US2946815A

US2946815A - 2-sulfamoylbenzoic acid esters

Info

Publication number: US2946815A
Application number: US798582A
Authority: US
Inventors: Glenn H Hamor
Original assignee: Individual
Current assignee: Individual
Priority date: 1959-03-11
Filing date: 1959-03-11
Publication date: 1960-07-26
Anticipated expiration: 1977-07-26

Description

Z-SULFAMOYLBENZOIC ACID ESTERS Glenn *H. Humor, University Park, Los Ang'eles 7, N Drawing. Filed Mar. 11, 1959, Ser. No. 798,582

1 Claims. c1. 260 470) Formula I when R; and R represent hydrogen or lower alkyl groups having Ho 6 carbon atoms and R represents a branched alkyl group having 3 to 6carbon atoms, a cycloalkyl group having 4 to 6carbon atoms or an unsaturatedalkyl grouph'aving 3 to 6 carbon atoms.

,Advantageous compounds of thisinvention are repre-- sented by the following structural formula:

Formula II S QeNHa -C O 0 R:

when R represents a branched alkyl group having, 3 to 6 carbon atoms. I

A particularly advantageous and preferred compound of this invention is isopropyl 2-sulfamoylbenzoate which possesses superior muscle relaxant activity with a minimum of side efiiects.

Surprisingly the compounds of this invention have been iound to have a higher order of muscle relaxant and anticonvulsant activity than the closest compounds of the prior art. For instance, the prior art compound most closely related structurally to the Z-sulfainoylbenzoate derivatives of this invention is ethyl 2 sulfamoy'lbenz'oate whosestructure is represented by Formula I when R; and R are hydrogen and R is ethyl iE. Shrader, I.

v Prakt. Chem., 95, 312-26 (1917); abstract, J. Chem.

Soc, 112, I, 709-710 (1917)]. The Shrader reference does not disclose any pharmacodynamic activity for this ethyl ester. The compounds of this invention have been unexpectedly found to have a significant level of muscle relaxant activity with a low level ofside effects while the prior art compound is much less active. For instance, in a standard test for muscle relaxant activity, namely protection against strychnine convulsions in mice, the ED for the. ethyl ester of the prior art compound is 99 rug/kg. While the ED forthe compound of this inventionmost closely related structurally, namely the i sois indeed surprising and unexpected.

propyl ester, is SOmgd/kg, at least twice as'a'ctive;

" nited States Patent Patented July 26, 1960 2 'Ihecompounds of invention are prepared according to the following synthetic procedures:

' lroee'dure '1 Procedure 3 According to Procedure 1 which is particularly useful for pre aring Branched alkyI esters of N-u'nsubstituted nlfemeylbenzoic acid, fsaccharin is treated with an er:- e'ess or "the appropriate alcohol in the presence of a mineral acid such as hydrochloric or sulfuric acid. The reaction mixture is, heated at from about 60 C. to the reflux temper ture of' the alcohol for a period of about 16 to about 72 ho rs. Filterin the reaction mixture, concentrating the filtrate, dissolving the residue in organic solvent such as ethyl acetate or ether, washing the organic solution with a dilute aqueous alkaline solution such as sodium or potassium bicarbonate solution and with water, drying'with a drying agent such as anhydrous inagnes'ium sulfate, filtering and concentrating in vacuo gives a solid material which is' conveniently re crystallized from aqueous alcohol such as methanol oiisopropanol to give the compounds of this invention. 7

According to. Procedure 2 which is particularly ad= vant'a'geous in the preparation of compounds in which the esterg'roup is unsaturated and/or the sulfamoyl group has one or two alkyl substituents, 2-sulfobenzoic anhy= dride (or acidlis converted to its dichloride by treat= ment with an excess of a clilorinating agent such as phosphorus trichlor ide, thionyl chloride or, preferably, phos phorus pentaehloride. veniently at reflux temperature for about two to aboutsix hours. crude 2-chlorosulfonylbenzoyl chloride as the residue: This dichloride is'heated with an excess of the appro priate alcohol at about '40 to about 55C. for about 16 to about 32 hours. 'Ihe,exces s alcohol is removed in acid 'eatment orthis 2 -chlorosulfonyl compound in an organic solvents'uchas ether or benzenew'ith a geese v 6f Oi Hi1 alkylamine and allflwing the mixture- The reactants are heated, con- 7 The reaction mixture is concentrated leaving" 7 to stand for about 24 to about 48 hours yields, upon filtration and concentration of the mixture, the 2-sulfamoylbenzoates of this invention.

