D-erythro-Hexonic acid, 2,4-dideoxy-3,5-O-(1-methylethylidene)-, 1,1-dimethylethyl ester, 6-acetate

White or grey white solid powder

The compound of formula (I-1){Tert-butyl 2 - ((4R, 6S) -6- (hydroxymethyl) -2, 2-dimethyl-1, 3-dioxan-4-yl) acetate}(1.0 g, 3.84 mmol, Jiangsu Alpha Pharmaceutical) was dissolved in 10 ml of methylene chloride (MC), pyridine (0.9 g, 11.52 mmol) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes.Acetyl chloride (0.66 g, 8.45 mmol) was added and the mixture was stirred at room temperature for 1 hour. 10 ml of water was added to the reaction mixture, and the mixture was stirred for 10 minutes, and the organic layer was separated. After 5 ml of methylene chloride was extracted twice, 10 ml of water was added thereto, followed by stirringThe organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and distilled under reduced pressure to obtain 0.98 g (yield: 86percent) of the compound of the formula I-2 in the form of a pale pink crystal.The 2 - ((4R, 6S) - 6-chloromethyl -2, 2-dimethyl -1, 3-dioxan-4-yl) acetic acid T-butyl ester (27.8g, 0 . 1mol) dissolved in 30mLN, in N-dimethyl formamide, adding sodium acetate (13.1g) and CuCl (1.3g), then heating to 120-130 °C stirring reaction 24h. Concentrated under reduced pressure, is added to the residues 280 ml normal heptane and increasing the temperature to 50-60 °C stirring 30 minutes. The filtering, and with normal heptane washing the filter cake, CuCl recycled, combining the filtrate. Saturated salt water for washing, separating, organic phase is concentrated under reduced pressure, the crude product is dissolved in 50 ml in normal heptane of heat, of a kind of white crystallized to obtain solid 29.4g, yield 97.6percent.In a flask were sequentially added 130 mL of N, N-dimethylformamide, 587.28 g of intermediate IV, 345.8g of sodium acetate, 23.4g of tetrabutyl ammonium bromide, the reaction was heated at 120 ° C for 4h;Until the HPLC test intermediates residual <0.5percent, the reaction was stopped; the system was cooled to 20 ~ 50 , stirred for 1 ~ 2h, 150g of water was added, 880g of petroleum ether, stirred at 20 ~ 50 0.5h, The organic phase was washed twice with 305 g * 2 of 10percent hydrochloric acid, 100 g of activated carbon was added, and the temperature was raised to 50-70 ° C. and stirred for 3-4 h.After filtration hot filtrate cooled to 0 ~ 10 ° C, stirring crystallization, and then filtered to obtain crude ADA.To ADA crude product was added 880g petroleum ether, 100g of activated carbon, stirring 50 ~ 70 3 ~ 4h, Filtration, the filtrate was cooled to 0 ~ 10 ° C, stirred crystallization, and filtered to give ADA boutique 542.97g, yield 85.1percent, HPLC purity of 99.83percent.30 g of the compound of formula 5 is dissolved in 200 ml of toluene, and 35 g of 2, 2-dimethoxypropane is added.The temperature was lowered to about 0 degrees, 0.3 g of methanesulfonic acid was added, and the reaction was stirred at 0 to 5 degrees for 4 hours.After the reaction, 100 ml of sodium hydrogencarbonate solution was added to adjust pH=8, and the layers were allowed to stand, and the aqueous layer was extracted once with 60 ml of toluene.The organic layers were combined, washed with 100ml of saturated brine. The organic layer was concentrated under reduced pressure and temperature within 80 degrees to dryness, to the residue was added 100ml of n-hexane, After heating and dissolving, 1 g of activated carbon was added for decolorization, and the mixture was filtered with a small amount of hot n-hexane. The combined filtrate was stirred and cooled to about 0 degree to be crystallized for 5 hours.After suction filtration, the cake was dried under reduced pressure at 50 °C to obtain 30.5 g of