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1
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With ammonia in methanol; water; toluene
T=30°C; 23.25 h; Hide Experimental Procedure
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Rx-ID: 6907730 Find similar reactions
Cephalon France; Organisation De Synthese Mondiale Orsymonde Patent: US2006/135621 A1, 2006 ; Location in patent: Page/Page column 22-23 ; Title/Abstract Full Text Show Details
32:
1.63 litres of methanol denatured with toluene, 0.1 litres of water and 425.1 g of methyl ester (1.474 moles) were placed in a 4 litre double jacket reactor. The temperature was raised to 30° C. and bubbling of ammonia was begun maintaining this temperature. The operation lasted 1 hour and 45 minutes and the mass of ammonia introduced was 200 g. Stirring was maintained for 21 hours 30 minutes, and then it was cooled with the temperature being set to 0° C. The medium was then filtered on No. 3 sintered glass and 57.2 g was obtained straight away, together with a filtrate which was evaporated to dryness. The residue was taken up in 1.2 litres of ethanol denatured with toluene and after filtration a second amount of 308.6 g was obtained. First crystallisation: The two amounts were pooled and recrystallised in 1.83 litres of ethanol denatured with toluene. Hot filtration yielded a filtrate which when cooled yielded a product which was filtered and dried under vacuum at 30° C. 162.2 g of a white product was obtained. Second crystallisation: These 162.2 g were mixed with 810 ml of ethanol denatured with toluene and heated under reflux to achieve complete dissolution. This was then allowed to crystallise by cooling with ice and then filtered through No. 4 sintered glass and dried under vacuum at 30° C. 147.3 g (-)-modafinil (CRL 40982) was obtained. Yield=36.6percent. Characteristics: Rotation power=-18.6 (4.9percent solution in methanol) Melting point=163° C.
2
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Rx-ID: 6907731 Find similar reactions
Cephalon France; Organisation De Synthese Mondiale Orsymonde
T=120°C; 3 h; Hide Experimental Procedure
Patent: US2006/135621 A1, 2006 ; Location in patent: Page/Page column 19 ; Title/Abstract Full Text Show Details
21:
The solvate of (-) or (+)-modafinil obtained in example 20 was converted into the amorphous form by heating at 120° C. for 3 hours. The powder X-ray diffraction spectrum obtained is shown in FIG. 16.
3
Synthesize Find similar 98.5%
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Stage #1: With titanium(IV) isopropylate; diethyl (2R,3R)-tartrate in water; toluene
T=55°C; 0.833333 h; Stage #2: With alpha,alpha-dimethylbenzyl hydroperoxide; N-ethyl-N,N-diisopropylamine in water; toluene
T=25°C; 1 h; Product distribution / selectivity; Hide Experimental Procedure
Rx-ID: 23230807 Find similar reactions
CEPHALON FRANCE
Patent: EP1516869 A1, 2005 ; Location in patent: Page/Page column 16 ; Title/Abstract Full Text Show Details
10:
Example 10 : Influence of the nature of the chiral ligand on the enantioselectivity The chiral ligands (R,R)-(+)-DET,(S,S)-(-)-DET,R-(-)-mandelic acid were tested, the other parameters being as defined in the above general procedure. [Table 10] EntryChiral ligandSolventsE. e. (percent)Purity (percent)Yield (percent)1(S,S)-(-)-DETethylacetate99>99.579.22(S,S)-(-)DETtoluene>99.5>99.588.43(R,R)-DETtoluene98.6>99.598.54R-(-)-mandelic acidethylacetate9.595.753 DET used as chiral ligand gives better enantioselectivity than mandelic acid under the conditions defined in the above general procedure. 90.3%
Stage #1: With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate in water; toluene
T=55°C; 0.833333 h; Stage #2: With alpha,alpha-dimethylbenzyl hydroperoxide; triethylamine in water; toluene
T=25°C; 1 h; Product distribution / selectivity; Hide Experimental Procedure
CEPHALON FRANCE
Patent: EP1516869 A1, 2005 ; Location in patent: Page/Page column 13; 15 ; Title/Abstract Full Text Show Details
4:
Asymmetric synthesis of (-)-2-(diphenylmethyl)sulphinylacetamideGeneral procedure for examples 1 to 10 : Diphenylmethylthioacetamide (7.70 g ; 0.03 mol ; 1.0 eq) was dissolved in the solvent (toluene ; 77 mL ; 10 vol.) under argon. To the solution were added (S,S)-(-)-diethyl-tartrate (1.23 g ; 0.006 mol; 0.2 eq) and titanium (IV) tetraisopropoxide (0.85 g ; 0.88 mL ; 0.003 mol; 0.1 eq) and water (27 μL minus the sum of water present in reactants and solvent already introduced ; 0.0015 mol ; 0.05 eq) at 55°C. In these conditions, the resulting chiral titanium complex has the stoichiometry (DET/Ti(OiPr)4/H2O : 2/1/0.5) and represents 0.1 eq of diphenylmethylthioacetamide. Stirring was maintained at 55°C during 50 minutes. After cooling to room temperature (25°C), were added to the mixture diisopropylethylamine (0.39 g ; 0.52 mL ; 0.003 mol ; 0.1 eq) and cumene hydroperoxide (4.55 g ; 5.0 mL ; 0.03 mol ; 1.0 eq). After contacting during about an hour, the formed precipitate is isolated by filtration. All the following experiments were performed in accordance with the conditions of the general procedure, by modifying parameters as indicated in tables 1-10.; Example 4 : Influence of the nature of the base on the enantioselectivity of the asymmetric oxidation The bases N,N-diethylisopropylamine and triethylamine were compared with regard to the yield and the enantioselectivity obtained, either in toluene or in ethyl acetate as solvent. The other parameters were
maintained as defined in the general procedure. [Table 4] EntryBaseSolventsE. e. (percent)Purity (percent)Yield (percent)1Diisopropylethylaminetoluene93> 99922Triethylaminetoluene94> 99.590.33Diisopropylethylamineethylacetate99.5> 99.573.54Triethylamineethylacetate99> 99.579.2 High enantioselectivities are obtained with triethylamine and diisopropylethylamine in ethylacetate. On the opposite, diisopropylethylamine and triethylamine give lower enantioselectivities but better yields in toluene. 90.3%
Stage #1: With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate in toluene
T=55°C; 0.833333 h; Stage #2: With alpha,alpha-dimethylbenzyl hydroperoxide; N-ethyl-N,N-diisopropylamine in toluene
T=25°C; 1 h; Product distribution / selectivity; Hide Experimental Procedure
CEPHALON FRANCE
Patent: EP1516869 A1, 2005 ; Location in patent: Page/Page column 13-14 ; Title/Abstract Full Text Show Details
2:
Asymmetric synthesis of (-)-2-(diphenylmethyl)sulphinylacetamideGeneral procedure for examples 1 to 10 : Diphenylmethylthioacetamide (7.70 g ; 0.03 mol ; 1.0 eq) was dissolved in the solvent (toluene ; 77 mL ; 10 vol.) under argon. To the solution were added (S,S)-(-)-diethyl-tartrate (1.23 g ; 0.006 mol; 0.2 eq) and titanium (IV) tetraisopropoxide (0.85 g ; 0.88 mL ; 0.003 mol; 0.1 eq) and water (27 μL minus the sum of water present in reactants and solvent already introduced ; 0.0015 mol ; 0.05 eq) at 55°C. In these conditions, the resulting chiral titanium complex has the stoichiometry (DET/Ti(OiPr)4/H2O : 2/1/0.5) and represents 0.1 eq of diphenylmethylthioacetamide. Stirring was maintained at 55°C during 50 minutes. After cooling to room temperature (25°C), were added to the mixture diisopropylethylamine (0.39 g ; 0.52 mL ; 0.003 mol ; 0.1 eq) and cumene hydroperoxide (4.55 g ; 5.0 mL ; 0.03 mol ; 1.0 eq). After contacting during about an hour, the formed precipitate is isolated by filtration. All the following experiments were performed in accordance with the conditions of the general procedure, by modifying parameters as indicated in tables 1-10.; Example 2 : Influence of the amount of water on the enantioselectivity of asymmetric oxidation In this experiment, the ratio of water was varied with respect to the titanium tetraisopropoxide from 0 to 1 equivalent, all the other parameters being as defined in the above general procedure. Notably, the ratio of the titanium chiral complex was maintained at 0.1 equivalent with respect to the diphenylmethylthioacetamide. [Table 2] EntryAmount of water (equivalent)E. e. (percent)Purity (percent)Yield (percent)1080-90.320.493> 999230.894> 9988419199.590 - = Not determined These results show that the amount of water has an effect on the enantioselectivity of the reaction. Thus, the best enantioselectivities are achieved when an amount of water comprised between 0.4 and 0.8 equivalents are used. On the opposite, the enantioselectivity drops notably in the absence of water.
88%
Stage #1: With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate in water; toluene
T=55°C; 0.833333 h; Stage #2: With alpha,alpha-dimethylbenzyl hydroperoxide; N-ethyl-N,N-diisopropylamine in water; toluene
T=25°C; 1 h; Product distribution / selectivity; Hide Experimental Procedure
CEPHALON FRANCE
Patent: EP1516869 A1, 2005 ; Location in patent: Page/Page column 13-16 ; Title/Abstract Full Text Show Details
1; 2; 3; 4; 5; 10:
Asymmetric synthesis of (-)-2-(diphenylmethyl)sulphinylacetamideGeneral procedure for examples 1 to 10 : Diphenylmethylthioacetamide (7.70 g ; 0.03 mol ; 1.0 eq) was dissolved in the solvent (toluene ; 77 mL ; 10 vol.) under argon. To the solution were added (S,S)-(-)-diethyl-tartrate (1.23 g ; 0.006 mol; 0.2 eq) and titanium (IV) tetraisopropoxide (0.85 g ; 0.88 mL ; 0.003 mol; 0.1 eq) and water (27 μL minus the sum of water present in reactants and solvent already introduced ; 0.0015 mol ; 0.05 eq) at 55°C. In these conditions, the resulting chiral titanium complex has the stoichiometry (DET/Ti(OiPr)4/H2O : 2/1/0.5) and represents 0.1 eq of diphenylmethylthioacetamide. Stirring was maintained at 55°C during 50 minutes. After cooling to room temperature (25°C), were added to the mixture diisopropylethylamine (0.39 g ; 0.52 mL ; 0.003 mol ; 0.1 eq) and cumene hydroperoxide (4.55 g ; 5.0 mL ; 0.03 mol ; 1.0 eq). After contacting during about an hour, the formed precipitate is isolated by filtration. All the following experiments were performed in accordance with the conditions of the general procedure, by modifying parameters as indicated in tables 1-10.; Example 1 : Influence of the ratio of the titanium chiral complex with respect to the diphenylmethylthioacetamide In this experiment, the ratio of the titanium chiral complex with respect of the diphenylmethylthioacetamide was varied from 0.05 to 0.3 equivalent, the stoichiometry of the chiral titanium complex DET/Ti(O-iPr)4/water : 2/1/0.4 being maintained constant, all the others parameters being as defined in the above general procedure. [Table 1] EntryTitanium complex/ sulphide (equivalent)Scale (mole)E. e. (percent)Purity (percent)Yield (percent)10.30.03> 99.5> 99.588.420.150.0693.6> 9989.730.10.0993> 999240.050.189295.595.4 These experiments show that the enantioselectivity decreases slightly with the amount of chiral titanium complex. However, yields increase when the amount of chiral titanium complex decreases.; Example 2 : Influence of the amount of water on the enantioselectivity of asymmetric oxidation In this experiment, the ratio of water was varied with respect to the titanium tetraisopropoxide from 0 to 1 equivalent, all the other parameters being as defined in the above general procedure. Notably, the ratio of the titanium chiral complex was maintained at 0.1 equivalent with respect to the diphenylmethylthioacetamide. [Table 2] EntryAmount of water (equivalent)E. e. (percent)Purity (percent)Yield (percent)1080-90.320.493> 999230.894> 9988419199.590 - = Not determined These results show that the amount of water has an effect on the enantioselectivity of the reaction. Thus, the best enantioselectivities are achieved when an amount of water comprised between 0.4 and 0.8 equivalents are used. On the opposite, the enantioselectivity drops notably in the absence of water.; Example 3 : Influence of the nature of the solvent on the enantioselectivity of the asymmetric oxidation In this experiment, the reaction was effected in ethyl acetate and methylene chloride and compared with toluene, the conditions being the same than in the above general procedure. [Table 3] EntrySolventE. e. (percent)Purity (percent)Yield (percent)1Toluene93> 99922Ethyl Acetate99.5> 99.873.53Methylene Chloride9898.861 Higher enantioselectivity is observed in ethylacetate than in methylene chloride or toluene, whereas a higher yield is achieved in toluene.; Example 4 : Influence of the nature of the base on the enantioselectivity of the asymmetric oxidation The bases N,N-diethyl-isopropylamine and triethylamine were compared with regard to the yield and the enantioselectivity obtained, either in toluene or in ethyl acetate as solvent. The other parameters were maintained as defined in the general procedure. [Table 4] EntryBaseSolventsE. e. (percent)Purity (percent)Yield (percent)1Diisopropylethylaminetoluene93> 99922Triethylaminetoluene94> 99.590.33Diisopropylethylamineethylacetate99.5> 99.573.54Triethylamineethylacetate99> 99.579.2 High enantioselectivities are obtained with triethylamine and diisopropylethylamine in ethylacetate. On the opposite, diisopropylethylamine and triethylamine give lower enantioselectivities but better yields in toluene.; Example 5 : Influence of the amount of base on the enantioselectivity of the asymmetric oxidation The ratio of base was varied from 0 to 0.2 equivalent with regard to diphenylmethylthioacetamide. [Table 5] EntryBaseAmount of base (eq)SolventsE. e. (percent)Purity (percent)Yield (percent)1--toluene66> 99862--ethylacetate74> 99703Diisopropylethylamine0.1toluene93> 99924Triethylamine0.1ethylacetate99> 99.579.25Triethylamine0.2ethylacetate94.3> 99.878.6 In the absence of base, the reaction rate was slow and the enantioselectivity was weak (66 - 74 percent range). The reaction rate increased with the addition of a base in the reaction mixture. The enantioselectivity is very high with 0.1 eq of triethylamine in ethylacetate. It can be noticed that the enantioselectivity slightly decreases when the amount of base increases up to 0.2 equivalent.; Example 10 : Influence of the nature of the chiral ligand on the enantioselectivity The chiral ligands (R,R)-(+)-DET,(S,S)-(-)-DET,R-(-)-mandelic acid were tested, the other parameters being as defined in the above general procedure. [Table 10] EntryChiral ligandSolventsE. e. (percent)Purity (percent)Yield (percent)1(S,S)-(-)-DETethylacetate99>99.579.22(S,S)-(-)-DETtoluene>99.5>99.588.43(R,R)DETtoluene98.6>99.598.54R-(-)-mandelic acidethylacetate9.595.753 DET used as chiral ligand gives better enantioselectivity than mandelic acid under the conditions defined in the above general procedure. 73.5%
Stage #1: With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate in water; ethyl acetate
T=55°C; 0.833333 h; Stage #2: With alpha,alpha-dimethylbenzyl hydroperoxide; N-ethyl-N,N-diisopropylamine in water; ethyl acetate
T=25°C; 1 h; Product distribution / selectivity; Hide Experimental Procedure
CEPHALON FRANCE
Patent: EP1516869 A1, 2005 ; Location in patent: Page/Page column 13-15 ; Title/Abstract Full Text Show Details
3; 4:
Asymmetric synthesis of (-)-2-(diphenylmethyl)sulphinylacetamideGeneral procedure for examples 1 to 10 : Diphenylmethylthioacetamide (7.70 g ; 0.03 mol ; 1.0 eq) was dissolved in the solvent (toluene ; 77 mL ; 10 vol.) under argon. To the solution were added (S,S)-(-)-diethyl-tartrate (1.23 g ; 0.006 mol; 0.2 eq) and titanium (IV) tetraisopropoxide (0.85 g ; 0.88 mL ;
0.003 mol; 0.1 eq) and water (27 μL minus the sum of water present in reactants and solvent already introduced ; 0.0015 mol ; 0.05 eq) at 55°C. In these conditions, the resulting chiral titanium complex has the stoichiometry (DET/Ti(OiPr)4/H2O : 2/1/0.5) and represents 0.1 eq of diphenylmethylthioacetamide. Stirring was maintained at 55°C during 50 minutes. After cooling to room temperature (25°C), were added to the mixture diisopropylethylamine (0.39 g ; 0.52 mL ; 0.003 mol ; 0.1 eq) and cumene hydroperoxide (4.55 g ; 5.0 mL ; 0.03 mol ; 1.0 eq). After contacting during about an hour, the formed precipitate is isolated by filtration. All the following experiments were performed in accordance with the conditions of the general procedure, by modifying parameters as indicated in tables 1-10.; Example 3 : Influence of the nature of the solvent on the enantioselectivity of the asymmetric oxidation In this experiment, the reaction was effected in ethyl acetate and methylene chloride and compared with toluene, the conditions being the same than in the above general procedure. [Table 3] EntrySolventE. e. (percent)Purity (percent)Yield (percent)1Toluene93> 99922Ethyl Acetate99.5> 99.873.53Methylene Chloride9898.861 Higher enantioselectivity is observed in ethylacetate than in methylene chloride or toluene, whereas a higher yield is achieved in toluene.; Example 4 : Influence of the nature of the base on the enantioselectivity of the asymmetric oxidation The bases N,Ndiethyl-isopropylamine and triethylamine were compared with regard to the yield and the enantioselectivity obtained, either in toluene or in ethyl acetate as solvent. The other parameters were maintained as defined in the general procedure. [Table 4] EntryBaseSolventsE. e. (percent)Purity (percent)Yield (percent)1Diisopropylethylaminetoluene93> 99922Triethylaminetoluene94> 99.590.33Diisopropylethylamineethylacetate99.5> 99.573.54Triethylamineethylacetate99> 99.579.2 High enantioselectivities are obtained with triethylamine and diisopropylethylamine in ethylacetate. On the opposite, diisopropylethylamine and triethylamine give lower enantioselectivities but better yields in toluene. 61%
Stage #1: With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate in dichloromethane; water
T=55°C; 0.833333 h; Stage #2: With alpha,alpha-dimethylbenzyl hydroperoxide; N-ethyl-N,N-diisopropylamine in dichloromethane; water
T=25°C; 1 h; Product distribution / selectivity; Hide Experimental Procedure
CEPHALON FRANCE
Patent: EP1516869 A1, 2005 ; Location in patent: Page/Page column 13-15 ; Title/Abstract Full Text Show Details
3:
Asymmetric synthesis of (-)-2-(diphenylmethyl)sulphinylacetamideGeneral procedure for examples 1 to 10 : Diphenylmethylthioacetamide (7.70 g ; 0.03 mol ; 1.0 eq) was dissolved in the solvent (toluene ; 77 mL ; 10 vol.) under argon. To the solution were added (S,S)-(-)-diethyl-tartrate (1.23 g ; 0.006 mol; 0.2 eq) and titanium (IV) tetraisopropoxide (0.85 g ; 0.88 mL ; 0.003 mol; 0.1 eq) and water (27 μL minus the sum of water present in reactants and solvent already introduced ; 0.0015 mol ; 0.05 eq) at 55°C. In these conditions, the resulting chiral titanium complex has the stoichiometry (DET/Ti(OiPr)4/H2O : 2/1/0.5) and represents 0.1 eq of diphenylmethylthioacetamide. Stirring was maintained at 55°C during 50 minutes. After cooling to room temperature (25°C), were added to the mixture diisopropylethylamine (0.39 g ; 0.52 mL ; 0.003 mol ; 0.1 eq) and cumene hydroperoxide (4.55 g ; 5.0 mL ; 0.03 mol ; 1.0 eq). After contacting during about an hour, the formed precipitate is isolated by filtration. All the following experiments were performed in accordance with the conditions of the general procedure, by modifying parameters as indicated in tables 1-10.; Example 3 : Influence of the nature of the solvent on the enantioselectivity of the asymmetric oxidation In this experiment, the reaction was effected in ethyl acetate and methylene chloride and compared with toluene, the conditions being the same than in the above general procedure. [Table 3] EntrySolventE. e. (percent)Purity (percent)Yield (percent)1Toluene93> 99922Ethyl Acetate99.5> 99.873.53Methylene Chloride9898.861 Higher enantioselectivity is observed in ethylacetate than in methylene chloride or toluene, whereas a higher yield is achieved in toluene. A
B
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4
Synthesize Find similar Rx-ID: 23230808 Find similar reactions
A: 42%
Stage #1: With titanium(IV) isopropylate; diethyl (2R,3R)-tartrate in dichloromethane; water
T=-30 - 20°C; 0.833333 h; Stage #2: With alpha,alpha-dimethylbenzyl hydroperoxide in dichloromethane; water
T=-30 - -25°C; 1.75 h; Conversion of starting material; Hide Experimental Procedure
CEPHALON FRANCE
Patent: EP1516869 A1, 2005 ; Location in patent: Page/Page column 17-18 ; Title/Abstract Full Text Show Details
1:
General Procedure for Comparative Examples 1 to 3 : Oxidation of sulphide in accordance with the method described by Kagan et al. Organic Syntheses, John Wiley and Sons INC. ed., 1993 ; vol. VIII,. 464-467. Water (0.27 mL, 0.015 mol, 1.0 eq) was added dropwise at room temperature (20°C) to a solution of diethyltartrate (DET) (6.19 g, 0.03 mol, 2.0 eq) and titanium (IV) isopropoxide (4.26 g, 4.43 mL, 0.015 mol, 1.0 eq) in 125 mL of anhydrous methylene chloride, under nitrogen. Stirring was maintained until the yellow solution became homogeneous (30 min) and the sulphide (0.03 mol, 2.0 eq) was added. The solution was cooled to -30°C and left in contact for 50 minutes at -30°C. Then, cumene hydroperoxide (4.57 g, 5.0 mL, 0.03 mol, 2.0 eq) was added and the mixture was kept at -25°C for 15 hours. After this time, 5 mL of water were added, and the solution was stirred during 1 h 30. The medium was filtered on clarcel and the filtrate worked up depending on the suphoxide obtained. As an example, when the sulfoxide of diphenylmethylthioacetic acid was generated, the compound was extracted with 3 x 100 mL of an aqueous solution of K2CO3 (0.6 M). The aqueous phases were collected, filtered on clarcel, acidified by addition of 150 mL of an aqueous solution of chlorhydric acid 4N (pH .approx/equal. 1). The precipitate formed is filtered on a fritted glass, rinsed with water and then dried in vacuo at 35°C.Comparative Example 1 : Enantioselectivity of asymmetric oxidation of sulphides of formula (II) with n = 1 according to X = -NH2, -OCH3, -OH The above general procedure for comparative examples was applied to diphenylmethylthioacetamide, methyldiphenylmethylthioacetate or diphenylmethylthioacetic acid as sulphide, and by using either (R,R)-DET or (S,S)-DET. [Table 11] PrecursorDETEe percentConversion rate (percent)Diphenylmethylthioacetamide(R,R)-(+)-DET4290Methyldiphenylmethylthioacetate(R,R)-(+)-DET1040Diphenylmethylthioacetic acid(R,R)-(+)-DET5070Diphenylmethylthioacetic acid(S, S)-(-)-DET5083 Stage #1: With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate in water; ethyl acetate
T=25 - 55°C; 0.166667 - 0.833333 h; Stage #2: With alpha,alpha-dimethylbenzyl hydroperoxide; triethylamine in water; ethyl acetate
T=25 - 55°C; 0.0833333 - 1 h; Product distribution / selectivity;
CEPHALON FRANCE
Patent: EP1516869 A1, 2005 ; Location in patent: Page/Page column 13; 15-16 ; Title/Abstract Full Text Show Details
Hide Experimental Procedure
4; 5; 6; 7; 8; 9; 10:
Asymmetric synthesis of (-)-2-(diphenylmethyl)sulphinylacetamideGeneral procedure for examples 1 to 10 : Diphenylmethylthioacetamide (7.70 g ; 0.03 mol ; 1.0 eq) was dissolved in the solvent (toluene ; 77 mL ; 10 vol.) under argon. To the solution were added (S,S)-(-)-diethyl-tartrate (1.23 g ; 0.006 mol; 0.2 eq) and titanium (IV) tetraisopropoxide (0.85 g ; 0.88 mL ; 0.003 mol; 0.1 eq) and water (27 μL minus the sum of water present in reactants and solvent already introduced ; 0.0015 mol ; 0.05 eq) at 55°C. In these conditions, the resulting chiral titanium complex has the stoichiometry (DET/Ti(OiPr)4/H2O : 2/1/0.5) and represents 0.1 eq of diphenylmethylthioacetamide. Stirring was maintained at 55°C during 50 minutes. After cooling to room temperature (25°C), were added to the mixture diisopropylethylamine (0.39 g ; 0.52 mL ; 0.003 mol ; 0.1 eq) and cumene hydroperoxide (4.55 g ; 5.0 mL ; 0.03 mol ; 1.0 eq). After contacting during about an hour, the formed precipitate is isolated by filtration. All the following experiments were performed in accordance with the conditions of the general procedure, by modifying parameters as indicated in tables 1-10.; Example 4 : Influence of the nature of the base on the enantioselectivity of the asymmetric oxidation The bases N,N-diethylisopropylamine and triethylamine were compared with regard to the yield and the enantioselectivity obtained, either in toluene or in ethyl acetate as solvent. The other parameters were maintained as defined in the general procedure. [Table 4] EntryBaseSolventsE. e. (percent)Purity (percent)Yield (percent)1Diisopropylethylaminetoluene93> 99922Triethylaminetoluene94> 99.590.33Diisopropylethylamineethylacetate99.5> 99.573.54Triethylamineethylacetate99> 99.579.2 High enantioselectivities are obtained with triethylamine and diisopropylethylamine in ethylacetate. On the opposite, diisopropylethylamine and triethylamine give lower enantioselectivities but better yields in toluene.; Example 5 : Influence of the amount of base on the enantioselectivity of the asymmetric oxidation The ratio of base was varied from 0 to 0.2 equivalent with regard to diphenylmethylthioacetamide. [Table 5] EntryBaseAmount of base (eq)SolventsE. e. (percent)Purity (percent)Yield (percent)1--toluene66> 99862--ethylacetate74> 99703Diisopropylethylamine0.1toluene93> 99924Triethylamine0.1ethylacetate99> 99.579.25Triethylamine0.2ethylacetate94.3> 99.878.6 In the absence of base, the reaction rate was slow and the enantioselectivity was weak (66 - 74 percent range). The reaction rate increased with the addition of a base in the reaction mixture. The enantioselectivity is very high with 0.1 eq of triethylamine in ethylacetate. It can be noticed that the enantioselectivity slightly decreases when the amount of base increases up to 0.2 equivalent.; Example 6 : Influence of the temperature of formation of the chiral titanium complex on the enantioselectivity of the asymmetric oxidation The titanium chiral complex composed of DET/Ti/H2O : 2/1/0.5 was prepared at 55°C or at 25°C (according to the above procedure) and the enantioselectivity obtained compared. [Table 6] EntryTemperature (°C)SolventsE. e. (percent)Purity (percent)Yield (percent)155ethylacetate99> 99.579.2225ethylacetate65.6> 9963.5 The preparation of the titanium chiral complex at 25°C during 50 minutes results in a lower enantioselectivity. A prolonged time is thus required to form the titanium chiral complex and to achieve a better enantioselectivity.; Example 7 : Influence of the time of formation of the chiral titanium complex on the enantioselectivity of the asymmetric oxidation The time of formation of the titanium chiral complex was varied from 10 minutes to 50 minutes in ethyl acetate, the other parameters being as defined in the above general procedure. [Table 7] EntryTime (minutes)SolventsE. e. (percent)Purity (percent)Yield (percent)110ethylacetate87.5> 99.579.7230ethylacetate9199.579.2350ethylacetate99> 99.579.2 A time of formation of 50 minutes is necessary and sufficient to obtain an enantioselectivity close to superior to 99 percent.Example 8 : Influence of the temperature of the oxidation reaction on the enantioselectivity of the asymmetric oxidation. The oxidation step, corresponding to the introduction of the oxidizing agent, was carried at 25°C and 55°C in ethylacetate, the other parameters being as defined in the above general procedure. [Table 8] EntryTemperature (°C)SolventsE. e. percentPurity percentYield percent125ethylacetate99> 99.579.2255ethylacetate94.397.881.8 The temperature of 55°C is deleterious for the enantioselectivity and the purity of the product obtained.Example 9 : Influence of the addition time of the oxidizing agent on the enantioselectivity of the asymmetric oxidation The impact of addition time of the oxidizing agent on the enantioselectivity of the reaction was tested. Thus, cumene hydroperoxide (CuOOH) was added upon either 5 or 40 minutes, the other parameters being as defined in the above general procedure. [Table 9] EntryTime (minutes)SolventsE. e. (percent)Purity (percent)Yield (percent)15ethylacetate99>99.579.2240*ethylacetate>99.899.564.7* CuOOH was diluted in ethylacetate. The addition time of the oxidizing agent does not have significant influence on the enantioselectivity.; Example 10 : Influence of the nature of the chiral ligand on the enantioselectivity The chiral ligands (R,R)-(+)-DET,(S,S)-(-)-DET,R-(-)-mandelic acid were tested, the other parameters being as defined in the above general procedure. [Table 10] EntryChiral ligandSolventsE. e. (percent)Purity (percent)Yield (percent)1(S,S)-(-)-DETethylacetate99>99.579.22(S,S)(-)-DETtoluene>99.5>99.588.43(R,R)-DETtoluene98.6>99.598.54R-(-)-mandelic acidethylacetate9.595.753 DET used as chiral ligand gives better enantioselectivity than mandelic acid under the conditions defined in the above general procedure. Stage #1: With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate in water; ethyl acetate
T=55°C; 0.833333 h; Stage #2: With alpha,alpha-dimethylbenzyl hydroperoxide in water; ethyl acetate
T=25°C; 1 h; Product distribution / selectivity; Hide Experimental Procedure
CEPHALON FRANCE
Patent: EP1516869 A1, 2005 ; Location in patent: Page/Page column 13; 15 ; Title/Abstract Full Text Show Details
5:
Asymmetric synthesis of (-)-2-(diphenylmethyl)sulphinylacetamideGeneral procedure for examples 1 to 10 : Diphenylmethylthioacetamide (7.70 g ; 0.03 mol ; 1.0 eq) was dissolved in the solvent (toluene ; 77 mL ; 10 vol.) under argon. To the solution were added (S,S)-(-)-diethyl-tartrate (1.23 g ; 0.006 mol; 0.2 eq) and titanium (IV) tetraisopropoxide (0.85 g ; 0.88 mL ; 0.003 mol; 0.1 eq) and water (27 μL minus the sum of water present in reactants and solvent already introduced ; 0.0015 mol ; 0.05 eq) at 55°C. In these conditions, the resulting chiral titanium complex has the stoichiometry (DET/Ti(OiPr)4/H2O : 2/1/0.5) and represents 0.1 eq of diphenylmethylthioacetamide. Stirring was maintained at 55°C during 50 minutes. After cooling to room temperature (25°C), were added to the mixture diisopropylethylamine (0.39 g ; 0.52 mL ; 0.003 mol ; 0.1 eq) and cumene hydroperoxide (4.55 g ; 5.0 mL ; 0.03 mol ; 1.0 eq). After contacting during about an hour, the formed precipitate is isolated by filtration. All the following experiments were performed in accordance with the conditions of the general procedure, by modifying parameters as indicated in tables 1-10.; Example 5 : Influence of the amount of base on the enantioselectivity of the asymmetric oxidation The ratio of base was varied from 0 to 0.2 equivalent with regard to diphenylmethylthioacetamide. [Table 5] EntryBaseAmount of base (eq)SolventsE. e. (percent)Purity (percent)Yield (percent)1--toluene66> 99862--ethylacetate74> 99703Diisopropylethylamine0.1toluene93> 99924Triethylamine0.1ethylacetate99> 99.579.25Triethylamine0.2ethylacetate94.3> 99.878.6 In the absence of base, the reaction rate was slow and the enantioselectivity was weak (66 - 74 percent range). The reaction rate increased with the addition of a base in the reaction mixture. The enantioselectivity is very high with 0.1 eq of triethylamine in ethylacetate. It can be noticed that the enantioselectivity slightly decreases when the amount of base increases up to 0.2 equivalent.
Stage #1: With titanium(IV) isopropylate; diethyl (2S,3S)-tartrate in water; toluene
T=55°C; 0.833333 h; Stage #2: With alpha,alpha-dimethylbenzyl hydroperoxide in water; toluene
T=25°C; 1 h; Product distribution / selectivity; Hide Experimental Procedure
CEPHALON FRANCE
Patent: EP1516869 A1, 2005 ; Location in patent: Page/Page column 13; 15 ; Title/Abstract Full Text Show Details
5:
Asymmetric synthesis of (-)-2-(diphenylmethyl)sulphinylacetamideGeneral procedure for examples 1 to 10 : Diphenylmethylthioacetamide (7.70 g ; 0.03 mol ; 1.0 eq) was dissolved in the solvent (toluene ; 77 mL ; 10 vol.) under argon. To the solution were added (S,S)-(-)-diethyl-tartrate (1.23 g ; 0.006 mol; 0.2 eq) and titanium (IV) tetraisopropoxide (0.85 g ; 0.88 mL ; 0.003 mol; 0.1 eq) and water (27 μL minus the sum of water present in reactants and solvent already introduced ; 0.0015 mol ; 0.05 eq) at 55°C. In these conditions, the resulting chiral titanium complex has the stoichiometry (DET/Ti(OiPr)4/H2O : 2/1/0.5) and represents 0.1 eq of diphenylmethylthioacetamide. Stirring was maintained at 55°C during 50 minutes. After cooling to room temperature (25°C), were added to the mixture diisopropylethylamine (0.39 g ; 0.52 mL ; 0.003 mol ; 0.1 eq) and cumene hydroperoxide (4.55 g ; 5.0 mL ; 0.03 mol ; 1.0 eq). After contacting during about an hour, the formed precipitate is isolated by filtration. All the following experiments were performed in accordance with the conditions of the general procedure, by modifying parameters as indicated in tables 1-10.; Example 5 : Influence of the amount of base on the enantioselectivity of the asymmetric oxidation The ratio of base was varied from 0 to 0.2 equivalent with regard to diphenylmethylthioacetamide. [Table 5] EntryBaseAmount of base (eq)SolventsE. e. (percent)Purity (percent)Yield (percent)1--toluene66> 99862--ethylacetate74> 99703Diisopropylethylamine0.1toluene93> 99924Triethylamine0.1ethylacetate99> 99.579.25Triethylamine0.2ethylacetate94.3> 99.878.6 In the absence of base, the reaction rate was slow and the enantioselectivity was weak (66 - 74 percent range). The reaction rate increased with the addition of a base in the reaction mixture. The enantioselectivity is very high with 0.1 eq of triethylamine in ethylacetate. It can be noticed that the enantioselectivity slightly decreases when the amount of base increases up to 0.2 equivalent.
5
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Cephalon France; Organisation De Synthese Mondiale Orsymonde Patent: US2006/135621 A1, 2006 ; Location in patent: Page/Page column 19 ; Title/Abstract Full Text Show Details
6
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Rx-ID: 23850594 Find similar reactions
Cephalon France; Organisation De Synthese Mondiale Orsymonde
T=110°C; 16 h; Product distribution / selectivity; Hide Experimental Procedure
Patent: US2006/135621 A1, 2006 ; Location in patent: Page/Page column 17 ; Title/Abstract Full Text Show Details
10.a: a) 1 g of the monodimethyl carbonate solvate of (-)-modafinil heated to 110° C. for 16 hours converted into a white solid identified as being (-)-modafinil form I by its powder X-ray diffraction spectrum.
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Rx-ID: 23850595 Find similar reactions
Cephalon France; Organisation De Synthese Mondiale Orsymonde Patent: US2006/135621 A1, 2006 ;
Location in patent: Page/Page column 17 ; Title/Abstract Full Text Show Details
10.b: a) 1 g of the monodimethyl carbonate solvate of (-)-modafinil heated to 110° C. for 16 hours converted into a white solid identified as being (-)-modafinil form I by its powder X-ray diffraction spectrum. b) The use of (+)-modafinil (CRL 40983) under the same conditions led to the same results.
8
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Rx-ID: 23850596 Find similar reactions
Cephalon France; Organisation De Synthese Mondiale Orsymonde
T=100°C; 8 h; Product distribution / selectivity; Hide Experimental Procedure
Patent: US2006/135621 A1, 2006 ; Location in patent: Page/Page column 17 ; Title/Abstract Full Text Show Details
9.a: a) 1 g of acetonitrile solvate of (-)-modafinil heated to 100° C. for 8 hours converted into a white solid identified as being (-)-modafinil form I by its powder X-ray diffraction spectrum
9
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Cephalon France; Organisation De Synthese Mondiale Orsymonde Patent: US2006/135621 A1, 2006 ; Location in patent: Page/Page column 17 ; Title/Abstract Full Text Show Details
9.b: a) 1 g of acetonitrile solvate of (-)-modafinil heated to 100° C. for 8 hours converted into a white solid identified as being (-)-modafinil form I by its powder X-ray diffraction spectrum. b) The use of (+)-modafinil (CRL 40983) under the same conditions led to the same results.
10
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Rx-ID: 24797373 Find similar reactions
CEPHALON INC.
Patent: WO2006/30278 A1, 2006 ; Location in patent: Page/Page column 7-9 ;
T=25°C; Resolution of racemate; Purification / work up; Hide Experimental Procedure
Title/Abstract Full Text Show Details
1; 2; 3; 4; 5; 6:
Examples 1-4: 1 kg Scale Column Chiralpak AD Mobile Phase methanol Column Length 9.7 cm avg Column I. D. 2.5 cm No. of Columns 6 Column Configuration 1.2 / 2.3 / 1.7 / 0.8 Feed Concentration 18 g/l Temperature 25 °C; Examples 5-6: 500 kg Scale Column: Chiralpak AD Mobile Phase methanol Column Length columns 1-5: 10 cm; column 6: 7.1 cm No. of Columns 6 Column Configuration 1.2 / 2.3 / 1.7 / 0.8 Feed Concentration 18 (g/l) Temperature: 25 0C
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With water in water
T=30°C; 168 h; Hide Experimental Procedure
Rx-ID: 25846448 Find similar reactions
TEVA PHARMACEUTICAL INDUSTRIES LTD.; TEVA PHARMACEUTICALS USA, INC.
Patent: WO2007/98273 A2, 2007 ; Location in patent: Page/Page column 17 ; Title/Abstract Full Text Show Details
3:
Example 3 - Preparation of armodafinil hemihydrateArmodafinil Form A (200 mg) was exposed to 100percent humidity for 7 days at 300C. Under these conditions, armodafinil Form A transformed to armodafinil Form I, as shown in the table below. The XRD diffractogram of armodafinil Form I is illustrated in Figure 3.
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Rx-ID: 25846447 Find similar reactions
With water in water
T=30 - 60°C; 312 h; Hide Experimental Procedure
TEVA PHARMACEUTICAL INDUSTRIES LTD.; TEVA PHARMACEUTICALS USA, INC.
Patent: WO2007/98273 A2, 2007 ; Location in patent: Page/Page column 20 ; Title/Abstract Full Text Show Details
15:
Example 15 - Preparation of armodafinil monohydrateTable 1. TGA and XRD results for armodafinil Form I exposed to 100percent RelativeHumidity at 300C for 13 daysTable 2. TGA and XRD results for armodafinil Form I exposed to 100percent Relative Humidity at 600C for 13 days
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Cephalon France; Organisation De Synthese Mondiale Orsymonde Patent: US2006/135621 A1, 2006 ; Location in patent: Page/Page column 18 ; Title/Abstract Full Text Show Details
14
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Rx-ID: 23833209 Find similar reactions
92%
T=20°C; 72 h; Hide Experimental Procedure
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Cephalon France; Organisation De Synthese Mondiale Orsymonde Patent: US2006/135621 A1, 2006 ; Location in patent: Page/Page column 18 ; Title/Abstract Full Text Show Details
19.a:preparation of (-)-modafinil solvates and of (+)-modafinil; example 19; preparation of the acetonitrile solvate of (-)-modafinil a) Crystals of polymorphic form I of (-)-modafinil were suspended in acetonitrile for 3 days at 20° C. The solid recovered was identified as an acetonitrile solvate by X-ray diffraction. The solvate corresponded to a true solvate having a stoichiometry of 1-1, identified as being the acetonitrile solvate of (-)-modafinil by its powder X-ray diffraction spectrum. Yield 92percent.
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Rx-ID: 23800987 Find similar reactions
Cephalon France; Organisation De Synthese Mondiale Orsymonde
Patent: US2006/135621 A1, 2006 ; Location in patent: Page/Page column 19 ; Title/Abstract Full Text Show Details
16
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Rx-ID: 23838631 Find similar reactions
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Cephalon France; Organisation De Synthese Mondiale Orsymonde
T=3 - 80°C; 1 - 48 h; Hide Experimental Procedure
Patent: US2006/135621 A1, 2006 ; Location in patent: Page/Page column 19 ; Title/Abstract Full Text Show Details
20.a:
a) 75 mg of d or l-modafinil were suspended in acetic acid in Minimax reactors in order to achieve a concentration of 15percent (weight/volume). The crystallisation medium, which was constantly stirred, was raised to an initial temperature of 60° C. or 80° C. using a temperature gradient of 3° C./min. After 30 minutes the medium was cooled slowly (-0.6° C./min) or rapidly (-300° C./min) until a final temperature of 3° C. was obtained, and was then held at this final temperature for a minimum of 1 hour or a maximum of 48 hours. Under these experimental conditions the acetic acid solvate was obtained and identified by its powder X-ray diffraction spectrum.
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Cephalon France; Organisation De Synthese Mondiale Orsymonde Patent: US2006/135621 A1, 2006 ; Location in patent: Page/Page column 18 ; Title/Abstract Full Text Show Details
18
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Rx-ID: 23831755 Find similar reactions
88%
T=10°C; Heating / reflux; Hide Experimental Procedure
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Cephalon France; Organisation De Synthese Mondiale Orsymonde Patent: US2006/135621 A1, 2006 ; Location in patent: Page/Page column 18 ; Title/Abstract Full Text Show Details
18.a:preparation of (-)-modafinil solvates and of (+)-modafinil; example 18; preparation of the dimethyl carbonate solvate of (-)-modafinil a) 20 ml of dimethyl carbonate were added to 2 g of (-)-modafinil and refluxed. The reaction mixture was stirred for 10 minutes until the (-)-modafinil completely dissolved. The solution was cooled slowly (-0.5° C./min) down to 10° C. with stirring. The reaction mixture was then filtered through sintered glass (No. 3). Analysis of the dimethyl carbonate solvate of modafinil yielded a mass of approximately 24percent starting from around 50° C. down to 110° C. The stoichiometry of the dimethyl carbonate solvate is therefore 1-1. This is therefore a true solvate, identified as being the dimethyl carbonate solvate of (-)-modafinil by its powder X-ray diffraction spectrum. Yield 88percent.