* 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 hydrogenchloride In water at 20 - 30℃; for 7 h;
in room temperature,Hydrochloric acid (21 mL, 21 mmol, 1 M) was added(3aS, 3bR, 7aS, 8aS) -2,2,5,5-tetramethyltetrahydro-3aaH- [1,3] dioxolo [4 ', 5': 4,5] Furo [3,2-d] [1,3] dioxane 1b (110 g, 477.72 mmol)In aqueous solution (450 mL),The resulting reaction was stirred at room temperature for 7 hours.The mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution,And concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (600 mL)The insoluble matter was removed by filtration,The filter cake was washed with ethyl acetate (100 mL x 3), the filtrates were combined, concentrated under reduced pressure,To give the title compound 1c as a yellow oil (70.0 g, 77.0percent).
Reference:
[1] RSC Advances, 2016, vol. 6, # 46, p. 39758 - 39761
[2] Tetrahedron, 1981, vol. 37, p. 1685 - 1690
[3] Patent: CN106892948, 2017, A, . Location in patent: Paragraph 0188; 0189; 0190; 0191
[4] Helvetica Chimica Acta, 1938, vol. 21, p. 263,267
[5] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 4-7, p. 703 - 706
[6] Tetrahedron, 1988, vol. 44, # 15, p. 4721 - 4736
[7] Collection of Czechoslovak Chemical Communications, 2006, vol. 71, # 7, p. 1063 - 1087
[8] Patent: US2009/30198, 2009, A1, . Location in patent: Page/Page column 7
[9] Patent: US2010/16422, 2010, A1, . Location in patent: Page/Page column 4
[10] Collection of Czechoslovak Chemical Communications, 2011, vol. 76, # 5, p. 503 - 536
[11] Patent: WO2012/140596, 2012, A1, . Location in patent: Page/Page column 54-55
2
[ 609-06-3 ]
[ 67-64-1 ]
[ 114861-22-2 ]
Yield
Reaction Conditions
Operation in experiment
86%
Stage #1: at 20 - 24℃; for 17.25 h; Industry scale Stage #2: With hydrogenchloride In water at 20℃; for 6 h;
6. EXAMPLES Aspects of this invention can be understood from the following examples.6.1. Synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro [2.3-d][13]dioxol-5-yl)(morpholino)methanone To a 12L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(-)-xylose (504.40 g, 3.360 mol), acetone (5L, reagent grade) and anhydrous MgSO4 powder (811.23g, 6.740 mol / 2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO4 (50 mL, 0.938 mol / 0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24°C over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all L-xylose had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH = 8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50percent w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wtpercent water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23g, 86percent yield, 96.7 areapercent pure by GC). 1H NMR (400 MHz, DMSO-d6)δ1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93 - 4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). 13C NMR (101MHz, DMSO-d6) δ26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73. To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H2O (125 mL, 5X) was added NaHC03 (33.0g, 3.0 equiv), NaBr (2.8g, 20 molpercent) and TEMPO (0.40g, 2 molpercent) at 20°C. The mixture was cooled to 0-5°C and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20°C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20°C for 1h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2X). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0g, 79percent). 1H NMR (methanol-d4), δ 6.00 (d, J= 3.2 Hz, 1H), 4.72 d, J= 3.2 Hz, 1H), 4.53 (d, J= 3.2 Hz, 1H), 4.38 (d, J= 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H). To a solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (5.0g, 24.5 mmol) in THF (100 mL, 20X) was added TBTU (11.8g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20°C for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20°C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64percent) as a white solid. 1H NMR (CDCl3), 8 6.02 (d, J= 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J= 3.2 Hz, 1H), 4.58 (d, J= 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
Reference:
[1] Patent: EP2332947, 2011, A1, . Location in patent: Page/Page column 6-7
[2] Nucleosides and Nucleotides, 1995, vol. 14, # 3-5, p. 611 - 617
[3] Organic Letters, 2002, vol. 4, # 22, p. 3951 - 3953
[4] Bioorganic and Medicinal Chemistry, 2008, vol. 16, # 22, p. 9830 - 9836
3
[ 41546-31-0 ]
[ 67-64-1 ]
[ 114861-22-2 ]
Yield
Reaction Conditions
Operation in experiment
97.79%
at 0℃; for 6 h;
Taking a 500 ml three-neck bottle, by adding L-xylose (20g, 133mmol), acetone (300 ml), cooled to 0 °C, stirring next adds by drops 20 ml concentrated sulfuric acid, 0 °C stirring under 6h, reaction liquid clarification, lower the temperature to -10 °C, by adding 1M (in other words 1mol/L) NaOH solution to adjust the pH to neutral, evaporate acetone, saturated salt water, EA (ethyl acetate) extraction, drying, colorless oily liquid shall turns on lathe does, as a single will protect the xylose (compound 1) with the double will mixture of protection of xylose. The mixture is dissolved in 100 ml methanol, add 50 ml water, 40g732-type cation exchange resin, stirring the mixture at room temperature for one day, filtration, filtrate bombycinous oily liquid product shall turns on lathe does 24.77g, that is, for the compound 1, yield 97.79percent.