a pure white solid, that is, a compound of the formula 1 in a yield of 88.1percent, and a GC purity of 99.2percent.A mixture of 35.0 g of t-butyl (4R-cis)- (6-chloromethyl)-2, 2-dimethyl- 1, [3-DIOXANE-4-YL-ACETATE, ] 14.8 g of tetrabutyl phosphonium bromide, 16.0 g of potassium acetate and 5.9 g of toluene were heated to [105 °C] under reduced pressure. After 22 hours at this temperature the reaction mixture was cooled to ambient temperature after which 400 g of heptane and 350 g of water were added. The organic phase was washed with 150 g of water and subsequently treated with 3.0 g of activated carbon. After filtration of the carbon, the solution was concentrated and subsequently cooled to-10 °C after which crystallised product was isolated by means of filtration. Yield 24.9 g (76percent) of a white crystalline materialExample 8 - Preparation of tert-butyl 2-[(4R, 6S)-2, 2-dimethyl-6-[(rnethyl- carbonyloxy)methyl]-1 , 3-dioxan-4-yl]acetate from tetra-n-butyl ammonium acetateIn a 100ml_ round vessel was added crude tert-butyl 2-[(4R, 6S)-6-(chloromethyl)- 2, 2-dimethyl-1 , 3-dioxan-4-yl]acetate (5.0g) and tetra-n-butyl ammonium acetate (4.3g). The mixture was heated to 115°C and became liquid at ~50°C. The mixture was heated for 7 hours.Heptane (15mL) was added to the reaction and the mixture stirred for 5 minutes at 70°C before decanting the heptane phase. The mixture was further extracted with heptane (2 x 10ml_) at 70°C. The combined heptane extracts were washed with water (10mL) and then filtered through a bed of celite filter aid. The heptane filtrate was partially evaporated then cooled to -10°C. The pale yellow crystals were filtered and dried, yield = 1.1g with a purity of 99.1 percent by HPLC.To a solution of ieri-butyl 2-((4R, 6S)-6-(chloromethyl)-2, 2-dimethyl-l, 3-dioxan-4- yl)acetate (10 g) in NMP (300 mL) was added tetra butyl ammonium acetate (30 g) at 25°C. Resulting reaction mixture was heated to 95°C and stirred for 24 h. After cooling to room temperature, water (450 mL) was added and then extracted with n-heptane (3 X 150 mL). To the combined organic layer was added activated charcoal (1 g) and stirred for 5 h, filtered the activated charcoal and filtrate was concentrated to obtained crude product, which was further recrystallized from n-heptane to obtain off white solid material (7.2g, 99.2percent GC purity and 99.5percent de). Gas Chromatographic system: Instrument : Gas Chromatograph equipped with FID detector. Column : DB-5, length: 30 mtr. , Dia.: 0.53mm, 5.0μιη Capillary Column. Detector : Flame Ionization Detector. Carrier gas : Nitrogen. Gas Chromatograph parameters: Carrier gas pressure : 8.0 psi. Detector Temperature : 280°C Injector Temperature : 280°C Injection volume Split ratio Retention time: Approximate retention time for compound [XI] is about 12.0 minTo a solution of tert-b tyl 2-((4R, 6S)-6-(chloromethyl)-2, 2-dimethyl-l, 3-dioxan-4- yl)acetate (10 g, 60percent de) in NMP (300 mL) was added tetra butyl ammonium acetate (30 g) at 25°C. Resulting reaction mixture was heated to 85°C and stirred for 24 h. After cooling to room temperature, water (450 mL) was added and then extracted with n- heptane (3 X 150 mL). To the combined organic layer was added activated charcoal (1 g) and stirred for 5 h, filtered off the activated charcoal and filtrate was concentrated to obtained product as off white solid material (7.2g, 65percent de).

Molecular Weight:302.36
XLogP3:1.6
Hydrogen Bond Acceptor Count:6
Rotatable Bond Count:7
Exact Mass:302.17293854
Monoisotopic Mass:302.17293854
Topological Polar Surface Area:71.1
Heavy Atom Count:21
Complexity:382
Defined Atom Stereocenter Count:2
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes