CA2485428A1 - A process for the preparation of modafinil - Google Patents
A process for the preparation of modafinil Download PDFInfo
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- CA2485428A1 CA2485428A1 CA002485428A CA2485428A CA2485428A1 CA 2485428 A1 CA2485428 A1 CA 2485428A1 CA 002485428 A CA002485428 A CA 002485428A CA 2485428 A CA2485428 A CA 2485428A CA 2485428 A1 CA2485428 A1 CA 2485428A1
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- diphenylmethyl
- sulfinyl
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- acetate
- acetic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C315/00—Preparation of sulfones; Preparation of sulfoxides
- C07C315/02—Preparation of sulfones; Preparation of sulfoxides by formation of sulfone or sulfoxide groups by oxidation of sulfides, or by formation of sulfone groups by oxidation of sulfoxides
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Optical Modulation, Optical Deflection, Nonlinear Optics, Optical Demodulation, Optical Logic Elements (AREA)
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Abstract
A process for the preparation of 2-[(diphenylmethyl)sulfinyl]acetamide (I) comprising the oxidation of sodium 2-[(diphenylmethyl)sulfenyl]acetate to th e corresponding sulfoxide and the derivatization of the latter to amide.</SDOA B>
Description
A PROCESS FOR THE PREPARATION OF MODAFINIL
FIELD OF THE INVENTION
The present invention relates psychostimulants, in particular to a novel process for the preparation of 2-[(diphenylmethyl)sulfinyl]acetarnide (1), also known as modafinil.
TECHNOLOGICAL BACKGROUND
Modafmil (1) is an al-adrenergic agonist having psychostimulant activity, used for the treatment of idiopathic narcoplepsy.
NHZ
S
(1) At present, a number of known synthetic procedures (US 4,177,290, FR
2582038 and EP 0283362) involve as key intermediate 2-[(diphenylmethyl)sulfenyl]acetic acid chloride (2), which is converted to amide (3) by treatment with ammonia and is then oxidized with hydrogen peroxide (scheme 1) Scheme 1 /
NH3 Hz02 COCl ~ ~ ~ S~CONHz ---~ (1) (2) (3) All these methods share the fact that oxidation with hydrogen peroxide is not selective to the sulfoxide, but also affords the sulfone (4):
FIELD OF THE INVENTION
The present invention relates psychostimulants, in particular to a novel process for the preparation of 2-[(diphenylmethyl)sulfinyl]acetarnide (1), also known as modafinil.
TECHNOLOGICAL BACKGROUND
Modafmil (1) is an al-adrenergic agonist having psychostimulant activity, used for the treatment of idiopathic narcoplepsy.
NHZ
S
(1) At present, a number of known synthetic procedures (US 4,177,290, FR
2582038 and EP 0283362) involve as key intermediate 2-[(diphenylmethyl)sulfenyl]acetic acid chloride (2), which is converted to amide (3) by treatment with ammonia and is then oxidized with hydrogen peroxide (scheme 1) Scheme 1 /
NH3 Hz02 COCl ~ ~ ~ S~CONHz ---~ (1) (2) (3) All these methods share the fact that oxidation with hydrogen peroxide is not selective to the sulfoxide, but also affords the sulfone (4):
S~~o CONHz / O
(4) US 4,177,290 discloses an alternative process for the application on an industrial scale (scheme 2). Benzhydrol (5), thiourea (6) and 2-chloroacetic acid (7) are reacted in the presence of hydrobromic acid to obtain 2-[(diphenylmethyl)sulfenyl]acetic acid (8), which is oxidized with hydrogen peroxide to afford 2-[2-[(diphenylmethyl)sulfmyl]acetic acid (9). This is reacted with NaHC03 and dimethyl sulfate and the resulting methyl ester (10) is converted to modafinil by treatment with ammonia.
Scheme 2 (5) (6) (~) (8) I i I i MezS04 ~S COOH ~ I ~ S~COOMe --~ (1) I / O NaHC03 / p i i HS NH Cl COOH H Br HzOz I OH + ~ + a ~ S~COOH
/ NHz (9) (10) However, the final product is difficult to purify from 2-[2-[(diphenylmethyl)sulfinyl]acetic acid (9) and the methyl ester (10) thereof (two recrystallization steps are necessary) and the overall process yield is 41%. Moreover, the process involves the use of dimethyl sulfate, which is a cancerogenic reagent.
