CA2391978A1 - Process for the preparation of sulfamides - Google Patents
Process for the preparation of sulfamides Download PDFInfo
- Publication number
- CA2391978A1 CA2391978A1 CA002391978A CA2391978A CA2391978A1 CA 2391978 A1 CA2391978 A1 CA 2391978A1 CA 002391978 A CA002391978 A CA 002391978A CA 2391978 A CA2391978 A CA 2391978A CA 2391978 A1 CA2391978 A1 CA 2391978A1
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- optionally substituted
- alkyl
- formula
- phenyl
- aryl
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- 0 *NS(N(*)*)(=O)=O Chemical compound *NS(N(*)*)(=O)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/34—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfuric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/04—Preparation of sulfones; Preparation of sulfoxides by reactions not involving the formation of sulfone or sulfoxide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/36—One oxygen atom
- C07D263/38—One oxygen atom attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
A process for the production of an aryl sulfamide having formula (I), in whi ch R1, R2 and R3 are each hydrogen, alkyl, cycloalkyl or aryl, provided that at least one of R1, R2 and R3 is aryl,which comprises reacting a compound of formula (II) where R4, R5, R6, R7, R8 and R9 are each hydrogen, alkyl or ary l, and n is 0 or 1, with an amine of the formula R2R3NH (III), in the presence of a strong base.
Description
PROCESS FOR THE PREPARATION OF SULFAMIDES
This invention relates to a process for producing sulfamides, and to novel intermediates used in the process.
Sulfamides are conventionally prepared by the use of strongly electrophilic reagents such as sulfamoyl chloride, sulfonyl dichloride, phosphorus oxychloride or phosphorus pentachloride. Belgian patent 667.311 discloses a method of making sulfamides employing an N-alkyl sulfamoyl chloride. However, all such reagents involve aggressive synthetic methods, and indeed can be inconvenient or dangerous in their practical, industrial, application.
The invention provides a process for the production of aryl sulfamides that avoids the use of the above hazardous materials and conditions, and gives a high yield.
The process of the invention is for the production of an aryl sulfamide having the formula O
R
N- S -N
~ \
~ ~ R3 R
O
in which R1, R2 and R3 are each hydrogen, alkyl, cycloalkyl or aryl, provided that at least one of R1, R2 and R3 is aryl, which comprises reacting a compound of the formula O O
N- S -N
~~ ~R$
R ~ R4 ~ ~ R' R5 Rs n where R4, R5, R6, R~, R8 and R9 are each hydrogen, alkyl or aryl, and n is 0 or 1, with an amine of the formula R2R3NH (III), in the presence of a strong base.
The reaction can be carried out at ambient temperature or at the reflux temperature of the solvent in which the reaction is performed, and generally the temperature of the reaction is chosen in the range of from 0~ C. to 100~ C. A polar, aprotic, solvent is preferred, as, for example, acetonitrile.
A strong base is required for the reaction to proceed, and examples include triethylamine, 1,8-diazabicyclo[5,4,0]under-7-ene(DBU), 1,5-diazabicyclo[4,3,0]non-5-ene(DBN) or 1,4-diazabicyclo[2,2,2]octane(TED). Preferably from one to three equivalents of base are employed.
In the above formulae, an alkyl group can be substituted or unsubstituted, and is preferably C1_6 alkyl, being branched or unbranched. A cycloalkyl group preferably containing from 3 to 9 carbon atoms, and may, for example, be substituted by one to three alkyl groups such as methyl. When substituted, the alkyl group can be substituted by halo, C1-6 alkoxy, C3_9 cycloalkyl, optionally substituted phenyl or optionally substituted heteroaryl. An aryl group can be, for example, naphthyl or, preferably, phenyl, and can be substituted or unsubstituted. A substituted aryl group is substituted with one or more, preferably one to three, substituents selected from, for example, an electron-donating substituent such as, for example, C1_4 alkyl, C1_4 alkoxy, C1_4 alkylthio, hydroxy, amino, or an electron-withdrawing substituent such as, for example, carboxy, nitro, cyano, trifluoromethyl, halo, C1_4 alkyl-SO- and C1_4 alkyl-S02-.
Preferably, R1, R2 and R3 are selected from hydrogen, C1_6 alkyl and optionally substituted phenyl. In formula (II) above, R4, R5, R6, R~, R8 and R9 are preferably hydrogen, and n is preferably 0. It may, nevertheless, be desirable to employ a terminal moiety in which one or more of R4 to R9 is alkyl or aryl, for instance, in the preparation of stereoisomers.
It has been found that the nature of the substituent on an aryl group, for example a substituted phenyl, can surprisingly affect the reaction. Electron-donating substituents assist the reaction. Thus it is preferred that the substituent R1 is optionally substituted alkyl or phenyl optionally substituted with an electron-donating substituent, and a preferred process is one for the preparation of a compound of the formula O
~
N- S -N
/ \
( ) R3 R
O
in which R1 is alkyl or phenyl optionally substituted with an electron-donating substituent, and R2 and R3 are each hydrogen, alkyl or optionally substituted phenyl, provided that R1 is phenyl optionally substituted with an electron-donating substituent and/or R2 is optionally substituted phenyl, which comprises reacting a compound of the formula O O
~o N- S -N
R O
(IV) with an amine of the formula R2R3NH, in the presence of a strong base. A particularly preferred process is one for the production of a compound of the above formula in which R1 is C1-6 alkyl or phenyl optionally substituted with an electron-donating substituent, R2 is C1-6 alkyl or optionally substituted phenyl, and R3 is hydrogen, provided that R1 is phenyl optionally substituted with an electron-donating substituent and/or R2 is optionally substituted phenyl.
Compounds of formula (IV) where R1 is phenyl optionally substituted with an electron-donating substituent are novel, with the exception of compounds in which R1 is 3-methylbutyl or phenyl, and these novel compounds are included as an aspect of the present invention. They are stable, mainly crystalline solids, which can be readily isolated from the reaction medium.
Compounds of formula R2R3NH (III) employed in the above reactions are well known chemical compounds. As indicated above, some of the reactants of formula (II) are novel, but they can nevertheless be readily prepared by methods well known in the art. For example, compounds of formula (II) can be prepared by the reaction of chlorosulfonylisocyanate with an alcohol of formula Ra Rs R7 Hal C C C OH
r~
R5 R7 Rs n where Hal is chloro or bromo, to give O
II ~-~ R9 CI S - N
R
O Ra ~ ~ ~ R7 R5 Rs n which, in turn, when reacted with an amine of formula R1NH2, yields the desired compound of formula (II). The use of an appropriate optically pure alcohol can enable the production of diastereoisomers from which pure chiral sulfamides can be derived.
g Examples of reactions according to the invention are as follows:
The sulfamides of formula (I) can be put to many uses.
One such is disclosed in EP-A 0 897921, in which a sulfamide is cyclised to produce a benzothiadiazine dioxide intermediate employed in the preparation of pharmaceutically active compounds.
O~ ~ Et3N(2eqya-t3CN
~O
/ \ H . '~- Refluc Q /\
H-~-N~ -~ -~ Refl~nc VO
O
(l_ ~ ~/ \ ~''N(2e9Y~~
~I- -S~NHz RaB~nc O
O ~ \ /
~1 y O
O~'O + ~ / \ ~~ ~ \ H~O, O
O O OW-l / \ ~ ~ / \
~O
H_~ N V -1- ~~ O
O O
The following Examples illustrate the invention.
T7CTT1~?TT TT 1 1,1-Dimethylpropylamino-1-sulfonic acid (4-methylphenyl)-amide 2-Oxo-oxazolidine-3-sulfonic acid (4-methylphenyl)-amide To a 1 L reactor, charged with dichloromethane (176 ml) under an inert atmosphere (N2) was added chlorosulfonyl isocyanate (CSI) (34.8 ml, 56.6 g, 0.40 mol) and the solution was cooled to 5 ~C.
A solution of 2-bromoethanol(28.4 ml, 50.0 g, 0.40 mol, 1.0 equiv) in dichloromethane (176 ml) was added to the reaction mixture over 30 minutes under cooling to keep the temperature reaction mixture between 5-7 ~C.
After stirring for about 30 minutes, a solution of p-toluidine (48.0 g, 0.45 mol, 1.1 equiv) and triethylamine (125 ml, 90.5 g, 0.90 mol, 2.2 equiv) in dichloromethane(358 ml) was added to the reaction mixture over 30 minutes under cooling to keep the temperature reaction mixture around 5-7 ~C.
