* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With potassium <i>tert</i>-butylate; 1-butyl-3-methylimidazolium Tetrafluoroborate In tetrahydrofuran at 20℃; for 18 h; Molecular sieve
Example 1: with 7percent mol NHC (with respect to compound (1) ) at room temperature in THF .In an anhydrous flask containing about 7.85 g of activated 4A molecular sieves, methyl di- (2- thyenil ) glycolate (2), (R = Me, 3.97 g, 15.6 mmol) and scopine free base (1), (2.61 g, 16.8 mmol), were dissolved in THF (14 mL) . Separately, in a flask, 1- butyl-3-methylimidazolium tetrafluorborate (210 yL, 1.12 mmol), KOtBu/THF (960 yL, 0.96 mmol) and THF (1.0 mL) were stirred for 15 min at room temperature. Such mixture was then transferred with a syringe into the flask containing the scopine solution. Syringe and flask were washed with THF (2 x 0.5 mL) and the reaction mixture was stirred at room temperature for 18 hours. An HPLC control showed 86percent of expected product. After a total of 18 hours, the mixture was filtered, washing the sieves with THF (2 x 20. mL) . The filtrate was concentrated to dryness and the residue taken up with toluene (30 mL) and 1M HC1 (30 mL) . During phase separation, precipitation of a solid was observed; the resulting suspension was filtered, the solid washed with toluene (30 mL) and reunited to the separated aqueous phase. The pH of said aqueous suspension, cooled to 0°C, was basified by addition of solid K2CO3. The mixture was kept under stirring at 0°C for about 30 minutes, then the obtained solid was filtered, washed with cold water and dried, first over a filter, and subsequently at 45°C under vacuum for 18 hours. A white solid (3) was obtained; (4.30 g, 73percent, HPLC purity = 99.89percent).
42%
Stage #1: at 70℃; for 1 h; Stage #2: at 70℃; for 3 h;
The product of step (b) (2.00 g, 12.9 mmol) and the product of step (a) (3.61 g, 14.2 mmol) were melted together at 70° C., under a vacuum of 210 Torr for 1 h. Sodium hydride (60percent suspension in oil, 620 mg, 15.5 mmol) was added and the reaction mixture was stirred at 70° C. under 210 Torr for 3 h. The reaction mixture was allowed to cool to ambient temperature and then water (30 mL) and dichloromethane (30 mL) were added. The organic layer was separated and washed with water (2.x.20 mL), dried (magnesium sulfate), filtered and the solvent was removed under reduced pressure. The resulting residue was purified by flash chromatography (5percent MeOH/DCM) to give the title compound as a solid (2.03 g, 5.4 mmol, 42percent).
Stage #1: With sodium t-butanolate In tetrahydrofuran; toluene at 70 - 90℃; for 4.41667 h; Inert atmosphere Stage #2: With hydrogenchloride In dichloromethane; waterCooling with ice Stage #3: With sodium carbonate In water
Example 8 19.9 g (128.4 mmol) of scopine and 32.7 g methyl di(2-thienyl)glycolate (1 equivalent, 128.4 mmol) are weighed into a flask and the mixture is dissolved at 70°C in 120 ml of toluene. A 2M solution of sodium ferf-butoxide in tetrahydrofuran (32.1 ml, 0.5 equivalents, 64.2 mmol) is added dropwise to the solution of the reaction mixture stirred at 70 °C under inert argon atmosphere during 25 min. After the addition the reaction mixture was further stirred at 90°C and a pressure of 50 kPa for 4 hours, methanol being occasionally removed by distillation, in the end, the reaction mixture was concentrated to 55 ml by distilling toluene off at the pressure of 30 kPa, and diluted with dichloromethane (400 ml). Then, the solution is admixed to a mixture of 200 g of ice and 300 ml of 1 M HCI. The acidic phase is separated, alkalized with 2M Na2C03 and the free base of the scopine ester I is extracted with dichloromethane (3x 500 ml each). After drying with Na2S04 dichloromethane is evaporated at reduced pressure. The crude mixture (37.2 g) contained 84.7percent of the scopine ester I, 5.3percent of scopoline XI and 6.1 percent of scopoline ester XII (analyzed by gas chromatography). The crude reaction mixture was dissolved in acetonitrile (120 ml) and cooled to - 0°C. The crystallized product was filtered, washed with a minimum amount of cooled acetonitrile (30 ml) and dried in a vacuum drier at the temperature of 45°C for five hours. 28.1 g of the scopine ester I was obtained in the purity of 99.2percent (analyzed by gas chromatography), melting point 150.2-151.3 °C, and in the yield of 58percent.
41%
Stage #1: With potassium <i>tert</i>-butylate In toluene at 70 - 90℃; for 4.25 h; Inert atmosphere Stage #2: With hydrogenchloride In dichloromethane; waterCooling with ice Stage #3: With sodium carbonate In water
Example 6 0.50 g (3.22 mmol) of scopine and 0.82 g of methyl di(2-thienyl)glycolate (1 equivalent, 3.22 mmol) are weighed into a flask and the mixture is dissolved in 3 ml of toluene at 70°C. A solution of potassium terf-butoxide (0.18 g, 0.5 equivalents, 1.61 mmol) in toluene (3 ml) is added dropwise to the solution of the reaction mixture stirred at 70°C under inert argon atmosphere during 15 min. After the addition the reaction mixture was further stirred at 90°C and a pressure of 40-30 kPa for 4 h, methanol being occasionally removed by distillation, and in the end the solution was concentrated by distilling toluene off, and diluted with dichloromethane (10 ml). The solution is subsequently admixed to a mixture of ice and 2M HCI. The acidic phase is separated, alkalized with 2M Na2C03 and the free base of the scopine ester I is extracted with dichloromethane. After drying with Na2S0 dichloromethane is evaporated at reduced pressure. The crude mixture (0.82 g) contained 72.0percent of the scopine ester I, 18.4percent of scopoline XI and 5.6percent of scopoline ester XII (analyzed by gas chromatography). The crude reaction mixture was dissolved in acetonitrile, and cooled to -10°C. The crystallized product was filtered, washed with a minimum amount of cooled acetonitrile and dried in a vacuum drier at 45°C for five hours. 0.50 g of the scopine ester I was obtained, melting point 149.5-150.9°C, with the yield of 41 percent.
35.7 %Chromat.
Stage #1: With sodium hydride In toluene; mineral oil at 70 - 90℃; for 4.25 h; Inert atmosphere Stage #2: With hydrogenchloride In water; toluene; mineral oilCooling with ice Stage #3: With sodium carbonate In water
Example 2 (Reference example reproducing the method of patent EPQ418716) 0.50 g (3.22 mmol) of scopine and 0.82 g of methyl di(2-thienyl)glycolate (1 equivalent, 3.22 mmol) are weighed into a flask and the mixture is dissolved in 2.5 ml of toluene at 70°C. A suspension of sodium hydride (0. 3 g, 60percent dispersion of NaH in mineral oil, 1 equivalent, 3.22 mmol) in toluene (2.5 ml) is added dropwise to the solution of the reaction mixture stirred at 70°C and under inert argon atmosphere during 15 min. After the addition the reaction mixture was further stirred at 90°C and at a pressure of 40-30 kPa for 4 h, methanol being occasionally removed by distillation. The reaction mixture is subsequently admixed to a mixture of ice and 2M HCI. The acidic phase is separated, alkalized with 2M Na2C03 and the free base of the scopine ester I is extracted with dichloromethane. After drying with Na2S04 dichloromethane is evaporated at reduced pressure. The crude mixture (1.01 g) contained 24.2percent of the scopine ester I, 35.7percent of scopoline XI and 30.4percent of scopoline ester XII (analyzed by gas chromatography). The crude reaction mixture was dissolved in hot condition in acetonitrile, filtered, cooled to -32°C and left without being stirred at this temperature for 24 h. The crystallized product was filtered, washed with a minimum amount of cooled acetonitrile and dried in a vacuum drier at the room temperature for 20 hours. 0.26 g of the scopine ester I was obtained in the purity of 98.71 percent (analyzed with UPLC) and the yield of 21 percent.
Stage #1: With aluminum trichloride-diatomaceous earth In cyclohexane; acetonitrile at 20℃; for 0.5 h; Inert atmosphere; Molecular sieve Stage #2: at 65 - 70℃; for 3 h; Inert atmosphere; Molecular sieve
General procedure: In a 100 mL flask, 10g of scopine, 26 g of aluminum trichloride-diatomaceous earth catalyst and 50 ml of a cyclohexane/acetonitrile mixed solvent (volume ratio of cyclohexane to acetonitrile is 10:1) were added, pass nitrogen gas, then, after stirring at room temperature for 30 minutes, 16.4 g of methyl 2,2-bis(2-thienyl)glycolate was added and heated to 65-70C, stirred, the reaction was completed after 8 hours of reaction (the change in scopine content of 2,2-di(2-thienyl)glycolic acid was less than 1percent at 1 hour intervals). The reaction solution was diluted with 200 mL of dichloromethane, the insolubles were removed by filtration and the filtrate was washed twice with water and then with saturated brine. It was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give red-brown oil. Acetonitrile was added to dissolve the residue, and activated carbon was added at room temperature, after heating and refluxing for decoloration for half an hour, the solution was filtered while hot, and the filtrate was concentrated under reduced pressure to 1/4 volume and the concentration was stopped, after stirring for 5 hours at room temperature, the mixture was filtered, filter cake was washed with a small amount of acetonitrile and dried at room temperature to give a crude product of scopine 2 ,2-bis(2-thienyl)glycolate as a white solid, the crude product was purified with acetonitrile to obtain a high-quality product (21.4 g, content: 99.7percent) in a molar yield of 88percent. Specific reaction conditions and yields are shown in the table below, and other reaction conditions such as the amount of feed and the operation steps are referred to in Example 1-1.
41.1%
Stage #1: With 1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine In toluene at 30℃; for 24 h; Stage #2: at 30℃; for 2.5 h; Inert atmosphere
Preparative examrle 1 - Preraration of Scorine DithienylcilycolateScopolamine free base (1.50 g; 4,94 mmol, leq) and TBD (0.207 g; 7.42 mmol, 1.5 eq) were dissolved in 2 mL of toluene at 30 00. After stirring for 24 h at 30°C, MethylDithienylglycolate (1.26 g; 4,94 mmol, leq) was added to the reaction mixture. After stirring for an additional 2.5 h at 30°C under nitrogen atmosphere, a 10percent solution of citric acid was added. After layer separation, the aqueous layer was washed with CH2CI2 and then basified with 10percent Na2003 solution until a pH of 8.5 was reached. The aqueous layer was again extracted with CH2CI2. The collected organic layerswere then washed with a 10percent solution of Na2003 and water. Finally, the solvent was distilled off to obtain 0.765 g of Scopine Dithienylglycolate (41 .1percent) as a white solid.
Stage #1: With sodium t-butanolate In toluene at 70 - 90℃; for 4.25 h; Inert atmosphere Stage #2: With hydrogenchloride In dichloromethane; waterCooling with ice Stage #3: With sodium carbonate In water
Example 7 0.50 g (3.22 mmol) of scopine and 0.82 g of methyl di(2-thienyl)glycolate (1 equivalent, 3.22 mmol) are weighed into a flask and the mixture is dissolved in 3 ml of toluene at 70°C. A solution of sodium tert-butoxide (0.09 g, 0.3 equivalents, 0.97 mmol) in toluene (3 ml) is added dropwise to the solution of the reaction mixture stirred at 70°C under inert argon atmosphere during 15 min. After the addition the reaction mixture was further stirred at 90°C and a pressure of 40-30 kPa for 4 h, methanol being occasionally removed by distillation, and in the end the solution was concentrated by distilling toluene off, and diluted with dichloromethane (10 ml). The solution is subsequently admixed to a mixture of ice and 2M HCI. The acidic phase is separated, alkalized with 2M Na2C03 and the free base of the scopine ester I is extracted with dichloromethane. After drying with Na2S0 dichloromethane is evaporated at reduced pressure. The crude mixture (0.84 g) contained 67.5percent of the scopine ester I, 26.3percent of scopoline XI and 1.5percent of scopoline ester XII (analyzed by gas chromatography). The crude reaction mixture was dissolved in acetonitrile, and cooled to -10°C. The crystallized product was filtered, washed with a minimum amount of cooled acetonitrile and dried in a vacuum drier at 45°C for five hours. 0.41 g of the scopine ester I was obtained, melting point 150.3-151.0 °C, with the yield of 33percent.
57.3 %Chromat.
Stage #1: With sodium methylate In toluene at 70 - 90℃; for 5.25 h; Inert atmosphere Stage #2: With hydrogenchloride In water; tolueneCooling with ice Stage #3: With sodium carbonate In water
Example 3 (Reference example reproducing the method of patent EP0418716) 0.50 g (3.22 mmol) of scopine and 0.82 g of methyl di(2-thienyl)glycolate (1 equivalent, 3.22 mmol) are weighed into a flask and the mixture is dissolved in 4 ml of toluene at 70°C. 174 g of sodium methoxide (1 equivalent, 3.22 mmol) are gradually added in parts to the solution of the reaction mixture stirred at 90°C in the course of 15 min. After the addition the reaction mixture was further stirred at 90°C and a pressure of 30-10 kPa for 5 h, methanol being occasionally removed by distillation. The reaction mixture is subsequently admixed to a mixture of ice and 2M HCI. The acidic phase is separated, alkalized with 2M Na2C03 and the free base of the scopine ester I is extracted with dichloromethane. After drying with Na2S04 dichloromethane is evaporated at reduced pressure. The crude mixture (0.18 g) contained 1 1 .6percent of the scopine ester I, 57.3percent of scopoline XI and 1.4percent of scopoline ester XII (analyzed by gas chromatography).
With potassium carbonate In N,N-dimethyl-formamide at 70℃; for 24 h;
Example 2 Preparation of Desmethyl-Tiotropium (4) From Scopine Hydrochloride A suspension of 100 g (0.522 mol) scopine hydrochloride in 350 mL DMF was charged with 72 g (0.521 mol, 1.0 eq.) anhydrous potassium carbonate. After the gas evolution completed, a solution of 159 g (0.625 mol, 1.2 eq.) methyl di-(2-thienyl)glycolate (2) in 300 mL DMF were added. The reaction mixture was heated to 70° C. and vacuum (40 mbar) was applied. After one day, the mixture was cooled with ice and the pH lowered to 3 with 9percent HCl, keeping the temperature below 25° C. The mixture was washed twice with 400 mL toluene. The aqueous layer was basified with potassium carbonate and the resulting precipitate collected by filtration and washing with water until neutral pH. The raw product was purified by crystallization from acetonitrile, affording 142 g (72percent) product as light brown crystals.
60%
Stage #1: With sodium hydride In N,N-dimethyl-formamide at 5 - 10℃; Stage #2: With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 60℃; for 5 h;
Scopine HCl was taken in DMF (5vol), cooled to 5°C, and NaH (1.7eq) was added slowly maintaining the temperature at 5°C. The reaction was stirred for 1 hour at 100C and DBU (leq) and methyl di(2-thienyl)glycolate (leq) were added. The reaction was heated to 600C for 1 hour and a second portion of DBU (2eq) was added. The reaction was heated for a further 4 hours at 600C and monitored by TLC. After completion of the reaction, the mixture was cooled to 5°C and a solution of cone. HCl (2.5vol) in cold water (lOvol) at 100C (pH 2) was added. The mixture was washed with toluene and basified with aqueous sodium carbonate (7.5eq) to pH 10 and extracted with DCM (3 x lOvol). The combined DCM layer was washed with water (3 x lOvol) and DCM was distilled under vacuum (150 mbar) at 300C. The product was obtained as light brown solid. Molar Yield = 60percent; HPLC purity = 98percent.The crude base (3) was recrystallized from acetonitrile (5vol). Yield of crystallization = 86percent; HPLC purity > 99.8percent.
Reference：
[1] Australian Journal of Chemistry, 2006, vol. 59, # 1, p. 53 - 58
[2] Patent: US2003/236409, 2003, A1, . Location in patent: Page 7
[3] Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 2010, vol. 75, # 3, p. 1159 - 1162
7
[ 26447-85-8 ]
[ 1449372-70-6 ]
[ 136310-64-0 ]
Yield
Reaction Conditions
Operation in experiment
20.24 g
Stage #1: With diethylamine In N,N-dimethyl-formamide; acetone at 40 - 45℃; for 1.08333 h; Stage #2: for 2 h; Stage #3: With potassium carbonate In n-heptane; N,N-dimethyl-formamide at 90 - 95℃; Inert atmosphere
Scopine oxalate (47 g; 0.19 mol) was added to diethylamine (188 ml; 1.85 mol) followed by acetone (588 ml). The mixture was heated to a temperature between 40 °C and 45 °C, was stirred at 40 °C - 45 °C over 1 hour, was cooled to 20 °C - 25 °C and filtered. Acetone (588 ml) was added to the filtered salts, the suspension was heated to 40 °C - 45 °C, was stirred at 40 °C -45 °C over 1 hour, was cooled to 20 °C - 25 °C and filtered. The acetone filtered solution was combined with the filtered acetone/diethylamine solution. Acetone (588 ml) was added to the filtered salts, the mixture was heated to 40 °C - 45 °C, was stirred at 40 °C -45 °C over 1 hour, was cooled to 20 °C - 25 °C, was filtered and the salts were washed with acetone (188 ml). The solution and the wash were combined with the previously combined solutions. To the resulting solution dimethylformamide (30 ml) was added and the mixture was concentrated under vacuum at temperature below 45 °C until a final volume of 53 ml. MDTG (53.1 1 g; 0.21 mol) was added and the mixture stirred was for over 5 minutes. Then n-heptane (296 ml) was added followed by Zeolum 4A (23.5 g) and the mixture was stirred over 2 hours at room temperature. The zeolum was filtered and washed with n-heptane/DMF (30 ml; 3 ml). Anhydrous potassium carbonate (26.46 g; 0.19 mol) was added and the mixture was heated to a temperature between 90 °C and 95 °C under nitrogen atmosphere. The reaction mixture was stirred at 90 °C - 95 °C, under nitrogen atmosphere, until the reaction was considered complete. The content of MDTG in the reaction mixture was 3.74percent by HPLC. The reaction mixture was cooled to 80 °C, 2-methyltetrahydrofuran (876 ml) was added, the mixture was cooled to 20 °C - 25 °C, was filtered and the salts washed with 2-methyltetrahydrofuran (36 ml): The wash was combined with the main solution, and the combined solution was washed with brine (423 ml) until the content of DTG in the organic solution was 0.68percent. The content of N-demethyltiotropium in the organic solution was 90.58percent by HPLC. The organic solution was treated with activated charcoal, the activated charcoal was filtered, washed with 2- methytetrahydrofuran and the .wash was combined with the main solution. The combined solution was concentrated under vacuum at temperature equal to,.or lower than, 45 °C until a final volume of 71 ml. The suspension was cooled to -20 °C - (-15 °C), stirred at -20 °C - (-15 °C) over 12 hours, the product was filtered, washed with isopropanol (94 ml) previously cooled to 0 °C - 5 °C and was dried. N-demethyltiotropium (20.24 g) was obtained with a purity of 99.36percent by HPLC.
A dissolved mixture of scopine (500g, 3.22 mmol) a triethylamine (450 μΙ, 1 equiv.) in 4ml of tetrahydrofuran was gradually added dropwise to a stirred solution of oxalyl chloride (286 μΙ, 1.05 equiv.) and dimethylaminopyridine (19.7 mg, 0.05 equiv.) in tetrahydrofuran (4 mL) at the temperature of 0°C at the rate of 15 ml/h. The reaction mixture was stirred at 0°C for 2 hours. Subsequently, the mixture was cooled to -30°C and, during 1 h, a solution of 2-thienylmagnesium bromide (3 equivalents, 9.66ml of 1 M solution in tetrahydrofuran) was added dropwise and then the reaction mixturewas stirred at -30°C for another 2 h. The solution was then diluted with toluene (30 ml) and admixed to a mixture of 40 g of ice and 10 ml of 2M HCI. The acidic phase is separated, alkalized with 2M Na2C03 to pH 9 and the free base of the scopine ester I is extracted with dichloromethane (4x 20ml). After re-drying with Na2S04 dichloromethane is evaporated at a reduced pressure. The obtained crude product (0.750 g) with the purity of 82.98percent (analyzed with UPLC) was crystallized from acetonitrile by cooling of the solution to the temperature of -32°C for 80 h. The crystallized product was filtered, washed with a minimum quantity of cooled acetonitrile and dried freely at the room temperature. 0.323 g of the scopine ester of formula I, form B of the purity of 98.28percent (analyzed with UPLC) was obtained; melting point 117.4-118.0 °C in the yield of 31percent. The X-ray record is presented in the Annex in fig. 1a.
With vanadia; urea hydrogen peroxide adduct; In DMF (N,N-dimethyl-formamide); water; at 40 - 50℃; for 2 - 3h;
260 L of DMF are placed in a suitable reaction apparatus and heated to 50 C. Then 16.2 kg of tropenol ester (IV) are added and the mixture is stirred until a clear solution is obtained. After cooling to 40 C., hydrogen peroxide-urea complex (10.2 kg), water (13 L) and vanadium-(V)-oxide (0.7 kg) are added successively batchwise and the contents of the apparatus are heated to about 50 C. After 2-3 h stirring at constant temperature the mixture is cooled to about 20 C. The reaction mixture obtained is adjusted to about pH 4.0 with hydrochloric acid (36%). Prepared sodium bisulphite solution (2.4 kg in 24 L of water) is added. At an internal temperature of 35 C. the solvent is partially distilled off in vacuo (about 210 L). It is cooled to about 20 C. again and combined with Clarcel (3.2 kg). The pH is adjusted to about 2.0 with dilute hydrochloric acid (36%, 0.8 kg in about 440 L of water). The resulting solution is filtered and extracted with methylene chloride (58 L). The methylene chloride phase is discarded. Methylene chloride (130 L) is again added to the aqueous phase and the pH is adjusted to about 10.0 with a prepared soda solution (11.0 kg in 51 L of water). The methylene chloride phase is separated off and the aqueous phase is extracted with methylene chloride (136 L). Methylene chloride (about 175 L) is distilled off from the combined methylene chloride phases in a weak vacuum (600-700 mbar) at 40 C. The contents of the apparatus are cooled to 20 C., acetyl chloride (about 0.5 kg) is added and the mixture is stirred for about 40 minutes at 20 C. The reaction solution is transferred into a second apparatus. The pH is adjusted to 2.0 with a prepared hydrochloric acid solution (4.7 kg of 36% hydrochloric acid in 460 L of water) at 20 C. The methylene chloride phase is separated off and discarded. The aqueous phase is washed with methylene chloride (39 L). Then methylene chloride (130 L) is added and the pH is adjusted to 10.0 with a prepared soda solution (7.8 kg of soda in 38 L of water) at 20 C. After 15 min. stirring the organic phase is separated off and the aqueous phase is washed twice with methylene chloride (97 L and 65 L). The methylene chloride phases are combined and some of the methylene chloride (90 L) is distilled off in a weak vacuum at a temperature of 30-40 C. Then dimethylformamide (114 kg) is added and the remainder of the methylene chloride is distilled off in vacuo at 40 C. The contents of the apparatus are cooled to 20 C.
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