* 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.
170g of emtricitabine hydrochloride II (HPLC purity of 99.96percent), adding methanol 850mL, heating to 50 ~ 60 dissolved, cooling to 15 ~ 25 , adding dropwise 62g of triethylamine added about 6 ~ 8 minutes.The mixture was stirred at 15-25 ° C for 1 hour, concentrated in vacuo to remove methanol, 700 mL of methylene chloride was added and the mixture was stirred at 20-25 ° C for 1 hour.Filter, filter cake was added 500mL dichloromethane, atStirred at 20-25 ° C for 1 hour, filtered and the filter cake was washed twice with 250 mL of methylene chloride.138 g Emtricitabine I was obtained by vacuum drying at -0.08 ~ -0.1 MPa and 50 ~ 60 for 6 ~ 12 h. The HPLC purity was 99.94percent. The maximum single impurity was 0.04percent. The residue on ignition was 0.03percent. The yield was 93.2percent.
82%
With triethylamine In methanol at 25 - 65℃; for 0.25 h; Heating / reflux
Emtricitabine hydrochloride (100 g) was dissolved in methanol (500 ml). The mixture was stirred for 15 mins. Triethylamine (80 g) was added to the solution at 25- 35°C. The solution was heated to reflux and maintained at reflux temperature 60- 65°C for 60 mins. The reaction mass was cooled to 25-35°C and decolourised with activated carbon at 25-35°C. Filtrate was distilled under vacuum to thick residue below 500C. The mass was cooled to 25-35°C. Traces of methanol was removed by flushing with methylene chloride (100 ml). Methylene chloride was charged to the residue and heated to reflux. Reaction mass was maintained at reflux temperature for 2 hrs. The suspension was cooled to 250C. The reaction mass was maintained at 25- 35°C for 1 hr. Solid was collected by filtration and leached with methylene chloride (200 ml) and washed with methylene chloride (100 ml). The solid was dried at 45- 5O0C to get Emtricitabine (67 gm, 82percent). This technical grade Emtricitabine can be decolourised in IPA to get pharmaceutically accepted quality productWhile this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention
Reference：
[1] Patent: CN106478618, 2017, A, . Location in patent: Paragraph 0071; 0072; 0073-0074
[2] Patent: WO2009/84033, 2009, A2, . Location in patent: Page/Page column 10
[3] Patent: WO2011/107920, 2011, A1, . Location in patent: Page/Page column 13
[4] Organic Process Research and Development, 2006, vol. 10, # 3, p. 670 - 672
2
[ 764659-72-5 ]
[ 143491-57-0 ]
Yield
Reaction Conditions
Operation in experiment
70%
With sodium tetrahydroborate; dipotassium hydrogenphosphate; water; sodium hydroxide In ethanol at 20℃;
Potassium hydrogen phosphate (26.91 g, 117.9 mmol) was added to water (43 ml), stirred and dissolved,(2R, 5S) - (5-fluorocytosidin-1-yl) -1,3-oxathiolane-2-carboxylic acid L-menthyl ester (15 g, 37.5 mmol)Ethanol (106 ml) was added.Sodium borohydride (3 g, 79 mmol) was added dropwise at room temperature,Of 0.12 mol / L aqueous sodium hydroxide solution (14.4 ml).After completion of the dropwise addition, the mixture was stirred at room temperature until the reaction was complete. Static stratification.The organic layer was separated, adjusted to pH = 4 with 6 mol / L hydrochloric acid, and adjusted to pH 7 with 2 mol / L aqueous sodium hydroxide solution.Concentrated under reduced pressure. To the resulting residue was added water (200 ml) and washed with toluene (3 x 110 ml). Salicylic acid (5.19 g, 37.5 mmol) was added and the mixture was heated to 70-80 ° C.Inoculated, cooled to room temperature and filtered, dried in vacuo (80 ° C, 4 h)Deltamethasone salicylate (10.1 g, yield 70percent): Moisture (Karl Fischer Titration) 0.35percent
65%
Stage #1: With sodium tetrahydroborate In methanol at -5℃; for 5 h; Inert atmosphere Stage #2: With isopropyl alcohol In water at 60℃; for 1 h; Stage #3: With methanol In water
Example 1; Preparation of emtricitabine via B(0'Pr)3 A suspension of (2R,5S)-((1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl) 5-(4-amino-5- fluoro-2-oxopyrimidin-1 (2H)-yl)-1 ,3-oxathiolane-2-carboxylate (30.0 g) in MeOH (300 mL) was cooled to -7 °C under a nitrogen atmosphere. Then, NaBH4 (6.8 g) was added in portions for 1 h and the reaction mixture was stirred at -5 °C for 5 h. The resulting solution was heated to 5°C, water (105 mL) was added and was slowly titrated to pH 5.5 with 35percent aqueous H CI solution at 1 0 °C . The solution was concentrated under reduced pressure to 140 mL total internal volume. Toluene (90 mL) was added and the layers were separated after 10 min stirring. The aqueous phase was washed again with toluene (2 x 90 mL) and, after phase separation, neutralized (pH 7.5) with 25percent aqueous NaOH solution. Part of the solvent was evaporated under reduced pressure until reaching a internal volume of 60 mL. Celite (6 g) was charged to the aqueous solution and the mixture stirred for 5 min. Isopropanol (300 mL) was added and the solvent was evaporated under reduced pressure until the residual volume reached 75 mL. This last operation was repeated twice. Isopropanol (470 mL) was added and the suspension was heated to 60 °C, stirred for 1 h, filtered while hot and washed with hot isopropanol (2 x 30 mL). The filtrate and washing were combined and partially concentrated under reduced pressure to 75 mL total internal volume. MeOH (1 50 m L) was charged and the mixture was concentrated under reduced pressure to 75 mL, thus removing the boron species. Isopropanol (300 mL) was added and the solvent was evaporated under reduced pressure to 160 total internal volume. The suspension was heated to 80 °C and water (6 mL) was added . The resulting solution was cooled to 60 °C, seeded, stirred for 1 h at 60 °C, cooled to 0 °C and held at this temperature for 1 h. The solid was collected by filtration, washed with chilled isopropanol (2 x 15 mL) and dried in vacuo (40 °C) to give 12.1 g of emtricitabine (65percent yield; purity by H PLC 99.77 area percent; assay by H PLC 99.8percent w/w; boric acid and chloride not detected by capillary electrophoresis).
65%
at -7 - -5℃; for 6 h; Inert atmosphere
A suspension of (2R,5S)-((1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl) 5-(4-amino-5-fluoro-2-oxopyrimidin-1(2H)-yl)-1,3-oxathiolane-2-carboxylate (30.0 g) in MeOH (300 mL) was cooled to -7 °C under a nitrogen atmosphere. Then, NaBH4 (6.8 g) was added in portions for 1 h and the reaction mixture was stirred at -5 °C for 5 h. The resulting solution was heated to 5°C, water (105 mL) was added and was slowly titrated to pH 5.5 with 35percent aqueous HCl solution at 10 °C. The solution was concentrated under reduced pressure to 140 mL total internal volume. Toluene (90 mL) was added and the layers were separated after 10 min stirring. The aqueous phase was washed again with toluene (2 x 90 mL) and, after phase separation, neutralized (pH 7.5) with 25percent aqueous NaOH solution. Part of the solvent was evaporated under reduced pressure until reaching a internal volume of 60 mL. Celite (6 g) was charged to the aqueous solution and the mixture stirred for 5 min. Isopropanol (300 mL) was added and the solvent was evaporated under reduced pressure until the residual volume reached 75 mL. This last operation was repeated twice. Isopropanol (470 mL) was added and the suspension was heated to 60 °C, stirred for 1 h, filtered while hot and washed with hot isopropanol (2 x 30 mL). The filtrate and washing were combined and partially concentrated under reduced pressure to 75 mL total internal volume. MeOH (150 mL) was charged and the mixture was concentrated under reduced pressure to 75 mL, thus removing the boron species. Isopropanol (300 mL) was added and the solvent was evaporated under reduced pressure to 160 total internal volume. The suspension was heated to 80 °C and water (6 mL) was added. The resulting solution was cooled to 60 °C, seeded, stirred for 1 h at 60 °C, cooled to 0 °C and held at this temperature for 1 h. The solid was collected by filtration, washed with chilled isopropanol (2 x 15 mL) and dried in vacuo (40 °C) to give 12.1 g of emtricitabine (65percent yield; purity by HPLC 99.77 area percent; assay by HPLC 99.8percent w/w; boric acid and chloride not detected by capillary electrophoresis).
62%
With sodium tetrahydroborate; dipotassium hydrogenphosphate; water In isopropyl alcohol at 15 - 20℃;
To a 2.0 L capacity jacketed flask equipped with a mechanical stirrer, thermometer pocket, dipotassium hydrogen phosphate (147. lg) and water (330ml) was charged and stirred the reaction mixture for 15 minutes. To the reaction mixture then charged isopropyl alcohol (800ml) and further stirred for 15 minutes and cooled the reaction mixture to a temperature of 15°C to 20°C. Then charged FCME (lOOg) dissolved in isopropyl alcohol (100ml) to the reaction mixture and stirred at a temperature of 15°C to 20°C for 1 hour. A separately prepared solution of sodium borohydride (26g) dissolved in aqueous sodium hydroxide was added dropwise to the reaction mixture over the period of 1-1.5 hours. The reaction mixture further stirred for 4 - 5 hours and the two layers formed were separated. To the separated organic layer 20percent (v/v) dilute hydrochloric acid (4.6ml) was added dropwise to adjust the pH to 8.0-8.5 and the reaction mixture was further stirred for 15 minutes. The reaction mixture was then distilled out and the aqueous solution obtained was extracted with toluene (200ml). The reaction mixture then treated with charcoal (5g) and filtered. The filtrate obtained was distilled out to obtain a liquid and diluted with isopropyl alcohol (200ml), distilled out the isopropyl alcohol. Diluted the reaction mixture again with isopropyl alcohol (200ml) and distilled out. The reaction mixture further diluted with isopropyl alcohol (400ml) and refluxed the reaction mixture to a temperature of 85°C to 90°C for 30 minutes to obtain the residue. Cooled the reaction mixture and filtered, the filtrate obtained was then distilled out to obtain the residue. Diluted the residue obtained with ethanol (100ml) and distilled out. The reaction mixture again diluted with ethanol (200ml) and heated at a temperature of 85°C to 90°C for 30 minutes and then cooled at a temperature of 10°C to 15°C to precipitate the product, emtricitabine. The resulting product was filtered and washed with ethanol. Dry the product under vacuum.Yield = 62percentAssay = 98.7percentPurity = 99.86percent
57.4%
Stage #1: With dipotassium hydrogenphosphate In denaturated spirit; water at 15 - 30℃; for 0.5 h; Stage #2: With sodium tetrahydroborate; water In denaturated spirit; water at 15 - 30℃; for 2 h; Stage #3: With hydrogenchloride In water
Example 4: Preparation of EmtricitabineDenatured spirit (210 mL) and menthyl emtricitabine (24.5 g) were charged at 25- 30 0C. The mixture was cooled to 15-20 0C and charged with a solution of dipotassium hydrogen phosphate (30 g) and water (30 mL) at 25-300C and stirred for 0.5 hour at 25-30 0C. The stirred mixture was cooled to 15 0C and charged with sodium borohydride (4.66 g) and deionized water (30 mL) over 1.5 hour maintaining the temperature of the reaction mixture below 25 0C. The reaction mixture was stirred at the same temperature till the level of menthyl emtricitabine was less than 0.5 percent as measured by High Performance Liquid Chromatography. The reaction mixture was allowed to stand for 0.5 hour at 25-30 0C. The organic layer was separated and the pH adjusted to 7.2 with concentrated hydrochloric acid (0.5 mL) at 25-30 0C. To the resultant mixture activated carbon (3 g) was added at 25-30 0C. The mixture was stirred for 0.5 hour, filtered through hyflo bed and washed with denatured spirit (30 mL) at 25-30 0C. The stirred mixture was concentrated under vacuum (720 mmHg) at 45 0C to an oily residue. The residue was charged with absolute ethanol (75 mL) and the resultant mass was concentrated under vacuum (720 mm Hg) at 45 0C to a foamy residue. The foam was charged with absolute ethanol (75 mL) and the resultant mass was concentrated under vacuum (720 mmHg) at 45 0C to a foamy residue. The residue was charged with absolute ethanol (60 mL) at 25-30 0C and the temperature of the resultant mixture raised to 78 0C and the mixture was refluxed for 0.5 hour. The mixture was cooled slowly to 60 0C in 1 hour and stirred for 1 hour at 60 0C and further cooled to 25-30 0C in 1 hour and stirred at the same temperature for 4 hours. The solid so obtained was filtered, washed with ethyl acetate (30 mL) at 25- 30 0C and dried under vacuum at 40-45 0C for 12 hours to afford the title compound. Yield: 8.6 g (57.4percent) Purity: 99.65 percent (by HPLC)
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