After a stirring period of about 30 minutes 0.2N HCl (0.4 L) was added. Additional concentrated HC1 (37o w/w) was added until the pH of the water layer was ~2. After decantation and separation of the aqueous layer, the organic layer was washed with 0.05 N HCl (0.4 L) and water (0.4 L).
To the washed and separated organic layer, water (0.4 L) was added followed by the removal of dichloromethane under vacuum. The resulting suspension was stirred for an additional 30 minutes.
The reaction mixture was filtered and the filter cake washed with water (0.2 L) and dried at 50 ~C under reduced pressure to yield 90.82 g (0.355 mol) of crude 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl)-amide.
Crude 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl)-amide (50g) was suspended in dichloromethane (50 ml) and stirred for one hour at room temperature. The suspension was filtered, washed with dichloromethane (40 ml) and dried under vacuum at 50 ~C
to yield pure 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl)-amide (34.3 g). mp 159-160 ~C.
1,1-Dimethylpropylamino-1-sulfonic acid (4-methylphenyl)-amide Triethylamine (3.50 ml, 2.55 g, 25.2 mmol, 2.5 equiv) and tert-amylamine (1.50 ml, 1.12 g, 12.8 mmol, 1.3 equiv) were added to a solution of 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl)-amide (2.56 g, 10 mmol, 1.0 equiv) in acetonitrile (12.5 ml).
This mixture was heated at reflux for 8 h.
After cooling, water (40 ml) was added and the acetonitrile was removed by distillation under vacuum.
Dichloromethane (25 ml) was added to the resulting water emulsion and acidified with 1 ml HCl (37o w/w). After decantation and separation the organic layer was washed with 25 ml 0.05 N HCl and water (25 ml).
The organic layer was concentrated at room temperature under vacuum yielding the crude 1,1-Dimethylpropylamino-1-sulfonic acid (4-methylphenyl)-amide (1.802 g, 7.9 mmol) as a viscous yellow oil which slowly crystallised.
Crude 1,1-Dimethylpropylamino-1-sulfonic acid (4-methylphenyl)-amide (1.40 g, 6.13 mmol) was suspended in hexane (25 ml) and stirred at room temperature during 4 h.
The suspension was filtered, and the solid washed with hexane (10 ml). After drying the solid under vacuum at 50 ~C, pure 1,1-Dimethylpropylamino-1-sulfonic acid (4-methylphenyl)-amide (609 mg, 2.67 mmol) was obtained. mp 92.5-93 ~C.
4-Methvlphenvlylamino-1-sulfonic acid (4-methanesulfonylphenyl)-amide Triethylamine (7.0 ml, 5.10 g, 50 mmol, 2.5 equiv) and 4-methanesulfonyl-phenylamine(4.28 g, 25 mmol, 1.25 equiv) were added to a solution of 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl)-amide (5.12 g, 20 mmol) in acetonitrile (25 ml). This reaction mixture was heated at reflux for 8 hours.
After cooling, water (50 ml) was added and the acetonitrile was removed by distillation under vacuum.
'I'o the obtained water emulsion were added dichloromethane (40 ml) and HC1 (0.6 ml, 37o w/w).
After decantation and separation of the aqueous layer, 0.05 N HCl (25 ml) was added to the organic layer. At this stage crystallisation occurred. Dichloromethane was removed by distillation under vacuum at room temperature.
The resulting suspension was filtered and the solid washed with water (40m1) and dichloromethane (1 ml).
After drying under vacuum at 50 ~C, 4-methylphenylamino 1-sulfonic acid (4-methanesulfonylphenyl)-amide (4.64 g, 13.6 mmol) was obtained, mp 165.5-167 ~C.
1-Methvlethvlamino-1-sulfonic acid (4-methanesulfonylphenyl)-amide 2-Oxo-oxazolidine-3-sulfonic acid isopropyl-amide To a 250 L glass lined reactor initially charged with dichloromethane (42 L) was added chlorosulfonyl isocyanate (4.5 kg, 31.8 mol) at room temperature and under a nitrogen atmosphere. The reaction mixture was cooled to about 1 ~C. and a solution of 2-bromoethanol (4.00 kg, 1 equiv) in dichloromethane (14 L) was slowly added over 51 minutes in order to keep the reaction temperature between 0 and 10 ~C. Stirring of the reaction mixture was continued at the same temperature for a minimum of 30 minutes. Progress of the reaction was monitored by 1H-NMR. A mixture of isopropylamine (2.1 kg, 1.1 equiv) and triethylamine (7.1 kg) in dichloromethane (28 L) was then added at such an addition rate that the reaction temperature was maintained between 0 and 10 ~C. The solution was heated up to room temperature. Aqueous hydrochloric acid (~0.2 N, 28.5 kg) was then added and the pH of the reaction mixture was adjusted to about 2 by addition of concentrated hydrochloric acid (450 ml in 2 portions).
The reaction mixture was decanted and the separated organic layer washed with aqueous hydrochloric acid (28.1 kg, 0.05 N). The decanted and separated organic layer was washed with water (28 kg). To the decanted and separated organic layer, water (28 kg) was then added and the reactor was placed under vacuum to distil the maximum of dichloromethane while controlling the temperature below 25 ~C. (84.4 kg of distillate). The resulting suspension was stirred for a minimum of 2 hours at room temperature, filtrated, rinsed twice wish water (2 x 7 L) and dried under vacuum at about 50 ~C during 16 hours to afford the 2-oxo-oxazolidine-3-sulfonic acid isopropyl-amide, mp 107.5-108.5 ~C.
1-Methylethylamino-1-sulfonic acid (4-methanesulfonylphenyl)-amide A 100 L glass lined reactor was charged with acetonitrile (17.8 kg) and 4-methylsulfonylaniline hydrochloride (3.36 kg, 16.2 mol) under stirring at room temperature. Triethylamine (4.5 kg) and 2-oxo-oxazolidine-3-sulfonic acid isopropyl-amide (3.70 kg, 1.1 equiv) were then added at the same temperature. The reaction mixture was heated to reflux and stirred at the same temperature for a minimum of 6 hours. The solution was then slowly cooled to room temperature and kept agitated over night. Water was slowly added over 40 minutes and the reactor was placed under vacuum to distil as much as possible of acetonitrile (27.8 kg of distillate) while maintaining the reaction temperature below 40 ~C. The suspension was cooled to room 20 temperature and stirred for a minimum of 2 hours before filtering the product. The cake was rinsed with water (16.2 kg) and dried under vacuum at about 50 ~C. for a minimum of 16 hours to yield the 1-methylethylamino-1-sulfonic acid (4-methanesulfonylphenyl)-amide, mp 164-165 ~C.
This invention relates to a process for producing sulfamides, and to novel intermediates used in the process.
Sulfamides are conventionally prepared by the use of strongly electrophilic reagents such as sulfamoyl chloride, sulfonyl dichloride, phosphorus oxychloride or phosphorus pentachloride. Belgian patent 667.311 discloses a method of making sulfamides employing an N-alkyl sulfamoyl chloride. However, all such reagents involve aggressive synthetic methods, and indeed can be inconvenient or dangerous in their practical, industrial, application.
The invention provides a process for the production of aryl sulfamides that avoids the use of the above hazardous materials and conditions, and gives a high yield.
The process of the invention is for the production of an aryl sulfamide having the formula O
R
N- S -N
~ \
~ ~ R3 R
O
in which R1, R2 and R3 are each hydrogen, alkyl, cycloalkyl or aryl, provided that at least one of R1, R2 and R3 is aryl, which comprises reacting a compound of the formula O O
N- S -N
~~ ~R$
R ~ R4 ~ ~ R' R5 Rs n where R4, R5, R6, R~, R8 and R9 are each hydrogen, alkyl or aryl, and n is 0 or 1, with an amine of the formula R2R3NH (III), in the presence of a strong base.
The reaction can be carried out at ambient temperature or at the reflux temperature of the solvent in which the reaction is performed, and generally the temperature of the reaction is chosen in the range of from 0~ C. to 100~ C. A polar, aprotic, solvent is preferred, as, for example, acetonitrile.
A strong base is required for the reaction to proceed, and examples include triethylamine, 1,8-diazabicyclo[5,4,0]under-7-ene(DBU), 1,5-diazabicyclo[4,3,0]non-5-ene(DBN) or 1,4-diazabicyclo[2,2,2]octane(TED). Preferably from one to three equivalents of base are employed.
In the above formulae, an alkyl group can be substituted or unsubstituted, and is preferably C1_6 alkyl, being branched or unbranched. A cycloalkyl group preferably containing from 3 to 9 carbon atoms, and may, for example, be substituted by one to three alkyl groups such as methyl. When substituted, the alkyl group can be substituted by halo, C1-6 alkoxy, C3_9 cycloalkyl, optionally substituted phenyl or optionally substituted heteroaryl. An aryl group can be, for example, naphthyl or, preferably, phenyl, and can be substituted or unsubstituted. A substituted aryl group is substituted with one or more, preferably one to three, substituents selected from, for example, an electron-donating substituent such as, for example, C1_4 alkyl, C1_4 alkoxy, C1_4 alkylthio, hydroxy, amino, or an electron-withdrawing substituent such as, for example, carboxy, nitro, cyano, trifluoromethyl, halo, C1_4 alkyl-SO- and C1_4 alkyl-S02-.
Preferably, R1, R2 and R3 are selected from hydrogen, C1_6 alkyl and optionally substituted phenyl. In formula (II) above, R4, R5, R6, R~, R8 and R9 are preferably hydrogen, and n is preferably 0. It may, nevertheless, be desirable to employ a terminal moiety in which one or more of R4 to R9 is alkyl or aryl, for instance, in the preparation of stereoisomers.
It has been found that the nature of the substituent on an aryl group, for example a substituted phenyl, can surprisingly affect the reaction. Electron-donating substituents assist the reaction. Thus it is preferred that the substituent R1 is optionally substituted alkyl or phenyl optionally substituted with an electron-donating substituent, and a preferred process is one for the preparation of a compound of the formula O
~
N- S -N
/ \
( ) R3 R
O
in which R1 is alkyl or phenyl optionally substituted with an electron-donating substituent, and R2 and R3 are each hydrogen, alkyl or optionally substituted phenyl, provided that R1 is phenyl optionally substituted with an electron-donating substituent and/or R2 is optionally substituted phenyl, which comprises reacting a compound of the formula O O
~o N- S -N
R O
(IV) with an amine of the formula R2R3NH, in the presence of a strong base. A particularly preferred process is one for the production of a compound of the above formula in which R1 is C1-6 alkyl or phenyl optionally substituted with an electron-donating substituent, R2 is C1-6 alkyl or optionally substituted phenyl, and R3 is hydrogen, provided that R1 is phenyl optionally substituted with an electron-donating substituent and/or R2 is optionally substituted phenyl.
Compounds of formula (IV) where R1 is phenyl optionally substituted with an electron-donating substituent are novel, with the exception of compounds in which R1 is 3-methylbutyl or phenyl, and these novel compounds are included as an aspect of the present invention. They are stable, mainly crystalline solids, which can be readily isolated from the reaction medium.
Compounds of formula R2R3NH (III) employed in the above reactions are well known chemical compounds. As indicated above, some of the reactants of formula (II) are novel, but they can nevertheless be readily prepared by methods well known in the art. For example, compounds of formula (II) can be prepared by the reaction of chlorosulfonylisocyanate with an alcohol of formula Ra Rs R7 Hal C C C OH
r~
R5 R7 Rs n where Hal is chloro or bromo, to give O
II ~-~ R9 CI S - N
R
O Ra ~ ~ ~ R7 R5 Rs n which, in turn, when reacted with an amine of formula R1NH2, yields the desired compound of formula (II). The use of an appropriate optically pure alcohol can enable the production of diastereoisomers from which pure chiral sulfamides can be derived.
g Examples of reactions according to the invention are as follows:
The sulfamides of formula (I) can be put to many uses.
One such is disclosed in EP-A 0 897921, in which a sulfamide is cyclised to produce a benzothiadiazine dioxide intermediate employed in the preparation of pharmaceutically active compounds.
O~ ~ Et3N(2eqya-t3CN
~O
/ \ H . '~- Refluc Q /\
H-~-N~ -~ -~ Refl~nc VO
O
(l_ ~ ~/ \ ~''N(2e9Y~~
~I- -S~NHz RaB~nc O
O ~ \ /
~1 y O
O~'O + ~ / \ ~~ ~ \ H~O, O
O O OW-l / \ ~ ~ / \
~O
H_~ N V -1- ~~ O
O O
The following Examples illustrate the invention.
T7CTT1~?TT TT 1 1,1-Dimethylpropylamino-1-sulfonic acid (4-methylphenyl)-amide 2-Oxo-oxazolidine-3-sulfonic acid (4-methylphenyl)-amide To a 1 L reactor, charged with dichloromethane (176 ml) under an inert atmosphere (N2) was added chlorosulfonyl isocyanate (CSI) (34.8 ml, 56.6 g, 0.40 mol) and the solution was cooled to 5 ~C.
A solution of 2-bromoethanol(28.4 ml, 50.0 g, 0.40 mol, 1.0 equiv) in dichloromethane (176 ml) was added to the reaction mixture over 30 minutes under cooling to keep the temperature reaction mixture between 5-7 ~C.
After stirring for about 30 minutes, a solution of p-toluidine (48.0 g, 0.45 mol, 1.1 equiv) and triethylamine (125 ml, 90.5 g, 0.90 mol, 2.2 equiv) in dichloromethane(358 ml) was added to the reaction mixture over 30 minutes under cooling to keep the temperature reaction mixture around 5-7 ~C.
After a stirring period of about 30 minutes 0.2N HCl (0.4 L) was added. Additional concentrated HC1 (37o w/w) was added until the pH of the water layer was ~2. After decantation and separation of the aqueous layer, the organic layer was washed with 0.05 N HCl (0.4 L) and water (0.4 L).
To the washed and separated organic layer, water (0.4 L) was added followed by the removal of dichloromethane under vacuum. The resulting suspension was stirred for an additional 30 minutes.
The reaction mixture was filtered and the filter cake washed with water (0.2 L) and dried at 50 ~C under reduced pressure to yield 90.82 g (0.355 mol) of crude 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl)-amide.
Crude 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl)-amide (50g) was suspended in dichloromethane (50 ml) and stirred for one hour at room temperature. The suspension was filtered, washed with dichloromethane (40 ml) and dried under vacuum at 50 ~C
to yield pure 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl)-amide (34.3 g). mp 159-160 ~C.
1,1-Dimethylpropylamino-1-sulfonic acid (4-methylphenyl)-amide Triethylamine (3.50 ml, 2.55 g, 25.2 mmol, 2.5 equiv) and tert-amylamine (1.50 ml, 1.12 g, 12.8 mmol, 1.3 equiv) were added to a solution of 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl)-amide (2.56 g, 10 mmol, 1.0 equiv) in acetonitrile (12.5 ml).
This mixture was heated at reflux for 8 h.
After cooling, water (40 ml) was added and the acetonitrile was removed by distillation under vacuum.
Dichloromethane (25 ml) was added to the resulting water emulsion and acidified with 1 ml HCl (37o w/w). After decantation and separation the organic layer was washed with 25 ml 0.05 N HCl and water (25 ml).
The organic layer was concentrated at room temperature under vacuum yielding the crude 1,1-Dimethylpropylamino-1-sulfonic acid (4-methylphenyl)-amide (1.802 g, 7.9 mmol) as a viscous yellow oil which slowly crystallised.
Crude 1,1-Dimethylpropylamino-1-sulfonic acid (4-methylphenyl)-amide (1.40 g, 6.13 mmol) was suspended in hexane (25 ml) and stirred at room temperature during 4 h.
The suspension was filtered, and the solid washed with hexane (10 ml). After drying the solid under vacuum at 50 ~C, pure 1,1-Dimethylpropylamino-1-sulfonic acid (4-methylphenyl)-amide (609 mg, 2.67 mmol) was obtained. mp 92.5-93 ~C.
4-Methvlphenvlylamino-1-sulfonic acid (4-methanesulfonylphenyl)-amide Triethylamine (7.0 ml, 5.10 g, 50 mmol, 2.5 equiv) and 4-methanesulfonyl-phenylamine(4.28 g, 25 mmol, 1.25 equiv) were added to a solution of 2-oxo-oxazolidine-3-sulfonic acid (4-methylphenyl)-amide (5.12 g, 20 mmol) in acetonitrile (25 ml). This reaction mixture was heated at reflux for 8 hours.
After cooling, water (50 ml) was added and the acetonitrile was removed by distillation under vacuum.
'I'o the obtained water emulsion were added dichloromethane (40 ml) and HC1 (0.6 ml, 37o w/w).
After decantation and separation of the aqueous layer, 0.05 N HCl (25 ml) was added to the organic layer. At this stage crystallisation occurred. Dichloromethane was removed by distillation under vacuum at room temperature.
