* 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 oxalyl dichloride; In dichloromethane; at 20℃; for 16.5h;
Step 2; To a solution of <strong>[204589-82-2]3-{(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl}propionic acid</strong> (Vb; Z = CO2H) (30 g, 71.5 mmol) in dichloromethane (52 ml) was added 2M solution of oxalyl chloride in dichloromethane (53 ml, 106 mmol) and the mixture was stirred at room temperature for 16.5 h. Concentration in vacuo gave the acid chloride (Vb; Z = COCl) (31.45 g, quant.) as a viscous amber colored oil.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h;
Step-f: Preparation of compound of formula-X.; Compound of formula-IX (25gm) is dissolved in dichloromethane in a R.B.Flask. and catalytical amount of Dimethyl formamide is added. Oxalyl chloride is slowly added at ambient temperature, maintained the reaction mass for 3 hrs at ambient temperature. Distilled the solvent completely under vacuum and toluene is added and again distilled completely under vacuum. Toluene is added to the crude and cooled to 10-15C and then the palladium acetate and maintained for 15 minutes.4-fluorophenyl magnesium bromide is taken in another vessel under nitrogen atmosphere and cooled to 0 -5C and added anhydrous zinc chloride and stirred for 1 hr. This complex is added to the acid chloride reaction mass at ambient temperature and maintained for 45 minutes. Filtered the reaction mass through hyflow and washed with toluene and THF mixed solution. Distilled the solvent completely under vacuum, added dichloromethane and silica gel to the crude and distilled the solvent completely under vacuum, Cyclohexane is added to the silicagel mixture and stirred for 30 minutes and . filtered and washed with cyclohexane. Silicagel mixture is slurried with ethyl acetate and cyclohexane. Distilled both filtrates under vacuum to get the residue. (Yield: 18 gm).
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 25 - 35℃; for 3h;
Example-8:Preparation of compound of formula-10 Highly pure acid compound of formula-9 (25 grams) was dissolved in dichloromethane in R.B. Flask, and catalytical amount of dimethyl formamide was added. Oxalyl chloride was slowly added at 25-35C, stirred the reaction mixture for 3 hours at 25-350C temperature. Distilled off the solvent completely under reduced pressure and toluene was added and distilled off completely under reduced pressure. Toluene was added to the crude and cooled to 10-150C and then the palladium acetate and maintained for 15 minutes. 4-fluorophenyl magnesium bromide is taken in another vessel under nitrogen atmosphere and cooled to 0-50C and added anhydrous zinc chloride and stirred for 1 hr. This complex is added to the acid chloride reaction mass at ambient temperature and maintained for 45 minutes. Filtered the reaction mass through hyflow and washed with toluene and THF solution. Distilled the solvent completely under vacuum, added dichloromethane and silica gel to the crude and distilled the solvent completely under vacuum. Cyclohexane was added to the silicagel mixture and stirred for 30 minutes, filtered and washed with cyclohexane. Silicagel mixture was slurried with ethyl acetate and cyclohexane. Distilled both the filtrates under vacuum to get the residue. Yield: 18 grams
With oxalyl dichloride; In dichloromethane; at 10 - 20℃;Purification / work up;
Example 7: Preparation of 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-f3[(4-fluoro- phenvD-3-oxo-propyl1-azetidin-2-one Method A:3-[2-(4-Benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid (25 g) was dissolved in dichloromethane (150 ml) and then cooled to 1O0C under nitrogen. Oxalyl chloride (10 ml) was added dropwise at 10-150C and then the reaction mass was stirred at ambient temperature till reaction completion. Solvent was distilled off fully under vacuum at 5O0C to obtain 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl chloride. Tetrahydrofuran (150 ml) was added to the same and the reaction mass was cooled to -78C under nitrogen. Iron acetyl acetonate (0.84 g) was added and the reaction mass was further stirred at -78 to -85C for 5 minutes. A freshly prepared Grignard solution (prepared by using 2.86 g magnesium turnings, 20.82 g 4-bromofluoro benzene and 100 ml tetrahydrofuran) was added dropwise at -78 to -85C and after complete addition the reaction mass was stirred at -78 to -850C for 60 minutes. Reaction completion was checked by TLC/HPLC. The reaction mass was poured into a solution of IN hydrochloric acid (30 ml) and ice cold demineralized water (200 ml). pH was adjusted to 5-6 using IN hydrochloric acid (^ 20 ml). Methyl tertiarybutyl ether (200 ml) was added and the reaction was stirred at ambient temperature for 15 minutes. <n="21"/>Two layers were separated. The aqueous layer was extracted with methyl tertiarybutyl ether (100 ml) and the extraction was added to the main organic layer. The combined organic layer was washed with 0.5 N hydrochloric acid solution (2x100 ml), 1% aqueous sodium hydroxide solution (2x100 ml), 25% brine (2x100 ml) respectively. The organic layer was dried over sodium sulfate. Solvent was distilled off fully under vacuum at 50-550C to get 26g of 4-(4- benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo-propyl]-azetidin-2-one having purity 82.39% by HPLC.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 10 - 15℃;Purification / work up;