According to EP 0233106 and US 4,927,855, concerning modafmil optically active forms, optically active 2-[2-[(diphenylmethyl)sulfinyl]acetic acid (9) is converted to the methyl ester (10) with NaHC03 and dimethyl sulfate, then is subjected to a transamidation reaction with ammonia.
WO 02/10125 discloses a method for the preparation of modafinil and its polymorphs by oxidation of 2-[(diphenylmethyl)sulfenyl]acetamide (3) with hydrogen peroxide in the presence of a mineral acid and of an alcohol or a phase transfer catalyst; this overcomes the problem of overoxidation.
However, a recrystallization step is necessary to obtain the final product with pharmaceutically acceptable purity. It would therefore be advantageous to provide a method which not only prevents the sulfone formation, but also directly affords modafmil with a pharmaceutically acceptable purity.
DETAILED DISCLOSURE OF THE INVENTION
The present invention relates to a process for the preparation of 2-[(diphenylmethyl)sulfinyl ]acetamide (1) ~2 S
/
(1) comprising the following steps:
a) oxidation of sodium 2-[(diphenylmethyl)sulfenyl]acetate (11) S~COONa (11) with sodium hypochlorite to give sodium 2-[(diphenylmethyl)sulfinyl]acetate (12);
S~COONa / O
(12) b) hydrolysis of sodium 2-[(diphenylmethyl)sulfmyl]acetate (12) to give 2-[(diphenylmethyl)sulfmyl]acetic acid (9);
COOH
c) conversion of 2-[(diphenylmethyl)sulfinyl]acetic acid to 2-[(diphenylmethyl)sulfinyl]acetamide by treatment with a condensing agent and ammonia.
. Sodium 2-[(diphenylmethyl)sulfenyl]acetate (11) is a l~nown compound, in particular compound (15) is obtained as described in Zhongguo Yaowu Huaxue Zazhi, 9(2), 132-134 (1999) (scheme 3).
Scheme 3 /
base HS~COOEt Cl (14) ~ ~ S~COOEt / / (15) (13) a S~COONa (11) Reaction of diphenylchloromethane (13) and ethyl mercaptoacetate (14) in the presence of a base and at temperatures ranging from -10°C to 80°C, preferably from 0°C to 50°C, affords 2-[(diphenylmethyl)sulfenyl]acetic acid ethyl ester (15) in yields higher than 70%.
5 The reaction is carried out in the presence of bases such as alkali and alkaline-earth oxides and hydroxides, alkali and alkaline-earth carbonates and bicarbonates, alkoxides and alkoxides in alcoholic solution, in amounts ranging from 1 to 5 equivalents, preferably from 1.1 to 2 equivalents.
The solvent can be selected from toluene, chlorinated solvents, preferably dichloromethane, esters, preferably ethyl acetate, ethers, preferably diethyl ether, tetrahydrofuran, dipolar aprotic solvents, preferably dimethylformamide, cyclohexane, alcohols, preferably methanol, ethanol and isopropanol, ketones, preferably acetone, or a mixture thereof, in amounts ranging from 1 to 10 volumes, preferably from 3 to 6 volumes.
In the process of the present invention the ester of formula (15) is not isolated, but is directly hydrolysed to give the sodium salt (11) in the presence of aqueous solutions of oxides, hydroxides, alkali and alkaline-earth carbonates and bicarbonates in amounts ranging from 1 to 5 equivalents, preferably from 1.1 to 2 equivalents.
According to the invention, oxidation of salt (11) is performed distilling off the water-solvent mixture, taking up the residue with water and treating with a sodium hypochlorite aqueous solution at concentrations ranging from 2 to 30%, preferably from 5 to 15%, in amounts ranging from 1 to 5 equivalents, preferably from 1.1 to 2 equivalents. The reaction is carried out at temperatures ranging from -10 to ~0°C, preferably from 10 to 60°C.
After completion of the reaction, the mixture is extracted with an organic solvent, preferably toluene, and the aqueous phase is acidified with mineral ~ acids such as hydrochloric, sulfuric, phosphoric acids, preferably sulfuric acid, to give the corresponding 2-[(diphenylmethyl)sulfmyl]acetic acid (9), in yields of 75-80% on the isolated product, in substantially pure form and free from the corresponding sulfone. Intermediate compound sodium 2-[(diphenylmethyl)sulfinyl]acetate (12), which can optionally be isolated, is novel and is a further obj ect of the invention.