The resulting suspension was filtered and the solid washed with water (40m1) and dichloromethane (1 ml).
After drying under vacuum at 50 ~C, 4-methylphenylamino 1-sulfonic acid (4-methanesulfonylphenyl)-amide (4.64 g, 13.6 mmol) was obtained, mp 165.5-167 ~C.
1-Methvlethvlamino-1-sulfonic acid (4-methanesulfonylphenyl)-amide 2-Oxo-oxazolidine-3-sulfonic acid isopropyl-amide To a 250 L glass lined reactor initially charged with dichloromethane (42 L) was added chlorosulfonyl isocyanate (4.5 kg, 31.8 mol) at room temperature and under a nitrogen atmosphere. The reaction mixture was cooled to about 1 ~C. and a solution of 2-bromoethanol (4.00 kg, 1 equiv) in dichloromethane (14 L) was slowly added over 51 minutes in order to keep the reaction temperature between 0 and 10 ~C. Stirring of the reaction mixture was continued at the same temperature for a minimum of 30 minutes. Progress of the reaction was monitored by 1H-NMR. A mixture of isopropylamine (2.1 kg, 1.1 equiv) and triethylamine (7.1 kg) in dichloromethane (28 L) was then added at such an addition rate that the reaction temperature was maintained between 0 and 10 ~C. The solution was heated up to room temperature. Aqueous hydrochloric acid (~0.2 N, 28.5 kg) was then added and the pH of the reaction mixture was adjusted to about 2 by addition of concentrated hydrochloric acid (450 ml in 2 portions).
The reaction mixture was decanted and the separated organic layer washed with aqueous hydrochloric acid (28.1 kg, 0.05 N). The decanted and separated organic layer was washed with water (28 kg). To the decanted and separated organic layer, water (28 kg) was then added and the reactor was placed under vacuum to distil the maximum of dichloromethane while controlling the temperature below 25 ~C. (84.4 kg of distillate). The resulting suspension was stirred for a minimum of 2 hours at room temperature, filtrated, rinsed twice wish water (2 x 7 L) and dried under vacuum at about 50 ~C during 16 hours to afford the 2-oxo-oxazolidine-3-sulfonic acid isopropyl-amide, mp 107.5-108.5 ~C.
1-Methylethylamino-1-sulfonic acid (4-methanesulfonylphenyl)-amide A 100 L glass lined reactor was charged with acetonitrile (17.8 kg) and 4-methylsulfonylaniline hydrochloride (3.36 kg, 16.2 mol) under stirring at room temperature. Triethylamine (4.5 kg) and 2-oxo-oxazolidine-3-sulfonic acid isopropyl-amide (3.70 kg, 1.1 equiv) were then added at the same temperature. The reaction mixture was heated to reflux and stirred at the same temperature for a minimum of 6 hours. The solution was then slowly cooled to room temperature and kept agitated over night. Water was slowly added over 40 minutes and the reactor was placed under vacuum to distil as much as possible of acetonitrile (27.8 kg of distillate) while maintaining the reaction temperature below 40 ~C. The suspension was cooled to room 20 temperature and stirred for a minimum of 2 hours before filtering the product. The cake was rinsed with water (16.2 kg) and dried under vacuum at about 50 ~C. for a minimum of 16 hours to yield the 1-methylethylamino-1-sulfonic acid (4-methanesulfonylphenyl)-amide, mp 164-165 ~C.
Claims (4)
1. A process for the production of an aryl sulfamide having the formula in which R1, R2 and R3 are each hydrogen, alkyl, cycloalkyl or aryl, provided that at least one of R1, R2 and R3 is aryl, which comprises reacting a compound of the formula where R4, R5, R6, R7, R8 and R9 are each hydrogen, alkyl or aryl, arid n is 0 or 1, with an amine of the formula R2R3NH (III), in the presence of a strong base.
2. A process according to Claim 1 for the production of a compound in which R1 is alkyl or phenyl optionally substituted with an electron-donating substituent, and R2 and R3 are each hydrogen, alkyl or optionally substituted phenyl, provided that R1 is phenyl optionally substituted with an electron-donating substituent and/or R2 is optionally substituted phenyl, which comprises reacting a compound of the formula with an amine of the formula R2R3NH, in the presence of a strong base.
