* 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 In 1,2-dichloro-ethane at 0℃; for 1 h;
(S)-3-chloro-1,2-propanediol 1-(n-butyrate)(50.0 g, 0.277 mol, optical purity 99percent e.e.) was dissolved in 1,2-dichloroethane (200 ml), followed by addition of potassium tert-butoxide (32.6 g, 0.291 mol) in ice-cooling. The mixture was stirred for 1 hour. After the reaction, the reaction mixture was added into a separating funnel, washed with water (200 ml) twice, the organic layer was condensed under reduced pressure to give the subject compound, (R)-glycidyl n-butyrate (28.7 g, yield 72.0percent). The optical purity on the subject compound was 99percent e.e. by measurement by HPLC.
Reference：
[1] Letters in Organic Chemistry, 2011, vol. 8, # 4, p. 242 - 243
[2] Tetrahedron Letters, 2006, vol. 47, # 20, p. 3453 - 3457
[3] Patent: US2004/24254, 2004, A1, . Location in patent: Page 6
2
[ 2461-40-7 ]
[ 60456-26-0 ]
[ 57044-25-4 ]
Yield
Reaction Conditions
Operation in experiment
> 99 % ee
With thermomyces lanuginosa In 1,4-dioxane; aq. phosphate buffer at 30℃; for 2 h; Resolution of racemate; Enzymatic reaction
General procedure: In a 50 mL erlenmeyer flask containing 6 mL of phosphate buffer (1 M, pH 7), it was added the ester (0.36 mmol), lipase (5 mg), and dioxane (0.6 mL). The mixture was shaken (150 rpm) at 30 °C or 50 °C for a specified period of time (Table 2), while the pH was maintained at 7 by the periodic addition of aqueous 1 M solution of NaOH. It was considered 50percent hydrolysis of the substrate when half the equimolar amount of NaOH was consumed and, an aliquot of the reaction mixture was taken and analyzed by chiral HPLC or GC.
Reference：
[1] Journal of the American Chemical Society, 2002, vol. 124, # 7, p. 1307 - 1315
4
[ 2461-40-7 ]
[ 5309-42-2 ]
[ 60456-26-0 ]
[ 126254-87-3 ]
Reference：
[1] Journal of the American Chemical Society, 2002, vol. 124, # 7, p. 1307 - 1315
5
[ 2461-40-7 ]
[ 890051-54-4 ]
[ 890051-57-7 ]
[ 60456-26-0 ]
[ 65031-96-1 ]
Reference：
[1] Journal of Organometallic Chemistry, 2006, vol. 691, # 9, p. 1862 - 1872
6
[ 106-31-0 ]
[ 60456-23-7 ]
[ 60456-26-0 ]
Yield
Reaction Conditions
Operation in experiment
98.1 - 99.5 % ee
With triethylamine In dichloromethane at 0 - 20℃; for 1 h;
To 1.2 L of a methylene chloride solution of (S)-3-chloro-l,2-propanediol (200 g, 99.5percent ee) was added 519 g of potassium phosphate tribasic, and then the obtained solution was refluxed, under stirring, for 3 hours. The resulting solution was cooled to 0°C, and 220 g of trie thy lamine, 4 g of 4-(dimethylamino)pyridine, and 315 g of butanoic acid anhydride were dropwisely added to the solution. After additional stirring for 1 hour at a room temperature, the reaction mixture was successively washed with 2.2 L of 5percent aqueous potassium carbonate solution, 2 L of IN aqueous hydrogen chloride solution, and 1 L of water. The organic layer was dried with 50 g of anhydrous sodium sulfate and filtrated. The methylene chloride was evaporated under reduced pressure. Fractional distillation (90°C/19 mmHg) of the resulting residue gave 242 g of the targeted compound:- Yield: 92.7percent- Chemical purity: 99.4percent- Optical purity (GC) 99.5percent ee Comparative Example 1 Preparation of (R)-glycidyl butyrateTo 1.2 L of a methylene chloride solution of (S)-3-chloro-l,2-propanediol (200 g, 99.5percent ee) was added 338 g of potassium carbonate, and then the obtained solution was refluxed, under stirring, for 25 hours. The resulting solution was cooled to 0°C, and 220 g of triethylamine, 4 g of 4-(dimethylamino)pyridine, and 315 g of butanoic acid anhydride were dropwisely added to the solution. After additional stirring for 1 hour at a room temperature, the reaction mixture was successively washed with 2.2 L of 5percent aqueous potassium carbonate solution, 2 L of IN aqueous hydrogen chloride solution, and 1 L of water. The organic layer was dried with 50 g of anhydrous sodium sulfate and filtrated. The methylene chloride was evaporated under reduced pressure. Fractional distillation (90°C/19 mmHg) of the resulting residue gave ID g of the targeted compound:- Yield: 65.0percent- Chemical purity: 97.4percent- Optical purity (GC) 98.1percent eeAs shown in the above, the process according to the present invention provides glycidyl derivatives in high yield, with high chemical purity and high optical purity, compared to the conventional one in which the carbonate salt was used. In addition, the reaction rate of the phosphate salt is even faster than that of the carbonate salt. Therefore, the process according to the present invention is an industrially ad;vantageous one. Furthermore, the process according to the present invention can be applicable to the preparation of various glycidyl derivatives including a chiral glycidyl alkanoate as well as a chiral glycidyl sulfonate.
Stage #1: With n-butyllithium; butan-1-ol In tetrahydrofuran; hexane at -15 - 30℃; Inert atmosphere Stage #2: at -10 - 15℃; Stage #3: With water In tetrahydrofuran; hexane; ethyl acetate
Example 3: Preparation of(R)-[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methanol.[131] Take n-Butanol (51.5g) and THF (100ml) at 20-30°C under Nitrogen atmosphere.After cooling the mix add slowly n- Butyl lithium (1.6M in hexane) (391.7g) at 10 to 20°C maintain it for 45-60 minutes. Take THF (500ml) and N-Car- bobenzoxy-3-fluoro-4-morpholinylaniline (lOOg) at 20-30°C under Nitrogen atmosphere. Cool the mix at -15 to -5°C under stirring. To this solution add slowly n- Butyl lithium solution maintain for 45-60 minutes at -15 to -5°C, to this solution add slowly (R)-(-) Glycidyl butyrate (48.0g) maintain for 1 hour at -10 to -5°C. After completing addition raise the temperature to 8-13°C and maintain for 1 hour then take it to 13-15°C and maintain for 4-5 hours. Organic layer was separated by water (800ml) and Ethyl acetate (300ml). Filter wash the solid with mix of Ethyl acetate- n-Hexane dried in air tray dryer at 55-60°C. Yield: 0.765.: Percentage 85percentw/w.[132]
80%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; Inert atmosphere Stage #2: at -78 - 20℃;
To a solution of N-(3-Fluoro-4-morpholin-4-ylphenyl)carbamic acid benzyl ester (200 g, 0.606 mol) in THF (1600 mL) under nitrogen at -78°C was added n-butyllithium (416.7 mL, 1.6 M in hexane, 0.666 mol, 1.1 mol eq) over 1.5 h. The reaction mixture was stirred at - 78°C for 2 h, then a solution of R-(-)-glycidyl butyrate (104.7 g, 0.727 mol, 1.2 mol eq) in THF (200 mL) was added at -78°C over 1 h. After stirring at -78°C for 2 h, the reaction mass was warmed to room temperature and stirred for overnight. To the resulting thick slurry is then added saturated ammonium chloride (690 mL) followed by water (100 mL). After stirring at room temperature for 10 min THF layer was separated, aqueous layer was extracted with ethyl acetate (2 x 500 mL). The combined ethyl acetate layer was concentrated under vacuum at 50-55°C to get a residue in which THF layer was added and concentrated completely under vacuum at 50-55°C. Thus obtained solid mass was cooled to room temperature and ethyl acetate (1600 mL) was added. The mixture was heated to 55-60°C and kept stirring for 30 min. The mixture was cooled to 40-42°C, filtered over hyflo and then washed the bed with ethyl acetate (200 mL). The moisture content in the combined ethyl acetate layer was adjusted to 0.29percent by adding demineralised water and then cooled to 30°C. n-Hexane (1200 mL) was charged to the above ethyl acetate solution at 25-30°C and stirred for 12 hr, filtered the solid, washed with a mixture (1 : 1) of ethyl acetate and n-hexane (2 x 200 mL) and dried under vacuum at 50-55°C for 16 hr. The mother liquor was concentrated to dryness under vacuum at 50°C and crystallized from a mixture of ethyl acetate (600 mL) and cyclohexane (600 mL) to get the 2nd crop of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2- oxo-5-oxazolidinyl]methanol which matches with the 1 st crop in all respect to provide 142 g material with a combined 80percent yield. Percentage Yield: 80percent
80%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 3.5 h; Inert atmosphere Stage #2: at -78 - 20℃; Inert atmosphere
[0131] To a solution of N-(3-Fluoro-4-morpholin-4-ylphenyl)carbamic acid benzyl ester (200 g, 0.606 mol) in THF (1600 mL) under nitrogen at −78° C. was added n-butyllithium (416.7 mL, 1.6 M in hexane, 0.666 mol, 1.1 mol eq) over 1.5 h. The reaction mixture was stirred at −78° C. for 2 h, then a solution of R-(−)-glycidyl butyrate (104.7 g, 0.727 mol, 1.2 mol eq) in THF (200 mL) was added at −78° C. over 1 h. After stirring at −78° C. for 2 h, the reaction mass was warmed to room temperature and stirred for overnight. To the resulting thick slurry is then added saturated ammonium chloride (690 mL) followed by water (100 mL). After stirring at room temperature for 10 min THF layer was separated, aqueous layer was extracted with ethyl acetate (2×500 mL). The combined ethyl acetate layer was concentrated under vacuum at 50-55° C. to get a residue in which THF layer was added and concentrated completely under vacuum at 50-55° C. Thus obtained solid mass was cooled to room temperature and ethyl acetate (1600 mL) was added. The mixture was heated to 55-60° C. and kept stirring for 30 min. The mixture was cooled to 40-42° C., filtered over hyflo and then washed the bed with ethyl acetate (200 mL). The moisture content in the combined ethyl acetate layer was adjusted to 0.29percent by adding demineralised water and then cooled to 30° C. n-Hexane (1200 mL) was charged to the above ethyl acetate solution at 25-30° C. and stirred for 12 hr, filtered the solid, washed with a mixture (1:1) of ethyl acetate and n-hexane (2×200 mL) and dried under vacuum at 50-55° C. for 16 hr. The mother liquor was concentrated to dryness under vacuum at 50° C. and crystallized from a mixture of ethyl acetate (600 mL) and cyclohexane (600 mL) to get the 2nd crop of (R)—[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methanol which matches with the 1st crop in all respect to provide 142 g material with a combined 80percent yield. [0132] Percentage Yield: 80percent
77.7%
Stage #1: With n-butyllithium In tetrahydrofuran at -85 - -75℃; for 2 h; Stage #2: Heating
A solution of N-benzyloxycarbonyl-3-fluoro-4-morpholinoaniline (2.0 g, 6.06 mmol) and tetrahydrofuran, Cooled to -85 to -75 ° C, a solution of n-butyllithium (2.80 mL, 7.03 mmol)The reaction was continued for 2 hours.A solution of (R) -butyric acid glycidyl ester (0.90 g, 6.06 mmol) in tetrahydrofuran was then added dropwise and the temperature was naturally warmed to the reaction overnight.TLC monitoring, the reaction is completed.To the reaction was added 30 mL of saturated NH4Cl solution and dichloromethane, stirred for 2 minutes,The phases were separated and the aqueous phase was extracted with CH2Cl2. The organic phases were combined, washed with water, saturated NaCl solution,Dried over anhydrous Na2SO4 and concentrated to give the crude product.Recrystallization to give the product as a lavender powder(R) - [3- (3-fluoro-4-morpholinophenyl) -2-oxo-5-oxazolidinyl] methyl alcohol, 1.39 g,Yield: 77.7percent, chemical purity: 99.3percent; optical purity: 98.68percent.
70%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 3.5 h; Inert atmosphere Stage #2: at -78 - 20℃; Stage #3: With ammonium chloride In tetrahydrofuran; hexane; water at 20℃; for 0.166667 h;
Example-6(b): Preparation of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl] methanol (VIII) starting from N-carbobenzoxy-3-fluoro-4- morpholinylanilineN-carbobenzoxy-3-fluoro-4-morpholinylaniline (100 g) was dissolved in THF (800 ml). To the resulting solution, n-butyllithium (208 ml in hexane) was added under nitrogen at -78°C over 1.5h and stirred for 2h, further a solution of R-(-)-glycidyl butyrate (52.3 g in THF (100 ml)) was added and stirred for 2h. The reaction mixture was warmed to room temperature and stirred for overnight. To the resulting thick slurry saturated ammonium chloride (345 ml) was added followed by the addition of water (50 ml). It was stirred at room temperature for 10 min and THF layer was separated from aqueous layer. Aqueous layer was extracted with ethyl acetate (2 x 250 ml). The combined ethyl acetate layer was washed with water and concentrated to get a residue in which THF layer was added and further concentrated completely. The solid mass obtained was cooled to room temperature and ethyl acetate (600 ml) was added. The reaction mixture was heated to 60-65°C and was stirred for 30 min, which was further cooled to 40-45 °C. The cooled reaction mixture was filtered and was washed with ethyl acetate (100 ml). To the filtrate cyclohexane (450 ml) was added at 25-35°C in 5 min. The resulting mixture was stirred for 12h. The precipitated solid was filtered, washed with a mixture (1 :1) of ethyl acetate and cyclohexane and dried to obtain the titled compound (62 g) with 70percent yield.
64%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.5 h; Stage #2: at -78 - 20℃; Stage #3: With ammonium chloride In tetrahydrofuran; hexane; water
To a solution of 390 g of N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline in 5.50 L of tetrahydrofuran at -78°C under nitrogen was added 770ml of 1.6M n-butyl lithium/hexane over 30 min. Further 183.2 g of (R)-glycidyl butyrate in 300 ml of tetrahydrofuran was added to the obtained reaction mixture over 30 min followed by stirring for 1 hr at -78°C. After the completion of reaction, the reaction mass was allowed to come to ambient temperature gradually. After stirring the mixture overnight, 200 ml of saturated aqueous ammonium chloride was added, followed by 5 L of water. The aqueous layer was extracted with ethyl acetate (4 x 3.0 L) and the combined organic layer was concentrated to get a light purple solid. Yield: 249.6 g.; Percentage: 64percent w/w
78 g
Stage #1: With n-butyllithium In tetrahydrofuran at -30 - -20℃; Stage #2: at -30 - 50℃;
II. Preparation of (R)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl] methanol N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline (100 g) and tetrahydrofuran (1100.0 ml) at 25-30°C in RBF and cooled to -20°C to -30°C. n-BuLi (250.0ml) was added slowly for a period of 30-40 minutes to the reaction mixture at -20 °C to -30 °C and stirred for 35- 40 minutes. A solution of R-glycidyl butyrate (46. Ogm) in THF (50.0ml) was added to reaction mass at -20 °C to -30 °C within 20 to 30 minutes and maintained for 1 hour at -20 °C to -30 °C. The temperature of the reaction mass was slowly raised to 45-50°C within 40-60 minutes, maintained for 2 hours at 45-50 °C and then cooled to 25-30°C. The reaction mass was quenched with aqueous NH4C1 solution (5percent) (400.0ml) at 25-30°C and then toluene (400.0 ml) was charged at 25-30°C. Two layers were separated and the obtained organic layer was concentrated under vacuum at 40-45°C to get thick slurry. Toluene (300ml) was added to the residue at 25-30°C, stirred for 30 minutes at 25-30°C, cooled to 5-10°C and stirred for lhour. The suspension was filtered, washed the solid with toluene (2x100.0 ml) and dried in air oven for 30 mins at 25-30°C followed by at 40-45°C to obtain titled compound.Dry weight: 78gm
Reference：
[1] Synthetic Communications, 2010, vol. 40, # 6, p. 789 - 798
[2] Patent: WO2011/77310, 2011, A1, . Location in patent: Page/Page column 12
[3] Organic Syntheses, 2005, vol. 81, p. 112 - 120
[4] Patent: WO2013/111048, 2013, A1, . Location in patent: Page/Page column 19; 20
[5] Patent: US2015/25236, 2015, A1, . Location in patent: Paragraph 0131; 0132
[6] Patent: CN102617500, 2016, B, . Location in patent: Paragraph 0042; 0043
[7] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 3, p. 1302 - 1305
[8] Patent: WO2011/114210, 2011, A2, . Location in patent: Page/Page column 22
[9] Patent: WO2009/63505, 2009, A2, . Location in patent: Page/Page column 14
[10] J. Med. Chem., 1996, vol. 39, # 3, p. 673 - 679
[11] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 6, p. 857 - 859
[12] Organic and Biomolecular Chemistry, 2008, vol. 6, # 24, p. 4634 - 4642
[13] Patent: WO2013/72923, 2013, A1, . Location in patent: Page/Page column 16-17
[14] European Journal of Medicinal Chemistry, 2013, vol. 69, p. 779 - 785
[15] Patent: WO2015/68121, 2015, A1, . Location in patent: Page/Page column 14
[16] European Journal of Medicinal Chemistry, 2015, vol. 106, p. 120 - 131
13
[ 565176-83-2 ]
[ 60456-26-0 ]
[ 168828-82-8 ]
Yield
Reaction Conditions
Operation in experiment
80%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 3.5 h; Inert atmosphere Stage #2: at -78 - 20℃; Stage #3: With ammonium chloride In tetrahydrofuran; hexane; water at 20℃; for 0.5 h;
Example-S(a): Preparation of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2- oxo-5- oxazolidinyljmethanol (VIII) starting from N-carboethoxy-3-fluoro-4- morpholinylanilineN-carboethoxy-3-fluoro-4-morpholinylaniline (100 g) was dissolved in THF (500 ml). To the resulting solution, n-butyllithium (245 ml in hexane) was added under nitrogen at -78°C over 1.5h and stirred for 2h, further a solution of R-(-)-glycidyl butyrate (53.75 g, in THF (100 ml)) was added. The resulting solution was stirred at -78°C for 2h, further it was warmed to room temperature and stirred for overnight. To the resulting thick slurry, saturated ammonium chloride (345 ml) was added followed by the addition of water (300 ml). It was stirred at room temperature for 30 min and was concentrated. Further, water (500 ml) was added and the suspension was again stirred at 50-55°C for lh and then at 25-30°C for next lh. The solid mass was filtered, washed with water and suck dried for lh. The filtrate was extracted with toluene. To the combined toluene layer, the suck dried material obtained above was added and heated to reflux and further concentrated. The concentrated solution was cooled to room temperature and stirred for lh. The solid mass was filtered, washed with toluene and dried to obtain the titled compound (110 g) with 80percent yield.
Reference：
[1] Chemical and Pharmaceutical Bulletin, 2001, vol. 49, # 4, p. 353 - 360
15
[ 60456-26-0 ]
[ 149524-47-0 ]
[ 149524-42-5 ]
Yield
Reaction Conditions
Operation in experiment
81%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.33333 h; Inert atmosphere Stage #2: at -78℃; for 1 h; Inert atmosphere
General procedure: Compound 2 (2 mmol) was dissolved in anhydrous THF (10 mL) then cooled to -78 C under nitrogen followed by slow addition of 1M LHMDS in THF solution (1.7 mL, 1.7 mmol) over 20 min. The resulting mixture was subsequently stirred at -78° C for 1 h before (R)-(-)-glycidyl butyrate (0.24 g, 1.7 mmol) was added drop wise at -78° C and the mixture was stirred at this temperature for 1 h then allowed to gradually warm to room temperature under stirring for 12 hrs. The reaction was quenched with DDW (10 mL) followed by EtOAc (4 mL). Then the two layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then dissolved in DCM (10 mL) and allowed to stand overnight to get a white precipitate which was filtered and washed with DCM.
70%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667 h; Inert atmosphere Stage #2: at -78 - 20℃; Inert atmosphere
To a solution of N-carbobenzyloxy-3-fluoroaniline 2 (132 g, 538 mmol) in THF (1.3 L) at -78 °C added slowly n-butyllithium 1.6 M in n-hexane (370 mL, 600 mmol) under nitrogen condition. After the solution was stirred at -78 °C for 10 min, (R)-(-)-glycidyl butylate (84.0 mL, 600 mmol) was slowly added. The mixture was stirred at -78 °C for 2 h and stirred at room temperature for 24 h. After completion of the reaction, an aqueous saturated ammonium chloride (NH4Cl) solution was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was recrystallized from EtOAc and n-hexane to give the title compound (80 g, 70percent). 1H NMR (DMSO-d6): δ 7.51 (d, J = 12.0 Hz, 1H), 7.40 (m, 1H), 7.34 (m, 1H), 6.93 (t, J = 6.8 Hz, 1H), 5.21 (t, J = 5.6 Hz, 1H), 4.70 (m, 1H), 4.07 (t, J = 9.2 Hz, 1H), 3.83 (m, 1H), 3.68 (m, 1H), 3.55 (m, 1H).
70%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667 h; Inert atmosphere Stage #2: at -78 - 20℃; for 26 h;
Will be 132 gramsN-Benzyloxycarbonyl-3-fluoroaniline was dissolved1.3 liters of tetrahydrofuran,And the solution was cooled to -78 ° C.370 ml of n-butyllithium (1.6 mol / l, n-hexane) was slowly added to the solution under a nitrogen atmosphere and then stirred for 10 minutes.Will be 84 ml(R) - (-) - butyric acid glycidyl ester was slowly added to the reaction mixture,Glycidyl butyrateThe mixture was stirred at the same temperature for 2 hours and then allowed to react at room temperature for 24 hours. After completion of the reaction, an ammonium chloride solution was added to the solution and extracted with 0.5 liter of ethyl acetate at room temperature. The resulting organic layer was separated by brine and dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was dissolved in 100 ml of ethyl acetate and washed with n-hexane to give a white crystal which was purified to 80 g of the title compound in 70percent yield.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 23, p. 5310 - 5321
[2] European Journal of Medicinal Chemistry, 2011, vol. 46, # 4, p. 1027 - 1039
[3] Patent: CN106146559, 2016, A, . Location in patent: Paragraph 0044; 0045
[4] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 9, p. 1009 - 1014
[5] Patent: US2010/234615, 2010, A1, . Location in patent: Page/Page column 36
[6] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5266 - 5269
[7] Patent: WO2016/77818, 2016, A1, . Location in patent: Paragraph 0210; 0212
[8] Patent: WO2017/200979, 2017, A1, . Location in patent: Paragraph 0195
16
[ 60456-26-0 ]
[ 149524-42-5 ]
Yield
Reaction Conditions
Operation in experiment
70%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 0.166667 h; Stage #2: at -78 - 20℃; for 26 h; Stage #3: With water; ammonium chloride In tetrahydrofuran; hexane at 20℃;
132g of N-carbobenzyloxy-3-fluoroaniline 132g prepared in the Preparation example 1 was dissolved in 1.3L of tetrahydrofuran and the solution was cooled to- 78 °C. 370ml of n-buthyllitium (n-BuLi, 1. 6M/n-hexane) was slowly added to the solution in a nitrogen atmosphere, followed by stirring for 10 min. And 84ml of (R)- (-) -glycidylbuthylate was slowly added to the reaction mixture, stirred at the same temperature for 2 hours and allowed to react for 24 hours at room temperature. After completion of the reaction, the solution was added with ammonium chloride (NH4Cl) solution and extracted with 0. 5L of ethyl acetate at room temperature. The organic layer, thus separated, was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in 100ml of ethyl acetate and washed with n-hexane to give white crystals, which were purified to the title compound. 80g. Yield 70percent. IH NMR (DMSO-d6) 6 7. 85 (t, lH), 7.58 (dd, lH), 7.23 (dd, lH), 4.69 (m, lH), 4.02 (t, lH), 3.80 (dd, lH), 3.60 (br dd, 2H).
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -65 - -60℃; for 0.166667 h; Inert atmosphere Stage #2: at -65 - 25℃; for 20 h; Inert atmosphere
Methyl (3-fluorophenyl)carbamate (Formula IV, 70 g, Example 1) was dissolved in anhydrous tetrahydrofuran (420 mL) at ambient temperature, and then the solution wascooled to -65°C to -60°C under nitrogen atmosphere. n-Butyl lithium (1.6 M in hexane, 272 mL) was slowly added to the solution under nitrogen atmosphere, and then the reaction mixture was stirred for 10 minutes. (R)-(-)-Glycidyl butyrate (Formula V, when R1= n-propyl, 60.25 g) was slowly added to the reaction mixture under nitrogenatmosphere at -65°C to -60°C, and then the mixture was stirred for 20 hours at 20°C to25°C under nitrogen atmosphere. After completion of the reaction, ammonium chloride solution (7 g in 70 mL of deionized water) was added to the reaction mixture. Tetrahydrofuran was recovered under vacuum at 40°C to 45°C, followed by the addition of deionized water (500 mL) at 40°C to 45°C. The reaction mixture was allowed to attainambient temperature and then was stirred for two hours. The solid obtained was filtered, and then washed with deionized water (70 mL). The wet solid was dried at 50°C to 55°C to afford the title compound.Yield: 72.1 g
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 1996, vol. 6, # 9, p. 1009 - 1014
20
[ 510729-01-8 ]
[ 60456-26-0 ]
[ 444335-16-4 ]
Yield
Reaction Conditions
Operation in experiment
87%
With lithium tert-butoxide In tetrahydrofuran; methanol; N,N-dimethyl-formamide at 0 - 20℃; for 3 h;
119 g (367 mmol) of Compound XXIX was dissolved in 300 mL of tetrahydrofuran/150 mL of dimethylformamide, 38.19 g (477 mmol) of lithium-t butoxide was slowly added dropwise thereto at 0°C, the resulting solution was stirred for 10 minutes, 63 mL (440 mmol) of (R)-glycidyl butyrate and 21 mL (550 mmol) of methanol were added thereto, and the resultant solution was stirred at room temperature for 3 hours. Subsequently, pH of the reaction mixture was adjusted to approximately 6 using an aqueous ammonium chloride solution and then the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in 1000 mL of 80percent ethylacetate/hexane, was sequentially washed with water and an aqueous saturated sodium chloride solution (brine), and then dehydrated using anhydrous sodium sulfate, followed by concentration under reduced pressure and column chromatography, to obtain 93 g (320 mmol) of Compound B-I as a white solid (yield: 87percent). [0162] 1H NMR (600 MHz, CDCl3) δ 7.53 (m, 2H), 7.15 (dd, J1 = 9.0 Hz, J2 = 2.4 Hz, 1H), 4.77 (m, 1H), 4.00 (m, 3H), 3.77 (m, 1H), 2.10 (t, J = 6.0 Hz, 1H)
87%
Stage #1: With lithium tert-butoxide In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; Stage #2: at 20℃; for 3 h;
Preparation of Compound B-I 119 g (367 mmol) of Compound XXIX was dissolved in 300 mL of tetrahydrofuran/150 mL of dimethylformamide, 38.19 g (477 mmol) of lithium-t butoxide was slowly added dropwise thereto at 0° C., the resulting solution was stirred for 10 minutes, 63 mL (440 mmol) of (R)-glycidyl butyrate and 21 mL (550 mmol) of methanol were added thereto, and the resultant solution was stirred at room temperature for 3 hours. Subsequently, pH of the reaction mixture was adjusted to approximately 6 using an aqueous ammonium chloride solution and then the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in 1000 mL of 80percent ethylacetate/hexane, was sequentially washed with water and an aqueous saturated sodium chloride solution (brine), and then dehydrated using anhydrous sodium sulfate, followed by concentration under reduced pressure and column chromatography, to obtain 93 g (320 mmol) of Compound B-I as a white solid (yield: 87percent). [0174] 1H NMR (600 MHz, CDCl3) δ 7.53 (m, 2H), 7.15 (dd, J1=9.0 Hz, J2=2.4 Hz, 1H), 4.77 (m, 1H), 4.00 (m, 3H), 3.77 (m, 1H), 2.10 (t, J=6.0 Hz, 1H)
86.4%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane; <i>tert</i>-butyl alcohol at 0℃; for 0.5 h; Stage #2: at 0 - 20℃;
Butyl lithium (2.3M in n-hexanes, 118.3 ml, 0.272 mol, 1.06 eq) was added at -30° C. to anhydrous tert-butanol (25.0 g, 0.53 mol, 2.07 eq) in anhydrous THF (170 ml), under nitrogen. The mixture was stirred for 30 min at -30° C., and was then allowed to warm slowly to 0° C. After 30 min at 0° C., the (4-bromo-3-fluoro-phenyl)-carbamic acid benzyl ester (83 g, 0.256 mol, 1 eq) was added portionwise, keeping the temperature cold, and the mixture was stirred for an additional 30 min at 0° C. To this ice cold mixture, R(-)-glycidyl butyrate (39.7 ml, 0.288 mol, 1.12 eq) were added and the mixture allowed to come gradually to room temperature. The mixture was extracted with saturated sodium chloride solution and the organic phase was dried over MgSO4, filtrated and evaporated. The product was obtained after recrystallisation of the crude product with ethyl acetate, to give (64.1 g, 86.4percent).
80%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.33333 h; Inert atmosphere Stage #2: at -78℃; for 1 h; Inert atmosphere
General procedure: Compound 2 (2 mmol) was dissolved in anhydrous THF (10 mL) then cooled to -78 C under nitrogen followed by slow addition of 1M LHMDS in THF solution (1.7 mL, 1.7 mmol) over 20 min. The resulting mixture was subsequently stirred at -78° C for 1 h before (R)-(-)-glycidyl butyrate (0.24 g, 1.7 mmol) was added drop wise at -78° C and the mixture was stirred at this temperature for 1 h then allowed to gradually warm to room temperature under stirring for 12 hrs. The reaction was quenched with DDW (10 mL) followed by EtOAc (4 mL). Then the two layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then dissolved in DCM (10 mL) and allowed to stand overnight to get a white precipitate which was filtered and washed with DCM.
65%
Stage #1: With n-butyllithium In tetrahydrofuran; hexane at -78℃; for 1 h; Stage #2: at 20℃; for 24 h;
3.4.la (2.5 g, 7.7 mmol, 1.0 equiv) was dissolved in THE (20 mL) and cooled to -78°C. n-BuLi (2.5M in hexane) (0.59 g, 9.3 mmol, 1.2 equiv) was gradually added and the reaction mixture was stirred at -78 °C for 1 hour. (R)-oxiran-2-ylmethyl butyrate (1 .33 g, 9.3 mmol, 1.2 equiv) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (80-100 percent EtOAc in Hexane) to afford product 3.4.lb which was carry forwarded for next step. (1.46 g, 65percent yield). LCMS (mlz): 292.1 [M+H].
45.3%
Stage #1: With ammonium chloride; lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.25 h; Stage #2: at 20℃; for 61 h;
(4) Preparation of (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxylmethyl)oxazolidin -2-one Benzyl 4-bromo-3-fluorophenylcarbamate (20 g, 61.7 mmol) was dissolved in 180 mL THF, cooled to -78°C, and LiHMDS (1.0M in THF, 62.4 mL, 62.4 mmol) was added dropwise within 45 min. After continued to stir for 30 min, R-glycidyl butyrate (2.21 mL, 62.3 mmol) was added dropwise. After continued to react for 1 h at low temperature, it was warmed to room temperature and reacted for 60 h. The reaction was quenched with saturated ammonium chloride. Water was added, and extracted with ethyl acetate. The organic phase was dried, concentrated, and then separated by a silica gel column (petroleum ether : ethyl acetate =2: 1) to obtain 8.1 g of (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxylmethyl)oxazolidin-2-one, at a yield of 45.3 percent.
45.3%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; for 1.25 h; Stage #2: at -78 - 20℃; for 61 h;
Benzyl 4-bromo-3-fluorophenylcarbamate (20 g, 61.7 mmol) was dissolved in 180 mL THF, cooled to -78° C., and LiHMDS (1.0M in THY, 62.4 mL, 62.4 mmol) was added dropwise within 45 min. After continued to stir for 30 min, R-glycidyl butyrate (2.21 mL, 62.3 mmol) was added dropwise. After continued to react for 1 h at low temperature, it was warmed to room temperature and reacted for 60 h. The reaction was quenched with saturated ammonium chloride. Water was added, and extracted with ethyl acetate. The organic phase was dried, concentrated, and then separated by a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain 8.1 g of (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxylmethyl)oxazolidin-2-one, at a yield of 45.3percent.
Stage #1: With potassium <i>tert</i>-butylate; lithium tert-butoxide In tetrahydrofuran; acetonitrile at 25℃; for 2 h; Inert atmosphere Stage #2: for 3 h;
In a 1L three-necked bottle, 50 g of a compound of Formula X3, 400 ml of tetrahydrofuran and 400 ml of acetonitrile were added.Nitrogen gas, temperature 25°C, solids insolubleThen, 9.9 g of lithium tert-butoxide and 13.9 g of potassium tert-butoxide were added, and the solid matter dissolved.The reaction solution changed from colorless to yellow,After stirring for 2 hours, the reaction solution was added dropwiseR-(-)-glycidol butyric acid and compound of formula R 19.7 g,After completion of the addition, the reaction was incubated for 3 hours, and the sample was subjected to a TLC (developing solvent: chloroform/methanol = 10/1). After the spot of the compound of Formula X3 disappeared, the sample was dropped.Add dilute hydrochloric acid prepared from concentrated hydrochloric acid and water, adjust the pH to 8, fully stir for 30 minutes, the water bath temperature is 35°C to 55°C, and the vacuum degree -0.07MPa to -0.1MPa is concentrated under reduced pressure to stop flow.
85%
Stage #1: With lithium hexamethyldisilazane In tetrahydrofuran at 20℃; for 1.41667 h; Inert atmosphere Stage #2: With 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone In tetrahydrofuran at 20℃; for 15 h; Inert atmosphere; cooling with ice
A 5-L, three-neck, round-bottom flask was equipped with an overhead stirrer, a thermocouple, a 500-mL addition funnel and a nitrogen-inlet adapter. The flask was dried with a heat gun under a flow of nitrogen to an internal temperature of 60°C. The flask was charged with intermediate 7 (110.0 g, 0.272 mol, AMRI lot No. DUG-AF-202Q)) and anhydrous THF (2.2 L, 20 vol). The slurry was stirred and a light green solution formed. The addition funnel was charged with 1.0 M lithium hexamethyldisilazide (299 mL, 0.286 mol, 1.05 eq.). The LiHMDS solution was added dropwise to the solution of intermediate 7 over approximately 25 minutes. A red solution formed. The solution was stirred one hour at room temperature and then DMPU (34.9 g, 0.272 mol, 1 eq) was added, and the mixture turned to a yellow slurry. The batch was cooled in an ice bath to 5.7°C. R-(-)-Glycidyl butyrate (41.25 g, 0.286 mol, 1.05 eq) was then added in one portion. The mixture was stirred in the ice bath for 0.5 hour and then was warmed to room temperature and stirred overnight. The reaction formed a tan slurry at this point, and HPLC analysis after 15 hours indicated that there was approximately 87percent TR-700, 1.6percent intermediate 7, and approximately 7percent of the butyrate ester of TR-700. A small amount of sodium methoxide in methanol (11 mL, 0.1 vol) was added, and the batch was stirred for 1 hour to remove the residual ester. The in-process HPLC analysis at this point showed there was approximately 90.7percent TR-700 and 0.2percent of the butyrate ester. The reaction was quenched by the addition of 10percent w/w ammonium chloride solution (1.1 L, 10 vol). A modest exothermic event from 22°C to 25°C was observed upon addition of the ammonium chloride solution. The two-phase mixture was distilled to a pot temperature of 700C (atmospheric pressure) to remove approximately 2.2 L of the THF. This formed a thick slurry which is diluted with water (550 mL, 5 volumes). The slurry was cooled to room temperature (23.6°C) and was filtered. The filter cake was washed with water (1.1 L, 10 vol) and methanol (550 mL, 5 vol) to give TR-700 as a white solid. The wet cake was dried overnight in a vacuum oven at 500C to give 89.7 g of TR-700 (89percent yield) that was 97.8percent (AUC) by HPLC analysis. The TR-700 was further purified by reslurrying in 2.7 L (30 vol) of 4: 1 methanol/water at 700C, cooling to 230C, filtering and washing with methanol (180 ml). This removed some of the over-alkylated product that is observed. The purified TR- 700 was recovered in 96percent yield (85percent overall yield), and the purity was improved to 98.4percent (AUC) by HPLC analysis. The palladium content was 10 ppm.
Reference：
[1] Patent: CN107722056, 2018, A, . Location in patent: Paragraph 0058; 0060; 0062; 0063; 0064; 0068
[2] Patent: WO2010/42887, 2010, A2, . Location in patent: Page/Page column 19-20
Example 3: Preparation of(R)-[N-3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methanol.[131] Take n-Butanol (51.5g) and THF (100ml) at 20-30C under Nitrogen atmosphere.After cooling the mix add slowly n- Butyl lithium (1.6M in hexane) (391.7g) at 10 to 20C & maintain it for 45-60 minutes. Take THF (500ml) and N-Car- bobenzoxy-3-fluoro-4-morpholinylaniline (lOOg) at 20-30C under Nitrogen atmosphere. Cool the mix at -15 to -5C under stirring. To this solution add slowly n- Butyl lithium solution & maintain for 45-60 minutes at -15 to -5C, to this solution add slowly (R)-(-) Glycidyl butyrate (48.0g) & maintain for 1 hour at -10 to -5C. After completing addition raise the temperature to 8-13C and maintain for 1 hour & then take it to 13-15C and maintain for 4-5 hours. Organic layer was separated by water (800ml) and Ethyl acetate (300ml). Filter & wash the solid with mix of Ethyl acetate- n-Hexane & dried in air tray dryer at 55-60C. Yield: 0.765.: Percentage 85%w/w.[132]
80%
To a solution of N-(3-Fluoro-4-morpholin-4-ylphenyl)carbamic acid benzyl ester (200 g, 0.606 mol) in THF (1600 mL) under nitrogen at -78C was added n-butyllithium (416.7 mL, 1.6 M in hexane, 0.666 mol, 1.1 mol eq) over 1.5 h. The reaction mixture was stirred at - 78C for 2 h, then a solution of R-(-)-glycidyl butyrate (104.7 g, 0.727 mol, 1.2 mol eq) in THF (200 mL) was added at -78C over 1 h. After stirring at -78C for 2 h, the reaction mass was warmed to room temperature and stirred for overnight. To the resulting thick slurry is then added saturated ammonium chloride (690 mL) followed by water (100 mL). After stirring at room temperature for 10 min THF layer was separated, aqueous layer was extracted with ethyl acetate (2 x 500 mL). The combined ethyl acetate layer was concentrated under vacuum at 50-55C to get a residue in which THF layer was added and concentrated completely under vacuum at 50-55C. Thus obtained solid mass was cooled to room temperature and ethyl acetate (1600 mL) was added. The mixture was heated to 55-60C and kept stirring for 30 min. The mixture was cooled to 40-42C, filtered over hyflo and then washed the bed with ethyl acetate (200 mL). The moisture content in the combined ethyl acetate layer was adjusted to 0.29% by adding demineralised water and then cooled to 30C. n-Hexane (1200 mL) was charged to the above ethyl acetate solution at 25-30C and stirred for 12 hr, filtered the solid, washed with a mixture (1 : 1) of ethyl acetate and n-hexane (2 x 200 mL) and dried under vacuum at 50-55C for 16 hr. The mother liquor was concentrated to dryness under vacuum at 50C and crystallized from a mixture of ethyl acetate (600 mL) and cyclohexane (600 mL) to get the 2nd crop of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2- oxo-5-oxazolidinyl]methanol which matches with the 1 st crop in all respect to provide 142 g material with a combined 80% yield. Percentage Yield: 80%
80%
[0131] To a solution of N-(3-Fluoro-4-morpholin-4-ylphenyl)carbamic acid benzyl ester (200 g, 0.606 mol) in THF (1600 mL) under nitrogen at -78 C. was added n-butyllithium (416.7 mL, 1.6 M in hexane, 0.666 mol, 1.1 mol eq) over 1.5 h. The reaction mixture was stirred at -78 C. for 2 h, then a solution of R-(-)-glycidyl butyrate (104.7 g, 0.727 mol, 1.2 mol eq) in THF (200 mL) was added at -78 C. over 1 h. After stirring at -78 C. for 2 h, the reaction mass was warmed to room temperature and stirred for overnight. To the resulting thick slurry is then added saturated ammonium chloride (690 mL) followed by water (100 mL). After stirring at room temperature for 10 min THF layer was separated, aqueous layer was extracted with ethyl acetate (2×500 mL). The combined ethyl acetate layer was concentrated under vacuum at 50-55 C. to get a residue in which THF layer was added and concentrated completely under vacuum at 50-55 C. Thus obtained solid mass was cooled to room temperature and ethyl acetate (1600 mL) was added. The mixture was heated to 55-60 C. and kept stirring for 30 min. The mixture was cooled to 40-42 C., filtered over hyflo and then washed the bed with ethyl acetate (200 mL). The moisture content in the combined ethyl acetate layer was adjusted to 0.29% by adding demineralised water and then cooled to 30 C. n-Hexane (1200 mL) was charged to the above ethyl acetate solution at 25-30 C. and stirred for 12 hr, filtered the solid, washed with a mixture (1:1) of ethyl acetate and n-hexane (2×200 mL) and dried under vacuum at 50-55 C. for 16 hr. The mother liquor was concentrated to dryness under vacuum at 50 C. and crystallized from a mixture of ethyl acetate (600 mL) and cyclohexane (600 mL) to get the 2nd crop of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methanol which matches with the 1st crop in all respect to provide 142 g material with a combined 80% yield. [0132] Percentage Yield: 80%
77.7%
A solution of N-benzyloxycarbonyl-3-fluoro-4-morpholinoaniline (2.0 g, 6.06 mmol) and tetrahydrofuran, Cooled to -85 to -75 C, a solution of n-butyllithium (2.80 mL, 7.03 mmol)The reaction was continued for 2 hours.A solution of (R) -butyric acid glycidyl ester (0.90 g, 6.06 mmol) in tetrahydrofuran was then added dropwise and the temperature was naturally warmed to the reaction overnight.TLC monitoring, the reaction is completed.To the reaction was added 30 mL of saturated NH4Cl solution and dichloromethane, stirred for 2 minutes,The phases were separated and the aqueous phase was extracted with CH2Cl2. The organic phases were combined, washed with water, saturated NaCl solution,Dried over anhydrous Na2SO4 and concentrated to give the crude product.Recrystallization to give the product as a lavender powder(R) - [3- (3-fluoro-4-morpholinophenyl) -2-oxo-5-oxazolidinyl] methyl alcohol, 1.39 g,Yield: 77.7%, chemical purity: 99.3%; optical purity: 98.68%.
70%
Example-6(b): Preparation of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl] methanol (VIII) starting from N-carbobenzoxy-3-fluoro-4- morpholinylanilineN-carbobenzoxy-3-fluoro-4-morpholinylaniline (100 g) was dissolved in THF (800 ml). To the resulting solution, n-butyllithium (208 ml in hexane) was added under nitrogen at -78C over 1.5h and stirred for 2h, further a solution of R-(-)-glycidyl butyrate (52.3 g in THF (100 ml)) was added and stirred for 2h. The reaction mixture was warmed to room temperature and stirred for overnight. To the resulting thick slurry saturated ammonium chloride (345 ml) was added followed by the addition of water (50 ml). It was stirred at room temperature for 10 min and THF layer was separated from aqueous layer. Aqueous layer was extracted with ethyl acetate (2 x 250 ml). The combined ethyl acetate layer was washed with water and concentrated to get a residue in which THF layer was added and further concentrated completely. The solid mass obtained was cooled to room temperature and ethyl acetate (600 ml) was added. The reaction mixture was heated to 60-65C and was stirred for 30 min, which was further cooled to 40-45 C. The cooled reaction mixture was filtered and was washed with ethyl acetate (100 ml). To the filtrate cyclohexane (450 ml) was added at 25-35C in 5 min. The resulting mixture was stirred for 12h. The precipitated solid was filtered, washed with a mixture (1 :1) of ethyl acetate and cyclohexane and dried to obtain the titled compound (62 g) with 70% yield.
64%
To a solution of 390 g of N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline in 5.50 L of tetrahydrofuran at -78C under nitrogen was added 770ml of 1.6M n-butyl lithium/hexane over 30 min. Further 183.2 g of (R)-glycidyl butyrate in 300 ml of tetrahydrofuran was added to the obtained reaction mixture over 30 min followed by stirring for 1 hr at -78C. After the completion of reaction, the reaction mass was allowed to come to ambient temperature gradually. After stirring the mixture overnight, 200 ml of saturated aqueous ammonium chloride was added, followed by 5 L of water. The aqueous layer was extracted with ethyl acetate (4 x 3.0 L) and the combined organic layer was concentrated to get a light purple solid. Yield: 249.6 g.; Percentage: 64% w/w
ExampIe-3: (R)-fN-f3-(3-fluoro-4-morphoIinylphenylV-2-oxo-5- oxazolidinyll methyl] methane sulfonateTo a solution of 100 g of N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline in 500 mL of freshly distilled tetrahydrofuran at -80C under nitrogen, was added 105 mL of n-butyl lithium/hexane via syringe within 90 minutes, and the mixture stirred for 60 minutes. Further, a solution of 45.9 g of (R)-glycidylbutyrate in 80 mL of tetrahydrofuran was added within 90 minutes, and stirred for 60 minutes. The reaction mixture was removed from the dry ice bath, and allowed to come to ambient temperature. After stirring for 4-6 hours, the reaction mixture was quenched in 134 g of saturated aqueous ammonium chloride solution, followed by 500 mL of toluene, and the aqueous layer extracted with toluene. The combined organic layers were washed with 360 mL of brine. The organic layer was treated with 4 g activated charcoal and stirred for 30 minute and filtered. The filtrate was concentrated under vacuum at 60C to remove toluene completely. In the mixture of residue of (R)-N-[[3-[3-fluoro-4- mophiholinyl]-phenyl]-2-oxo-5-oxazolidinyl]methanol, 300 mL methylene dichloride and 46 g triethylamine mixture was added within 90 minutes. The reaction mixture was warmed to 45C and stirred for 3 hours. Methylene dichloride was removed under vacuum below 50C and the residue was cooled to room temperature. The residue were triturated with 500 mL of toluene and stirred for 1 hour and filtered. The wet-cake was washed with toluene and slurried in water for 1 hour. The solid was filtered and washed with water. The product dried at 60C to 65C to get 95 g (84%) of (R)-[N-[3-(3- fluoro-4-mo holinylphenyl)-2-oxo-5-oxazolidinyl]methyl]methane sulfonate.
78 g
II. Preparation of (R)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyl] methanol N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline (100 g) and tetrahydrofuran (1100.0 ml) at 25-30C in RBF and cooled to -20C to -30C. n-BuLi (250.0ml) was added slowly for a period of 30-40 minutes to the reaction mixture at -20 C to -30 C and stirred for 35- 40 minutes. A solution of R-glycidyl butyrate (46. Ogm) in THF (50.0ml) was added to reaction mass at -20 C to -30 C within 20 to 30 minutes and maintained for 1 hour at -20 C to -30 C. The temperature of the reaction mass was slowly raised to 45-50C within 40-60 minutes, maintained for 2 hours at 45-50 C and then cooled to 25-30C. The reaction mass was quenched with aqueous NH4C1 solution (5%) (400.0ml) at 25-30C and then toluene (400.0 ml) was charged at 25-30C. Two layers were separated and the obtained organic layer was concentrated under vacuum at 40-45C to get thick slurry. Toluene (300ml) was added to the residue at 25-30C, stirred for 30 minutes at 25-30C, cooled to 5-10C and stirred for lhour. The suspension was filtered, washed the solid with toluene (2x100.0 ml) and dried in air oven for 30 mins at 25-30C followed by at 40-45C to obtain titled compound.Dry weight: 78gm
To a solution of 4-(4-benzyloxycarbonylamino-2-fluoro-phenyl)-piperazine- 1-carboxylic acid benzyl ester (5.0 g, 10.78 mmol) in dry THF (50 mL) at -78 C was added a 2.5 M solution of n-butyllithium in hexane (4.5 mL, 10.78 mmol) and the resulting solution stirred for 1 h at -78 C. (R)-Glycidyl butyrate (1.55 g, 10.78 mmol) was added to the solution at -60 C and the solution warmed to room temperature overnight. To the reaction was added a saturated NH4CI solution (5 mL) and the aqueous layer extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with 30 % EtOAc/ hexanes at 40 C, sonicated for 15 minutes and cooled to 5 C. The powder generated was isolated by filtration, washed with cold EtOAc/ hexane (1 : 1 , v/v) and dried to afford 4.0 g (87%) of the title compound. NM1RH (400 MHz, CDCI3) delta (ppm): 7.46 (dd, J= 14.0, 2.4 Hz, 1H), 7.38 - 7.31 (m, 5H), 7.12 (dd, J = 9.0, 1.8 Hz, 1 H), 6.91 (t, J = 9.2 Hz, 1H), 5.16 (s, 2H), 4.77 - 4.71 (m, 1 H), 4.02 - 3.92 (m, 3H), 3.77 - 3.69 (br. s., 1H), 3.68 - 3.66 (m, 4H), 3.00 (br. s., 4H), 2.25 (brs, 1H). 19F NMR (376 MHz, CDC13) delta (ppm): -120.66 (dd, J = 14.6, 9.8 Hz, IF); MS (ESI) m/z = 430 (M+l , positive).
82%
To a mixture of 4.33 g (10.06 mmol) of 10 in 50 mL of dry THF at -78 C under argon was added 6.8 mL (10.88 mmol) of 1.6 M n-butyllithium-hexane dropwise over 5 min. After 1.5 h, 1.55 mL of <strong>[60456-26-0](R)-glycidyl butyrate</strong> 11 was added and the mixture allowed stirring at -78 C for 1 h and then at room temperature for 3.5 h (the mixture became thick with solid precipitation). Saturated aqueous ammonium chloride (25 mL) was added followed by 25 mL of ethyl acetate and 5 mL of water. The layers were separated, and the aqueous layer was extracted with ethyl acetate (3 × 25 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to provide 12 as a white solid. The solid was triturated with ethyl acetate-hexane (1: 1) in a warm water bath for 30 min and then refrigerated; the solids were collected by vacuum filtration to provide 12 as white solids. Yield 82%; mp 149-150 C; IR: upsilonmax (KBr) 3426 (OH), 1741 and 1664 (CO) cm-1; 1H NMR (CDCl3): 7.46 (dd, 1H, J = 14.5 and 2.5 Hz, H2 fluorobenzene), 7.39-7.37 (m, 4H, H2, H3, H5 and H6 phenyl), 7.36-7.32 (m, 1H, H4 phenyl), 7.13 (dd, 1H, J = 9 and 2.5 Hz, H6 fluorobenzene), 6.92 (t, 1H, J = 9 Hz, H5 fluorobenzene), 5.17 (s, 2H, benzylic CH2), 4.77-4.72 (m, 1H, H5 oxazolidinone), 4.03-3.98 (m, 2H, CH2OH), 3.97-3.93 (m, 1H, H4 oxazolidinone), 3.8-3.74 (m, 1H, H4 oxazolidinone), 3.68 (t, 4H, J = 5 Hz, piperazine), 3.02 (t, 4H, J = 5 Hz, piperazine); MS: m/z 429 (66, M+), 338 (25), 294 (33), 265 (40), 239 (25), 91 (100); Anal. Calcd for C22H24FN3O5: C, 61.53; H, 5.63; F, 4.42; N, 9.78. Found: C, 61.32; H, 5.54; F, 4.67; N, 10.02.
General procedure: Compound 2 (2 mmol) was dissolved in anhydrous THF (10 mL) then cooled to -78 C under nitrogen followed by slow addition of 1M LHMDS in THF solution (1.7 mL, 1.7 mmol) over 20 min. The resulting mixture was subsequently stirred at -78 C for 1 h before (R)-(-)-glycidyl butyrate (0.24 g, 1.7 mmol) was added drop wise at -78 C and the mixture was stirred at this temperature for 1 h then allowed to gradually warm to room temperature under stirring for 12 hrs. The reaction was quenched with DDW (10 mL) followed by EtOAc (4 mL). Then the two layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then dissolved in DCM (10 mL) and allowed to stand overnight to get a white precipitate which was filtered and washed with DCM.
70%
To a solution of N-carbobenzyloxy-3-fluoroaniline 2 (132 g, 538 mmol) in THF (1.3 L) at -78 C added slowly n-butyllithium 1.6 M in n-hexane (370 mL, 600 mmol) under nitrogen condition. After the solution was stirred at -78 C for 10 min, (R)-(-)-glycidyl butylate (84.0 mL, 600 mmol) was slowly added. The mixture was stirred at -78 C for 2 h and stirred at room temperature for 24 h. After completion of the reaction, an aqueous saturated ammonium chloride (NH4Cl) solution was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was recrystallized from EtOAc and n-hexane to give the title compound (80 g, 70%). 1H NMR (DMSO-d6): delta 7.51 (d, J = 12.0 Hz, 1H), 7.40 (m, 1H), 7.34 (m, 1H), 6.93 (t, J = 6.8 Hz, 1H), 5.21 (t, J = 5.6 Hz, 1H), 4.70 (m, 1H), 4.07 (t, J = 9.2 Hz, 1H), 3.83 (m, 1H), 3.68 (m, 1H), 3.55 (m, 1H).
70%
Will be 132 gramsN-Benzyloxycarbonyl-3-fluoroaniline was dissolved1.3 liters of tetrahydrofuran,And the solution was cooled to -78 C.370 ml of n-butyllithium (1.6 mol / l, n-hexane) was slowly added to the solution under a nitrogen atmosphere and then stirred for 10 minutes.Will be 84 ml(R) - (-) - butyric acid glycidyl ester was slowly added to the reaction mixture,Glycidyl butyrateThe mixture was stirred at the same temperature for 2 hours and then allowed to react at room temperature for 24 hours. After completion of the reaction, an ammonium chloride solution was added to the solution and extracted with 0.5 liter of ethyl acetate at room temperature. The resulting organic layer was separated by brine and dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was dissolved in 100 ml of ethyl acetate and washed with n-hexane to give a white crystal which was purified to 80 g of the title compound in 70% yield.
(5S)-3-(3-Fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1018). A solution of (3-fluoro-phenyl)-carbamic acid benzyl ester (1016, 39.2 g, 160.0 mmol) in anhydrous tetrahydrofuran (THF, 300 mL) was cooled down to -78 C. in a dry-ice-acetone bath before a solution of n-butyl lithium (n-BuLi, 2.5 M solution in hexane, 70.4 mL, 176 mmol, 1.1 equiv) in hexane was dropwise added at -78 C. under N2. The resulting reaction mixture was subsequently stirred at -78 C. for 1 h before a solution of (R)-(-)-glycidyl butyrate 1017 (25.37 g, 24.6 mL, 176 mmol, 1.1 equiv) in anhydrous THF (100 mL) was dropwise added into the reaction mixture at -78 C. under N2. The resulting reaction mixture was stirred at -78 C. for 30 min before being gradually warmed up to room temperature for 12 h under N2. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (200 mL), and the resulting mixture was stirred at room temperature for 1 h before ethyl acetate (EtOAc, 200 mL) was added. The two layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The white crystals were precipitated out from the concentrated solution when most of the solvents were evaporated. The residue was then treated with 20% EtOAc-hexane (100 mL) and the resulting slurry was further stirred at room temperature for 30 min. Tire solids were then collected by filtration and washed with 20% EtOAc-hexane (2×50 mL) to afford the crude, (5R)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1018, 24.4 g, 33.76 g theoretical, 72.3%) as white crystals, which were found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1018: 1H NMR (300 MHz, DMSO-d6) delta 3.34-3.72 (m, 2H), 3.83 (dd, 1H, J=6.2, 9.0 Hz), 4.09 (t, 1H, J=12.0 Hz), 4.68-4.75 (m, 1H), 5.23 (t, 1H, J=5.6 Hz, OH), 6.96 (m, 1H), 7.32-7.56 (m, 3H); C10H10FNO3, LCMS (EI) m/e 212 (M++H).
A solution of (3-fluorophenyl)-carbamic acid benzyl ester (1016, 39.2 g, 160.0 mmol) in anhydrous tetrahydrofuran (THF, 300 mL) was cooled dowel to -78 C in a dry-ice-acetone bath before a solution of n-butyllithium (n-BuLi, 2.5 M solution in hexane, 70.4 mL, 176 mmol, 1.1 equiv) in hexane was dropwise added at -78 C under nitrogen. The resulting reaction mixture was subsequently stirred at -78 C for 1 h before a solution of (R)-(-)-glycidyl butyrate 1017 (25.37 g, 24.6 mL, 176 mmol, 1.1 equiv) in anhydrous THF (100 mL) was dropwise added into the reaction mixture at-78 C under nitrogen. The resulting reaction mixture was stirred at -78 C for 30 mm before being gradually warmed up to room temperature for 12 h under nitrogen. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with water (200 mL), and the resulting mixture was stirred at room temperature for 1 h before ethyl acetate (EtOAc, 200 mL) was added. The two layers were separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (2 x 100 mL) and saturated NaC1 aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The white crystals were precipitated out from the concentrated solution when most of the solvents were evaporated. The residue was then treated with 20% EtOAchexane (100 mL) and the resulting slurry was further stirred at room temperature for 30 mm. The solids were then collected by filtration and washed with 20% EtOAc-hexane (2 x 50 mL) to afford the crude, (5R)-(3 -(3 -fluoro-phenyl)-5 -hydroxymethyl-oxazolidin-2-one (1018, 24.4 g, 33.76 g theoretical, 72.3%) as white crystals, which were found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1018: ?H NMR (300 MHz, DMSO-d6) oe 3.34 - 3.72 (m, 2H), 3.83 (dd, 1H, J= 6.2, 9.0 Hz), 4.09 (t, 1H, J 12.0 Hz), 4.68 -4.75 (m, 1H), 5.23 (t, 1H, J = 5.6 Hz, OH), 6.96 (m, 1H), 7.32 - 7.56 (m, 3H); C,0H,0FN03, LCMS (El) m/e 212 (M + H).
A solution of (3-fluorophenyl)-carbamic acid benzyl ester (1016, 39.2 g, 160.0 mmol) in anhydrous tetrahydrofuran (THF, 300 mL) was cooled dowel to -78 C in a dry-ice-acetone bath before a solution of -butyllithium (-BuLi, 2.5 M solution in hexanes, 70.4 mL, 176 mmol, 1.1 equiv) was added dropwise at -78 C under nitrogen. The resulting reaction mixture was subsequently stirred at -78 C for 1 h before a solution of (i?)-(-)-glycidyl butyrate 1017 (25.37 g, 24.6 mL, 176 mmol, 1.1 equiv) in anhydrous THF ( 100 mL) was added dropwise into the reaction mixture at-78 C under nitrogen. The resulting reaction mixture was stirred at -78 C for 30 min before being gradually warmed up to room temperature for 12 h under nitrogen. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with water (200 mL), and the resulting mixture was stirred at room temperature for 1 h before ethyl acetate (EtOAc, 200 mL) was added. The two layers were separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with water (2 x 100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgS04, and concentrated in vacuo. The white crystals were precipitated out from the concentrated solution when most of the solvents were evaporated. The residue was then treated with 20% EtOAc/hexanes (100 mL) and the resulting slurry was further stirred at room temperature for 30 min. The solids were then collected by filtration and washed with 20% EtOAc/hexanes (2 x 50 mL) to afford the crude, (5i?)-(3-(3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (1018, 24.4 g, 33.76 g theoretical, 72.3%) as white crystals, which were found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1018: NMR (300 MHz, DMSO-de) delta 3.34 - 3.72 (m, 2H), 3.83 (dd, 1H, J= 6.2, 9.0 Hz), 4.09 (t, 1H, J= 12.0 Hz), 4.68 -4.75 (m, 1H), 5.23 (t, 1H, J = 5.6 Hz, OH), 6.96 (m, 1H), 7.32 - 7.56 (m, 3H); C10H10FNO3, LCMS (EI) m/e 212 (M+ + H).
With lithium aluminium tetrahydride; n-butyllithium; In tetrahydrofuran; hexane; at -61 - 95℃; for 1h;Inert atmosphere;
2L glass reaction bottle installation reflex device, Add 700g of tetrahydrofuran, N2 replacement, Stirring 3g lithium aluminum hydride, Heated to reflux for 1 hour, The middle distillate of tetrahydrofuran was collected by distillation at 95 C. [0126] 2L N2 reaction flask replacement, Join the middle of tetrahydrofuran fraction, Stirring, 29.05 g of intermediate LT-3 was added. Open the cooling tank into the cooling fluid, The reaction flask temperature was cooled to -60 (± 1) C, A solution of 20.66 g of 2.5 M n-butyllithium in n-hexane was added dropwise, Control the reaction flask temperature Bi completed, 11.36g of (R) -glycidyl butyrate was added dropwise while maintaining the temperature under stirring, Control the reaction flask temperature The temperature was added and stirred for 1 hour. Close the cryogenic cooling tank, Warmed to room temperature reaction, HPLC endpoint. The reaction is over, To the bottle was added 500g of ethyl acetate, Stirring, Add purified water to wash three times (300g / time) The organic layer was collected, concentrate, freezing, Suction filtration, Got solid, 60 C hot air drying, Get white LT-4 solid, Yield: 90.86%.
77.21%
3.4 g of the reaction product obtained from the operation (3) and 50 ml of anhydrous tetrahydrofuran were added into a 100 ml triple-neck flask (dried at 120 C for more than 2 hours). Under a N2 atmosphere, 6.60 ml of 1 .6 M butyl lithium solution was added dropwise to the mixture at -78 C. The mixture was then stirred at -78 C for 80 minutes. The mixture gradually turned into a yellow-green solution. 1 .21 ml of (R)- glycidyl butyrate and 5 ml of anhydrous THF were then added dropwise into the mixture at -78 C, and the solution soon became clear. The reaction was carried out for 1 hour. The acetone bath was removed, and the temperature of the reaction mixture increased to room temperature. The reaction mixture was stirred for 16 hours, and a small amount of precipitates appeared. White solids were obtained. After running through silica gel column chromatography and recrystallization with a mixture of ethyl acetate and petroleum ether in a volumetric ratio of 1 :3, 2.34 g of white crystals were obtained. The yield was 77.21 %.
77.21%
100ml three-necked flask (120 baking more than 2 hours) to step (3)3.4 g of N-benzyloxycarbonyl-3-fluoro-4- (4'-phenylpiperazinyl) aniline and 50 ml of anhydrous tetrahydrofuran were obtained. -78 C,Under N2 protection, 1.6 M butyllithium solution (6.60 ml) was added dropwise. After stirring at -78 C for 80 minutes,Gradually turn into a yellow-green solution.1.21 ml of (R) -glycidyl butyrate and -78 C were added dropwise at -78 C5ml anhydrous tetrahydrofuran, the solution quickly becomes clear.The reaction for 1 hour, remove the acetone bath, warmed to room temperature, stirred for 16 hours,A small amount of precipitation appears. Got a white solid.After recrystallization from silica gel column chromatography and ethyl acetate: petroleum ether (1: 3 by volume), 2.34 g of white crystals were obtained in a yield of 77.21%.
A solution of [2- (N-T-BUTOXYCARBONYLPIPERAZINE)-5- (BENZYLOXYCARBONYL)] aminopyridine (30 g, [72. 8155] mmoles) dissolved in dry tetrahydrofuran (600 [ML)] was cooled [TO-78 C.] To this n-butyl lithium (23.3 g, 364.0776 mmoles, 15% solution in hexane) was added at-78 C drop wise with out raising the temperature. After complete addition, continued the stirring at-78 [C] for 1 hour. [THEN, (R) -GLYCIDYLBUTYRATE (15.73 G, 109.2232 MMOLES) WAS ADDED TO THE REACTION] mixture at-78 C and kept the reaction mixture to attain RT for 16 hours. Quenched the RM by adding ammonium chloride solution followed by water. The RM was extracted with ethyl acetate (3 x 500 ml), dried over anhydrous sodium sulphate and concentrated to dryness and purified over silica gel, using DCM and methanol as eluent. The pure compound was eluted in 1 to 2% methanol/DCM, to obtain the title compound (16. 5 g, yield 60%).
60%
A solution of 2- (PIPERAZINE-N-T-BUTOXYCARBONYL)-5- (BENZYLOXYCARBONYL) aminopyridine (30 g, 0. 0728155 moles) dissolved in dry tetrahydrofuran (600 ml) was cooled TO-78 C. To this n-butyl lithium (23.3 g, 0.3640776 moles, 15% solution in hexane) was added AT-78 C dropwise with out raising the temperature. After complete addition, continued the stirring at-78 C for 1 hour. Then, (R) -glycidylbutyrate (15.73 g, 0.1092232 moles) was added to the reaction mixture at-78 C and kept the reaction mixture AT-78 C O C O RT for 16 hours. Quenched the RM by adding ammonium chloride solution followed by water. The RM was extracted with ethyl acetate (3 x 500 ML), dried over anhydrous sodium sulphate and concentrated to dryness and purified over silica gel, using DCM and methanol as eluent. The pure compound was eluted in 1 to 2% methanol/DCM, to obtained the title compound (16.5 g, yield 60%).
To a stirred solution of tert-Butyl 4-(5-benzyloxycarbonylaminopyridin-2- yl)piperazine-l-carboxylate (10.0 g, 24.271 mmol), prepared as described in Intermediate 1, Method B, in dry THF (100 ml) was added 1.6 M ?-butyllithium in hexane (45.507 ml, 72.813 mmol) and the mixture was stirred at -78 "C for 30 min and (i?)-(-)-glycidyl butyrate (5.14 g, 36.407 mmol) was added over 5 min. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with saturated ammonium chloride solution (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with water (3 x 150 ml) and dried over anhydrous Na2SO4. The residue obtained after evaporation of the solvent was triturated with 7z-pentane to afford 6.78 g of the desired compound as an off-white solid; IR (KBr) 3415, 2979, 1728, 1691, 1422, 937 cm"1; 1H NMR (CDCl3, 300 MHz) delta 1.48 (s, 9H), 2.30-2.40 (m, IH), 3.45- 3.80 (m, 8H), 3.90-4.05 (m, 4H), 4.76 (br s, IH), 6.67 (d, J= 9.3 Hz, IH), 7.96 (dd, J= 2.7, 6.6 Hz, IH), 8.12 (d, J= 3.0 Hz, IH); MS (ESI) m/z 379.18 (MH)+.
With lithium perchlorate; In acetonitrile; at 20℃; for 16h;
To a stirred solution OF 7-AMINO-1, 3,4, 5-tetrahydro-benzo [b] azepin-2-one (0.90 g, 5.1 mmol) and (R) -glycidyl butyrate (0.74 g, 5.1 mmol) in anhydrous acetonitrile (45 mL), lithium perchlorate (0.70 g, 6.6 mmol) was added, and the mixture was stirred at room temperature for several hours. The solvent was removed under vacuum and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with water, saturated NaHCO3 and brine, dried over NA2S04 and concentrated under vacuum. Purification by column chromatography on silica gel (ethyl acetate/methanol 19: 1) gave (R)- Butyric acid 2-hydroxy-3-(2-oxo-2, 3,4, 5-TETRAHYDRO-LH-BENZO [b] azepin-7- ylamino) -propyl ester. Yield 1.2 g (75 %). H NMR (400 MHz, CDC13) 8 8.24 (s, 1H), 6.78 (d, 1H), 6.48 (m, 2H), 4.30 (br s, 1H), 4.20 (m, 2H), 4.10 (m, 1H), 3.92 (br s, 1H), 3.28 (m, 1H), 3.12 (m, 1H), 2.63 (t, 2H), 2.31 (t, 2H), 2.28 (m, 2H), 2.11 (m, 2H), 1.67 (m, 2H), 0.92 (t, 3H). MS: m/z 320 (M+).
132g of N-carbobenzyloxy-3-fluoroaniline 132g prepared in the Preparation example 1 was dissolved in 1.3L of tetrahydrofuran and the solution was cooled to- 78 C. 370ml of n-buthyllitium (n-BuLi, 1. 6M/n-hexane) was slowly added to the solution in a nitrogen atmosphere, followed by stirring for 10 min. And 84ml of (R)- (-) -glycidylbuthylate was slowly added to the reaction mixture, stirred at the same temperature for 2 hours and allowed to react for 24 hours at room temperature. After completion of the reaction, the solution was added with ammonium chloride (NH4Cl) solution and extracted with 0. 5L of ethyl acetate at room temperature. The organic layer, thus separated, was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in 100ml of ethyl acetate and washed with n-hexane to give white crystals, which were purified to the title compound. 80g. Yield 70%. IH NMR (DMSO-d6) 6 7. 85 (t, lH), 7.58 (dd, lH), 7.23 (dd, lH), 4.69 (m, lH), 4.02 (t, lH), 3.80 (dd, lH), 3.60 (br dd, 2H).
Intermediate 1: (5R)-5-(Hydroxymethyl)-3-(3-fluorophenyl)-1,3-oxazolidin-2-one; A stirred solution of 3-fluoroaniline (45.68g, 0.41mol) in toluene (447mL) was heated to 30C and treated with pyridine (39.1mL, 0.48mol). iso-Butyl chloroformate (62mL, 0.48mol) was added over about 0.5hour and the mixture was stirred for about 3 hours at 30C. Water (134mL) was added and the mixture was stirred at 30C before the layers were separated. The organic layer was further washed with water (134mL) and then distilled under reduced pressure until about 210mL of distillate was collected. The stirred residue was diluted with toluene (376mL) and tetrahydrofuran (376mL) and then cooled to -10C. A solution of n-butyl lithium in toluene (24.5%w/w, 3.3M, 113.6mL, 0.377mol) was added over 50 minutes, followed by addition of R-glycidyl butyrate (57.3mL, 0.40mol). The mixture was warmed to 40C over about 3 hours and this temperature was maintained for a further 1.5 hour before methanol (192.6mL) was added. The resultant clear solution was added to a mixture of acetic acid (24.5mL) and water (170mL) and the layers were allowed to separate. The organic extracts were stirred overnight with water (250mL), separated, and washed again with water (100mL), before distilling under reduced pressure to leave about 400mL of concentrate, which was cooled to 0C over a period of about 16 hours and stirred for a further 4 hours at this temperature to give a suspension. The solid was isolated by filtration, washed with toluene (50mL) and dried in vacuo at up to 40C to give the title compound (61.97g). MS (TOF): 212.0729 (M+I) for C10H10NO3F; calc. , 212.0723 ¹H NMR (400MHz, DMSO-d6) 8: 3.6 (ddd, 1H), 3.7 (ddd, 1H), 3.8 (dd, 1 H), 4.1 (t, 1H), 4.7 (m, 1H), 5.2 (t, 1H), 6.9 (m, 1H), 7.3 (ddd, 1H), 7.4 (td, 1H), 7.5 (dt, 1H).
Compound of formula (4) (90 g, 0.256 mol)Add 900 ml of dry tetrahydrofuran. Drop 1.0M lithium Hexamethyldisilazide hexane solution (267ml, 0.269mol),Stir at room temperature for 1h and cool to 0C.Add R-(-)-glycidyl butyrate(38.7g, 0.269mol),Stir 0.5h and warm to room temperature.Add 30% sodium methoxide in methanol (32 ml),Stir for 15 minutes and add 43 ml of 6M hydrochloric acid.The reaction solution was concentrated under reduced pressure.Obtain a white slurry, dilute with water (450 ml), filter,A white solid was obtained (HPLC content: Impurity a 0.01%, Impurity b 3%).The crude product is recrystallized from isopropanol to yield 71.82 g of whiteColor solid 1, namely (5R)-3-(4-benzyloxy-3-fluorophenyl)-5-hydroxymethyl oxazolidin-2-one (1), yield88.5%.
88.5%
The compound of formula (4) (90 g, 0.256 mol) was added to 900 ml of dry tetrahydrofuran. A 1.0 M solution of lithium hexamethyldisilazide in hexane (267 ml, 0.269 mol) was added dropwise, and after 1 h at room temperature the temperature was lowered to 0C and R-(-)-glycidyl butyrate (38.7 g, 0.269 mol) was added. Stir 0.5h,Raise to room temperature. A 30% solution of sodium methoxide in methanol (32 ml) was added and stirred for 15 minutes. Then 43 ml of 6M hydrochloric acid was added.The reaction solution was concentrated under reduced pressure to give a white slurry, which was diluted with water (450 ml, 5 volumes) and filtered.A white solid was obtained (HPLC: impurity a content 0.01%, impurity b content 3%).The crude product was recrystallized from isopropanol to give 71.82 g of white solid 1 in a yield of 88.5%.
87%
the suspension of compound 3 (40.00 g, 113.96 mmol, 1 eq) in THF (1.00 L) wascooled to- 78 C, and then n-BuLi (2.50 M in hexane 54.70 mL, 136.75 mmol, 1.2 eq) was addeddropwisely and stirred at -78 C for 0.5 h. Subsequently, (R)-oxiran-2-ylmethyl butyrate (20.35 g,141.31 mmol, 1.24 eq) in THF (0.50 L) was added dropwisely to the mixed solution within 30 min. Thereaction mixture was warmed up slowly and stirred at room temperature overnight. The mixture wasextracted with EtOAc (2.00 L*2) and brine (1.50 L). The organic layer was dried (MgSO4), filtered andconcentrated in vacuo to give compound 4 (31.50 g, 87%) as a yellow solid, m.p., 135-137 C. 1H-NMR(400 MHz, DMSO-d6) delta 7.58 (dd, J = 13.6, 2.4 Hz, 1H), 7.44 (d, J = 7.2 Hz, 2H), 7.39 (t, J = 7.4 Hz, 2H),7.33 (t, J = 6.8 Hz, 1H), 7.26 (t, J = 9.2 Hz, 1H), 7.22-7.16 (m, 1H), 5.22 (t, J = 5.6 Hz, 1H), 5.16 (s, 2H),4.67 (dd, J = 9.2, 5.6 Hz, 1H), 4.03 (t, J = 9.0 Hz, 1H), 3.78 (dd, J = 8.8, 6.4 Hz, 1H), 3.69-3.62 (m, 1H),3.58±3.50 (m, 1H). ESI-MS (m/z): 317.9 [M + H]+.
PREPARATION 14 (R)-3-(3-fluorophenyl)-5-(hydroxymethyl)-2-oxooxazolidine A mixture of N-(carbobenzyloxy)-3-fluoroaniline (1.000 g, 4.08 mmol) in dry tetrahydrofuran (10 ml) is cooled with a dry ice/acetone bath to about -78 and then nbutyllithium (1.87 ml of a 1.6M mixture in hexanes, 2.91 mmol) is added. (R)-glycidyl butyrate (0.420 g or 0.413 ml, 2.91 mmol) is then added via syringe and the cooling bath allowed to dissipate overnight, with the reaction mixture reaching 20-25. The reaction mixture is quenched by the careful addition of saturated aqueous ammonium chloride, the entire mixture transferred to a separatory funnel with dichloromethane washings, and the mixture extracted with dichloromethane. The combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure to give a concentrate which is purified by chromatography over silica gel, eluding with acetonitrile/chloroform (10/90) containing 1% methanol, to give the title compound.
(R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl butyrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With lithium bromide; In o-xylene;
PREPARATION 12 (R)-[3-(3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl butyrate A mixture of lithium bromide (0.181 g, 2.08 mmol), tri-n-butylphosphine oxide (0.454 g, 2.08 mmol), and dry o-xylene (10 ml) is azeotropically dried for 1 hr. After cooling below the reflux point, a mixture of (R)-glycidyl butyrate (5.000 g, 34.68 mmol) and 3-fluorophenyl isocyanate (4.755 g or 3.96 ml, 34.68 mmol) in dry o-xylene (10 ml) is added over 10 min to the hot mixture (some refluxing observed during the addition). When the addition is complete, the mixture is heated to reflux for 2 hr and then allowed to cool to 20-25o. The solvent is removed under reduced pressure and the residue chromatographed over silica gel, eluding with hexane/ethyl acetate (6:1, 4:1, and then 2:1), to give the title compound, [α]25D -46.7 (c 1.0, CHCl3); IR (mineral oil mull) 1758, 1615, 1591, 1498, 1229, 1197, 1169 cm-1; NMR (CDCl3, 300 MHz) δ 7.44, 7.34, 7.23, 6.86, 4.88, 4.39, 4.32, 4.13, 3.82, 2.33, 1.63, 0.92; MS (m/z) 281, 193, 180, 150, 148, 137, 123, 95, 43; HRMS (m/z)281.1068 (calc'd for C14 H16 FNO4 =281.1063).
With n-butyllithium; sodium chloride In tetrahydrofuran; hexane
XIII (5R)-3-(2-Methylthio-benzo[4,5-d]thiazol-6-yl)-5-hydroxymethyl-oxazolidin-2-one STR47
EXAMPLE XIII (5R)-3-(2-Methylthio-benzo[4,5-d]thiazol-6-yl)-5-hydroxymethyl-oxazolidin-2-one STR47 35.00 ml (87.64 mmol) of a 2.5M solution of n-butyllithium in n-hexane are slowly added to a stirred solution, cooled to -78° C., of 28.90 g (87.64 mmol) of 6-benzyloxycarbonylamino-2-methylthio-benzo[4,5-d]thiazole (Example III) and 1 mg of 1,10-phenanthroline hydrate in 280 ml of anhydrous THF until the colour changes. Thereafter, 12.40 g (87.64 mmol) of (R)-glycidyl butyrate are added dropwise and the reaction mixture is allowed to warm to room temperature in the course of 16 hours. 200 ml of saturated aqueous NH4 Cl solution are then added dropwise in the course of 15 minutes. The aqueous phase is extracted with 3*100 ml of ethyl acetate and the organic phases are combined, washed with 2*100 ml of NaCl solution and dried over MgSO4. After the solvent has been evaporated off in vacuo and the residue has been titrated with ether, 17.25 g (67%) of the title compound are obtained as colourless crystals. Melting point: 156° C. Rf =0.24 (toluene:ethyl acetate 1:4) MS (DCI, NH3) m/z=297 (M+H)+ 1 H-NMR (200 MHz, D6 -DMSO): δ=2.78 (s, 3H, SCH3); 3.6-3.8 (m, 2H, CH2 O); 3.90 (dd, J=7, 10 Hz, 1H, H-4 trans); 4.15 (dd, J=10, 10 Hz, 1H, H-4 cis); 4.72 (m, 1H, H-5); 5.25 (t, J=6 Hz, 1H, OH); 7.74 (dd, J=1.5, 10 Hz, 1H, benzothiazole H-5); 7.87 (d, J=10 Hz 1H, benzothiazole H-4); 8.18 (d, J=1.5 Hz, 1H, benzothiazole H-7).
With n-butyllithium; sodium chloride In tetrahydrofuran; ethanol; hexane
3 (5R)-3-(Quinolin-6-yl)-5-hydroxymethyl-oxazolidin-2-one STR45
EXAMPLE 3 (5R)-3-(Quinolin-6-yl)-5-hydroxymethyl-oxazolidin-2-one STR45 4.70 ml (11.78 mmol) of a 2.5M solution of n-butyllithium in n-hexane are slowly added to a stirred solution, cooled to -78° C., of 3.28 g (11.78 mmol) of 6-benzyloxycarbonylamino-quinoline and 1 mg of 1,10-phenanthroline hydrate in 30 ml of anhydrous THF until the colour changes. Thereafter, 1.67 ml (11.78 mmol) of (R)-glycidyl butyrate are added dropwise and the reaction mixture is allowed to warm to room temperature in the course of 16 hours. 30 ml of saturated aqueous NH4 Cl solution are then added dropwise in the course of 15 minutes. The aqueous phase is extracted with 3*60 ml of ethyl acetate and the organic phases are combined, washed with 2*50 ml of NaCl solution and dried over MgSO4. Evaporation of the solvent in vacuo, tritration of the residue with ether and recrystallization from 25 ml of ethanol gives 1.30 g (45%) of the title compound as colourless crystals. Melting point: 165° C. Rf =0.08 (toluene:ethyl acetate 1:4) MS (DCI, NH3) m/z=245 (M+H)+ 1H-NMR (250 MHz, D6 -DMSO) δ=3.6-3.8 (m, 2H, CH2 O); 4.00 (dd, J=7, 10 Hz 1H, H-4 trans); 4.25 (dd, J=10, 10 Hz, 1H, H-4 cis); 4.78 (m, 1H, H-5); 5.25 (t, J=6 Hz, 1H, OH); 7.52 (dd, J=6, 9 Hz, 1H, quinoline H-3); 7.92 (d, J=1.5 Hz, 1H, quinoline H-5); 8.02 (d, J=10 Hz, 1H, quinoline H-8); 8.3 (m, 2H, quinoline H-4,7); 8.82 (m, 1H, quinoline H-2).
5-Bromo-2-isocyanato-pyridine Hydrochloride[ No CAS ]
[ 814-29-9 ]
[ 60456-26-0 ]
[ 175391-64-7 ]
Yield
Reaction Conditions
Operation in experiment
With lithium bromide; triethylamine; In 5,5-dimethyl-1,3-cyclohexadiene; water;
EXAMPLE II (5R)-3-(5-Bromo-pyridin-2-yl)-5-butyryloxy-methyl-oxazolidin-2-one STR24 A suspension of 2.17 g (25 mmol) of lithium bromide and 5.46 g (25 mmol) of tributylphosphine oxide in 73 ml of xylene is boiled in a water separator for 1 h. A mixture of 58.5 ml (0.42 mol) of triethylamine and 66.6 g (0.42 mol) of (R)-glycidyl butyrate is added dropwise to this at boiling heat. At the same time, 98.2 g (0.42 mol) of the compound from Example I are added in portions in the course of 20 min. After addition is complete, the mixture is stirred under reflux for 1 h. It is allowed to cool to room temperature and the solvent is evaporated in vacuo. After chromatography of the residue on 1 kg of silica gel (toluene:ethyl acetate 95:5), 37.9 g (26%) of the title compound are obtained as an oil. Rf =0.43 (toluene:ethyl acetate 4:1) MS (FAB) m/z=343 (M+H)+ 1 H-NMR (250 MHz, D6 -DMSO): δ=0.81 (t, J=7 Hz, 3H, CH3 CH2); 1.5 (m, 2H, CH3 CH2 CH2 CO); 2.29 (t, J=7 Hz, 2H, CH3 CH2 CH2 CO); 3.91 (dd, J=7 Hz, 10 Hz, 1H, H-4 trans); 4.25 (dd, J=9 Hz, 10 Hz, 1H, H-4 cis); 4.36 (m, 2H, CH2 O); 4.97 (m, 1H, H-5); 8.08 (d, J=1 Hz, 2H, pyridyl H-3,4); 8.50 (d, J=1 Hz, pyridyl H-6).
1.i. (R)-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-hydroxymethyl-oxazolidin-2-one A solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (3.0 g, 10.5 mmol, prepared according to method C) in THF (60 mL) was cooled to -78 C. before the dropwise addition of n-BuLi (5.1 mL of a 2.5M solution in hexanes, 1.2 eq.). The mixture was stirred at -78 C. for 1 h and then warmed to -15 C. At this temperature <strong>[60456-26-0](R)-glycidyl butyrate</strong> (1.98 g, 1.2 eq.) was added dropwise. The mixture was stirred at rt overnight. Cs2CO3 (tip of a spatula) was added and the mixture heated at 40 C. until complete conversion. The mixture was diluted with EA and washed with sat. NH4Cl solution and water. The org. layer was dried over MgSO4 and concentrated. Chromatography on SiO2 (Hex/EA 2:1, 1:1) gave the desired intermediate as a beige solid (1.09 g, 41% yield). 1H NMR (DMSO d6) delta: 7.13 (d, J=2.5 Hz, 1H), 6.96 (dd, J=2.5, 8.9 Hz, 1H), 6.86 (d, J=8.9 Hz, 1H), 5.16 (t, J=5.8 Hz, 1H), 4.70-4.50 (m, 1H), 4.30-4.10 (m, 4H), 4.10-3.90 (m, 1H), 4.80-4.70 (m, 1H), 4.70-4.60 (m, 1H), 4.60-4.50 (m, 1H).
41%
1.iii) (R)-3-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-5-hydroxymethyl-oxazolidin-2-oneA solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (3.0 g, 10.5 mmol, prepared according to procedure C in THF (60 mL) was cooled to -78 C. before the drop wise addition of n-BuLi (5.1 mL of a 2.5 M solution in hex, 1.2 eq). The mixture was stirred at -78 C. for 1 h and then warmed to -15 C. At this temperature <strong>[60456-26-0](R)-glycidyl butyrate</strong> (1.98 g, 1.2 eq) was added drop wise. The mixture was stirred at rt overnight. Cs2CO3 (tip of a spatula) was added and the mixture heated at 40 C. until complete conversion. The mixture was diluted with EA and washed with sat. NH4Cl solution and water. The org. layer was dried over MgSO4 and concentrated. CC (hex/EA 2:1 to 1:1) gave the desired intermediate as beige solid (1.09 g, 41%).1H NMR (DMSO d6) delta: 7.13 (d, J=2.5 Hz, 1H), 6.96 (dd, J=2.5, 8.9 Hz, 1H), 6.86 (d, J=8.9 Hz, 1H), 5.16 (t, J=5.8, 1H), 4.70-4.50 (m, 1H), 4.30-4.10 (m, 4H), 4.10-3.90 (m, 1H), 4.80-4.70 (m, 1H), 4.70-4.60 (m, 1H), 4.60-4.50 (m, 1H).
41%
1 Hi) (K)-3-(2, 3-Dihydro-benzo[l, 4]dioxin-6-yl)-5-hydroxymethyl-oxazolidin-2-one A solution of (2,3-dihydro-benzo[l,4]dioxin-6-yl)-carbamic acid benzyl ester (3.0 g, 10.5 mmol, prepared according to procedure C in THF (60 mL) was cooled to -78C before the drop wise addition of n-BuLi (5.1 mL of a 2.5 M solution in hex, 1.2 eq). The mixture was stirred at -78C for 1 h and then warmed to -15C. At this temperature (7^-glycidyl butyrate (1.98 g, 1.2 eq) was added drop wise. The mixture was stirred at rt overnight. Cs2CO3 (tip of a spatula) was added and the mixture heated at 400C until complete conversion. The mixture was diluted with EA and washed with sat. NH4Cl solution and water. The org. layer was dried over MgSO4 and concentrated. CC (hex/EA 2:1 to 1 :1) gave the desired intermediate as beige solid (1.09 g, 41%). <n="91"/>1H NMR (DMSO d6) delta: 7.13 (d, J=2.5 Hz, IH), 6.96 (dd, J=2.5, 8.9 Hz, IH), 6.86 (d, J=8.9 Hz, IH), 5.16 (t, J=5.8, IH), 4.70-4.50 (m, IH), 4.30-4.10 (m, 4H), 4.10-3.90 (m, IH), 4.80-4.70 (m, IH), 4.70-4.60 (m, IH), 4.60-4.50(m, IH).
41%
Example 1 : (E)- [fS)-3-(2,3-dihydro-benzo [ 1 ,4] dioxin-6-yl)-2-oxo-oxazolidin- 5-ylmethyl]-3-(6-methoxy-[l,5]naphthyridin-4-yl)-acrylamide:; Li. (R)-3-(2 ,3-dihydro-benzo [ 1,4] dioxin-6-yl)-5-hydroxymethyl-oxazolidin-2-one:; A solution of (2,3-dihydro-benzo[l,4]dioxin-6-yl)-carbamic acid benzyl ester (3.0 g, 10.5 mmol, prepared according to method C) in THF (60 rnL) was cooled to -78C before the dropwise addition of n-BuLi (5.1 mL of a 2.5M solution in hexanes, 1.2 eq.). The mixture was stirred at -78C for 1 h and then warmed to -15C. At this temperature (R)- glycidyl butyrate (1.98 g, 1.2 eq.) was added dropwise. The mixture was stirred at rt overnight. CS2CO3 (tip of a spatula) was added and the mixture heated at 400C until complete conversion. The mixture was diluted with EA and washed with sat. NH4Cl solution and water. The org. layer was dried over MgSO4 and concentrated.Chromatography on SiO2 (Hex/EA 2:1, 1 :1) gave the desired intermediate as a beige solid(1.09 g, 41% yield).1H NMR (DMSO d6) delta: 7.13 (d, J = 2.5 Hz, IH), 6.96 (dd, J = 2.5, 8.9 Hz, IH), 6.86 (d, J = 8.9 Hz, IH), 5.16 (t, J = 5.8 Hz, IH), 4.70-4.50 (m, IH), 4.30-4.10 (m, 4H),4.10-3.90 (m, IH), 4.80-4.70 (m, IH), 4.70-4.60 (m, IH), 4.60-4.50 (m, IH).
(R)-3-(3-fluoro-4-(1,4-thiazepan-4-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
55%
To a solution of benzyl 3-fluoro-4-(1,4-thiazepan-4-yl)phenylcarbamate (8) (2.34 g, 6.5 mmol) in THF (10 mL) at - 78 C under a nitrogen gas atmosphere was added n-BuLi (4 ml, 9.7 mmol), then the mixture was stirred at -78C for 30 mm, after that the solution of (R)-oxiran-2-ylmethyl butyrate (1.4 g, 9.7 mmol) in THF was added to the mixture at -78C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford (R)-3 -(3 -fluoro-4-( 1 ,4-thiazepan-4-yl)phenyl)-5 -(hydroxymethyl)oxazolidin-2-one(9) (1.16 g, 55%) as a white solid. LC-MS (ESI) m/z = 327 [M+H].
Step 6.. To a stirred solution of the carbamate from Step 5 (3.0 g) in dry THF (33 ML) under N2 cooled to -78 C., is added dropwise via syringe a 1.6 M solution of NBuLi in hexane (5.4 ML).. The reaction mixture was stirred at -78 C. for 35 min, then R-glycidyl butyrate (1.2 ML) is added.. The reaction mixture is stirred at -78 C. for 30 min, then at room temperature overnight during which time a precipitate forms.. The reaction mixture is quenched with saturated aqueous NH4Cl (33 ML) and poured into EtOAc (100 ML).. The phases are separated.. The organic phase is washed with saturated aqueous NaHCO3 (50 ML), brine (50 ML), dried (MgSO4), filtered and concentrated.. The residue is purified by flash chromatography using EtOAc as the eluent to afford 2.5 g of a hydroxymethyl oxazolidinone.. Mp 100-102 C. Anal. Calcd for C15H19FN2O3S: C, 55.20; H, 5.87; N, 8.58; S, 9.82. Found: C, 55.09; H, 5.91; N, 8.36; S, 9.57.
5(R)-hydroxymethyl-3-(4-(1-benzyl-1,2,5,6-tetrahydropyrid-4yl)-3,5-difluorophenyl)oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
The benzylurethane from Reference Example 9C (5.54 g, 12.76 mmol) in 50 ml dry THF was cooled to -70 C. under nitrogen and 8.80 ml of 1.6M niBuLi in hexanes (14.08mmol) added dropwise at the same temperature. After 20 minutes at the same temperature a solution of <strong>[60456-26-0](R)-glycidyl butyrate</strong> (2.00 g, 13.88 mmol in 5 ml THF) was added dropwise and the mixture stirred for 30 minutes at -70 C., and then stirred to ambient temperature overnight. After quenching with 100 ml 10% ammonium chloride, the mixture was extracted with EtOAc and usual work-up to give an oily solid, which was purified by flash chromatography (Merck C60 silica, 5% MeOH/dichloromethane eluant) to give a crystalline solid (4.40 g, 86%). MS: ESP+ (M+H)=401.1H-NMR (250 MHz. DMSO-d6); delta=2.32 (m, 2H), 2.63 (t, 2H), 3.05 (m, 2H), 3.50-3.72 (m,4H), 3.82 (dd,1H), 4.06 (t,1H), 4.73 (m,1H), 5.18 (t,1H), 5.78 (m,1H).
d. Compound 6 Compound 5 (1.8683 g, 3.43 mmol) in dried tetrahydrofuran (20cm3) was subjected to aryl substitution and cooled to - 78 C. To this solution, n-BuLi (1.54 M in n-hexane; 2.5cm3, 3.85 mmol) was added slowly dropwise, and then stirred at the temperature for 10 min. (R)-glycidylbutyrate (0.6084 g, 4.22 mmol) dissolved in dried tetrahydrofuran (3cm3) was added slowly dropwise, and the mixture was cooled to room temperature and stirred for 20 minutes. water (30cm3) was added, and the mixture was extracted five times with ethyl acetate and dried over anhydrous sodium sulfate. After filtration, solvent was removed to obtain the residue (2.2370g). The residue was dissolved in methanol (20cm3), added with potassium carbonate (5.0776 g, 36.74 mmol) and stirred for 6 hours at room temperature. Water (30cm3) was added, and the mixture was extracted five times with ethyl acetate and dried over anhydrous sodium sulfate. The drying reagent was filtered out, and solvent was concentrated in vacuo. The residue was purified by silica gel column chromatography (BW-200,30 g, eluant: 50 % ? 100 % ethyl acetate In-hexane ? 2 % methanol / dichloromethane) to afford Compound 6 (1.5838 g, 3.01 mmol). Yield: 88 %. 1H NMR (CDCl3) delta = 1.34-1.47 (9H, Boc), 2.59 (1H, br, OH), 3.16-3.40 (6H, m), 3.70-3.82 (1H, m), 3.89-4.27 (5H, m), 4.68-4.78 (1H, m, CH2CHCH2OH), 5.06-5.30 (2H, m, CH2Ph), 6.83-6.93 (1H, m), 7.02-7.13 (1H, m), and 7.27-7.46 (6H, m).
88%
d. Compound 6 Compound 5 (1.8683 g, 3.43 mmol) in dried THF (20cm3) was subjected to aryl substitution and cooled to -78 C. To this solution, n-BuLi (1.54 M in n-hexane; 2.5cm3, 3.85 mmol) was added slowly dropwise, and stirred at this temperature for 10 min. (R)-glycidylbutyrate (0.6084 g, 4.22 mmol) in dried THF (3cm3) was added slowly dropwise, and the mixture was cooled to room temperature and stirred for 20 minutes. Water (30cm3) was added, and the mixture was extracted five times with EtOAc and dried over anhydrous sodium sulfate. After filtration, the solvent was removed to obtain the residue (2.2370g). The residue was dissolved in methanol (20cm3), added with potassium carbonate (5.0776 g, 36.74 mmol) and stirred for 6 hours at room temperature. Water (30cm3) was added, and the mixture was extracted five times with EtOAc and dried over anhydrous sodium sulfate. The drying reagent was filtered out, and the solvent was concentrated in vacuo. The residue was purified by silica gel column chromatography (BW-200, 30 g, eluant: 50 % ? 100 % EtOAc/n-hexane ? 2 % methanol/dichloromethane) to afford Compound 6 (1.5838 g, 3.01 mmol). Yield: 88 %. 1H NMR (CDCl3) delta = 1.34-1.47 (9H, Boc), 2.59 (1H, br,OH), 3.16-3.40 (6H, m), 3.70-3.82 (1H, m), 3.89-4.27 (5H, m), 4.68-4.78 (1H, m, CH2CHCH2OH), 5.06-5.30 (2H, m, CH2Ph), 6.83-6.93 (1H, m), 7.02-7.13 (1H, m), and 7.27-7.46 (6H, m).
Synthesis of Compound (48) To a solution of carbobenzoxy compound (47, 363mg) in THF (10ml), 1.54M BuLi hexane solution (0.60ml) is added and stirred under argon atmosphere at -78. After 10 minutes, <strong>[60456-26-0](R)-glycidyl butyrate</strong> (241mg) in THF (2ml) is added and stirred at the temperature for 10 min. and additional 19 hours at room temperature. After the reaction, NH4Cl aqueous solution is added and extracted with chloroform-methanol (9: 1). After dryness (Na2SO4), solvent is removed. The residue in methanol (10ml) is added with potassium carbonate (173mg) and stirred for 15 minutes. NH4Cl aqueous solution is added and extracted with chloroform-methanol (9:1). After dryness (Na2SO4), solvent is removed. The residue is purified by silica gel chromatography (chloroform-methanol (9: 1)) to afford 291mg (87 %) of Compound (48) as colorless syrup. 48: colorless syrup; 1H-NMR (300MHz, CDCl3) delta 1.51 (s, 9H), 3.33-3.43 (m, 4H), 3.71-3.82 (m, 3H), 3.90-4.02 (m, 3H), 4.07 (t, 5, 2H), 4.70-4.79 (m, 1H), 7.06-7.17 (m, 2H); IR (CHCl3) numax 1752, 1705, 1690 cm-1; MS e/m 429 (M+, 6), 326 (5), 299 (9), 271 (17), 242 (11), 168 (10), 154 (8), 57 (100).
87%
General procedure: To a solution of3a(20.018g, 34.60mmol) in tetrahydrofuran (200mL) at-78C under an argon atmosphere was added dropwise 1.58Mn-butyl lithium/n-hexane (24.0mL, 37.92mmol) over 10min. Further <strong>[60456-26-0](R)-glycidyl butyrate</strong> (5.4847g, 38.04mmol) in tetrahydrofuran (10mL) was added dropwise to the reaction mixture over 10min, followed by stirring for 1h at the same temperature. Then the reaction mixture was allowed to come gradually to ambient temperature. Stirring was continued for 21h, then water (300mL) was added, and the aqueous layer was extracted with AcOEt. The combined organic layer was washed with brine, and dried. Evaporation of the solvent followed by silica gel (250g) column chromatography of the residue usingn-hexane/AcOEt (1:1 to 0:1) and CHCl3/MeOH (97:3 to 9:1) as eluents afforded4a(17.489g, 93%).
87%
Synthesis of Compound (48) To a solution of carbobenzoxy compound (47, 363mg) in THF (10ml), 1.54M BuLi hexane solution (0.60ml) is added and stirred under argon atmosphere at -78C. After 10 minutes, <strong>[60456-26-0](R)-glycidyl butyrate</strong> (241mg) in THF (2ml) is added and stirred at the temperature for 10 min. and additional 19 hours at room temperature. After the reaction, aqueous NH4Cl solution is added and extracted with chloroform-methanol (9:1). After dryness (NasSO4), the solvent is removed. The residue in methanol (10ml) is added with potassium carbonate (173mg) and stirred for 15 minutes. Aqueous NH4Cl solution is added and extracted with chloroform-methanol (9:1). After dryness (Na2SO4), the solvent is removed. The residue is purified by silica gel chromatography (chloroform-methanol (9: 1)) to afford 291mg (87 %) of Compound (48) as colorless syrup. 48: colorless syrup; 1H-NMR (300MHz, CDCl3) delta 1.51 (s, 9H), 3.33-3.43 (m, 4H), 3.71-3.82 (m, 3H), 3.90-4.02 (m, 3H), 4.07 (t, 5, 2H), 4.70-4.79 (m, 1H), 7.06-7.17 (m, 2H); IR (CHCl3) numax 1752, 1705, 1690 cm-1; MS e/m 429 (M+, 6), 326 (5), 299 (9), 271 (17), 242 (11), 168 (10), 154 (8), 57 (100).
e. Compound 20 Compound 19 (6.2841 g, 11.91 mmol) was dissolved in dried tetrahydrofuran (50cm3), followed by subjected to aryl substitution and cooled to -78 C. To this solution, n-BuLi (1.58 M in n-hexane; 8.0cm3,12.64 mmol) was added slowly dropwise, followed by stirring at this temperature for 5 min. <strong>[60456-26-0](R)-glycidyl butyrate</strong> (1.9001 g, 13.18 mmol) in dried tetrahydrofuran (2cm3) was added slowly dropwise, and cooled to room temperature and stirred for 21 hour. Water (50cm3) was added and the mixture was extracted four times with ethyl acetate, washed once with saturated aqueous sodium chloride. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out. Solvent was removed, and the residue was then purified by silica gel column chromatography (BW-200,80 g, eluant: 50 % ? 100 % ethyl acetate /n-hexane) to afford Compound 20 (4.0759 g, 8.258 mmol). Yield: 69 %. 1H NMR (CDCl3) delta = 1.43 (18H, s,Boc×2), 2.75 (1H, brs, OH), 3.10-4.26 (12H, m), 4.69-4.79 (1H, m), 6.53 (1H, d,J = 9.3 Hz), 7.82-7.92 (1H, m), and 8.07-8.12 (1H, m).
69%
With n-butyllithium; In tetrahydrofuran; hexane; at -78 - 20℃;
e. Compound 20 Compound 19 (6.2841 g, 11.91 mmol) was dissolved in dried THF (50cm3) and subjected to aryl substitution and cooled to -78 C. To this solution, n-BuLi (1.58 M in n-hexane; 8.0cm3, 12.64 mmol) was added slowly dropwise, followed by stirring at this temperature for 5 min. <strong>[60456-26-0](R)-glycidyl butyrate</strong> (1.9001 g, 13.18 mmol) in dried THF (2cm3) was added dropwise slowly, and left to cool at room temperature and stirred for 21 hour. Water (50cm3) was added, and the mixture was extracted four times with EtOAc, and washed once with brine. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out. The solvent was removed, and the residue was purified by silica gel column chromatography (BW-200, 80 g, eluant: 50 % ? 100 % EtOAc/n-hexane) to afford Compound 20 (4.0759 g, 8.258 mmol). Yield: 69 %. 1H NMR (CDCl3) delta = 1.43 (18H, s, Boc×2), 2.75 (1H, brs, OH), 3.10-4.26 (12H, m), 4.69-4.79 (1H, m), 6.53 (1H, d, J = 9.3 Hz), 7.82-7.92 (1H, m), and 8.07-8.12 (1H, m).
e. Compound 30 Compound 29 (7.2419 g, 12.14 mmol) in dried tetrahydrofuran (60cm3) was subjected to aryl substitution and cooled to - 78C. To this solution, n-BuLi (1.54 M in n-hexane; 8.8cm3,13.55 mmol) was added slowly dropwise, and followed by stirred for 5 min. at this temperature. <strong>[60456-26-0](R)-glycidyl butyrate</strong> (1.9622 g, 13.61 mmol) in dried tetrahydrofuran (2cm3 ) was then added slowly dropwise, and cooled to room temperature and stirred for 20 minutes. Water (50cm3) was added to the mixture, which was extracted five times with ethyl acetate, and dried over anhydrous sodium sulfate. The drying reagent was filtered out, and solvent was removed. The residue (8.9592 g) was dissolved in methanol (50cm3) and added with potassium carbonate (5.0460 g, 36.51 mmol). The mixture was stirred at room temperature for 1 hour. Methanol was removed, and water (50cm3) was added and extracted five times with ethyl acetate. After dryness over anhydrous sodium sulfate, the drying reagent was filtered out, and solvent was removed. Purification by silica gel column chromatography (BW-200,120 g, eluant: 50 % ? 1 % methanol / ethyl acetate) afforded Compound 30 (5.5651 g, 9.89 mmol). Yield: 81 %. 1H NMR (CDCl3) delta = 1.36 (9H, s,Boc), 2.81 (1H, t,J = 6.3 Hz, CH2OH), 3.03-4.16 (12H, m), 4.68-4.78 (1H, m), 5.07-5.32 (2H, m,OCH2Ph), 7.12 (2H, br d,J = 9 Hz), and 7.28-7.40 (5H, m).
81%
General procedure: To a solution of3a(20.018g, 34.60mmol) in tetrahydrofuran (200mL) at-78C under an argon atmosphere was added dropwise 1.58Mn-butyl lithium/n-hexane (24.0mL, 37.92mmol) over 10min. Further <strong>[60456-26-0](R)-glycidyl butyrate</strong> (5.4847g, 38.04mmol) in tetrahydrofuran (10mL) was added dropwise to the reaction mixture over 10min, followed by stirring for 1h at the same temperature. Then the reaction mixture was allowed to come gradually to ambient temperature. Stirring was continued for 21h, then water (300mL) was added, and the aqueous layer was extracted with AcOEt. The combined organic layer was washed with brine, and dried. Evaporation of the solvent followed by silica gel (250g) column chromatography of the residue usingn-hexane/AcOEt (1:1 to 0:1) and CHCl3/MeOH (97:3 to 9:1) as eluents afforded4a(17.489g, 93%).
Carbamate 320 (3.60g, 12.16 mmol) was dissolved in 10 mL tetrahydrofuran, and the solution cooled TO-78C. n-Butyllithium (2.5 M in hexane, 7.6 mL, 12.16 mmol) was added slowly, and the mixture allowed to stir for 45 min AT-78C. R- (-)-Glycidyl butyrate (1.75 mL, 12.16 mmol) was added, and the mixture was stirred for 1 h AT-78C. The bath was removed and the reaction allowed to stir overnight at room temperature. The reaction was quenched with 25 mL saturated ammonium chloride solution, and partitioned with ethyl acetate and water. The aqueous layer was extracted thrice with ethyl acetate, and the combined organic layer was washed with brine, dried (NA2S04), and evaporated to yield 321 (2.80 g, 88% yield) of suitable purity for use in subsequent reactions. Data for 321: 1HNMR (300 MHz, CDC13) : 8 7.59 (s, 1H), 7. 33 (s, 1H), 4. 68 (m, 1H), 3.91 (m, 3H), 3.67 (dd, J= 16,4 Hz, 1H).
To a solution of (5-oxo-5,6, 7,8-tetrahydro-naphthalen-2-yl)-carbamic acid benzyl ester (153.0 g, 0.518 mol) in TE (1.7 L) at >-70 C was added lithium (trimethylsilyl) amide (1.0 M in TB, 544 mL, 0.54 mol) AT-70 C, and the mixture was stirred for 1 hour. (R)- (-) Glycidyl butyrate (77.0 mL, 0.54 mol) was added over 40 minutes. The solution was stirred for 2 hours at-70 C and allowed to warm to room temperature overnight. The reaction was quenched with 300 mL of saturated NH4CL ; the layers were separated and the organic layer was concentrated. The residue was triturated with 25 % ethyl acetate in heptane several times to give 250 g (92 % yield) of the title compound.
To a solution of [4- (3, 6-DIHYDRO-2H-PYRIDIN-1-YL)-3-FLUORO-PHENYL]- carbamic acid benzyl ester (1.54 g, 4.72 mmol) in 20 mL OF THF was added 5.2 mL of lithium hexamethyldisilazide (LHMDS) (1.0 M in THF, 5.19 mmol) at-78 C. After 30 minutes, 0.8 mL (5.66 mmol) OF R- (-)-GLYCIDYLBUTYRATE was added and the reaction mixture was warmed up to room temperature and stirred overnight. The reaction was then quenched with saturated NH4Cl solution, extracted with dichloromethane, and dried over MGS04. Solvent was removed and the residue was purified by column chromatography (10% methanol/dichloromethane) to give 1.21 g (87%) of the desired product as a white solid. HPLC : retention time 3.33 minutes, Purity >99%; [M+H] + 293.3.
Step 4: Preparation of (R)-{N-3-[3,5-difluoro-4-(7,7-ethylenedioxy-5-azaspiro[2,4]heptan-5-yl)phenyl]-2-oxo-5-oxazolidinyl}To a solution of N-carbobenzyloxy-[3,5-difluoro-4-(7,7-ethylenedioxy-5-azaspiro[2,4]heptan-5-yl)phenyl]aniline (2.1 g, 5.1 mmol), obtained in Step 3, in purified tetrahydrofuran (50 mL) was dropwise added 1.6 M n-butyl lithium-hexane solution (3.5 mL, 5.6 mmol) at -78 C. 10 min later, droplets of <strong>[60456-26-0](R)-glycidyl butyrate</strong> (0.8 mL, 4.7 mmol) were slowly added. The temperature was elevated to room temperature with stirring for 16 hours. After the reaction terminated, the reaction mixture was mixed with a saturated aqueous ammonium chloride solution (10 mL) and then extracted with ethyl acetate and water. The organic phase thus formed was dried over anhydrous magnesium sulfate and filtered. After the removal of the solvent through vacuum distillation, the filtrate was purified using column chromatography (n-hexane/ethyl acetate=1:1) to afford the target compound (1.3 g, yield 66%).1H-NMR (300 MHz, CDCl3) delta 0.64 (t, 2H, J=5.4 Hz), 0.94 (t, 2H, J=5.4 Hz), 3.47 (d, 2H, J=1.5 Hz), 3.57 (d, 2H, J=2.4 Hz), 3.88 (d, 2H, J=8.5 Hz), 3.94 (s, 4H), 3.97 (d, 2H, J=8.5 Hz), 4.71 (m, 1H), 7.15 (s, 1H), 7.30 (s, 1H); 13C-NMR (300 MHz, CDCl3) delta 8.6, 25.6, 46.6, 59.1, 62.7, 65.1, 72.9, 107.7, 108.1, 112.8, 114.5, 114.6, 129.0, 133.8, 150.2, 154.9.
66%
Step 4: Preparation of(Rs)-(N-3-[3.5-difluoro-4-(7.7-ethylenedioxy-5-azaspiro[2.41heptan-5-yls)phenyll-2-oxo -5-oxazolidinyl)[109] To a solution of N-car- bobenzyloxy-[3,5-difluoro-4-(7,7-ethylenedioxy-5-azaspiro[2,4]heptan-5-yl)phenyl]an iline (2.1 g, 5.1 mmol), obtained in Step 3, in purified tetrahydrofuran (50 rnL) was dropwise added 1.6 M n-butyl lithium-hexane solution (3.5 rnL, 5.6 mmol) at -78 0C. 10 min later, droplets of <strong>[60456-26-0](R)-glycidyl butyrate</strong> (0.8 mL, 4.7 mmol) were slowly added. The temperature was elevated to room temperature with stirring for 16 hours. After the reaction terminated, the reaction mixture was mixed with a saturated aqueous ammonium chloride solution (10 mL) and then extracted with ethyl acetate and water. The organic phase thus formed was dried over anhydrous magnesium sulfate and filtered. After the removal of the solvent through vacuum distillation, the filtrate was purified using column chromatography (n-hexane/ethyl acetate = 1:1) to afford the target compound (1.3 g, yield 66%).[110] 1H-NMR (300 MHz, CDCl3) delta 0.64 (t, 2H, J = 5.4 Hz), 0.94 (t, 2H, J = 5.4 Hz), 3.47 (d, 2H, J = 1.5 Hz), 3.57 (d, 2H, J = 2.4 Hz), 3.88 (d, 2H, J = 8.5 Hz), 3.94 (s, 4H), 3.97 (d, 2H, J= 8.5 Hz), 4.71 (m, IH), 7.15 (s, IH), 7.30 (s, IH).[I l l] 13C-NMR (300 MHz, CDCl3) delta 8.6, 25.6, 46.6, 59.1, 62.7, 65.1, 72.9, 107.7, 108.1, 112.8, 114.5, 114.6, 129.0, 133.8, 150.2, 154.9.
In a 1L three-necked bottle, 50 g of a compound of Formula X3, 400 ml of tetrahydrofuran and 400 ml of acetonitrile were added.Nitrogen gas, temperature 25C, solids insolubleThen, 9.9 g of lithium tert-butoxide and 13.9 g of potassium tert-butoxide were added, and the solid matter dissolved.The reaction solution changed from colorless to yellow,After stirring for 2 hours, the reaction solution was added dropwiseR-(-)-glycidol butyric acid and compound of formula R 19.7 g,After completion of the addition, the reaction was incubated for 3 hours, and the sample was subjected to a TLC (developing solvent: chloroform/methanol = 10/1). After the spot of the compound of Formula X3 disappeared, the sample was dropped.Add dilute hydrochloric acid prepared from concentrated hydrochloric acid and water, adjust the pH to 8, fully stir for 30 minutes, the water bath temperature is 35C to 55C, and the vacuum degree -0.07MPa to -0.1MPa is concentrated under reduced pressure to stop flow.
85%
A 5-L, three-neck, round-bottom flask was equipped with an overhead stirrer, a thermocouple, a 500-mL addition funnel and a nitrogen-inlet adapter. The flask was dried with a heat gun under a flow of nitrogen to an internal temperature of 60C. The flask was charged with intermediate 7 (110.0 g, 0.272 mol, AMRI lot No. DUG-AF-202Q)) and anhydrous THF (2.2 L, 20 vol). The slurry was stirred and a light green solution formed. The addition funnel was charged with 1.0 M lithium hexamethyldisilazide (299 mL, 0.286 mol, 1.05 eq.). The LiHMDS solution was added dropwise to the solution of intermediate 7 over approximately 25 minutes. A red solution formed. The solution was stirred one hour at room temperature and then DMPU (34.9 g, 0.272 mol, 1 eq) was added, and the mixture turned to a yellow slurry. The batch was cooled in an ice bath to 5.7C. R-(-)-Glycidyl butyrate (41.25 g, 0.286 mol, 1.05 eq) was then added in one portion. The mixture was stirred in the ice bath for 0.5 hour and then was warmed to room temperature and stirred overnight. The reaction formed a tan slurry at this point, and HPLC analysis after 15 hours indicated that there was approximately 87% TR-700, 1.6% intermediate 7, and approximately 7% of the butyrate ester of TR-700. A small amount of sodium methoxide in methanol (11 mL, 0.1 vol) was added, and the batch was stirred for 1 hour to remove the residual ester. The in-process HPLC analysis at this point showed there was approximately 90.7% TR-700 and 0.2% of the butyrate ester. The reaction was quenched by the addition of 10% w/w ammonium chloride solution (1.1 L, 10 vol). A modest exothermic event from 22C to 25C was observed upon addition of the ammonium chloride solution. The two-phase mixture was distilled to a pot temperature of 700C (atmospheric pressure) to remove approximately 2.2 L of the THF. This formed a thick slurry which is diluted with water (550 mL, 5 volumes). The slurry was cooled to room temperature (23.6C) and was filtered. The filter cake was washed with water (1.1 L, 10 vol) and methanol (550 mL, 5 vol) to give TR-700 as a white solid. The wet cake was dried overnight in a vacuum oven at 500C to give 89.7 g of TR-700 (89% yield) that was 97.8% (AUC) by HPLC analysis. The TR-700 was further purified by reslurrying in 2.7 L (30 vol) of 4: 1 methanol/water at 700C, cooling to 230C, filtering and washing with methanol (180 ml). This removed some of the over-alkylated product that is observed. The purified TR- 700 was recovered in 96% yield (85% overall yield), and the purity was improved to 98.4% (AUC) by HPLC analysis. The palladium content was 10 ppm.
84.4%
Under the protection of nitrogen, to a 100 L reactor, 2.60 kg (6.43 mol) of terdazolamide phosphate intermediate II and 50 L of anhydrous tetrahydrofuran were added and stirred to dissolve. 7.07 liters of 1 mol / L lithium hexamethyldisilazide in tetrahydrofuran solution was added dropwise.Stir at 10 15 for 2 hours, add 1,3-dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU) 0.83Kg, and lower the temperature to 0 5 . Add R-glycidyl butyrate 0.97Kg. Stir overnight at 10 C to 15 C to obtain a light yellow slurry.A solution of 33 g of sodium methoxide dissolved in 330 mL of methanol was added and stirred for 1 hour. Add ammonium chloride solution with a mass concentration of 10% (the mass concentration means the mass of ammonium chloride as a percentage of the total mass of ammonium chloride water) 17L.The two-phase mixture was concentrated. Water (13 L, 5 volumes) was added to the concentrated slurry, cooled to room temperature, and filtered. The filter cake was slurried with methanol and water (volume ratio 4: 1) (70 L), then filtered, and filtered The cake was rinsed with 12L of methanol and 12L of water, and the wet product was dried in a vacuum (pressure -0.01MPa -0.1MPa) drying oven at 45 C- 55 C for 8 hours 12 hours to obtain the white solid as terdazolamide phosphate intermediate V 2.01Kg, yield 84.4%. HPLC purity: 99.21%.
Stage #1: C16H17F3N2O3 With lithium tert-butoxide In tetrahydrofuran; acetonitrile at 5℃; Inert atmosphere;
Stage #2: (R)-glycidyl butyrate In tetrahydrofuran; acetonitrile at 17 - 20℃;
1
Compound of Example 1Intermediate 5 (17.0 g, 49 mmol) was dissolved in anhydrous THF (10 mL) and CH3CN (34 mL) at 5° C. under nitrogen. ButOLi (powder, 4.3 g, 54 mmol) was added slowly and the resulting solution was stirred for another 1 h at 5° C. (R)-Glycidyl butyrate (14.1 mL, 99 mmol) was added dropwise. The mixture was stirred for 3 h and allowed to warm up to 17-20° C. The reaction mixture was cooled to 5° C. and quenched carefully with aq. acetic acid solution (1.0 M, 85 mL). The solid was dissolved after stirring for 3 h at 5° C. The mixture was condensed under vacuum, and the residue was re-dissolved in DCM (100 mL) and washed with water (50 mL). The DCM phase was condensed under vacuum. The residue was dissolved in CH3OH (34 mL) and cooled to 10° C. Then 10% aq. K2CO3 solution (30 mL) was added slowly. The mixture was warmed up to 20° C. and stirred for 2 h. After cooling to 5° C., aq. acetic acid solution (1.0 M, 50 mL) was added dropwise to adjust the pH to ca. 6-7. The mixture was extracted with DCM (3×60 mL). The combined DCM layers were washed with brine (80 mL) and 1% aq. HCl (30 mL), dried over MgSO4, filtered and condensed on vacuum. The solid obtained was washed with a mixture of EtOAc (15 mL) and heptane (15 mL) for 2 h at 75° C., filtered and dried. The product was obtained as an off-white solid (11.1 g, 65%). 1H NMR (400 MHz, DMSO-d6): 7.55 (m, 1H); 7.46 (d, J=7.6 Hz, 1H); 5.24 (t, J=4.8 Hz, 1H); 5.04 (d, J=8.0 Hz, 1H); 4.75 (m, 1H); 4.09 (t, J=4.8 Hz, 1H); 3.86 (t, J=7.2 Hz, 3H); 3.67 (m, 1H); 3.55 (m, 1H); 3.30 (s, 2H). MS (m/z): 343 [M+H].
2.5a (3 g, 10.66 mmol, 1.0 equiv) was dissolved in THE (16 mL) and cooled to -70 C. n-BuLi (2.5M in hexane) (1.36 g, 21.32 mmol, 2.0 equiv) was gradually added and the reaction mixture was stirred at -70 C for 1 hour. (R)-oxiran-2-ylmethyl butyrate (1.46 g, 12.79 mmol, 1.2 equiv) was added drop wise and the reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (0-2 % MeOH in dichloromethane) to afford product 2.5b (2.1 g, 79.6 % yield). LCMS (mlz): 248.3 [M+H]. 1H NMR (400 MHz, DMSO) 6 8.05 (dd, J = 8.2,0.8 Hz, 1 H), 7.83 - 7.77 (m, 2H), 7.71 - 7.65 (m, 1 H), 5.21 (d, J = 29.6 Hz, 1 H), 4.76 - 4.67 (m, 1H), 4.15 (t, J = 8.9 Hz, 1H), 4.05 (d, J = 3.2 Hz, 3H), 3.90 (dt, J = 12.0, 6.0 Hz, 1H), 3.70 (dd, J 12.2, 3.1 Hz, 1H), 3.59 (dd, J 12.2, 3.9 Hz, 1H).
52%
Step 1: Preparation of ( R )-5-(hydroxymethyl)-3-(l-methyl-lH-indazol-5-yl)oxazolidin-2- oneLithium bis(trimethylsilyl)amide (IM in THF, 35.46 ml, 0.035 mol) is added dropwise to benzyl l-methyl-lH-indazol-5-ylcarbamate (5.Og, 0.0173 mol) in THF at -78 0C and the mixture stirred for 90 minutes. R-Glycidyl butyrate (2.76 ml, 0.019 mol) is added, the reaction mixture allowed to warm to room temperature and stirred for 14 h. The reaction is quenched with saturated aqueous ammonium chloride, diluted with water and extracted with dichloromethane. The organic layer is washed with brine, dried (Na2SO4) and evaporated. The residue is purified by flash column chromatography (20% EtOAc/Hexane) to give the title compound (2.7 g, 52%); HPLC (SYMMETRY Ci8 3.5 muM, 4.6 x 30 mm <n="26"/>column; gradient elution 2%-98% MeCN with 0.1% TFA over 10 min; 2 mL/min rate): retention time = 3.153 min; MS (m/z): (M+H)+ 249.3
1-[(4-(5R)-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
To a solution of l-(4-benzyloxycarbonylamino-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2.0 g, 4.9 mmol), in dry THF (15 mL) was added "BuLi (5.5 mL, 8.8 mmol, 1.6 M solution in hexane) dropwise under nitrogen atmosphere at -78 C. The reaction mixture was stirred at the same temperature for Ih and then (Lambda)-glycidyl butyrate (0.75 mL, 5.4 mmol) was added dropwise over a period of 5 min. The reaction mixture was stirred at -78 C for additional 2h and then warmed to r.t. The progress of reaction was monitored by TLC and on completion, the reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (4x20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.31: 9.69 MeOH: CHCl3) to provide the title compound (1.8 g, 96%) as off white solid. ESIMS (m/z): 373.8 (M-I)
ethyl 1-(4-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenyl)cyclopropanecarboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86%
Step 2: Preparation of ethyl l-(4-(5-(hvdroxymethyl)-2-oxooxazolidin-3- yl)phenyl)cvclopropanecarboxylate [XIV]To a stirring solution of isoamyl alcohol 1.58mL (0.0147mol) in 60mL THF at - 78 C was slowly added 6.2mL [15%W/V (in Hexane)] n-BuLi under nitrogen environment. Then slowly charged l-(4-(((benzyloxy) carbonyl) amino) phenyl) cyclopropanecarboxylate (5g, 0.0147mol) dissolved in 15mL of THF. Again 6.2mL of n-BuLi was added in reaction mix. Then charged R (-) glycidyl butarate (2.05mL, 0.0147mol) at -78 C and reaction mixture was stirred at room tempreture for lh. Reaction mixture was quenched by adding saturated ammonium chloride solution and extracted with ethyl acetate to gave 3.9g titled compound in 86% yield.
With lithium tert-butoxide; In tetrahydrofuran; at 20℃; for 24h;
Example 5: Preparation of 4-(4-((R)-5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one (compound VII) To a solution of benzyl 4-(3-oxomorpholino)phenylcarbamate (3.00 g, 9.20 mmol) in anhydrous THF (28 mL) was added dropwise a solution of 'BuOLi in THF (1.0 M, 18.4 mL, 18.4 mmol). (R)-Glycidyl butyrate (1.43 mL, 10.1 mmol) was added and the mixture was stirred at room temperature for 24 h. After dilution with a saturated NH4CI solution (20 mL), THF was evaporated under reduced pressure and the aqueous phase was extracted with CH2Cl2 (8 x 20 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude obtained was suspended in EtOAc (10 mL). The suspension was heated to reflux temperature for 30 min, was cooled to room temperature and was filtered. The filtrate was washed with cold EtOAc, affording 4-(4-((R)-5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin- 3-one (or compound VII) (2.139 g, 80%) as a brownish solid.1H NMR (400 MHz, CDCI3) delta 7.59 (d, J = 9.2 Hz, 2 H), 7.34 (d, J = 9.2 Hz, 2 H), 4.75-4.70 (m, 1 H), 4.34 (s, 2 H), 4.05-3.93 (m, 5 H), 3.76-3.71 (m, 3 H).
Example-S(a): Preparation of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2- oxo-5- oxazolidinyljmethanol (VIII) starting from N-carboethoxy-3-fluoro-4- morpholinylanilineN-carboethoxy-3-fluoro-4-morpholinylaniline (100 g) was dissolved in THF (500 ml). To the resulting solution, n-butyllithium (245 ml in hexane) was added under nitrogen at -78C over 1.5h and stirred for 2h, further a solution of R-(-)-glycidyl butyrate (53.75 g, in THF (100 ml)) was added. The resulting solution was stirred at -78C for 2h, further it was warmed to room temperature and stirred for overnight. To the resulting thick slurry, saturated ammonium chloride (345 ml) was added followed by the addition of water (300 ml). It was stirred at room temperature for 30 min and was concentrated. Further, water (500 ml) was added and the suspension was again stirred at 50-55C for lh and then at 25-30C for next lh. The solid mass was filtered, washed with water and suck dried for lh. The filtrate was extracted with toluene. To the combined toluene layer, the suck dried material obtained above was added and heated to reflux and further concentrated. The concentrated solution was cooled to room temperature and stirred for lh. The solid mass was filtered, washed with toluene and dried to obtain the titled compound (110 g) with 80% yield.
With (acetao)(aqua)(S,S)-N,N′-bis(3,5-di-tert-butylsalicylidene-1,2-cyclohexanediamino)-cobalt(III); water In tetrahydrofuran at 0℃; for 12h; optical yield given as %ee;
Step 4: Preparation of 1-[4-(5R)-Hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenyl]-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl esterTo a solution of 1-(4-benzyloxycarbonylamino-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (2.0 g, 4.9 mmol), in dry THF (15 mL) was added ?BuLi (5.5 mL, 8.8 mmol, 1.6 M solution in hexane) dropwise under nitrogen atmosphere at -78 C. The reaction mixture was stirred at the same temperature for 1 h and then <strong>[60456-26-0](R)-glycidyl butyrate</strong> (0.75 mL, 5.4 mmol) was added dropwise over a period of 5 min. The reaction mixture was stirred at -78 C. for additional 2 h and then warmed to r.t. The progress of reaction was monitored by TLC and on completion, the reaction mixture was quenched with saturated NH4Cl solution (10 mL) and extracted with ethyl acetate (4×20 mL). The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.31:9.69 MeOH:CHCl3) to provide the title compound (1.8 g, 96%) as off white solid.ESIMS (m/z): 373.8 (M-1)
tert-butyl 1'-(4-(benzyloxycarbonylamino)-2-fluorophenyl)-2-oxa-3-azaspiro[bicyclo[2.2.1]heptane-7,4'-piperidine]-3-carboxylate[ No CAS ]
[ 60456-26-0 ]
[ 1380494-51-8 ]
[ 1380494-43-8 ]
Yield
Reaction Conditions
Operation in experiment
85%; 5%
Compound 7 (0.41 g, 0.80 mmol) was dissolved in 4 mL of anhydrous tetrahydrofuran in a 10-mL oven-dried, round-bottomed flask. The solution was cooled to -78 C using dry ice-acetone bath and n-butyl lithium (1.6 M in hexane, 1.0 mL, 1.6 mmol) was added. After stirred at that temperature for 15 min, the solution was treated with <strong>[60456-26-0](R)-glycidyl butyrate</strong> (0.15 mL, 1.0 mmol) and slowly warmed to 25 C. After stirred for additional 2 h, the reaction mixture was quenched with sat. NH4Cl (3 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on a silica gel column (hexanes:ethyl acetate = 1:1) to give 8a (0.32 g, 85%) and 8b (22 mg, 5%) as light yellow oils. 8a: IR (neat, cm-1): 3421 (br), 2968, 2360, 1732, 1516; 1H NMR (500 MHz, CDCl3) delta 7.43 (d, J = 14.2 Hz, 1H), 7.09 (m, 1H), 6.94 (m, 1H), 4.70-4.78 (m, 1H), 4.10-4.32 (m, 2H), 4.08 (m, 2H), 3.93-4.01 (m, 3H), 3.72-3.80 (m, 1H), 2.92-3.14 (m, 4H), 1.74-2.00 (m, 8H), 1.49 (s, 9H); 13C NMR (125 MHz, CDCl3) delta 156.5, 154.6, 154.5, 136.6, 133.1, 119.3, 113.8, 107.4, 83.3, 81.9, 72.8, 64.3, 62.7, 49.4, 46.4, 28.8, 28.2, 28.0, 27.1; HRMS (FAB) calcd for C24H32FN3O6 (M)+: 477.2275; found 477.2293; 8b: IR (neat, cm-1): 2966, 1715, 1517; 1H NMR (600 MHz, CDCl3) delta 7.42 (dd, J = 14.0, 2.4 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.95 (t, J = 9.1 Hz, 1H), 4.85 (m, 1H), 4.38 (dd, J = 12.3, 3.8 Hz, 1H), 4.26-4.34 (m, 3H), 3.78 (dd, J = 8.8, 6.2 Hz, 1H), 3.00-3.12 (m, 4H), 2.32 (t, J = 7.6 Hz, 2H), 1.80-2.00 (m, 8H), 1.62-1.67 (m, 2H), 1.50 (s, 9H), 0.92 (t, J = 7.3 Hz, 3H); 13C NMR (150 MHz, CDCl3) delta 173.2, 156.4, 154.8, 154.0, 136.9, 136.8, 133.0, 119.4, 113.8, 107.5, 105.2, 81.7, 70.0. 63.8, 49.7, 47.2, 35.8, 28.3, 18.3, 13.6. Ester 8b can be converted to 8a by the following procedure: A 10-mL oven-dried, round-bottomed flask was charged with compound 8b (66 mg, 0.12 mmol) and sodium hydroxide (40 mg, 1.0 mmol) in a mixture of THF-H2O 1:1 (4 mL). After stirred at room temperature for 1 h, the solution was neutralized with 1 N HCl and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed sequentially with sat. NaHCO3 (5 mL), brine (5 mL), dried over Na2SO4, filtered, and evaporated under reduced pressure to give 8a in quantitative yield.
Stage #1: C13H17FN4O2 With methanol; lithium tert-butoxide In tetrahydrofuran; N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: (R)-glycidyl butyrate In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 10h;
1.1a
Synthesis of Compound 1aWhile the compound VI (30.5 g, 109 mmol) was put into a mixing solution of THF (300 mL) and DMF (150 mL) and was stirred, MeOH (8.8 mL, 218 mmol) and tBuOLi (26.1 g, 327 mmol) were slowly added thereto over 10 minutes at 0° C., followed by stirring for 20 minutes. (R)-glycidyl butyrate (31.4 mL, 218 mmol) was added to this solution and stirred for 10 hours at room temperature. Sat. NH4Cl (100 mL) was added to this solution and neutralized with 1N HCL, and the reactant was concentrated under reduced pressure. After the resultant was diluted with ethyl acetate (400 mL) and then was washed with distilled water (300 mL). The water layer was extracted again with dichloromethane (300 mL×4). After the organic layer was collected to be dried over Na2SO4, the resultant was filtered, followed by concentration under reduced pressure. Then, the filtrate was triturated with hexane and washed with ethylether. After this solid was heated again in isopropanol, a solid formed by cooling the resultant was filtered, thereby obtaining Compound 1a (22.5 g, 67%) as white solid.1H NMR (600 MHz, DMSO-d6) δ=7.59 (dd, J1=13.8 Hz, J2=2.4 Hz, 1H), 7.33-7.30 (m, 2H), 6.84 (s, 1H), 5.23 (t, J=5.4 Hz, 1H), 4.70 (m, 1H), 4.07 (t, J=9.0 Hz, 1H), 3.82 (m, 1H), 3.71 (t, J=4.8 Hz, 2H), 3.69-3.54 (m, 2H), 2.87 (t, J=4.8 Hz, 2H), 2.61 (s, 3H)LCMS: 309 (M+H+) for C14H17-FN4O3
Step 7 Preparation of 2-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-3-oxazolidiny]phenyl]-hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2'-[1,3]dioxolane] 24.12 g (58.5 mmol) of 2-[4-[[(benzyloxy)carbonyl]amino]-2-fluorophenyl]-hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2'-[1,3]dioxolane] prepared in the step 6 was dissolved in 250 ml of tetrahydrofuran, the temperature was cooled to -78 C., and 44 ml (70.4 mmol) of 1.6 M n-butyllithium was slowly added over 30 minutes. After the reaction mixture was stirred for 1 hour, 9.11 ml (60.0 mmol) of (-)-<strong>[60456-26-0](R)-glycidyl butyrate</strong> was added dropwise over 30 minutes, and the mixture was stirred for 12 hours while raising the temperature to room temperature. After the reaction was completed, the solvent was removed under reduced pressure, 250 ml of ethyl acetate was added, the mixture was washed with a saturated aqueous solution of ammonium chloride and distilled water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to obtain 21.4 g (97%) of the title compound, of which NMR data is as follows. 1H NMR (CDCl3, 300 MHz) delta 7.35 (m, 1H), 7.07 (m, 1H), 6.73 (t, J=9.2 Hz, 1H), 4.72 (m, 1H), 3.99 (part A of AB system, J=8.7 Hz, 1H), 3.94 (part B of AB system, J=8.7 Hz, 1H), 3.92 (s, 4H), 3.76 (m, 2H), 3.30 (m, 2H), 3.21 (m, 2H), 2.81 (m, 2H), 2.10 (dd, J=13.3, 8.3 Hz, 2H), 1.81 (dd, J=13.3, 3.4 Hz, 2H)
General procedure: To a solution of3a(20.018g, 34.60mmol) in tetrahydrofuran (200mL) at-78C under an argon atmosphere was added dropwise 1.58Mn-butyl lithium/n-hexane (24.0mL, 37.92mmol) over 10min. Further <strong>[60456-26-0](R)-glycidyl butyrate</strong> (5.4847g, 38.04mmol) in tetrahydrofuran (10mL) was added dropwise to the reaction mixture over 10min, followed by stirring for 1h at the same temperature. Then the reaction mixture was allowed to come gradually to ambient temperature. Stirring was continued for 21h, then water (300mL) was added, and the aqueous layer was extracted with AcOEt. The combined organic layer was washed with brine, and dried. Evaporation of the solvent followed by silica gel (250g) column chromatography of the residue usingn-hexane/AcOEt (1:1 to 0:1) and CHCl3/MeOH (97:3 to 9:1) as eluents afforded4a(17.489g, 93%). Amorphous solid;1H NMR (CDCl3)delta=1.32-1.52 (9H, m,t-C4H9), 2.46 (1H, br, OH), 3.16-3.60 (6H, m, -CH2-), 3.69-3.80 (1H, m, -CH2-), 3.87-4.27 (5H, m, -CH2-), 4.67-4.77 (1H, m, oxazolidinone-H5), 5.05-5.28 (2H, m, Ar-CH2O), 6.87 (1H, t,J=9.1Hz, Ar-H5), 7.02-7.13 (1H, m, Ar-H6), and 7.27-7.46 (6H, m, Ar-H); EI-LRMSm/z: 544 (M+).
With lithium tert-butoxide; In tetrahydrofuran; methanol; N,N-dimethyl-formamide; at 0 - 20℃; for 3h;
119 g (367 mmol) of Compound XXIX was dissolved in 300 mL of tetrahydrofuran/150 mL of dimethylformamide, 38.19 g (477 mmol) of lithium-t butoxide was slowly added dropwise thereto at 0C, the resulting solution was stirred for 10 minutes, 63 mL (440 mmol) of <strong>[60456-26-0](R)-glycidyl butyrate</strong> and 21 mL (550 mmol) of methanol were added thereto, and the resultant solution was stirred at room temperature for 3 hours. Subsequently, pH of the reaction mixture was adjusted to approximately 6 using an aqueous ammonium chloride solution and then the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in 1000 mL of 80% ethylacetate/hexane, was sequentially washed with water and an aqueous saturated sodium chloride solution (brine), and then dehydrated using anhydrous sodium sulfate, followed by concentration under reduced pressure and column chromatography, to obtain 93 g (320 mmol) of Compound B-I as a white solid (yield: 87%). [0162] 1H NMR (600 MHz, CDCl3) delta 7.53 (m, 2H), 7.15 (dd, J1 = 9.0 Hz, J2 = 2.4 Hz, 1H), 4.77 (m, 1H), 4.00 (m, 3H), 3.77 (m, 1H), 2.10 (t, J = 6.0 Hz, 1H)
87%
Preparation of Compound B-I 119 g (367 mmol) of Compound XXIX was dissolved in 300 mL of tetrahydrofuran/150 mL of dimethylformamide, 38.19 g (477 mmol) of lithium-t butoxide was slowly added dropwise thereto at 0 C., the resulting solution was stirred for 10 minutes, 63 mL (440 mmol) of <strong>[60456-26-0](R)-glycidyl butyrate</strong> and 21 mL (550 mmol) of methanol were added thereto, and the resultant solution was stirred at room temperature for 3 hours. Subsequently, pH of the reaction mixture was adjusted to approximately 6 using an aqueous ammonium chloride solution and then the reaction mixture was concentrated under reduced pressure. The concentrate was dissolved in 1000 mL of 80% ethylacetate/hexane, was sequentially washed with water and an aqueous saturated sodium chloride solution (brine), and then dehydrated using anhydrous sodium sulfate, followed by concentration under reduced pressure and column chromatography, to obtain 93 g (320 mmol) of Compound B-I as a white solid (yield: 87%). [0174] 1H NMR (600 MHz, CDCl3) delta 7.53 (m, 2H), 7.15 (dd, J1=9.0 Hz, J2=2.4 Hz, 1H), 4.77 (m, 1H), 4.00 (m, 3H), 3.77 (m, 1H), 2.10 (t, J=6.0 Hz, 1H)
86.4%
Butyl lithium (2.3M in n-hexanes, 118.3 ml, 0.272 mol, 1.06 eq) was added at -30 C. to anhydrous tert-butanol (25.0 g, 0.53 mol, 2.07 eq) in anhydrous THF (170 ml), under nitrogen. The mixture was stirred for 30 min at -30 C., and was then allowed to warm slowly to 0 C. After 30 min at 0 C., the (4-bromo-3-fluoro-phenyl)-carbamic acid benzyl ester (83 g, 0.256 mol, 1 eq) was added portionwise, keeping the temperature cold, and the mixture was stirred for an additional 30 min at 0 C. To this ice cold mixture, R(-)-glycidyl butyrate (39.7 ml, 0.288 mol, 1.12 eq) were added and the mixture allowed to come gradually to room temperature. The mixture was extracted with saturated sodium chloride solution and the organic phase was dried over MgSO4, filtrated and evaporated. The product was obtained after recrystallisation of the crude product with ethyl acetate, to give (64.1 g, 86.4%).
80%
General procedure: Compound 2 (2 mmol) was dissolved in anhydrous THF (10 mL) then cooled to -78 C under nitrogen followed by slow addition of 1M LHMDS in THF solution (1.7 mL, 1.7 mmol) over 20 min. The resulting mixture was subsequently stirred at -78 C for 1 h before (R)-(-)-glycidyl butyrate (0.24 g, 1.7 mmol) was added drop wise at -78 C and the mixture was stirred at this temperature for 1 h then allowed to gradually warm to room temperature under stirring for 12 hrs. The reaction was quenched with DDW (10 mL) followed by EtOAc (4 mL). Then the two layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then dissolved in DCM (10 mL) and allowed to stand overnight to get a white precipitate which was filtered and washed with DCM.
65%
3.4.la (2.5 g, 7.7 mmol, 1.0 equiv) was dissolved in THE (20 mL) and cooled to -78C. n-BuLi (2.5M in hexane) (0.59 g, 9.3 mmol, 1.2 equiv) was gradually added and the reaction mixture was stirred at -78 C for 1 hour. (R)-oxiran-2-ylmethyl butyrate (1 .33 g, 9.3 mmol, 1.2 equiv) was added and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (80-100 % EtOAc in Hexane) to afford product 3.4.lb which was carry forwarded for next step. (1.46 g, 65% yield). LCMS (mlz): 292.1 [M+H].
45.3%
(4) Preparation of (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxylmethyl)oxazolidin -2-one Benzyl 4-bromo-3-fluorophenylcarbamate (20 g, 61.7 mmol) was dissolved in 180 mL THF, cooled to -78C, and LiHMDS (1.0M in THF, 62.4 mL, 62.4 mmol) was added dropwise within 45 min. After continued to stir for 30 min, R-glycidyl butyrate (2.21 mL, 62.3 mmol) was added dropwise. After continued to react for 1 h at low temperature, it was warmed to room temperature and reacted for 60 h. The reaction was quenched with saturated ammonium chloride. Water was added, and extracted with ethyl acetate. The organic phase was dried, concentrated, and then separated by a silica gel column (petroleum ether : ethyl acetate =2: 1) to obtain 8.1 g of (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxylmethyl)oxazolidin-2-one, at a yield of 45.3 %.
45.3%
Benzyl 4-bromo-3-fluorophenylcarbamate (20 g, 61.7 mmol) was dissolved in 180 mL THF, cooled to -78 C., and LiHMDS (1.0M in THY, 62.4 mL, 62.4 mmol) was added dropwise within 45 min. After continued to stir for 30 min, R-glycidyl butyrate (2.21 mL, 62.3 mmol) was added dropwise. After continued to react for 1 h at low temperature, it was warmed to room temperature and reacted for 60 h. The reaction was quenched with saturated ammonium chloride. Water was added, and extracted with ethyl acetate. The organic phase was dried, concentrated, and then separated by a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain 8.1 g of (R)-3-(4-bromo-3-fluorophenyl)-5-(hydroxylmethyl)oxazolidin-2-one, at a yield of 45.3%.
To a solution of benzyl (4-bromo-3-fluorophenyl)carbamate (50.Og, 154 mmol) inTHF (600 mL) was added lithium tert-butoxide (37.Og, 463 mmol) at 0C. The mixture was stirred at 20C for 2 hours, and then (R)-oxiran-2-ylmethyl butyrate (44.5 g, 309 mmol) at 20Cwas added. The resulting mixture was stirred at 20C for 16 hours, and then concentratedHC1 was added to adjust the pH to 7. The organic solvent was removed under reduced pressure, and the residue was diluted with EtOAc (400 mL), washed with water (400 mL x 2) and brine (500 mL), dried over Na2504, filtered and concentrated to give the crude product, which was purified by column chromatography (5i02, PE: EtOAc = 1: 1) to give the product (R)-3-(4- bromo-3 -fluorophenyl)-5 -(hydroxymethyl)oxazolidin-2-one as a solid.
To the Cbz compound 10a (100 mg, 0.25 mmol) in dry THF (5 mL) at -78 C., n-BuLi 2.0 M (0.15 mL, 0.28 mmol) is added, stirred for 30 min and then glycidylbutyrate 16 (0.04 mL, 0.0.28 mmol) is added drop wise at -78 C., and allowed to stir at 25 C. for overnight. RM is quenched with saturated NH4Cl (5 mL) and extracted with EtOAc (2*10 mL). The organic layer is washed with brine (5 mL), dried and concentrated. The product is purified by column chromatography on silica gel using hexane-EtOAc mixtures to obtain the product as an off-white solid (75 mg) 82% yield. 1H NMR (400 MHz, CDCl3): delta7.11-7.03 (m, 2H), 4.75-4.70 (m, 1H), 3.91-3.87 (m, 3H), 3.74 (t, J=12 Hz, 1H), 3.28 (t, J=6.19 Hz, 4H), 0.09 (s, 6H). 13C NMR (100 MHz, CDCl3): delta 158.7 (dd, J=245.6, 9.7), 154.3, 133.3 (t, J=13.6 Hz), 126.9 (t, J=14.7 Hz), 102.3 (m), 72.7, 62.7, 51.8, 46.2, 15.5, -3.0. ESI-MS: IR (CHCl3): nu 3401, 2401, 1754, 1511, 1252, 1260 cm-1. M.P: 126-128 C. ESI-MS: 379.02 (M+Na).
(R)-5-(hydroxymethyl)-3-(4-methoxybenzyl)oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79.4%
6.1a (3.7 g, 13.6 mmol, 1.0 equiv) was dissolved in THE (40 mL) and cooled to -70C. n-BuLi (2.5M in hexane) (0.96 g, 15.0 mmol, 1.1 equiv) was gradually added and the reaction mixture was stirred at -70 C for 1 hour. (R)-oxiran-2-ylmethyl butyrate (2.16 g, 15.0 mmol, 1.1 equiv) was added drop wise and the reaction mixture was stirred at -70 C for 1 hour. The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated to afford a crude residue. The residue was purified by silica gel column chromatography (50-60 % EtOAc in Hexane) to afford product 6.1b (2.54 g, 79.4 % yield). LCMS (mlz): 238.3 [M+H]. 1H NMR (400 MHz, DMSO) 6 7.20 (d, J = 8.6 Hz, 2H), 7.01 - 6.86 (m, 2H), 5.11 (t, J 5.7 Hz, 1H), 4.50 (d, J= 8.9 Hz, 1H), 4.35-4.17 (m, 2H), 3.74 (d, J = 5.1 Hz, 3H), 3.60-3.49 (m, 1H), 3.47-3.37 (m, 2H), 3.18 (dd, J = 8.5, 6.6 Hz, 1H).
(R)-3-(4-bromophenyl)-5-(hydroxymethyl)oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
General procedure: Compound 2 (2 mmol) was dissolved in anhydrous THF (10 mL) then cooled to -78 C under nitrogen followed by slow addition of 1M LHMDS in THF solution (1.7 mL, 1.7 mmol) over 20 min. The resulting mixture was subsequently stirred at -78 C for 1 h before (R)-(-)-glycidyl butyrate (0.24 g, 1.7 mmol) was added drop wise at -78 C and the mixture was stirred at this temperature for 1 h then allowed to gradually warm to room temperature under stirring for 12 hrs. The reaction was quenched with DDW (10 mL) followed by EtOAc (4 mL). Then the two layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then dissolved in DCM (10 mL) and allowed to stand overnight to get a white precipitate which was filtered and washed with DCM.
65.6%
1.la (6.0 g, 19.6 mmol, 1.0 equiv) was dissolved in THE (60 mL) and cooled to -75 C. nBuLi (1 .51g, 23.5 mmol, 1.2 equiv) was gradually added and the reaction mixture was stirred at -75 C for 1 hour. (R)-oxiran-2-ylmethyl butyrate (2.82 g, 19.6 mmol, 1.0 equiv) was added, the reaction mixture was stirred at -75 C for 1 hour, allowed to attain room temperature, and stirred at room temperature overnight. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (50-60% EtOAc/Hexane) to afford product 1.lb (3.5 g, 65.6 % yield). LCMS (mlz): 274.1 [M+H]. 1H NMR(400 MHz, DMSO d6) 6 7.64 -7.49 (m, 4H), 5.23 (t, J = 5.7 Hz, 1H), 4.71 (td, J = 9.4, 3.7 Hz, 1H), 4.08 (t, J =9.0 Hz, 1H), 3.82 (dd, J= 8.8, 6.2 Hz, 1H), 3.68 (ddd, J 12.3, 5.5, 3.4 Hz, 1H), 3.56 (ddd, J = 12.3, 5.8, 4.1 Hz, 1H).
(R)-5-(hydroxymethyl)-3-(4-((3,5,6-trimethyl pyrazine-2-yl)methoxy)phenyl)oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79.9%
With lithium hexamethyldisilazane; In tetrahydrofuran; at -78 - 20℃; for 24h;Inert atmosphere;
The A2 (1.17g, 3 . 1mmol, preparation method with embodiment 3) for 100 C benzene belt to the water, and then dry the benzene steams. Under the protection of nitrogen injection anhydrous THF (12 ml), at -78 C lower stirring. Slow injection bistrimethylsilyl amino lithium (5.76 ml, 5 . 76mmol), injected several times (more than 10 min), after the completion, stirring for 30 min, then slowly injection <strong>[60456-26-0](R)-glycidyl butyrate</strong> ester (0.66 ml, 4 . 5mmol), after the, in -78 C reaction 1h allowing the reaction system after the natural temperature raising to room temperature, reaction 24h, stop the reaction, add 5 ml saturated NH4Cl solution quenching, using ethyl acetate (40 ml × 3) extraction, crude turns on lathe does under reduced pressure. With acetone: hexane = 1:4 mixed solvent recrystallization, cooling separating white solid; or petroleum ether: acetone = 2:1 as the eluting agent to silica gel column chromatography purification, the white solid obtained 1a (0.85g, 79.9%).
(2R)-3-(4-benzyloxy-3-fluoro-phenylamino)-2-hydroxy-propyl butanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
62 g
In isopropyl alcohol; for 28h;Reflux;
4-Benzyloxy-3-fluoro-aniline (55 g), isopropyl alcohol (550 ml) and (R)-glycidyl butyrate (36.6 g) were taken into a reaction flask at room temperature (25-30C), and the resulting mass was heated to reflux and then stirred for 28 hours at the same temperature. After completion of the reaction, the solvent was distilled under vacuum to obtain a residue. Diisopropyl ether (560 ml) was added to the residue at the room temperature and theresulting solution was heated to reflux, followed by stirring for 15 minutes at the same temperature. The reaction mass was cooled to 25-30C and then stirred for 30 minutes at the same temperature. The separated solid was filtered and then washed with diisopropyl ether (100 ml) to produce 62 g of (2R)-3-(4-benzyloxy-3-fluoro-phenylamino)-2-hydroxy- propyl butanoate (Purity by HPLC: 98.6%).
Methyl (3-fluorophenyl)carbamate (Formula IV, 70 g, Example 1) was dissolved in anhydrous tetrahydrofuran (420 mL) at ambient temperature, and then the solution wascooled to -65C to -60C under nitrogen atmosphere. n-Butyl lithium (1.6 M in hexane, 272 mL) was slowly added to the solution under nitrogen atmosphere, and then the reaction mixture was stirred for 10 minutes. (R)-(-)-Glycidyl butyrate (Formula V, when R1= n-propyl, 60.25 g) was slowly added to the reaction mixture under nitrogenatmosphere at -65C to -60C, and then the mixture was stirred for 20 hours at 20C to25C under nitrogen atmosphere. After completion of the reaction, ammonium chloride solution (7 g in 70 mL of deionized water) was added to the reaction mixture. Tetrahydrofuran was recovered under vacuum at 40C to 45C, followed by the addition of deionized water (500 mL) at 40C to 45C. The reaction mixture was allowed to attainambient temperature and then was stirred for two hours. The solid obtained was filtered, and then washed with deionized water (70 mL). The wet solid was dried at 50C to 55C to afford the title compound.Yield: 72.1 g
benzyl 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenylcarbamate[ No CAS ]
[ 60456-26-0 ]
(5R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3-fluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
To a solution of benzyl4-(3 -thia-8-aza-bicyclo[3 .2.1 ]octan-8-yl)-3 -fluorophenylcarbamate (12) (4.34 g, 11.6 mmol) in THF (10 mL) at - 78 C under a nitrogen gas atmosphere was added n-BuLi (7.3 ml, 17.5 mmol), then the mixture was stirred at -78C for 30 mm, after that the solution of (R)-oxiran-2-ylmethyl butyrate (2.5 g, 17.4 mmol) in THF was added to the mixture at -78C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford (5R)-3 -(4-(3 -thia-8-aza-bicyclo[3 .2.1]Octan-8-yl)-3 -fluorophenyl)-5 -(hydroxymethyl)oxazolidin-2-one (13) (3.03 g, 77%) as a white solid. LC-MS (ESI) m/z = 339 [M+Hfb.
benzyl 4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenylcarbamate[ No CAS ]
[ 60456-26-0 ]
(5R)-3-(4-(3-thia-8-aza-bicyclo[3.2.1]octan-8-yl)-3,5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
To a solution of benzyl4-(3 -thia-8-aza-bicyclo[3 .2.1 ]octan-8-yl)-3 , 5-difluorophenylcarbamate (12) (3.0 g,7.7 mmol) in THF (10 mL) at - 78 C under a nitrogen gas atmosphere was added n-BuLi (4.8 ml, 11.5 mmol), then the mixture was stirred at -78C for 30 mm, after that the solution of (R)-oxiran-2-ylmethyl butyrate (1.66 g, 11.5 mmol) in THF was added to the mixture at -78C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford (5R)-3 -(4-(3 -thia-8-aza-bicyclo[3 .2.1 ]octan-8-yl)-3 , 5-difluorophenyl)-5-(hydroxymethyl)oxazolidin-2-one (13) (2.3 g, 84%) as a white solid.LC-MS (ESI) m/z = 357 [M+H].
(R)-3-(3,5-difluoro-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
To a solution of (7) (1.6 g, 4.6 mmol) in THF (10 mL) at - 78 C under a nitrogen gas atmosphere was added n-BuLi (2.8 ml, 6.8 mmol), then the mixture was stirred at -78C for 30 mm, after that the solution of (R)-oxiran-2-ylmethyl butyrate (980 mg, 6.8 mmol) in THF was added to the mixture at -78C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford (8) (1.2 g, 84%) as a white solid.LC-MS (ESI) m/z = 327 [M+H].
(R)-3-(3-fluoro-4-(2-oxa-6-azaspiro[3.3]heptan-6-yl)phenyl)-5-(hydroxymethyl)oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
84%
To a solution of (7) (1.6 g, 4.7 mmol) in THF (10 mL) at - 78 C under a nitrogen gas atmosphere was added n-BuLi (2.9 ml, 7.0 mmol), then the mixture was stirred at -78C for 30 mm, after that the solution of (R)-oxiran-2-ylmethyl butyrate (1 g, 7.0 mmol) in THF was added to the mixture at -78C, then warmed to room temperature and stirred for overnight, monitored by TLC. Quenched with ammonium chloride, extracted with EA, the organic layer was concentrated under reduced pressure, and the crude material was purified by silica gel column chromatography (DCM: MeOH = 70: 1) to afford (8) (1.2 g, 84%) as a white solid. LC-MS (ESI) m/z = 309 [M+H].
(R)-3-(4-bromo-3-hydroxyphenyl)-5-(hydroxymethyl)oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
90%
General procedure: Compound 2 (2 mmol) was dissolved in anhydrous THF (10 mL) then cooled to -78 C under nitrogen followed by slow addition of 1M LHMDS in THF solution (1.7 mL, 1.7 mmol) over 20 min. The resulting mixture was subsequently stirred at -78 C for 1 h before (R)-(-)-glycidyl butyrate (0.24 g, 1.7 mmol) was added drop wise at -78 C and the mixture was stirred at this temperature for 1 h then allowed to gradually warm to room temperature under stirring for 12 hrs. The reaction was quenched with DDW (10 mL) followed by EtOAc (4 mL). Then the two layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then dissolved in DCM (10 mL) and allowed to stand overnight to get a white precipitate which was filtered and washed with DCM.
(R)-5-(hydroxymethyl)-3-(5-iodopyridin-2-yl)oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
General procedure: Compound 2 (2 mmol) was dissolved in anhydrous THF (10 mL) then cooled to -78 C under nitrogen followed by slow addition of 1M LHMDS in THF solution (1.7 mL, 1.7 mmol) over 20 min. The resulting mixture was subsequently stirred at -78 C for 1 h before (R)-(-)-glycidyl butyrate (0.24 g, 1.7 mmol) was added drop wise at -78 C and the mixture was stirred at this temperature for 1 h then allowed to gradually warm to room temperature under stirring for 12 hrs. The reaction was quenched with DDW (10 mL) followed by EtOAc (4 mL). Then the two layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then dissolved in DCM (10 mL) and allowed to stand overnight to get a white precipitate which was filtered and washed with DCM.
benzyl (4-bromo-3-methoxyphenyl)carbamate[ No CAS ]
[ 60456-26-0 ]
(R)-3-(4-bromo-3-methoxyphenyl)-5-(hydroxymethyl)oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
General procedure: Compound 2 (2 mmol) was dissolved in anhydrous THF (10 mL) then cooled to -78 C under nitrogen followed by slow addition of 1M LHMDS in THF solution (1.7 mL, 1.7 mmol) over 20 min. The resulting mixture was subsequently stirred at -78 C for 1 h before (R)-(-)-glycidyl butyrate (0.24 g, 1.7 mmol) was added drop wise at -78 C and the mixture was stirred at this temperature for 1 h then allowed to gradually warm to room temperature under stirring for 12 hrs. The reaction was quenched with DDW (10 mL) followed by EtOAc (4 mL). Then the two layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then dissolved in DCM (10 mL) and allowed to stand overnight to get a white precipitate which was filtered and washed with DCM.
(R)-2-fluoro-4-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)benzoic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
87%
General procedure: Compound 2 (2 mmol) was dissolved in anhydrous THF (10 mL) then cooled to -78 C under nitrogen followed by slow addition of 1M LHMDS in THF solution (1.7 mL, 1.7 mmol) over 20 min. The resulting mixture was subsequently stirred at -78 C for 1 h before (R)-(-)-glycidyl butyrate (0.24 g, 1.7 mmol) was added drop wise at -78 C and the mixture was stirred at this temperature for 1 h then allowed to gradually warm to room temperature under stirring for 12 hrs. The reaction was quenched with DDW (10 mL) followed by EtOAc (4 mL). Then the two layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then dissolved in DCM (10 mL) and allowed to stand overnight to get a white precipitate which was filtered and washed with DCM.
benzyl (4-((tert-butyldimethylsilyl)oxy)-3-fluorophenyl)carbamate[ No CAS ]
[ 60456-26-0 ]
C16H24FNO4Si[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
94%
General procedure: Compound 2 (2 mmol) was dissolved in anhydrous THF (10 mL) then cooled to -78 C under nitrogen followed by slow addition of 1M LHMDS in THF solution (1.7 mL, 1.7 mmol) over 20 min. The resulting mixture was subsequently stirred at -78 C for 1 h before (R)-(-)-glycidyl butyrate (0.24 g, 1.7 mmol) was added drop wise at -78 C and the mixture was stirred at this temperature for 1 h then allowed to gradually warm to room temperature under stirring for 12 hrs. The reaction was quenched with DDW (10 mL) followed by EtOAc (4 mL). Then the two layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then dissolved in DCM (10 mL) and allowed to stand overnight to get a white precipitate which was filtered and washed with DCM.
benzyl (3-((tert-butyldimethylsilyl)oxy)-4-methoxyphenyl)carbamate[ No CAS ]
[ 60456-26-0 ]
(R)-3-(3-((tert-butyldimethylsilyl)oxy)-4-methoxyphenyl)-5-(hydroxymethyl)oxazolidin-2-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
General procedure: Compound 2 (2 mmol) was dissolved in anhydrous THF (10 mL) then cooled to -78 C under nitrogen followed by slow addition of 1M LHMDS in THF solution (1.7 mL, 1.7 mmol) over 20 min. The resulting mixture was subsequently stirred at -78 C for 1 h before (R)-(-)-glycidyl butyrate (0.24 g, 1.7 mmol) was added drop wise at -78 C and the mixture was stirred at this temperature for 1 h then allowed to gradually warm to room temperature under stirring for 12 hrs. The reaction was quenched with DDW (10 mL) followed by EtOAc (4 mL). Then the two layers were separated and the aqueous layer was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with saturated aqueous sodium chloride (3×5 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was then dissolved in DCM (10 mL) and allowed to stand overnight to get a white precipitate which was filtered and washed with DCM.
Chemistry
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Material Science
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