Transformation of acid (9) into modafinil is carried out by treatment with condensing agents and ammonia. The conventional method of chemical activation of the carboxylic group, i.e. the transformation of the acid into the corresponding chloride, is not compatible with the sulfoxide group (see Oae "Organic Chemistry of Sulfur" Plenum Press N.Y. 1977 page 406), which would be reduced to sulfide under these conditions.
The condensing agent is preferably selected from N,N'-carbonyldiimidazole, N,N'-carbonylditriazole, dicyclohexylcarbodiimide, preferably N,N'-carbonyldiimidazole, in amounts ranging from 1 to 5 equivalents, preferably from 1.1 to 2.0 equivalents. The reaction solvent is selected from toluene, chlorinated solvents, preferably dichloromethane, esters, preferably ethyl acetate, ethers, preferably diethyl ether, tetrahydrofuran, dipolar aprotic solvents, preferably dimethylformamide, cyclohexane, ketones, preferably acetone, in amounts ranging from 1 to 10 volumes, preferably from 3 to 6 volumes. According to a preferred embodiment of the invention the solvent is dichloromethane. The reaction is carried out at a temperature ranging from -10 to 50°C, preferably from 0 to 20°C.
The reaction proceeds through a reactive intermediate which is not isolated and which is reacted with gas ammonia at a temperature ranging from -10 to 30°C, preferably from 0 to 10°C, to yield modafmil.
Ammonia can be used either in gaseous phase or in aqueous solution, at concentrations ranging from 5 to 30% and in amounts ranging from 1 to 5 equivalents, preferably from 1.2 to 2 equivalents.
The product is obtained in yields of 70-75% with respect to [(diphenylmethyl)sulfinyl]acetic acid and with % HPLC purity > 99.5%.
The invention is illustrated in greater detail by the following examples.
EXAMPLES
Example l: preparation of 2-f (diphenvlmethvl)sulfinvllacetic acidW91 81.5 g of a 21% sodium ethoxide solution in ethanol (0.237 mols of sodium ethoxide), kept under inert atmosphere, is added with 28.6 g (0.237 mols) of ethyl mercaptoacetate (14). The stirred mixture is heated to 30-35°C
inner temperature and 45 g (0.22 mols) of diphenylchloromethane (13) are added thereto in 15'. After completion of the addition, the mass is kept under stirring at 30-35°C for 4h. After completion of the reaction, 24 ml of a 30%
sodium hydroxide solution (0.239 moll) are added in 15=20', keeping the inner temperature at 30=35°C. After completion of the addition, the mixture is kept under stirring for about 30', then solvents are distilled off until reaching inner temperature of 100°C, gradually adding an equal volume of water to the distillate during the operation.
The mass is cooled to 40=45°C inner temperature and 360 ml of a 5%
sodium hypochlorite aqueous solution (0.24 mols) are added, in about 2 hours.
15' After the end of the addition, the mass is cooled to 20=25°C inner temperature, added with 180 ml of toluene and acidified with 88 ml of 50%
sulfuric acid, keeping pH at 2; the precipitated product is filtered, washed with water to neutrality, then squeezed and dried in oven under vacuum at a temperature of 55=60°C, thereby obtaining 44 g (0.16 mols) of 2-[(diphenylmethyl)sulfinyl]acetic acid (9) (yield: 73%).
1H-NMR (CDC13, 8 ppm): 3.20=3.25 (d, 1H); 3.63-3.68 (d, 1H) (J = 12 Hz); 5.29 (s, 1H); 7.38=7.49 (m, 10 H) Example 2: preparation of 2-[(diphenylmethyl)sulfinyl]acetamide modafinil Method 1 A solution of 10 g (0.036 mots) of 2-[(diphenylmethyl)sulfinyl]acetic acid (9) in 66 g of dichloromethane cooled at 15°C is added with 6.8 g (0.042 mols) of N,N'-carbonyldiimidazole in 5 portions of 1.3 g each. After completion of the addition, the mass is cooled to 0-5°C and gas ammonia is bubbled therein. After that, the inner temperature is brought to 20-25°C
keeping these conditions for about 30', then the mixture is diluted with 50 ml of water. The phases are separated, the organic phase is added with 40 ml of water and dichloromethane is distilled off at atmospheric pressure.
The mass is cooled to 20-25°C and added with 20 ml of ethyl acetate, keeping stirring for about 1 hour; the precipitate is filtered, washed with water to obtain 6.9 g (0.025 mols) of 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) (yield: 70%, HPLC purity >99.5%).
1H-NMR (CDCl3, 8 ppm): 3.22-3.27 (d, 1H); 3.63=3.68 (d, 1H) (J = 12 Hz); 5.32 (s, 1H); 7.38=7.49 (m, 10 H).
Example 3: preparation of 2-[(diphen~hyl)sulfinyllacetamide (modafinil~
Method Z
A solution of 20 g (0.073 mols) of 2-[(diphenylmethyl)sulfinyl]acetic acid (9) in 132 g of dichloromethane cooled at 15°C is added with 13.6 g (0.084 mols) of N,N'-carbonyldiimidazole in 5 portions of 2.7 g each. After completion of the addition, the mass is cooled to 0-5°C and added with ml (1.06 mols) of a 15% aqueous ammonia solution. After that, the inner temperature is brought to 20-25°C keeping these conditions for about 30', then the mixture is diluted with 100 ml of water. The phases are separated, the lower organic phase is added with 80 ml of water and dichloromethane is distilled off at atmospheric pressure.
The mass is cooled to 20-25°C and added with 40 ml of ethyl acetate, keeping stirring for about 1 hour; the precipitate is filtered and washed with water to obtain 14.4 g of 2-[(diphenylmethyl)sulfmyl]acetamide (modafinil) (yield: 72.2%, HPLC purity > 99.5%).
1H-NMR (CDC13, d ppm): 3.22=3.27 (d, 1H); 3.63-3.68 (d, 1H) (J = 12 Hz); 5.32 (s, 1H); 7.38=7.49 (m, 10 H).
Scheme 2 (5) (6) (~) (8) I i I i MezS04 ~S COOH ~ I ~ S~COOMe --~ (1) I / O NaHC03 / p i i HS NH Cl COOH H Br HzOz I OH + ~ + a ~ S~COOH
/ NHz (9) (10) However, the final product is difficult to purify from 2-[2-[(diphenylmethyl)sulfinyl]acetic acid (9) and the methyl ester (10) thereof (two recrystallization steps are necessary) and the overall process yield is 41%. Moreover, the process involves the use of dimethyl sulfate, which is a cancerogenic reagent.
According to EP 0233106 and US 4,927,855, concerning modafmil optically active forms, optically active 2-[2-[(diphenylmethyl)sulfinyl]acetic acid (9) is converted to the methyl ester (10) with NaHC03 and dimethyl sulfate, then is subjected to a transamidation reaction with ammonia.
WO 02/10125 discloses a method for the preparation of modafinil and its polymorphs by oxidation of 2-[(diphenylmethyl)sulfenyl]acetamide (3) with hydrogen peroxide in the presence of a mineral acid and of an alcohol or a phase transfer catalyst; this overcomes the problem of overoxidation.
However, a recrystallization step is necessary to obtain the final product with pharmaceutically acceptable purity. It would therefore be advantageous to provide a method which not only prevents the sulfone formation, but also directly affords modafmil with a pharmaceutically acceptable purity.
DETAILED DISCLOSURE OF THE INVENTION
The present invention relates to a process for the preparation of 2-[(diphenylmethyl)sulfinyl ]acetamide (1) ~2 S
/
(1) comprising the following steps:
a) oxidation of sodium 2-[(diphenylmethyl)sulfenyl]acetate (11) S~COONa (11) with sodium hypochlorite to give sodium 2-[(diphenylmethyl)sulfinyl]acetate (12);
S~COONa / O
(12) b) hydrolysis of sodium 2-[(diphenylmethyl)sulfmyl]acetate (12) to give 2-[(diphenylmethyl)sulfmyl]acetic acid (9);
COOH
c) conversion of 2-[(diphenylmethyl)sulfinyl]acetic acid to 2-[(diphenylmethyl)sulfinyl]acetamide by treatment with a condensing agent and ammonia.
. Sodium 2-[(diphenylmethyl)sulfenyl]acetate (11) is a l~nown compound, in particular compound (15) is obtained as described in Zhongguo Yaowu Huaxue Zazhi, 9(2), 132-134 (1999) (scheme 3).
Scheme 3 /
base HS~COOEt Cl (14) ~ ~ S~COOEt / / (15) (13) a S~COONa (11) Reaction of diphenylchloromethane (13) and ethyl mercaptoacetate (14) in the presence of a base and at temperatures ranging from -10°C to 80°C, preferably from 0°C to 50°C, affords 2-[(diphenylmethyl)sulfenyl]acetic acid ethyl ester (15) in yields higher than 70%.
5 The reaction is carried out in the presence of bases such as alkali and alkaline-earth oxides and hydroxides, alkali and alkaline-earth carbonates and bicarbonates, alkoxides and alkoxides in alcoholic solution, in amounts ranging from 1 to 5 equivalents, preferably from 1.1 to 2 equivalents.
The solvent can be selected from toluene, chlorinated solvents, preferably dichloromethane, esters, preferably ethyl acetate, ethers, preferably diethyl ether, tetrahydrofuran, dipolar aprotic solvents, preferably dimethylformamide, cyclohexane, alcohols, preferably methanol, ethanol and isopropanol, ketones, preferably acetone, or a mixture thereof, in amounts ranging from 1 to 10 volumes, preferably from 3 to 6 volumes.
In the process of the present invention the ester of formula (15) is not isolated, but is directly hydrolysed to give the sodium salt (11) in the presence of aqueous solutions of oxides, hydroxides, alkali and alkaline-earth carbonates and bicarbonates in amounts ranging from 1 to 5 equivalents, preferably from 1.1 to 2 equivalents.
According to the invention, oxidation of salt (11) is performed distilling off the water-solvent mixture, taking up the residue with water and treating with a sodium hypochlorite aqueous solution at concentrations ranging from 2 to 30%, preferably from 5 to 15%, in amounts ranging from 1 to 5 equivalents, preferably from 1.1 to 2 equivalents. The reaction is carried out at temperatures ranging from -10 to ~0°C, preferably from 10 to 60°C.
After completion of the reaction, the mixture is extracted with an organic solvent, preferably toluene, and the aqueous phase is acidified with mineral ~ acids such as hydrochloric, sulfuric, phosphoric acids, preferably sulfuric acid, to give the corresponding 2-[(diphenylmethyl)sulfmyl]acetic acid (9), in yields of 75-80% on the isolated product, in substantially pure form and free from the corresponding sulfone. Intermediate compound sodium 2-[(diphenylmethyl)sulfinyl]acetate (12), which can optionally be isolated, is novel and is a further obj ect of the invention.
Transformation of acid (9) into modafinil is carried out by treatment with condensing agents and ammonia. The conventional method of chemical activation of the carboxylic group, i.e. the transformation of the acid into the corresponding chloride, is not compatible with the sulfoxide group (see Oae "Organic Chemistry of Sulfur" Plenum Press N.Y. 1977 page 406), which would be reduced to sulfide under these conditions.
The condensing agent is preferably selected from N,N'-carbonyldiimidazole, N,N'-carbonylditriazole, dicyclohexylcarbodiimide, preferably N,N'-carbonyldiimidazole, in amounts ranging from 1 to 5 equivalents, preferably from 1.1 to 2.0 equivalents. The reaction solvent is selected from toluene, chlorinated solvents, preferably dichloromethane, esters, preferably ethyl acetate, ethers, preferably diethyl ether, tetrahydrofuran, dipolar aprotic solvents, preferably dimethylformamide, cyclohexane, ketones, preferably acetone, in amounts ranging from 1 to 10 volumes, preferably from 3 to 6 volumes. According to a preferred embodiment of the invention the solvent is dichloromethane. The reaction is carried out at a temperature ranging from -10 to 50°C, preferably from 0 to 20°C.
The reaction proceeds through a reactive intermediate which is not isolated and which is reacted with gas ammonia at a temperature ranging from -10 to 30°C, preferably from 0 to 10°C, to yield modafmil.
Ammonia can be used either in gaseous phase or in aqueous solution, at concentrations ranging from 5 to 30% and in amounts ranging from 1 to 5 equivalents, preferably from 1.2 to 2 equivalents.
The product is obtained in yields of 70-75% with respect to [(diphenylmethyl)sulfinyl]acetic acid and with % HPLC purity > 99.5%.
The invention is illustrated in greater detail by the following examples.
EXAMPLES
Example l: preparation of 2-f (diphenvlmethvl)sulfinvllacetic acidW91 81.5 g of a 21% sodium ethoxide solution in ethanol (0.237 mols of sodium ethoxide), kept under inert atmosphere, is added with 28.6 g (0.237 mols) of ethyl mercaptoacetate (14). The stirred mixture is heated to 30-35°C
inner temperature and 45 g (0.22 mols) of diphenylchloromethane (13) are added thereto in 15'. After completion of the addition, the mass is kept under stirring at 30-35°C for 4h. After completion of the reaction, 24 ml of a 30%
sodium hydroxide solution (0.239 moll) are added in 15=20', keeping the inner temperature at 30=35°C. After completion of the addition, the mixture is kept under stirring for about 30', then solvents are distilled off until reaching inner temperature of 100°C, gradually adding an equal volume of water to the distillate during the operation.
The mass is cooled to 40=45°C inner temperature and 360 ml of a 5%
sodium hypochlorite aqueous solution (0.24 mols) are added, in about 2 hours.
15' After the end of the addition, the mass is cooled to 20=25°C inner temperature, added with 180 ml of toluene and acidified with 88 ml of 50%
sulfuric acid, keeping pH at 2; the precipitated product is filtered, washed with water to neutrality, then squeezed and dried in oven under vacuum at a temperature of 55=60°C, thereby obtaining 44 g (0.16 mols) of 2-[(diphenylmethyl)sulfinyl]acetic acid (9) (yield: 73%).
1H-NMR (CDC13, 8 ppm): 3.20=3.25 (d, 1H); 3.63-3.68 (d, 1H) (J = 12 Hz); 5.29 (s, 1H); 7.38=7.49 (m, 10 H) Example 2: preparation of 2-[(diphenylmethyl)sulfinyl]acetamide modafinil Method 1 A solution of 10 g (0.036 mots) of 2-[(diphenylmethyl)sulfinyl]acetic acid (9) in 66 g of dichloromethane cooled at 15°C is added with 6.8 g (0.042 mols) of N,N'-carbonyldiimidazole in 5 portions of 1.3 g each. After completion of the addition, the mass is cooled to 0-5°C and gas ammonia is bubbled therein. After that, the inner temperature is brought to 20-25°C
keeping these conditions for about 30', then the mixture is diluted with 50 ml of water. The phases are separated, the organic phase is added with 40 ml of water and dichloromethane is distilled off at atmospheric pressure.
The mass is cooled to 20-25°C and added with 20 ml of ethyl acetate, keeping stirring for about 1 hour; the precipitate is filtered, washed with water to obtain 6.9 g (0.025 mols) of 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) (yield: 70%, HPLC purity >99.5%).
1H-NMR (CDCl3, 8 ppm): 3.22-3.27 (d, 1H); 3.63=3.68 (d, 1H) (J = 12 Hz); 5.32 (s, 1H); 7.38=7.49 (m, 10 H).
Example 3: preparation of 2-[(diphen~hyl)sulfinyllacetamide (modafinil~
Method Z
A solution of 20 g (0.073 mols) of 2-[(diphenylmethyl)sulfinyl]acetic acid (9) in 132 g of dichloromethane cooled at 15°C is added with 13.6 g (0.084 mols) of N,N'-carbonyldiimidazole in 5 portions of 2.7 g each. After completion of the addition, the mass is cooled to 0-5°C and added with ml (1.06 mols) of a 15% aqueous ammonia solution. After that, the inner temperature is brought to 20-25°C keeping these conditions for about 30', then the mixture is diluted with 100 ml of water. The phases are separated, the lower organic phase is added with 80 ml of water and dichloromethane is distilled off at atmospheric pressure.
The mass is cooled to 20-25°C and added with 40 ml of ethyl acetate, keeping stirring for about 1 hour; the precipitate is filtered and washed with water to obtain 14.4 g of 2-[(diphenylmethyl)sulfmyl]acetamide (modafinil) (yield: 72.2%, HPLC purity > 99.5%).
1H-NMR (CDC13, d ppm): 3.22=3.27 (d, 1H); 3.63-3.68 (d, 1H) (J = 12 Hz); 5.32 (s, 1H); 7.38=7.49 (m, 10 H).
Claims (8)
1. A process for preparation of 2-[(diphenylmethyl)sulfinyl ]acetamide (1) comprising the following steps:
a) oxidation of sodium 2-[(diphenylmethyl)sulfenyl]acetate (11) with sodium hypochlorite to give sodium 2-[(diphenylmethyl)sulfinyl]acetate (12) b) hydrolysis of sodium 2-[(diphenylmethyl)sulfinyl]acetate to give 2-[(diphenylmethyl)sulfinyl]acetic acid (9) c) conversion of 2-[(diphenylmethyl)sulfinyl]acetic acid (9) to 2-[(diphenylmethyl)sulfinyl]acetamide (1) by treatment with a condensing agent and ammonia.
a) oxidation of sodium 2-[(diphenylmethyl)sulfenyl]acetate (11) with sodium hypochlorite to give sodium 2-[(diphenylmethyl)sulfinyl]acetate (12) b) hydrolysis of sodium 2-[(diphenylmethyl)sulfinyl]acetate to give 2-[(diphenylmethyl)sulfinyl]acetic acid (9) c) conversion of 2-[(diphenylmethyl)sulfinyl]acetic acid (9) to 2-[(diphenylmethyl)sulfinyl]acetamide (1) by treatment with a condensing agent and ammonia.
2. A process as claimed in claim 1, wherein the condensing agent is selected from N,N'-carbonyldiimidazole, N'N'-carbonylditriazole and dicyclohexylcarbodiimide.
3. A process as claimed in claim 2, wherein the condensing agent is N,N'-carbonyldiimidazole.
4. A process as claimed in claim 1, wherein the amount of sodium hypochlorite ranges from 1 to 5 equivalents.
5. A process as claimed in claim 4, wherein the amount of sodium hypochlorite ranges from 1.1 to 2 equivalents.
6. A process as claimed in claim 1, wherein sodium hypochlorite is used in aqueous solution at concentrations ranging from 2 to 30%.
7. A process as claimed in claim 6, wherein sodium hypochlorite is used in aqueous solution at concentrations ranging from 5 to 15%. sodium
8. Sodium 2-[(diphenylmethyl)sulfinyl]acetate.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2002MI000991A ITMI20020991A1 (en) | 2002-05-10 | 2002-05-10 | PROCEDURE FOR THE SYNTHESIS OF MODAFINIL |
| ITMI2002A000991 | 2002-05-10 | ||
| PCT/EP2003/004229 WO2003095423A1 (en) | 2002-05-10 | 2003-04-23 | A process for the preparation of modafinil |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2485428A1 true CA2485428A1 (en) | 2003-11-20 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002485428A Abandoned CA2485428A1 (en) | 2002-05-10 | 2003-04-23 | A process for the preparation of modafinil |
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| Country | Link |
|---|---|
| US (1) | US7057068B2 (en) |
| EP (1) | EP1503983B1 (en) |
| JP (1) | JP4351626B2 (en) |
| KR (1) | KR20040108789A (en) |
| AT (1) | ATE364593T1 (en) |
| AU (1) | AU2003227668A1 (en) |
| CA (1) | CA2485428A1 (en) |
| DE (1) | DE60314410T2 (en) |
| DK (1) | DK1503983T3 (en) |
| EA (1) | EA007327B1 (en) |
| ES (1) | ES2286429T3 (en) |
| IL (1) | IL165121A0 (en) |
| IT (1) | ITMI20020991A1 (en) |
| MX (1) | MXPA04011141A (en) |
| PL (1) | PL371679A1 (en) |
| PT (1) | PT1503983E (en) |
| WO (1) | WO2003095423A1 (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002010125A1 (en) | 2000-07-27 | 2002-02-07 | Teva Pharmaceutical Industries Ltd. | Crystalline and pure modafinil, and process of preparing the same |
| ITMI20051971A1 (en) * | 2005-10-18 | 2007-04-19 | Dipharma Spa | PROCEDURE FOR THE PREPARATION OF - MODAFINIL |
| EP1986994A2 (en) * | 2006-02-21 | 2008-11-05 | Teva Pharmaceutical Industries Ltd | Novel crystalline forms of armodafinil and preparation thereof |
| EP2159219A3 (en) * | 2006-03-01 | 2010-12-15 | Teva Pharmaceutical Industries Ltd. | An improved process for the preparation of armodafinil |
| KR20090031618A (en) * | 2006-07-12 | 2009-03-26 | 엘란 코포레이션, 피엘씨 | Nanoparticulate formulations of modafinil |
| WO2009025791A2 (en) * | 2007-08-16 | 2009-02-26 | Teva Pharmaceutical Industries Ltd. | Purification of armodafinil |
| EP1911739A3 (en) | 2007-11-05 | 2008-09-17 | Dipharma Francis S.r.l. | Crystalline form of (S)-2-phenylethylammonium (R)-diphenyl-methanesulphinyl-acetate |
| US9616068B2 (en) | 2014-10-27 | 2017-04-11 | Pohela LLC | Animal training using cognitive enhancement |
| CN114044730B (en) * | 2021-11-26 | 2024-04-23 | 台州学院 | Synthesis method of sulfoxide compound |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE221261C (en) | ||||
| DE2546319C2 (en) | 1975-10-16 | 1986-02-27 | Dr. Karl Thomae Gmbh, 7950 Biberach | Cyclohexylphenyl derivatives, processes for their preparation and agents containing them |
| GB1584462A (en) * | 1977-03-31 | 1981-02-11 | Lafon Labor | N-diaryl-malonamide and diarylmethyl-sulphinyl-acetamide derivatives and pharmaceutical compositions containing them |
| FR2593809B1 (en) * | 1986-01-31 | 1988-07-22 | Lafon Labor | BENZHYDRYLSULFINYLACETAMIDE, PROCESS FOR PREPARATION AND THERAPEUTIC USE |
| US4964893A (en) * | 1986-04-17 | 1990-10-23 | Monsanto Company | Benzhydryl compounds as herbicide antidotes |
| WO2002010125A1 (en) * | 2000-07-27 | 2002-02-07 | Teva Pharmaceutical Industries Ltd. | Crystalline and pure modafinil, and process of preparing the same |
-
2002
- 2002-05-10 IT IT2002MI000991A patent/ITMI20020991A1/en unknown
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2003
- 2003-04-23 PL PL03371679A patent/PL371679A1/en not_active IP Right Cessation
- 2003-04-23 AU AU2003227668A patent/AU2003227668A1/en not_active Abandoned
- 2003-04-23 KR KR10-2004-7018040A patent/KR20040108789A/en not_active Application Discontinuation
- 2003-04-23 WO PCT/EP2003/004229 patent/WO2003095423A1/en active IP Right Grant
- 2003-04-23 AT AT03725083T patent/ATE364593T1/en not_active IP Right Cessation
- 2003-04-23 DE DE60314410T patent/DE60314410T2/en not_active Expired - Lifetime
- 2003-04-23 ES ES03725083T patent/ES2286429T3/en not_active Expired - Lifetime
- 2003-04-23 EA EA200401235A patent/EA007327B1/en not_active IP Right Cessation
- 2003-04-23 US US10/513,881 patent/US7057068B2/en not_active Expired - Fee Related
- 2003-04-23 JP JP2004503444A patent/JP4351626B2/en not_active Expired - Fee Related
- 2003-04-23 EP EP03725083A patent/EP1503983B1/en not_active Expired - Lifetime
- 2003-04-23 PT PT03725083T patent/PT1503983E/en unknown
- 2003-04-23 CA CA002485428A patent/CA2485428A1/en not_active Abandoned
- 2003-04-23 MX MXPA04011141A patent/MXPA04011141A/en active IP Right Grant
- 2003-04-23 DK DK03725083T patent/DK1503983T3/en active
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| ES2286429T3 (en) | 2007-12-01 |
| AU2003227668A1 (en) | 2003-11-11 |
| KR20040108789A (en) | 2004-12-24 |
| ATE364593T1 (en) | 2007-07-15 |
| US7057068B2 (en) | 2006-06-06 |
| PL371679A1 (en) | 2005-06-27 |
| US20050154063A1 (en) | 2005-07-14 |
| PT1503983E (en) | 2007-07-31 |
| DK1503983T3 (en) | 2007-09-10 |
| MXPA04011141A (en) | 2005-07-01 |
| EA007327B1 (en) | 2006-08-25 |
| WO2003095423A1 (en) | 2003-11-20 |
| ITMI20020991A1 (en) | 2003-11-10 |
| DE60314410T2 (en) | 2008-02-14 |
| JP2005525420A (en) | 2005-08-25 |
| DE60314410D1 (en) | 2007-07-26 |
| EA200401235A1 (en) | 2005-06-30 |
| EP1503983A1 (en) | 2005-02-09 |
| ITMI20020991A0 (en) | 2002-05-10 |
| JP4351626B2 (en) | 2009-10-28 |
| EP1503983B1 (en) | 2007-06-13 |
| IL165121A0 (en) | 2005-12-18 |
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