3. A process according to Claim 2 for the production of a compound in which R1 is C1-6 alkyl or phenyl optionally substituted with an electron-donating substituent, R2 is C1-6 alkyl or optionally substituted phenyl, and R3 is hydrogen, provided that R1 is phenyl optionally substituted with an electron-donating substituent and/or R2 is optionally substituted phenyl.
4. A compound of the formula where R1 is phenyl optionally substituted with an electron-donating substituent are novel, with the exception of compounds in which R1 is 3-methylbutyl or phenyl.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9927302.1 | 1999-11-18 | ||
| GB9927302A GB2356398A (en) | 1999-11-18 | 1999-11-18 | Preparation of arylsulfamides |
| PCT/US2000/028877 WO2001036383A1 (en) | 1999-11-18 | 2000-11-03 | Process for the preparation of sulfamides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2391978A1 true CA2391978A1 (en) | 2001-05-25 |
Family
ID=10864756
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002391978A Abandoned CA2391978A1 (en) | 1999-11-18 | 2000-11-03 | Process for the preparation of sulfamides |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP1235795A1 (en) |
| JP (1) | JP2003514797A (en) |
| AU (1) | AU1434301A (en) |
| CA (1) | CA2391978A1 (en) |
| GB (1) | GB2356398A (en) |
| WO (1) | WO2001036383A1 (en) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002070467A1 (en) | 2001-02-26 | 2002-09-12 | 4Sc Ag | Derivatives of diphenylurea, diphenyloxalic acid diamide and diphenylsulfuric acid diamide and their use as medicaments |
| WO2003006424A1 (en) | 2001-07-10 | 2003-01-23 | 4Sc Ag | Novel compounds as anti-inflammatory, immunomodulatory and anti-proliferatory agents |
| GB0423554D0 (en) | 2004-10-22 | 2004-11-24 | Cancer Rec Tech Ltd | Therapeutic compounds |
| EP2013207B1 (en) | 2006-04-26 | 2012-04-25 | Cancer Research Technology Limited | Imidazo[4,5-b]pyridin-2-one compounds and analogs thereof as cancer therapeutic compounds |
| US8198279B2 (en) | 2007-12-19 | 2012-06-12 | Institute Of Cancer Research: Royal Cancer Hospital (The) | Pyrido[2,3-b]pyrazin-8-substituted compounds and their use |
| GB0807609D0 (en) | 2008-04-25 | 2008-06-04 | Cancer Rec Tech Ltd | Therapeutic compounds and their use |
| CN101569864B (en) * | 2008-04-29 | 2011-08-03 | 中山大学 | Chiral sulfonamide organic micromolecule catalyst and application thereof |
| NZ706154A (en) | 2010-02-01 | 2016-09-30 | Cancer Rec Tech Ltd | 1-(5-tert-butyl-2-phenyl-2h-pyrazol-3-yl)-3-[2-fluoro-4-(1-methyl-2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-7-yloxy)-phenyl]-urea and related compounds and their use in therapy |
| GB201320732D0 (en) | 2013-11-25 | 2014-01-08 | Cancer Rec Tech Ltd | Methods of chemical synthesis |
| GB201320729D0 (en) | 2013-11-25 | 2014-01-08 | Cancer Rec Tech Ltd | Therapeutic compounds and their use |
| CN108250121A (en) * | 2016-12-28 | 2018-07-06 | 上海长森药业有限公司 | Sulfonamide-arylamides and its medicinal usage for treating hepatitis B |
-
1999
- 1999-11-18 GB GB9927302A patent/GB2356398A/en not_active Withdrawn
-
2000
- 2000-11-03 CA CA002391978A patent/CA2391978A1/en not_active Abandoned
- 2000-11-03 JP JP2001538874A patent/JP2003514797A/en not_active Withdrawn
- 2000-11-03 WO PCT/US2000/028877 patent/WO2001036383A1/en not_active Application Discontinuation
- 2000-11-03 AU AU14343/01A patent/AU1434301A/en not_active Abandoned
- 2000-11-03 EP EP00976591A patent/EP1235795A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU1434301A (en) | 2001-05-30 |
| WO2001036383A1 (en) | 2001-05-25 |
| JP2003514797A (en) | 2003-04-22 |
| EP1235795A1 (en) | 2002-09-04 |
| GB2356398A (en) | 2001-05-23 |
| GB9927302D0 (en) | 2000-01-12 |
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