9 According to Procedure 3 whichis'a particularly advantageous procedure for the preparation of cycloakyl esters of 2-sulfamylbenzoic acid in which the sulfamyl group may optionally have alkyl substituents, 2-sulfobenzoic anhydride is treated with an excess of the appropriate alcohol at about 35 to about 50 C; for approximately 4 to 8 hours. Removal of the excess alcohol in vacuo leaves, as the residue, the 2-sulfobenzoate which -is treated With a chlorinating agent such as phosphorus trichloride, thionyl chloride or, preferably, phosphorus pentachloride. The reactants are heated, conveniently at reflux temperature, for about two to about four hours Concentration of the reaction mixture gives, as. the residue, the-ester of 2- chlorosulr'onylbenzoate which is treated with an excess'of ammonia or an alkylamine in an organic solvent such as ether or benzene. The reaction mixture is allowed to stand for'about 24 to about 48 hours, then worked up, conveniently, by filtering and concentrating the filtrate to give the 2-sulfamoylbenzoate of this invention.

The following examples are not limiting but are illustrative of compounds of this invention and will serve to makefully apparent all the compounds embraced by the general formula given above.

Example 1 A suspension of 45.8 g. of saccharin in,200 of isopropanol immersed in an ice bath is saturated with hydrogen chloride. The mixture 'is heated in afpres'sure bottle at 70 C. for three days, then filtered. The'filtrate is concentrated in vacuo and the residue is dissolved in ethyl acetate and washed with 5% aqueous sodium bicarbonate and with water. The solution is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a white solid which is recrystallized from aqueous methanol to give isopropyl 2-sulfamoylbenzoate, M.P., 7275 C.

Example 2 A mixture of g. of saccharin, 20 drops of concen- 4 7.0 g. of dimethylamine in other solution. The resulting mixture is allowed to standfor 36 hours, then filtered. The excess dimethylamine is removed in vacuo. The ethereal residue is washed with water, dried and stripped of solvent to give isopropyl 2-(N,N-dimethylsulfamoyl) benzoate, an orange viscous oil.

Example b' To an ether solution of 5.0 g. of isopropyl Z-chlorosulfonylbenzoate, prepared as in Example 4, is added 5.0

g. of hexylarnine in ether solution. The resulting mixture is allowed to stand for 36 hours, then filtered. The mixture is concentrated in vacuo. The residue is isopropyl 2- (N-hexylsulfamoyl) -benzoate.

Example 6 An ethereal solution of 5.0 g. of dihexylamine is added to an ether solution of 5 .0 g. of isopropyl 2-chlorosulfonylbenzoate, prepared as in Example 4. The resulting solution is allowed to stand at room temperature for 36 hours. Working up as in Example 5 yields isopropyl 2(N,N-dihexylsulfamoyl) -benzoate.

1 Example 7 Example, 8

Ten grams of- 2-chlorosulfonylbenzoyl chloride, prepared as in Example 3, is heated at C. with ml. of allyl alcohol for 4 hours. The excess allyl alcohol is removed in vacuo. The residue is dissolved in etherand trated sulfuric acid and 200 ml. .of isobutyl alcohol is refluxed for 16 hours. the filtrate is concentrated in vacuo. The residue is'taken up in ethyl acetate, washed with 5% aqueous sodium bicarbonate solution and with water. .The ethyl acetate solution is, dried over magnesium sulfate, filtered" and concentrated in vacuo. The white solid residue. is recrystallized from aqueous methanol to give isobutyl 2-sulfamoylbenzoate.

Example 3 A mixture of 50.0 g. of 2-sulfobenzoic anhydride and 100.0 g. of phosphorus pentachloride is refluxed for two hours. Low boiling material is removed in vacuo, leaving as the residue crude 2-chlorosulfony1benzoy1 chloride.

Five grams of this dichloride is heated in 50 m1. of isopropanol at 50 C. for 2 hours. The excess alcohol is removed in vacuo. The residue, crude isopropyl Z-chloro- A mixture'of 10.0 g. of 2-chlorosulfonylbenzoyl chloride, prepared as in Example 3, and 75 ml. of isopropanol is heated at 45 C. for 24 hours. The excess alcohol is removed in vacuo. The residue, crude isopropyl 2-chlorosulfonylbenzoate, is dissolved inether and then added to The reaction mixture is'filtereid and added to 3.0 g. of ammonia in either. The resulting mix-. ture is allowed to stand at room temperature for 36 hours, filtered and concentrated to give as the oily residue, allyl 2-sulfamoylbenzoate.

Example 9 A mixture of 5.0 g. of Z-chlorosulfonylbenzoyl chloride, prepared as in Example 3, and 25 ml. of propargyl alcohol is heated at 50 C. for 4 hours.- The excess alcohol is removed in vacuo and the residue is taken up in ether. This ethereal solution is added to 2.0 g. of ammonia in ether and the resulting solution is allowed to stand at room temperature for 36 hours. Filtration and concentration of the filtrate gives propargyl 2-sulfamoylbenzoate.

Example 10 j Example 11 A-mixture of 5.0 g. of 2 -chlorosulfonylbenzoyl chlo' ride, prepared as in Example 3, and 50 ml. of S-hexen-l-ol is heated at 50 C. for 6 hours. The excess alcohol is removed in vacuo and the residue is dissolved in ether and added to 50 ml. of an ether solution saturated with ammonia. The resulting mixture is allowed to stand for 36 hours, then filtered. The filtrate is concentrated to give as the residue S-hexenyl l-sulfarnoylbenzoate.

Example 12 Three grams of o-sulfobenzoic anhydride are dissolved in 15 m1. of cyclobutanol by gentle warming. The solution is hQ lQQ at 40 C, for six' hours, then the excess cyclobutanol is removed in vacuo. The resulting oily solid, cyciohutyl 2-sullobenzoate, is heated at refiux with 5.0 g. oi" phosphorus pentachloride for three hours. The phosphorus oxychloride which forms is removed in vacuo and the residue dissolved in ether and washed with ice water. The ethereal solution of cyclobutyl 2-chlorosulfonylbenzoate is treated with 5.0 g. of anhydrous ammonia. The resulting mixture is allowed to stand at room temperature for 24 hours, then filtered. The filtrate is evaporated leaving an oil which solidifies on treatment with water. Recrystallization of this solid material from aqueous isopropanol gives cyclobutyl 2-sulfamoylbenzoate as a white solid.

Example 13 A mixture of 3.0 g. of o-sulfobenzoic anhydride and ml. of cyclopentanol is heated at 40 C. for six hours. The excess alcohol is removed in vacuo to give, as the residue, cyclopentyl 2-sulfobenzoate which is then re- Example 14 Four grams of o-sulfobenzoic anhydride is heated with i 20 ml. of cyclohexanol at 40'for.six hours. The excess cyclohexanol is removed in vacuo to give, as the residue, cyclohexyl Z-sulfobenzoate which is refluxed with 7.0 g. of phosphorus pentachloride for three hours. The phosphorus oxychloride which forms is removed in vacuo.

The residue is dissolved in ether and Washed with ice A mixture of 35.0 g. of saccharin, 20 drops of concentrated sulfuric acid and 200 ml. of sec-butyl alcohol is refluxed for 16 hours. The reaction mixture is filtered and concentrated in vacuo. The residue is dissolved in ethyl acetate, washed with 5% aqueous sodium bicarbonateand with water. Drying the ethyl acetate solution over magnesium sulfate, filtering, concentrating in vacuo and recrystallizing the residue from aqueous methanol gives secbutyl Z-sulfarnoylbenzoate.

Example 16 2 Five grams of o-sulfobenzoic anhydride are dissolved in 25 m1. of t-butyl alcohol by gentle warming. Heating the solution at .45 C. for six hours and removing the excess t-butanol in vacuo gives, as the residue, t-butyl 8 O aN in which R and R are members selected from the group consisting of hydrogen and lower alkyl and R is a member selected from the group consisting of a branched alkyl group having from 3 to 6 carbon atoms, a cycloalkyl group having from 4 m6 carbon atoms and an unsaturated acyclic 'hydrocarbon g'roup having from .3 to 6 carbon atoms. H

2. A chemical compound having the structural formula:

in which R is a branched alkyl group having from 3 to 6 carbon atoms.

3. Isopropyl 2-sulfamoylbenzoate.

4. Tertiary butyl 2-sulfamoylbenzoate.

5. Secondary butyl 2-sulfamoylbenzoate.

6. Allyl 2-sulfamoylbenzoate.

7. Proparg'yl 2-sulfamoylbenzoate.

References Cited in the file of this patent UNITED STATES PATENTS Seifert May 24, 1898 OTHER REFERENCES Beilstein: XI, 378 (1928).

Claims

1. A CHEMICAL COMPOUND HAVING THE STRUCTURAL FORMULA: