N-[(1,1-Dimethylethoxy)carbonyl]-O-methyl-D-serine

A solution of N-Boc-D-serine (22g, 0.107 mol) in dry tetrahydrofuran (352ml) was cooled to °C and the reaction mixture aged at 0-5A suspension of N-Boc-D-serine (22g, 0.107 mol) and tetrabutylammonium bromide (1.3g, 0.004mol) in toluene (110ml) was cooled to <10The above prepared compound of formula I (20.5g, 0 . 100mol) cooling the aqueous solution to 0-10°C. Maintain 0-10°C, at the same time by adding drops of sulfuric acid dimethyl ester (50.5g, 0 . 400mol) and 50percent sodium hydroxide (36.0g, 0 . 450mol), reaction mixture in 0-10 °C reaction 6 hours. After the reaction, the reaction liquid maintain 0-10°C, with 50percent citric acid dyeworks to pH= 2-3, then with dichloromethane (1×123 ml, 2×82 ml) to extract and after drying with anhydrous sodium sulfate is distilled under reduced pressure to dry obtains the type compound II 21.9g (yield 100percent, HPLC purity 92.9percent, chiral purity 98.0percent).Synthesis of (R)-2-N-Boc-amino-3-methoxypropanoic acid[0155] A suspension of N-Boc-D-serine (17.6 g, 86 mmol) and tetrabutylammonium bromide (1.04 g, 3.23 mmol) in toluene (90 mL) was cooled with an ice-bath with stirring. To the reaction mixture was added 20percent sodium hydroxide (14 mL, 86 mmol) and the resulting mixture was stirred for thirty minutes. Dimethyl sulphate (43.3 g, 343 mmol) and 50percent sodium hydroxide (20.3 mL, 388 mmol) were added and the reaction mixture was stirred at < 10 °C for 3 hours. Water (60 ml) was then added to the mixture and the resulting two phases were separated. The aqueous phase was washed with dichloromethane (100 mL x 2). The aqueous phase was then acidified to a pH of <3.5 with 50percent citric acid and extracted with methylene chloride (100 mL Into a 2 L, four-necked RB flask was charged 90 ml of water and 40 g of sodium hydroxide. D-Serine is added to the solution at 20-25° C. Boc anhydride (150 g) is slowly added to the reaction mass keeping the temperature below 20° C. To a stirred aqueous solution of sodium hydroxide (23.1 g of NaOH in 150 ml of water) was added D-serine (30 g) lot wise at 2G-25°C and BOC anhydride (74.7 g) at 10-15°C. The traction mixture was stirred at 20-25 Methyl N-(tert-butoxycarbonyl)-O-methyl-D-serinate (2.0 g, 85. 7 mmol) was dissolved in tetrahydrofuran (40 ml) and water (20 ml) and lithium hydroxide mono hydrate (1. 8 g, 42.9 mmol) added. The mixture was stirred for 4 hours at room temperature, concentrated under reduced pressure to remove most of the tetrahydrofuran and then acidified by the addition of concentrated hydrochloric acid. The solution was extracted with ethyl acetate (three times). The combined organics were dried (MgS04), filtered and evaporated under reduced pressure to give N-(tert-butoxycarbonyl)-O-methyl-D-serine (1.9 g, 100percent) as a colourless oil; IH NMR spectrum : (DMSO d6) 1.37 (s, 9H), 3.23 (s, 3H), 3.53 (m, 2H), 4. 18 (m, 1H), 6.87 (d, 1H), 12.60 (brs, 1H).In a 1000 mL three-necked flask, 400 mL of toluene and 40 g of N-tert-butoxycarbonyl-D-serine (Boc-D-serine)The stirring temperature was lowered to 0-5 ° C, 36.5 g of 30percent potassium hydroxide solution was added dropwise.After stirring for 30 minutes, Then 72.65 g of methyl p-toluenesulfonate was added, Tetrabutylammonium bromide 4g, Then 43.68 g of 50percent potassium hydroxide solution was added dropwise.After reaction at 0-5 ° C for 8 hours, Add water 200mL and layered, The aqueous layer was washed with 100 mL of toluene, Discard the organic layer.The combined aqueous layers were then cooled to below 15 [deg.] C and acidified with 50percent phosphoric acid to pH = 2-3.5, Extraction with dichloromethane (200 mL * 3)The combined organic layers were added 30g of anhydrous sodium sulfate and stirred overnight.The next day filterThe filtrate was concentrated to dryness under reduced pressure, 42.9 g of light yellow oil, Yield: 100percent, HPLC purity: 98.0percent, Chiral purity: 99.4percent.The above prepared compound of formula I (20.5g, 0 . 100mol) cooling the aqueous solution to 0-10°C, maintain 0-10°C, drop at the same time add iodomethane (28.4g, 0 . 20mol) and 50percent sodium hydroxide (36.0g, 0 . 450mol), reaction mixture in 0-10 °C reaction 6 hours, after the reaction, the reaction liquid maintain 0-10°C, with 50percent citric acid dyeworks to pH= 2-3, then with dichloromethane (1×123 ml, 2×82 ml) extraction and drying with anhydrous sodium sulfate, then distilled under reduced pressure to dry obtains the type compound II 21.9g (yield 100percent, chiral purity 98.5percent).The above prepared compound of formula I (20.5g, 0 . 100mol) cooling the aqueous solution to 0-10C, maintain 0-10C, drop at the same time add iodomethane (28.4g, 0 . 20mol) and 50% sodium hydroxide (36.0g, 0 . 450mol), reaction mixture in 0-10 C reaction 6 hours, after the reaction, the reaction liquid maintain 0-10C, with 50% citric acid dyeworks to pH= 2-3, then with dichloromethane (1×123 ml, 2×82 ml) extraction and drying with anhydrous sodium sulfate, then distilled under reduced pressure to dry obtains the type compound II 21.9g (yield 100%, chiral purity 98.5%).Preparation of (R)-2-((tert-butoxy)carbonylamino)-3-methoxypropanoic acidTetrahydrofuran (350 ml), sodium hydride (40 gm) and imidazole (5 gm) were added and then cooled to 0 to 5C. To the reaction mixture was added a solution N-Boc- D-serine (100 gm) in tetrahydrofuran (900 ml) for 30 minutes and then maintained for 30 minutes at 0 to 5C. Methyl iodide (85 gm) was added to the reaction mixture and then maintained for 30 minutes. The temperature of the reaction mass was raised to room temperature and maintained for 2 hours. To the reaction mass was added methanol (50 ml) and then concentrated to obtain a residual mass. To the residual mass was added water (1000 ml) and then the layers were separated. The pH of the aqueous layer was adjusted to 2.8 with aqueous citric acid (50%) and extracted with methylene chloride. Then concentrated to obtain a residual solid of (R)-2-((tert-butoxy)carbonylamino)-3- methoxypropanoic acid (75 gm).1, 1'-carbonyldiimidazole (1.9 g) was added to a dichloromethane solution (10 ml) containing In a 1000 mL three-necked flask, 400 mL of toluene and 40 g of N-tert-butoxycarbonyl-D-serine (Boc-D-serine)The stirring temperature was lowered to 0-5 C, 36.5 g of 30% potassium hydroxide solution was added dropwise.After stirring for 30 minutes, Then 72.65 g of methyl p-toluenesulfonate was added, Tetrabutylammonium bromide 4g, Then 43.68 g of 50% potassium hydroxide solution was added dropwise.After reaction at 0-5 C for 8 hours, Add water 200mL and layered, The aqueous layer was washed with 100 mL of toluene, Discard the organic layer.The combined aqueous layers were then cooled to below 15 [deg.] C and acidified with 50% phosphoric acid to pH = 2-3.5, Extraction with dichloromethane (200 mL * 3)The combined organic layers were added 30g of anhydrous sodium sulfate and stirred overnight.The next day filterThe filtrate was concentrated to dryness under reduced pressure, 42.9 g of light yellow oil, Yield: 100%, HPLC purity: 98.0%, Chiral purity: 99.4%.42.9 g of Compound II was dissolved in 400 mL of anhydrous methanol, Cooled to 0-5 C, Thionyl chloride was added dropwise at this temperature 50g, The reaction was stirred for 2 hours until the temperature reached to room temperature.Some solvents were distilled off under reduced pressure, When the remaining amount is 50 g, Under stirring, dry ethyl acetate (400 mL) was added.After stirring for 30 minutes, filter, The filtrate was concentrated to dryness under reduced pressure, 32.5g of white solid was obtained.Yield: 89.2%, HPLC purity: 98.2%.