Method B:3-[2-(4-Benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid (10Og) was dissolved in dichloromethane (500 ml) and N,7V-dimethylformamide (2 ml) under nitrogen and then cooled to 1O0C. Oxalyl chloride (40 ml) was added slowly at 10-150C and then the reaction mass was stirred at ambient temperature till reaction completion. Solvent was then distilled off fully to get 3-[2-(4-benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionyl chloride. Tetrahydrofuran (600 ml) was added to the same and the reaction mass was cooled to - 780C under nitrogen. Iron acetyl acetonate (3.75 g) was added and the reaction mass was further stirred at -90 to -780C for 2 minutes. A freshly prepared Grignard solution (prepared by using 15.76 g of magnesium turnings, 114.9g of l-bromo-4-fluoro benzene, a pinch of iodine and 400 ml of tetrahydrofuran) was added dropwise at -90 to -800C. After complete addition, the reaction mass was stirred at same temperature till reaction completion (monitored by HPLC). The reaction mass was poured into cold demineralized water (750 ml). Methyl tertiary butyl ether (400 ml) was added and the reaction mixture was stirred at ambient temperature for 15 minutes. The product was filtered through hyflo bed. The hyflo bed was washed with methyl tertiary-butyl ether (400ml). Organic layer was separated from the filtrate and then washed with brine. The organic layer was dried over sodium sulfate. Solvent was distilled off fully under vacuum at 50- 550C to obtain 4-(4-benzyloxy-phenyl)-l-(4-fluoro-phenyl)-3-[3[(4-fluoro-phenyl)-3-oxo- propyl]-azetidin-2-one.
With oxalyl dichloride; In dichloromethane; at 22℃; for 16h;
Step 4): To a solution of the product of Step 3 (0.94 g, 2.2 mmol) in CH3OH (3 ml), was added water (1 ml) and LiOH.H2O (102 mg, 2.4 mmole). The reaction mixture was stirred at 22 C. for 1 h and then additional LiOH.H2O (54 mg, 1.3 mmole) was added. After a total of 2 h, HCl (1N) and EtOAc was added, the layers were separated, the organic layer was dried and concentrated in vacuo. To a solution of the resultant product (0.91 g, 2.2 mmol) in CH2Cl2 at 22 C., was added CICOCOCI (0.29 ml, 3.3 mmol) and the mixture stirred for 16 h. The solvent was removed in vacuo.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 48℃;
EXAMPLE 8; PREPARATION OF (3R,4S)-1-(4-FLUOROPHENYL)-3-[3-(4-FLUOROPHENYL)-3-OXOPROPYL]-4-(4-BENZYLOXYPHENYL)-2-AZETIDONONE (FORMULA XI); 37.5 ml of tetrahydrofuran and 2.9 g of magnesium turnings were taken into a round bottom flask and the mixture was heated to 48 C. 0.3 g of iodine was added to it. 3.0 ml of 1-bromo 4-fluoro benzene was added to it. Then another 17.0 ml of 1-bromo 4-fluorobenzene was added to the reaction mass slowly. The reaction mass was then cooled to 0 C. and 116.3 g of zinc chloride was added to it. In a separate round bottom flask 25 g of (3R,4S)-1-(4-fluorophenyl)-3-[3-(hydroxy)-3-oxopropyl]-4-(4-benzyloxyphenyl)-2-azetidonone of Formula VIII, 125 ml of dichloromethane and 0.5 ml of dimethylformamide were taken and stirring given. 11.4 ml of oxalyl chloride was added to the reaction mass. Reaction completion was checked using thin layer chromatography. After completion of the reaction, the reaction mass was distilled completely at 63 C. 25 ml of toluene was added to the reaction mass and again distilled off completely. To the residue obtained, 125 ml of toluene was added and the reaction mass was cooled to 10 C. 0.5 g of palladium acetate was added to it. The reaction mass containing 4-fluorophenyl zinc chloride prepared above was added to the reaction mass. The reaction mass was maintained at 10 to 11 C. for 20 minutes. Reaction completion was checked using thin layer chromatography. After the reaction was completed, 125 ml of 1 N hydrochloric acid was added to the reaction mass followed by 125 ml of ethyl acetate. The organic layer was separated and washed with 125 ml of water followed by washing with 125 ml of 10% sodium bicarbonate solution. The organic layer was distilled completely at 65 C. To the residue, 25 ml of dichloromethane and 150 ml of cyclohexane was added. 50% of the solvent was distilled from the reaction mass. 75 ml of cyclohexane was added to the reaction mass and again 50% of the solvent was distilled. Another 75 ml of cyclohexane was added to the reaction mass and kept for stirring. The reaction mass was stirred at 30 C. for 4 hours and then the cyclohexane layer was decanted. Another 100 ml of cyclohexane was added to the reaction mass and sitirred for 30 minutes. The cyclohexane layer was decanted and the residue was distilled at 70 C. to remove the solvent completely to yield 20.3 g of the title compound. (Yield 68.5%) Purity by HPLC: 93.15%.
Hydrolysis step (Step 1) optimization Example 1. 3-{(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl}propionic acid (Vb; Z = CO2H) Procedure 1: Hydrolysis with KOH in THF/t-BuOH = 1/3, small scale To a solution of methyl 3-{(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl}propionate (Vb; Z = CO2Me) (1.6 g, 3.7 mmol) in tetrahydrofuran (1 ml) and tert-butanol (3 ml) was added powdered potassium hydroxide (244 mg, 3.7 mmol). The mixture was stirred at room temperature for 1 h, then additional amount of powdered potassium hydroxide (90 mg, 1.3 mmol) was added and stirring continued for 1 h. 1M hydrochloric acid (5 ml) and ethyl acetate (18 ml) were added, the organic layer was washed 3 times with water and dried over sodium sulfate. Concentration in vacuo afforded the acid (Vb; Z = CO2H) (1.5 g, 95%) as a viscous oil. Procedure 2: Hydrolysis with KOH in THF/t-BuOH = 1/3, larger scale To a solution of methyl 3-{(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl}propionate (Vb; Z = CO2Me) (32 g, 74 mmol) in tetrahydrofuran (20 ml) and tert-butanol (60 ml) was added powdered potassium hydroxide (4.88 g, 74 mmol). The mixture was stirred at room temperature for 1.5 h. Then 1M hydrochloric acid (100 ml) and ethyl acetate (200 ml) were added. The organic layer was washed 3 times with water and dried over sodium sulfate. Concentration in vacuo afforded the acid (Vb; Z = CO2H) (30.9 g, 99%) as an amber foam.
92%
Procedure 5: Hydrolysis with KOH in THF To a solution of methyl 3-{(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl}propionate (Vb; Z = CO2Me) (50 mg, 0.146 mmol) in tert-butanol (1.5 ml) was added powdered potassium hydroxide (13 mg, 0.232 mmol). The mixture was stirred at room temperature for 2 h, then 0.5M hydrochloric acid (2 ml) and tert-butyl methyl ether (15 ml) were added. The organic layer was washed 3 times with water, dried over sodium sulfate and concentrated in vacuo to obtain the acid (Vb; Z = CO2H (45 mg, 92%) as a viscous oil.
89%
EXAMPLES Reference example (EP 0720599, example 6). Synthesis of ezetimibe from methyl 3-{(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl}propionate (Vb; Z = CO2Me) Procedure 1: To a solution of methyl 3-{(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl}propionate (Vb; Z = CO2Me) (1.6 g, 3.7 mmol) in methanol (3.5 ml) and water (1.5 ml) was added lithium hydroxide monohydrate (155 mg, 3.7 mmol). The mixture was stirred at room temperature for 1.5 h, then additional amount of lithium hydroxide monohydrate (54 mg, 1.3 mmol) was added and stirring continued for 3 h. 1M hydrochloric acid (5 ml) and ethyl acetate (15 ml) were added, the organic layer was washed 3 times with water and dried over sodium sulfate. Concentration in vacuo afforded the acid (Vb; Z = CO2H) (1.4 g, 89%) as an amber colored foam.Procedure 2: To a solution of methyl 3-{(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl}propionate (Vb; Z = CO2Me) (32 g, 74 mmol) in methanol (70 ml) and water (30 ml) was added lithium hydroxide monohydrate (3.1 g, 74 mmol). The mixture was stirred at room temperature for 1.5 h, then additional amount of lithium hydroxide monohydrate (1.08 g, 26 mmol) was added and stirring continued for 5.45 h. 1M hydrochloric acid (100 ml) and ethyl acetate (110 ml) were added, the organic layer was washed with water and dried over sodium sulfate. Concentration in vacuo afforded the acid (Vb; Z = CO2H) (31.86 g, quant.) as an amber colored foam.
89 - 92%
Procedure 3: Hydrolysis with t-BuOK + H2O in THF To a solution of methyl 3-{(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl}propionate (Vb; Z = CO2Me) (100 mg, 0.231 mmol) in tetrahydrofuran (2 ml) and water (10 mg, 0.462 mmol) was added potassium tert-butoxide (0.54 g, 1.85 mmol). The resulting suspension was stirred at room temperature for 72 h, then 1M hydrochloric acid (2 ml) and diethyl ether (20 ml) were added. The organic layer was washed 3 times with water and dried over sodium sulfate. Concentration in vacuo afforded the acid (Vb; Z = CO2H) (86 mg, 89%) as a viscous oil.Procedure 4: Hydrolysis with t-BuOK in H2O/ THF mixture To a solution of methyl 3-{(2S,3R)-2-[4-(benzyloxy)phenyl]-1-(4-fluorophenyl)-4-oxoazetidin-3-yl}propionate (Vb; Z = CO2Me) (50 mg, 0.146 mmol) in tetrahydrofuran (4 ml) and water (53 mg, 2.92 mmol) was added potassium tert-butoxide (0.54 g, 1.85 mmol). The resulting suspension was stirred at room temperature for 1 h, then heated to 50 C for additional 1.5 h. After cooling to room temperature, 0.5M hydrochloric acid (2 ml) and diethyl ether (10 ml) were added to the reaction mixture. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford the acid (Vb; Z = CO2H) (45 mg, 92%) as a viscous oil.
Step-e: Preparation of compound of formula-IX.; Compound of formula- VIII (25 gm) is dissolved in acetone (25ml) in a cleaned R.B.Flask. Water (62.5 ml) and sodium hydroxide (2.8 gm) added to the reaction mass. Maintained the reaction mass for 3 hrs at ambient temperature. Reaction mass quenched with water and pH adjusted to 6.5-7.0 with aqueous hydrochloric acid. Reaction mass extracted with ethyl acetate and distilled the solvent completely under vacuum to give residue of the compound. It is used into next stage without any purification. Yield: 22 gm.
Example-5:Preparation of compound of formula-9:Aqueous sodium hydroxide solution (2.8 grams in 62.5 ml of water) is added to a solution of 25 grams of compound of formula-8 and 25 ml of acetone. Stirred the reaction mixture for 3 hours at ambient temperature. Quenched the reaction mixture with water. Adjusted the reaction mixture pH to 6.7 with aqueous hydrochloric acid. Extracted the <n="20"/>reaction mixture with ethyl acetate. Distilled the solvent completely under reduced pressure to get the residue compound of formula-9. Yield: 22 grams.
Step 4): To a solution of the product of Step 3 (0.94 g, 2.2 mmol) in CH3OH (3 ml), was added water (1 ml) and LiOH.H2O (102 mg, 2.4 mmole). The reaction mixture was stirred at 22 C. for 1 h and then additional LiOH.H2O (54 mg, 1.3 mmole) was added. After a total of 2 h, HCl (1N) and EtOAc was added, the layers were separated, the organic layer was dried and concentrated in vacuo. To a solution of the resultant product (0.91 g, 2.2 mmol) in CH2Cl2 at 22 C., was added CICOCOCI (0.29 ml, 3.3 mmol) and the mixture stirred for 16 h. The solvent was removed in vacuo.
EXAMPLE 7 PREPARATION OF (3R,4S)-1-(4-FLUOROPHENYL)-3-[3-(HYDROXY)-3-OXOPROPYL]-4-(4-BENZYLOXYPHENYL)-2-AZETIDONONE (FORMULA IX) 50 g of (3R,4S)-1-(4-fluorophenyl)-3-[3-(methoxy)-3-oxopropyl]-4-(4-benzyloxyphenyl)-2-azetidonone of Formula VII was taken into a round bottom flask and 50 ml of acetone was added to it. A solution of 5.9 g of sodium hydroxide in 125 ml of water was prepared and added to the reaction mass. Reaction completion was checked using thin layer chromatography. After the reaction was completed, 150 ml of water was added to it. pH of the reaction mass was adjusted to 6.6 with 100 ml of 1 N hydrochloric acid solution. The reaction mass was then extracted with 400 ml of ethyl acetate in two equal lots. The organic layer was distilled under a vacuum of 250 mm Hg at a temperature of 62 C. to get 54 g of the title compound.
Example-6:Preparation of Tertiarybutylamine salt of 3-((3R,4S)-l-(4-fluorophenyl)-2-oxo-4-(4- (benzyloxy)phenyl)azetidin-3-yl)propionic acid compound of formula-la:Aqueous sodium hydroxide solution (2.5 grams in 62.5 ml of water) added to a solution of 25 grams of residue compound of formula-9 and 50 ml of acetone. Stirred the reaction mixture for 5 hours at 20-25C. Quenched the reaction mixture with sodium chloride solution. Adjusted pH of the reaction mixture to 3.6 with aqueous hydrochloric acid solution. Extracted the reaction mixture with 150. ml of ethyl acetate. Separated the organic and aqueous phases. Extracted the aqueous layer with ethyl acetate. Dried the organic layer over sodium sulfate. Added 6 ml of tertiarybutylamine to the organic layer at 20-25C. Stirred the reaction mixture for 30-45 minutes at 20-25C. Distilled the solvent completely under reduced pressure. Added 125 ml of acetone and 12.5 ml of water to the reaction mixture and stirred for 15 minutes. Heated the reaction mixture to 50-55C and stirred for 30 minutes. Slowly cooled to 20-25C and stirred for one hour. Filtered the precipitated solid and dried at 25-30C to get the title compound of formula- IaYield: 22.5 grams. HPLC Purity: 98.94 %
4
[ 75-64-9 ]
[ 204589-82-2 ]
C4H11N*C25H22FNO4[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
at 20 - 25℃; for 0.5 - 0.75h;Purification / work up;
Example-6:Preparation of Tertiarybutylamine salt of 3-((3R,4S)-l-(4-fluorophenyl)-2-oxo-4-(4- (benzyloxy)phenyl)azetidin-3-yl)propionic acid compound of formula-la:Aqueous sodium hydroxide solution (2.5 grams in 62.5 ml of water) added to a solution of 25 grams of residue compound of formula-9 and 50 ml of acetone. Stirred the reaction mixture for 5 hours at 20-25C. Quenched the reaction mixture with sodium chloride solution. Adjusted pH of the reaction mixture to 3.6 with aqueous hydrochloric acid solution. Extracted the reaction mixture with 150. ml of ethyl acetate. Separated the organic and aqueous phases. Extracted the aqueous layer with ethyl acetate. Dried the organic layer over sodium sulfate. Added 6 ml of tertiarybutylamine to the organic layer at 20-25C. Stirred the reaction mixture for 30-45 minutes at 20-25C. Distilled the solvent completely under reduced pressure. Added 125 ml of acetone and 12.5 ml of water to the reaction mixture and stirred for 15 minutes. Heated the reaction mixture to 50-55C and stirred for 30 minutes. Slowly cooled to 20-25C and stirred for one hour. Filtered the precipitated solid and dried at 25-30C to get the title compound of formula- IaYield: 22.5 grams. HPLC Purity: 98.94 %
With hydrogenchloride; In dichloromethane; water; at 25 - 30℃; for 1h;pH 1.8;Purification / work up;
Example-7: Preparation of high pure 3-((3R, 4S)-l-(4-fluorophenyl)-2-oxo-4-(4-(benzyloxy) phenyl) azetidin-3-yl)propionic acid compound of formula-9:25 grams of tertiarybutylamine salt compound of formula-9a dissolved in 125 ml of dichloromethane. Adjusted the pH of the solution to 1.8 with dilute hydrochloric acid at 25-30C. Stirred the reaction mixture for an hour at 25-30C. Separated the organic and aqueous phases. Extract the aqueous layer with dichloromethane. Washed the organic layer with vacuum salt. Distilled the solvent completely under reduced pressure at below <n="21"/>450C. The residue treated with cyclohexane. Heated the reaction mixture to reflux. Stirred the reaction mixture at reflux for one hour. Filtered the precipitated solid and dried to get a highly pure title compound 3-((3R,4S)-l-(4-fluorophenyl)-2-oxo-4-(4- (benzyloxy)phenyl)azetidin-3 -yl)propionic acid. Yield: 22.5 grams; M.R.: 96-100C HPLC Purity: 98.85 %
Example 6; Preparation of 342-(4-benzyloxy-phenylVl-(4-fluorophenylV4-oxo-azetidin-3- yU-propionic acid3-[2-(4-Benzyloxy-phenyl)-l-(4-fluorophenyl)-4-oxo-azetidin-3-yl]-propionic acid benzyl ester (100 g) was taken in tetrahydrofuran (800 ml) at ambient temperature. A solution of lithium hydroxide (5.20 g) in demineralized water (350 ml) was added and the reaction mass was stirred at ambient temperature till reaction completion (monitored by HPLC). After reaction completion demineralized water (1.0 L) and ethyl acetate (500 ml) were added and stirred for 15 minutes. The two layers were separated. Organic layer was extracted with demineralized water (300 ml) and the aqueous layers were combined. IN hydrochloric acid solution (200 ml) and ethyl acetate (800 ml) were added to the combined aqueous layer and stirred for 15 minutes. The two layers were separated. Organic layer was washed with demineralized water (LO 1 L). Solvent was removed by distillation under vacuum at 50-550C. Ethyl acetate (lOOml) was added and then the reaction mass was heated to get a clear solution. Hexane (500ml) was added slowly and then the reaction mass was slowly cool to 25-300C and maintained for 10 hours. The solid was filtered and washed with hexane (100 ml). The solid was dried under vacuum at 50-550C to get 80 g of the title compound having purity of 96.87% by HPLC.
Example 1: Preparation of trans-N-methoxy-N-methyl-3(R)-(3-[2-oxo-4(S)-(4-benzyloxyphenyl)- l-(4-fluorophenyl)-azetidinyl]propanamide.To a solution of trans-3(R)-(3-[2-oxo-4(S)-(4-benzyloxyphenyl)-l-(4-fluorophenyl)- azetidinyl]propanoic acid (12g, 0.0286mol) in tetrahydrofuran (60ml), N3N- carbonyldmidazole (5.56g, 0.0343mol) was added over a period of 10 to 15 minutes at 270C to 3O0C and stirred for another 1 hour. To this, N,O-dimethylhydroxylamine salt (3.35g, 0.0343mol) was added at 270C to 3O0C and stirred for 2 another hours. After completion of reaction (TLC solvent system, ethyl acetate.hexane; 30:70), 60ml of ethyl acetate and 50ml of water was added and stirred for 15 minutes. Organic layer was separated, washed with 0.5N aqueous HCl (2x30ml) followed by 5% aqueous sodium bicarbonate (2x30ml) and saturated aqueous sodium chloride (40ml). Organic layer wphis dried over sodium sulphate, filtered and concentrated under vacuum to product.1H-NMR (400MHz) delta in ppm (CDCl3): 2.15 (m, 2H), 2.6 (t, 2H), 3.06 (m, 4H), 3.56 (s, 3H), 4.6 (d, IH), 4.98 (s, 2H), 7.05 (m, 13H)
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; In dichloromethane; water; at 20℃; for 6h;Inert atmosphere;
To a solution of 19 (40.0 mg, 0.10 mmol) and PhI(OAc)2 (64.0 mg, 0.20 mmol) in CH2Cl2 (1.0 ml) and H2O (0.5 ml) was added TEMPO (3.0 mg, 0.02 mmol) and the reaction mixture was stirred for 6 h at room temperature. After addition of aq. Na2S2O3, the organic materials were extracted with CH2Cl2 two times. The combined organic phases were washed with brine, and dried over Na2SO4. After filtration, the volatile materials were removed under reduced pressure to give an oily residue, which was purified by column chromatography (SiO2, hexane/AcOEt = 2:1 with 3% formic acid) to give the compound 2 (32.0 mg, 0.08 mmol) in 77% yield as a yellow oil.
In methanol; at 20℃; for 0.166667h;Inert atmosphere;
To a solution of 2 (32.0 mg, 0.08 mmol) in MeOH (3 ml) was added trimethylsilyl diazomethane (9.6 mg, 0.08 mmol) and the reaction mixture was stirred for 10 min atroom temperature. After addition of formic acid and water, the organic materials were extracted with CH2Cl2 two times. The combined organic phases were washed with brine, and dried over Na2SO4. After filtration, the volatile materials were removed under reduced pressure to give an oily residue, which was purified by column chromatography (SiO2, hexane/AcOEt = 5:1) to give the compound 2a (16.5 mg, 0.04 mmol) as a yellow oil.
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