. Process for the preparation of 2-methoxy-4-(N-t-butylaminocarbonyl) beinzenesulfonyl chloride by sulfonating m-hydroxybenzoic acid, methylating the hydroxy group of the resulting sulfonic acid or its salt, transforming the carboxylic acid group and the sulfonic acid group to acid chloride groups and reacting the 4-chlorosulfonyl-3-methoxy-benzoyl chloride with t-butylamine, which comprises carrying out the sulfonation of the 3-hydroxy-benzoic acid of the formula II

II
With 96% sulfuric acid, separating the resulting 3-hydroxy-4-sulfobenzoic acid of the formula III

in the form of its salt of the general formula IV, - wherein Z stands for alkali metal or ammonium group-, methylating the compound of the general formula IV


IV.

9

in the presence of a phase transfer catalyst at a pH value of about 11.5, transforming the 3-methoxy-4-sulfobenzoic acid mono salt of the general formula V.


v.

and reacting the compound of the formula VI
- wherein the meaning of Z is as defined above - to the acid chloride of the formula VI,


with t-butylamine used in equimolar amount or in a small excess, in the presence of an acid binding agent, in aprotic solvent, at low temperature.
2. Process as claimed in claim 1 wherein the sulfonation reaction is carried out with excess amount of 96% sulfuric acid, using the sulfuric acid also as the solvent of the reaction.
3. Process as claimed in claim 2 wherein the reaction is carried out at a temperature between 60°C and 120°C, preferably at 90°C.
10

4. Process as claimed in claim 1, wherein the compound of the formula IV


IV.

is separated in the form of its sodium, potassium or ammonium salt, preferably in the form of its potassium salt.
5. Process as claimed in claim 1 the phase transfer catalyst is
tetrabutylammonium hydroxide or trimethylben2ylammonium hydroxide
or the salts thereof, preferably tetrabutylammonium chloride or
trimethylbenzylammonium chloride.
6. Process as claimed in claim 1 comprises carrying out the
methylation of the compound of the general formula IV


IV.

wherein the meaning of Z is as defined in claim 1 in water or in the mixture of water and a water-immiscible solvent.
7. Process as claimed in claim 6 comprises using as water immiscible solvent toluene, xylene or dichloromethane.
11

8. Process as claimed in claim 1 wherein the compound of the general formula V

is separated in the form of its sodium, potassium or ammonium salt, preferably in the form of its potassium salt.
9. Process as claimed in claim 1, wherein acid binding agent is
trialkylamines, dialkylanilines, terciary-alkylamines, preferably
tercbutylamine.
10. Process as claimed in claim 1, wherein the aprotic solvent is
chlorinated hydrocarbons, such as dichloromethane, dichloroethane,
chloroform; acetonitrile or acetone, preferably dichloromethane or
acetone.
11. Process as claimed in claim 1, wherein the reaction of 3-methoxy-
4-chlorosulfonyl-benzoyl chloride with t-butylamine is carried at a
temperature between (-40)°C and room temperature, preferably
between (-5)°C and (-10)°C.
12
Dated this 20th day of December, 2001.