CA1102803A - Process for the production of substituted sulphoximides - Google Patents
Process for the production of substituted sulphoximidesInfo
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- CA1102803A CA1102803A CA345,046A CA345046A CA1102803A CA 1102803 A CA1102803 A CA 1102803A CA 345046 A CA345046 A CA 345046A CA 1102803 A CA1102803 A CA 1102803A
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Abstract
ABSTRACT OF THE DISCLOSURE
Novel substituted sulphoximides of the general formula in which R1 and R2 independently of each other represent phenyl, R3 and R4 which may be the same or different represent optionally substituted straight chain or branched lower alkyl, or together with the nitrogen atom, form a pyrrolidino, piperidino or morpholino ring, R5 represents a hydrogen atom or a straight chain or branched lower alkyl group, X is an inorganic or organic anion of a physiologically compatible acid and n has the value 0 or 1 are prepared by reacting an S,S-diaryl sulphoximide of the general formula II
with formaldehyde and a secondary amine of the formula
Novel substituted sulphoximides of the general formula in which R1 and R2 independently of each other represent phenyl, R3 and R4 which may be the same or different represent optionally substituted straight chain or branched lower alkyl, or together with the nitrogen atom, form a pyrrolidino, piperidino or morpholino ring, R5 represents a hydrogen atom or a straight chain or branched lower alkyl group, X is an inorganic or organic anion of a physiologically compatible acid and n has the value 0 or 1 are prepared by reacting an S,S-diaryl sulphoximide of the general formula II
with formaldehyde and a secondary amine of the formula
Description
~lazsc3 This invention relates to substituted sulphoximides corresponding to the following general formula ,Rl ,R3 0 = S ~ N - CH2 - N - R4 . (R5X) (I) R2 -- .
in which Rl and R2 independently of one another represent optionally substituted aryl, R3 and R4, which may be the same or different, represent optionally substituted, straight-chain or branched alkyl or, together with the nitrogen atom, form a pyrrolidino, piperidino or morpholino ring, R5 represents a hydrogen atom or a straight-chain or branched alkyl group, X is an inorganic or organic anion of a physiologically compatible acid and n has the value O or 1, and to the salts of these compounds.
The present invention also relates to medicaments which are characterised in that, in addition to a standard excipient and/or diluent, they contain an effective quantity of at least one substituted sulphoximide of the type described above.
In general formula (I), the substituents Rl and R2, which may be the same or different, represent optionally substituted aryl groups. The groups Rl and R are preferably phenyl groups.
The groups R and R , which may be the same or different, are alkyl groups, such as straight-chain or branched alkyl groups containing from 1 to 12 carbo atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms ,~
,~1 8~
and, most preferably, from 1 to 3 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl or hexyl groups. Preferably, the groups R3 and R4 each represent an ethyl group. In addition, the radieals R3 and R4, together with the nitrogen atom, may form a heterocyclie ring, particularly a pyrrolidino, piperidino or morpholino ring. -The radieal R5 represents a hydrogen atom or a straightchain or branched alkyl group, particularly a lower alkyl group containing from 1 to 6 and preferably from 1 to 3 carbon atoms. The radical R5 preferably represents a methyl group.
X represents an inorganic or organie anion of a physiologieally compatible aeid, partieularly hydroehlorie or hydrobromie aeid, whilst n has the value O or 1.
15The compounds aeeording to the invention may be produced by reacting an S,S-diaryl sulphoximide corresponding to the following general formula ,Rl O - S = NH (II) in whieh Rl and R2 are as defined above, with formaldehyde and a seeondary amine eorresponding to the following general formula IN \
R4 (III) in which R3 and R are as defined above, in a water-immiseible solvent on the lines of a Mannieh synthesis and optionally converting the compound obtained into 8~3 its tertiary salt.
The reaction takes place in accordance with the following scheme:
R R3 Rl R3 , 2 < R4 ~~~~~~~ 0=S N-CH -N C
The reaction is carried out in a water-immiscible solvent, the water of reaction being azeotropically removed through a water separator. Examples of suitable water-immiscible solvents are benzene, toluene and xylene, benzene being preferred.
According to the invention, the reaction is carried out at the boiling temperature of the solvent used or of the azeotrope formed with water. The reaction time is generally from 2 to 8 hours. The molar ratio between the individual starting compounds is from 1:1:1 to 1:1:4, preferably 1:1:1.
After the calculated amount of water has been separated in the water separator, the water-immiscible solvent is evaporated off under normal or reduced pressure. If the product is obtained as an oil, it may be purified by fractionation in a fine vacuum. Solid products may be purified in the usual way bY recrystallisation under dry conditions. In this way, the required N-dialkyl aminomethyl-S,S-diaryl sulphoximides may be separated off from unreacted starting material and bis-(dialkylamino)-methanes and bis-(S,S-diaryl sulphoximido)-methanes possibly formed as secondary products.
The tertiary salts are produced for example by standard alkylation methods in dry, inert solvents, such as ethers or acetonitrile.
The compounds corresponding to formula I show .~
pharmacological activity, for example as spasmolytics, which makes them appear suitable for use as medicaments.
The compounds according to the invention were tested for their spasmolytic and broncholytic activity both in vivo and also in vitro. They proved to be highly effective spasmolytics with neurotropic and musculotropic activity by comparison with atropine. Bronchospasms induced by histamine and acetyl choline were persistently eliminated.
The favourable effect after intragastral and intraduodenal administration is indicative of good enteral resorption. The compounds according to the invention proved to be relatively non-toxic in the acute toxicity test.
Particulars of the pharmacological properties of the compounds according to the invention are given in Tables I
to III.
_ble Acute toxicity LD50-values after 1 week's observation in male NMRI-mice Compound Administration LD50(confidence limits route p< 0.05) mg/kg Example 2 i.g. 330.98 (224.48 - 487.99) Example 3 i.g. 319.55 (254.95 - 400.53) Example 2 i.v. 7.91 (6.78 - 9.22) Example 3 i.v. 7.33 (5.94 - 9.04) Table II
Spasmolysis in vitro Guinea pigs~ileum-pA2-values Agonist ACH Histamine BaC12 ~ mpound ED50 (mole) Example 2 8.21 ~ 0.25 8.1 ~ 0.21 approx.lxlO
Example 3 8.0 ~ 0.23 8.0 ~ 0.35 approx.3.3xlO
,,j ` - 6 ~ 28~
Table III
.
Broncholysis Compound . 50 ~ ~g ~ g) i.d. 100 ( g/ g) 1 minute after 30 minutes after administration administration Hi ACH Hi ACH
_ _ Example 2 0.3 1.2 25 50 Example 3 0.5 2.5 25 50 The compounds according to the invention may be made up into medicaments in the usual way, i.e. in the form of tablets, capsules, dra~ees, drops, suppositories, injections or preparations for inhalation.
They may he administered orally, rectally or by inhalation or injection. The invention is illustrated by the following examples.
EX~PLE 1 N-pyrrolidinomethyl-S,S-diphenyl sulphoximide:
5.4 g 10.025 mole) of S,S-diphenyl sulphoximide, 1.8 g (0.025 mole) of pyrrolidine and 2.2 g of 35 ~ formaldehyde solution are boiled in 100 ml of benzene in a water separator until the calculated quantity of water has been separated (approximately 1 hour). The solvent is then evaporated.
Removal of the last traces of solvent by distillation in a fine vacuum leaves an oily product which crystallises at room temperature.
Colourless crystals. M.p.: 59 to 61C
Yield: 7.4 g (98% of the theoretical) Analysis: C17H20N2OS MW: 300.43 Calculated: C = 67.97 H = 6.71 N = 9.32 S = 10.67 Abserved: C = 67.72 H = 6.16 N = 8.78 S = 10.85 11~2B~3 H-NMR (CDC13): 1.5 to 1.95 and 2.5 to 2.95 (m, pyrrolidine), 4.1 (s,CH2), 7.2 to 8.2 (m, arom, CH) IR (KBr): 3060, 2950, 2860, 1580, 1475, 1440, 1390, 1350 1230 (N=S=O asym.), 1150, 1120, (N=S=0 sym.), 1070, 1025, 1000, 880, 760, 730.
N-(N'methyl-pyrrolidinium-methyl)-S,S-diphenyl sulphoximide bromide:
6 g (0.02 mole) of N-pyrrolidinomethyl-S,S-diphenyl sulphoximide are dissolved in 150 ml of anhydrous acetonitrile and the resulting solution is cooled to around -40C in an inert gas atmosphere. 9.5 g (0.1 mole) of methyl bromide are added to the intensively stirred solution, followed by stirring for about 12 hours with gradual heating to room temperature. The solvent is then removed in a rotary evaporator. The residue is purified by recrystallisation from acetonitrile~ether.
Colourless crystals. M.p.: 138 to 140C
Yield: 6.7 g (85~ of the theoretical) Analysis: C18 23 2 MW: 395.36 Calculated: C = 54.68 H = 5.86 N = 7.08 S = 8.11 Observed: C = 54.55 H = 5.75 N = 7.09 S = 8.05 H-NMR (DMSO-d6): 1.8 to 2.3 and 3.3 to 3.8 (m, pyrrolidine), 3.15 (s, C~3), 4.6 ~s, CH2), 7.5 to 8.3 (m, arom, CH) IR (KBr): 3040, 3000, 2980, 1575, 1465, 1440, 1405, 1295, 1260, 1230, (N=S=0 asym.), 1150 (N=S-0 sym.), 1080, 1020, 990, 960, 930, 900, 885, 775.
N-(N'-methyl-pyrrolidinium-methyl)-S,S-diphenyl sulphoximide chloride:
In a l-litre three-neckéd flask equipped with a stirrer, ~l~Z8~3 thermometer, gas inlet tube and drying tube, 18 g (0.06 mole) of N-pyrrolidinomethyl-S,S-diphenyt sulphoximide are dissolved in 250 ml of anhydrous ace-tonitrile and the resulting solution cooled to around -40C in an inert gas atmosphere. Methyl chloride is introduced in excess into the intensively stirred solution for about 2 hours, followed by stirring for about 12 hours at around -20C. The solution is then concentrated _ vacuo to approximately half its volume. The quaternary salt is precipitated by the addition of dry ether, filtered off in the absence of moisture, washed with dry ether and dried _ vacuo.
Colourless crystals. M.p : 148 to 150 C. Hygroscopic Yield: 12 g (100% of the theoretical). MW: 350.91 H-NMR (CDC13): 1.9 to 2.5 and 3.5 to 4.1 ~m,pyrrolidine), 3.4 (s, CH3), 4.75 (s, CH2), 7.3 to 8.2 (m, arom, CH).
IR (KBr): 3300 to 3600 ~H20), 3050, 3000, 1580, 1465, 1450, 1410, 1300, 1265, 1235 (N=S=0 asym.), 1155 ~N=S=0 sym.), 1085, 1025, 995, 965, 930, 905, 885, 780.
N-diethylaminomethyl-S,S-diphenyl sulphoximide:
6.5 g (0.03 mole) of S,S-diphenyl sulphoximide, 2.2 g (0.03 mole) of diethylamine and 2.6 g of 35 % formaldehyde solution are boiled in 100 ml of ben~ene in a water separator until the calculated quantity of water has been separated (approximately 3 hours). The solvent is then evaporated and the residual oil is distilled in a fine vacuum ~B~p~o 01 = 70 C).
Colourless oil.
Yield: 8.8 g (96 % of the theoretical) Analysis: C17H22N2OS MW: 302.44 Calculated: C = 67.51 % H = 7.33 ~ N = 9.26 % S = 10.60 %
~,~
.
~l~Z8~3 g Observed: C = 67.55 % H = 7.36 % N = 9.21 % S = 10.56 %
H-NMR (C~13): 0.95 to 1.30 (t, 2CH3), 2.55 to 3.0 (q, 2CH2), 4.2 (s,CH2), 7.2 to 8.2 (m, arom. CH) IR (film): 3070, 2970, 2930, 1470, 1410, 1380, 1240, (N=S=0 asym.), 1210. 1130 (N-S=0 sym.), 1100, 1070 1030, 1000, 760, 730, N-(N'diethyl methylammonium methyl)-S,S-diphenyl sulphoximide bromide:
6 g (0.02 mole) of N-diethylaminomethyl-S, S-diphenyl sulphoximide are dissolved in 150 ml of anhydrous acetonitrile and the resulting solution is cooled to around -40C in an inert gas atmosphere. 9.5 g (0.1 mole) of methyl bromide are added to the intensively stirred solution, followed by stirring for about 12 hours with gradual heating to room temperature. The solvent is then removed in a rotary evaporator.
The residue is purified by recrystallisation from acetonitrile~
ether.
Colourless crystals. M.p.: 94 to 95C
Yield: 7.7 g (97% of the theoretical) Analysis: C18H25BrN2OS MW: 397.38 Calculated: C = 54.41 % H = 6.34 % N - 7-05 % S = 8.07 %
Br = 20.11 %
Observed: C = 54 35 % H = 6.28 % N = 7.11 % S = 8.12 %
Br = 20.20 %
H-NMR (CDC13): 1.1 to 1.6 (t, 2CH3), 3 2 Is, CH3), 3.3 to 3.8 (q, 2CH2), 4.65 (s, CH2), 7.2 to 8.2 (m, arom. CH).
IR (KBr): 3090, 3010, 2980, 1635, 1485, 1500, 1390, 1250 (N=S=0 asym.), 1220, 1165, IN=S=0 sym.), 1100, 1050, 1000, 905, 815, 770, 745.
8~3 N- piperidinomethyl-S,S-diphenyl sulphoximide:
10 9 g (0.05 mole) of S,S-diphenyl sulphoximide, 4.3 g (0.05 mole) of piperidine and 6 g of 35 % formaldehyde solution are boiled in 100 ml of benzene in a water separator until the calculated quantity of water has been separated (approximately
in which Rl and R2 independently of one another represent optionally substituted aryl, R3 and R4, which may be the same or different, represent optionally substituted, straight-chain or branched alkyl or, together with the nitrogen atom, form a pyrrolidino, piperidino or morpholino ring, R5 represents a hydrogen atom or a straight-chain or branched alkyl group, X is an inorganic or organic anion of a physiologically compatible acid and n has the value O or 1, and to the salts of these compounds.
The present invention also relates to medicaments which are characterised in that, in addition to a standard excipient and/or diluent, they contain an effective quantity of at least one substituted sulphoximide of the type described above.
In general formula (I), the substituents Rl and R2, which may be the same or different, represent optionally substituted aryl groups. The groups Rl and R are preferably phenyl groups.
The groups R and R , which may be the same or different, are alkyl groups, such as straight-chain or branched alkyl groups containing from 1 to 12 carbo atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 6 carbon atoms ,~
,~1 8~
and, most preferably, from 1 to 3 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl or hexyl groups. Preferably, the groups R3 and R4 each represent an ethyl group. In addition, the radieals R3 and R4, together with the nitrogen atom, may form a heterocyclie ring, particularly a pyrrolidino, piperidino or morpholino ring. -The radieal R5 represents a hydrogen atom or a straightchain or branched alkyl group, particularly a lower alkyl group containing from 1 to 6 and preferably from 1 to 3 carbon atoms. The radical R5 preferably represents a methyl group.
X represents an inorganic or organie anion of a physiologieally compatible aeid, partieularly hydroehlorie or hydrobromie aeid, whilst n has the value O or 1.
15The compounds aeeording to the invention may be produced by reacting an S,S-diaryl sulphoximide corresponding to the following general formula ,Rl O - S = NH (II) in whieh Rl and R2 are as defined above, with formaldehyde and a seeondary amine eorresponding to the following general formula IN \
R4 (III) in which R3 and R are as defined above, in a water-immiseible solvent on the lines of a Mannieh synthesis and optionally converting the compound obtained into 8~3 its tertiary salt.
The reaction takes place in accordance with the following scheme:
R R3 Rl R3 , 2 < R4 ~~~~~~~ 0=S N-CH -N C
The reaction is carried out in a water-immiscible solvent, the water of reaction being azeotropically removed through a water separator. Examples of suitable water-immiscible solvents are benzene, toluene and xylene, benzene being preferred.
According to the invention, the reaction is carried out at the boiling temperature of the solvent used or of the azeotrope formed with water. The reaction time is generally from 2 to 8 hours. The molar ratio between the individual starting compounds is from 1:1:1 to 1:1:4, preferably 1:1:1.
After the calculated amount of water has been separated in the water separator, the water-immiscible solvent is evaporated off under normal or reduced pressure. If the product is obtained as an oil, it may be purified by fractionation in a fine vacuum. Solid products may be purified in the usual way bY recrystallisation under dry conditions. In this way, the required N-dialkyl aminomethyl-S,S-diaryl sulphoximides may be separated off from unreacted starting material and bis-(dialkylamino)-methanes and bis-(S,S-diaryl sulphoximido)-methanes possibly formed as secondary products.
The tertiary salts are produced for example by standard alkylation methods in dry, inert solvents, such as ethers or acetonitrile.
The compounds corresponding to formula I show .~
pharmacological activity, for example as spasmolytics, which makes them appear suitable for use as medicaments.
The compounds according to the invention were tested for their spasmolytic and broncholytic activity both in vivo and also in vitro. They proved to be highly effective spasmolytics with neurotropic and musculotropic activity by comparison with atropine. Bronchospasms induced by histamine and acetyl choline were persistently eliminated.
The favourable effect after intragastral and intraduodenal administration is indicative of good enteral resorption. The compounds according to the invention proved to be relatively non-toxic in the acute toxicity test.
Particulars of the pharmacological properties of the compounds according to the invention are given in Tables I
to III.
_ble Acute toxicity LD50-values after 1 week's observation in male NMRI-mice Compound Administration LD50(confidence limits route p< 0.05) mg/kg Example 2 i.g. 330.98 (224.48 - 487.99) Example 3 i.g. 319.55 (254.95 - 400.53) Example 2 i.v. 7.91 (6.78 - 9.22) Example 3 i.v. 7.33 (5.94 - 9.04) Table II
Spasmolysis in vitro Guinea pigs~ileum-pA2-values Agonist ACH Histamine BaC12 ~ mpound ED50 (mole) Example 2 8.21 ~ 0.25 8.1 ~ 0.21 approx.lxlO
Example 3 8.0 ~ 0.23 8.0 ~ 0.35 approx.3.3xlO
,,j ` - 6 ~ 28~
Table III
.
Broncholysis Compound . 50 ~ ~g ~ g) i.d. 100 ( g/ g) 1 minute after 30 minutes after administration administration Hi ACH Hi ACH
_ _ Example 2 0.3 1.2 25 50 Example 3 0.5 2.5 25 50 The compounds according to the invention may be made up into medicaments in the usual way, i.e. in the form of tablets, capsules, dra~ees, drops, suppositories, injections or preparations for inhalation.
They may he administered orally, rectally or by inhalation or injection. The invention is illustrated by the following examples.
EX~PLE 1 N-pyrrolidinomethyl-S,S-diphenyl sulphoximide:
5.4 g 10.025 mole) of S,S-diphenyl sulphoximide, 1.8 g (0.025 mole) of pyrrolidine and 2.2 g of 35 ~ formaldehyde solution are boiled in 100 ml of benzene in a water separator until the calculated quantity of water has been separated (approximately 1 hour). The solvent is then evaporated.
Removal of the last traces of solvent by distillation in a fine vacuum leaves an oily product which crystallises at room temperature.
Colourless crystals. M.p.: 59 to 61C
Yield: 7.4 g (98% of the theoretical) Analysis: C17H20N2OS MW: 300.43 Calculated: C = 67.97 H = 6.71 N = 9.32 S = 10.67 Abserved: C = 67.72 H = 6.16 N = 8.78 S = 10.85 11~2B~3 H-NMR (CDC13): 1.5 to 1.95 and 2.5 to 2.95 (m, pyrrolidine), 4.1 (s,CH2), 7.2 to 8.2 (m, arom, CH) IR (KBr): 3060, 2950, 2860, 1580, 1475, 1440, 1390, 1350 1230 (N=S=O asym.), 1150, 1120, (N=S=0 sym.), 1070, 1025, 1000, 880, 760, 730.
N-(N'methyl-pyrrolidinium-methyl)-S,S-diphenyl sulphoximide bromide:
6 g (0.02 mole) of N-pyrrolidinomethyl-S,S-diphenyl sulphoximide are dissolved in 150 ml of anhydrous acetonitrile and the resulting solution is cooled to around -40C in an inert gas atmosphere. 9.5 g (0.1 mole) of methyl bromide are added to the intensively stirred solution, followed by stirring for about 12 hours with gradual heating to room temperature. The solvent is then removed in a rotary evaporator. The residue is purified by recrystallisation from acetonitrile~ether.
Colourless crystals. M.p.: 138 to 140C
Yield: 6.7 g (85~ of the theoretical) Analysis: C18 23 2 MW: 395.36 Calculated: C = 54.68 H = 5.86 N = 7.08 S = 8.11 Observed: C = 54.55 H = 5.75 N = 7.09 S = 8.05 H-NMR (DMSO-d6): 1.8 to 2.3 and 3.3 to 3.8 (m, pyrrolidine), 3.15 (s, C~3), 4.6 ~s, CH2), 7.5 to 8.3 (m, arom, CH) IR (KBr): 3040, 3000, 2980, 1575, 1465, 1440, 1405, 1295, 1260, 1230, (N=S=0 asym.), 1150 (N=S-0 sym.), 1080, 1020, 990, 960, 930, 900, 885, 775.
N-(N'-methyl-pyrrolidinium-methyl)-S,S-diphenyl sulphoximide chloride:
In a l-litre three-neckéd flask equipped with a stirrer, ~l~Z8~3 thermometer, gas inlet tube and drying tube, 18 g (0.06 mole) of N-pyrrolidinomethyl-S,S-diphenyt sulphoximide are dissolved in 250 ml of anhydrous ace-tonitrile and the resulting solution cooled to around -40C in an inert gas atmosphere. Methyl chloride is introduced in excess into the intensively stirred solution for about 2 hours, followed by stirring for about 12 hours at around -20C. The solution is then concentrated _ vacuo to approximately half its volume. The quaternary salt is precipitated by the addition of dry ether, filtered off in the absence of moisture, washed with dry ether and dried _ vacuo.
Colourless crystals. M.p : 148 to 150 C. Hygroscopic Yield: 12 g (100% of the theoretical). MW: 350.91 H-NMR (CDC13): 1.9 to 2.5 and 3.5 to 4.1 ~m,pyrrolidine), 3.4 (s, CH3), 4.75 (s, CH2), 7.3 to 8.2 (m, arom, CH).
IR (KBr): 3300 to 3600 ~H20), 3050, 3000, 1580, 1465, 1450, 1410, 1300, 1265, 1235 (N=S=0 asym.), 1155 ~N=S=0 sym.), 1085, 1025, 995, 965, 930, 905, 885, 780.
N-diethylaminomethyl-S,S-diphenyl sulphoximide:
6.5 g (0.03 mole) of S,S-diphenyl sulphoximide, 2.2 g (0.03 mole) of diethylamine and 2.6 g of 35 % formaldehyde solution are boiled in 100 ml of ben~ene in a water separator until the calculated quantity of water has been separated (approximately 3 hours). The solvent is then evaporated and the residual oil is distilled in a fine vacuum ~B~p~o 01 = 70 C).
Colourless oil.
Yield: 8.8 g (96 % of the theoretical) Analysis: C17H22N2OS MW: 302.44 Calculated: C = 67.51 % H = 7.33 ~ N = 9.26 % S = 10.60 %
~,~
.
~l~Z8~3 g Observed: C = 67.55 % H = 7.36 % N = 9.21 % S = 10.56 %
H-NMR (C~13): 0.95 to 1.30 (t, 2CH3), 2.55 to 3.0 (q, 2CH2), 4.2 (s,CH2), 7.2 to 8.2 (m, arom. CH) IR (film): 3070, 2970, 2930, 1470, 1410, 1380, 1240, (N=S=0 asym.), 1210. 1130 (N-S=0 sym.), 1100, 1070 1030, 1000, 760, 730, N-(N'diethyl methylammonium methyl)-S,S-diphenyl sulphoximide bromide:
6 g (0.02 mole) of N-diethylaminomethyl-S, S-diphenyl sulphoximide are dissolved in 150 ml of anhydrous acetonitrile and the resulting solution is cooled to around -40C in an inert gas atmosphere. 9.5 g (0.1 mole) of methyl bromide are added to the intensively stirred solution, followed by stirring for about 12 hours with gradual heating to room temperature. The solvent is then removed in a rotary evaporator.
The residue is purified by recrystallisation from acetonitrile~
ether.
Colourless crystals. M.p.: 94 to 95C
Yield: 7.7 g (97% of the theoretical) Analysis: C18H25BrN2OS MW: 397.38 Calculated: C = 54.41 % H = 6.34 % N - 7-05 % S = 8.07 %
Br = 20.11 %
Observed: C = 54 35 % H = 6.28 % N = 7.11 % S = 8.12 %
Br = 20.20 %
H-NMR (CDC13): 1.1 to 1.6 (t, 2CH3), 3 2 Is, CH3), 3.3 to 3.8 (q, 2CH2), 4.65 (s, CH2), 7.2 to 8.2 (m, arom. CH).
IR (KBr): 3090, 3010, 2980, 1635, 1485, 1500, 1390, 1250 (N=S=0 asym.), 1220, 1165, IN=S=0 sym.), 1100, 1050, 1000, 905, 815, 770, 745.
8~3 N- piperidinomethyl-S,S-diphenyl sulphoximide:
10 9 g (0.05 mole) of S,S-diphenyl sulphoximide, 4.3 g (0.05 mole) of piperidine and 6 g of 35 % formaldehyde solution are boiled in 100 ml of benzene in a water separator until the calculated quantity of water has been separated (approximately
2 to 3 hours). The benzene is then evaporated and the residual oil is distllled in a fine vacuum (B~p~ o o1=65C).
Yield: 15 g (95 ~ of the theoretical).
Analysis: C18H22N2OS MW: 314.45 Calculated C = 68.75 % H = 7.05 ~ N = 8.91 % S = 10.20 ~
Observed: C = 68.78 % H = 7.07 ~ N = 8.99 % S = 10.28 %
H-NMR (CDC13): 1.2 to 1.8 and 2.3 to 2.9 (m, piperidine), 4.02 (s,CH2), 7.2 to 8.2 (m, arom CH).
15 IR (Film): 3050, 2920, 2840, 1575, 1470, 1440, 1365, 1300, 1235, (N-S=0 asym.), 1200, 1130, (N-S=0 sym.), 1100, 1060, 1035, 1020, 990, 870, 860, 760, 725.
N-(N'-methyl-piperidinium-methyl)-S,S-diphenyl sulphoximide bromide:
9.4 g ~0 03 mole) of N-piperidinomethyl-S,S-diphenyl sulphoximide are dissolved in 200 m' of anhydrous acetonitrile and the resulting solution cooled to around -40C in an inert gas atmosphere. 14.5 g (0.15 Mole) of methyl bromide are added to the intensively stirred solution, followed by stirring for about 12 hours with gradual heating to room temperature. The solvent is then removed in a rotary evaporator. The residue is purified by recrystallisation from acetonitrile~ether.
30 Colourless crystals. M.p.: 104 to 105 C.
Yield: 12 g (98 % of the theoretical).
Analysis: ClgH25BrN2Os MW: 409.39 i~2~ 3 Calculated: C = 55.74 % H = 6.15 % N = 6.84 % S 3 7.83 ~
sr = 19. 52%
r)hserved: C = 55.80 % H - 6.21 % N = 6.87 % S = 7.88 %
Br = 19. 60%
5~ NMR (CDC13): 1.6 to 2.2 and 3.5 to 4.1 (m, piperidine), 4 8 (s , CH2), 7.3 to 8.3 (m, arom. CH ) .
IR (KBr): 3050j 2960, 2940, 1450, 1320, 1300, 1280, 1250 (N=S=0 asym.), 1190, 1175, (N=S=0 sym . ), 1150, 1095, 1035, 1000, 950, 885, 825, 775, 735.
10 ~: YAMPLE 8 ,~_ .-morpholinomethyl-S,S-diphenyl sulphoximide:
2.2 g (0.01 mole) of S,S-diphenyl sulphoximide, 1.3 g (0.015 mole) of morpholine and 1.5 g of 35 ~ formaldehyde solution are boiled in 50 ml of benzene in a water separator 15 until the calculated quantity of water has been separated (approximately 4 hours). Concentration of the benzene by evaporation leaves a thick oil consisting of a mixture of N-morpholinomethyl~S~S~diphen~l sulphoximide ana bis-morpholino methane as secondary product. The secondary product is 20 distilled off in a fine vacuum ~B~p~ o ol=60C). The residue consists of N-morpholinomethyl-S,S-diphenyl sulphoximide.
Pale yellow coloured oil.
~rield: 2.4 g ~76% of the theoretical).
Analysis: C17H20N202S MW: 316.42 25 Calculatecl:C = 64.53 % H = 6.37 % N = 8.85 % S = 10.13 %
Observed: C = 64.59 % H = 6.43 % N = 8.93 % S = 10.20 %
H-NMR (CDC13): 2.50 to 2.82 and 3.60 to 3.92 (m, morpholine), 4.0 (s,CH2), 7.2 to 8.2 (m, arom CH).
IR (Film): 3040, 2940, 2900, 2815, 1575, 1465, 1440, 1390, 1355, 1225, (N=S=O asym.), 1120, (N=S=O sym. ), 1065, 995, 855, 800, 755, 720.
2B ~3 N-(N'-methyl-morpholinium-methyl)-S,S-diphenyl sulphoximide bromide:
9.5 g (0.03 mole) of N-morpholinomethyl-S,S-diphenyl sulphoximide are dissolved in 200 ml of anhydrous acetonitrile and the resulting solution cooled to around -40C in an inert gas atmosphere. 14.5 g (0.15 mole) of methyl bromide are added to the intensively stirred solution, followed by stirring for about 12 hours with gradual heating to room temperature. The solvent is then removed in a rotary evaporator. The residue is purified by recrystallisation from anhydrous acetonitrile~ether.
Colourless crystals. Highly hygroscopic.
M.p.: approximately room temperature.
Yield: 11 g (90 % of the theoretical).
H-~MR (CDC13): 2.55 to 2.8 and 4.0 to 4.25 (m, morpholine),
Yield: 15 g (95 ~ of the theoretical).
Analysis: C18H22N2OS MW: 314.45 Calculated C = 68.75 % H = 7.05 ~ N = 8.91 % S = 10.20 ~
Observed: C = 68.78 % H = 7.07 ~ N = 8.99 % S = 10.28 %
H-NMR (CDC13): 1.2 to 1.8 and 2.3 to 2.9 (m, piperidine), 4.02 (s,CH2), 7.2 to 8.2 (m, arom CH).
15 IR (Film): 3050, 2920, 2840, 1575, 1470, 1440, 1365, 1300, 1235, (N-S=0 asym.), 1200, 1130, (N-S=0 sym.), 1100, 1060, 1035, 1020, 990, 870, 860, 760, 725.
N-(N'-methyl-piperidinium-methyl)-S,S-diphenyl sulphoximide bromide:
9.4 g ~0 03 mole) of N-piperidinomethyl-S,S-diphenyl sulphoximide are dissolved in 200 m' of anhydrous acetonitrile and the resulting solution cooled to around -40C in an inert gas atmosphere. 14.5 g (0.15 Mole) of methyl bromide are added to the intensively stirred solution, followed by stirring for about 12 hours with gradual heating to room temperature. The solvent is then removed in a rotary evaporator. The residue is purified by recrystallisation from acetonitrile~ether.
30 Colourless crystals. M.p.: 104 to 105 C.
Yield: 12 g (98 % of the theoretical).
Analysis: ClgH25BrN2Os MW: 409.39 i~2~ 3 Calculated: C = 55.74 % H = 6.15 % N = 6.84 % S 3 7.83 ~
sr = 19. 52%
r)hserved: C = 55.80 % H - 6.21 % N = 6.87 % S = 7.88 %
Br = 19. 60%
5~ NMR (CDC13): 1.6 to 2.2 and 3.5 to 4.1 (m, piperidine), 4 8 (s , CH2), 7.3 to 8.3 (m, arom. CH ) .
IR (KBr): 3050j 2960, 2940, 1450, 1320, 1300, 1280, 1250 (N=S=0 asym.), 1190, 1175, (N=S=0 sym . ), 1150, 1095, 1035, 1000, 950, 885, 825, 775, 735.
10 ~: YAMPLE 8 ,~_ .-morpholinomethyl-S,S-diphenyl sulphoximide:
2.2 g (0.01 mole) of S,S-diphenyl sulphoximide, 1.3 g (0.015 mole) of morpholine and 1.5 g of 35 ~ formaldehyde solution are boiled in 50 ml of benzene in a water separator 15 until the calculated quantity of water has been separated (approximately 4 hours). Concentration of the benzene by evaporation leaves a thick oil consisting of a mixture of N-morpholinomethyl~S~S~diphen~l sulphoximide ana bis-morpholino methane as secondary product. The secondary product is 20 distilled off in a fine vacuum ~B~p~ o ol=60C). The residue consists of N-morpholinomethyl-S,S-diphenyl sulphoximide.
Pale yellow coloured oil.
~rield: 2.4 g ~76% of the theoretical).
Analysis: C17H20N202S MW: 316.42 25 Calculatecl:C = 64.53 % H = 6.37 % N = 8.85 % S = 10.13 %
Observed: C = 64.59 % H = 6.43 % N = 8.93 % S = 10.20 %
H-NMR (CDC13): 2.50 to 2.82 and 3.60 to 3.92 (m, morpholine), 4.0 (s,CH2), 7.2 to 8.2 (m, arom CH).
IR (Film): 3040, 2940, 2900, 2815, 1575, 1465, 1440, 1390, 1355, 1225, (N=S=O asym.), 1120, (N=S=O sym. ), 1065, 995, 855, 800, 755, 720.
2B ~3 N-(N'-methyl-morpholinium-methyl)-S,S-diphenyl sulphoximide bromide:
9.5 g (0.03 mole) of N-morpholinomethyl-S,S-diphenyl sulphoximide are dissolved in 200 ml of anhydrous acetonitrile and the resulting solution cooled to around -40C in an inert gas atmosphere. 14.5 g (0.15 mole) of methyl bromide are added to the intensively stirred solution, followed by stirring for about 12 hours with gradual heating to room temperature. The solvent is then removed in a rotary evaporator. The residue is purified by recrystallisation from anhydrous acetonitrile~ether.
Colourless crystals. Highly hygroscopic.
M.p.: approximately room temperature.
Yield: 11 g (90 % of the theoretical).
H-~MR (CDC13): 2.55 to 2.8 and 4.0 to 4.25 (m, morpholine),
3.3 (s, CH3), 4.95 (s,CH2), 7.4 to 8.4 (m, arom. CH).
Claims (4)
1. A process for the preparation of substituted sulphoximides of the general formula in which R1 and R2 independently of each other represent phenyl, R3 and R4 which may be the same or different represent optionally substituted straight chain or branched lower alkyl, or together with the nitrogen atom, form a pyrrolidino, piperidino or morpholino ring, R5 represents a hydrogen atom or a straight chain or branched lower alkyl group, X is an inorganic or organic anion of a physiologically compatible acid and n has the value 0 or 1 which comprises reacting an S,S-diaryl sulphoximide of the general formula II
in which R1 and R2 have the above-stated meanings with formaldehyde and a secondary amine of the general formula in which R3 and R4 have the above-stated meanings, optionally with subsequent conversion to the tertiary salt when n is by reaction with a compound R5X in which R5 and X have the above-stated meanings.
in which R1 and R2 have the above-stated meanings with formaldehyde and a secondary amine of the general formula in which R3 and R4 have the above-stated meanings, optionally with subsequent conversion to the tertiary salt when n is by reaction with a compound R5X in which R5 and X have the above-stated meanings.
2. A process as claimed in claim 1 in which the first-named reaction is carried out in a water immiscible solvent.
3. A process as claimed in claim 1 in which the first-named reaction is carried out in a water immiscible solvent with azeotropic removal of water formed in the reaction.
4. Compounds of formula I as defined in claim 1 when prepared by a process as claimed in any one of claims 1 to 3 or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA345,046A CA1102803A (en) | 1980-02-04 | 1980-02-04 | Process for the production of substituted sulphoximides |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA345,046A CA1102803A (en) | 1980-02-04 | 1980-02-04 | Process for the production of substituted sulphoximides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1102803A true CA1102803A (en) | 1981-06-09 |
Family
ID=4116177
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA345,046A Expired CA1102803A (en) | 1980-02-04 | 1980-02-04 | Process for the production of substituted sulphoximides |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1102803A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991010648A1 (en) * | 1990-01-06 | 1991-07-25 | Pfizer Limited | Diphenylsulphoximine muscarinic receptor antagonists |
-
1980
- 1980-02-04 CA CA345,046A patent/CA1102803A/en not_active Expired
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1991010648A1 (en) * | 1990-01-06 | 1991-07-25 | Pfizer Limited | Diphenylsulphoximine muscarinic receptor antagonists |
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