58 g
at 25℃; for 2.5 h;
To amixture of (3S, 4S, 5S) -5- (hydroxymethyl) oxolane-2,3,4-triol 49.6g andacetone 1500mL, sulfuric acid 33mL was dropped at 30 or less, and wasstirred for 2.5 hours at 25 and cooled to 15 below. 28percent aqueousammonia solution 83mL was added slowly to the reaction mixture so that pH = 7 ~8, and the insoluble materials were filtered off, and the filtrate wasconcentrated under reduced pressure until 180g, and then concentratedhydrochloric acid2.6mL / water 160mL were added, and further acetone 40mL was added, and themixture was stirred for 20 minutes at 60 . After the additionof sodium hydrogen carbonate 18g to the reaction mixture, the acetone was distilledoff under reduced pressure, and was separatedby the addition of sodium chloride 60g and ethyl acetate 350mL. The aqueouslayer was extracted with ethyl acetate 300 mL, and the organic layer was driedover sodium sulfate, and the solvent was removed under reduced pressure to givea colorless oil 58 g of (3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2 , 2-dimethyl- tetrahydro -2H- furo [2,3-d] [1,3] dioxole-6-ol
Reference:
[1] Journal of Organic Chemistry, 2000, vol. 65, # 26, p. 9214 - 9219
[2] Patent: CN105646629, 2016, A, . Location in patent: Paragraph 0074; 0075; 0076; 0077
[3] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 4-7, p. 649 - 652
[4] Tetrahedron, 2001, vol. 57, # 42, p. 8851 - 8859
[5] Journal of the American Chemical Society, 1987, vol. 109, # 7, p. 2205 - 2208
[6] Tetrahedron Letters, 1985, vol. 26, # 38, p. 4639 - 4642
[7] Helvetica Chimica Acta, 1998, vol. 81, # 11, p. 2043 - 2052
[8] Journal of Organic Chemistry, 2003, vol. 68, # 6, p. 2376 - 2384
[9] Patent: JP2015/172033, 2015, A, . Location in patent: Paragraph 0241-0244
4
[ 87-72-9 ]
[ 67-64-1 ]
[ 114861-22-2 ]
Reference:
[1] Tetrahedron Letters, 2014, vol. 55, # 2, p. 475 - 478
[2] Nucleosides, Nucleotides and Nucleic Acids, 2000, vol. 19, # 1-2, p. 219 - 236
[3] Tetrahedron, 1998, vol. 54, # 44, p. 13529 - 13546
[4] Tetrahedron, 2008, vol. 64, # 23, p. 5551 - 5562
[5] Tetrahedron, 2008, vol. 64, # 9, p. 2090 - 2100
[6] Journal of Medicinal Chemistry, 2009, vol. 52, # 20, p. 6201 - 6204
To the suspension of L(-) xylose (19.15 g, 127.5 mmol) and MgSO4 (30.72 g,255.0 mmol) in acetone (190 mL) at room temperature was added concentrated H2SO4(1.9 mL). 12 After this time, the reaction mixture (all L - (-) - xylose consumed) wasfiltered and the combined solids were washed with acetone (2 times, 20 mL per wash).The yellow filtrate was neutralized to pH ~ 9 with NH4OH solution while stirring. Thesuspended solids were removed by filtration. The filtrate was concentrated to give thebis-acetonide intermediate as a yellow oil. The yellow oil was suspended in water (5mL) and the pH was adjusted from 9 to 2 with 1 N HCl in water. The reaction mixturewas stirred at room temperature for 12 hours. The resulting mixture was neutralized bythe addition of 25percent (w / w) K3PO4 in water until the pH was about 7. The mixture wasextracted with EtOAc. The organic layer was dried over MgSO4, filtered andconcentrated in vacuo. The crude product was purified by silica gel columnchromatography to give the title compound (12.63 g, 52percent) as a yellow oil.
Reference:
[1] Journal of Medicinal Chemistry, 1996, vol. 39, # 14, p. 2835 - 2843
15
[ 114861-22-2 ]
[ 1103738-17-5 ]
Yield
Reaction Conditions
Operation in experiment
79%
With trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide In methanol; water; acetone at 0 - 20℃; for 24 h;
To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0 g, 131 mmol) in acetone (375 mL, 15.x.) and H2O (125 mL, 5.x.) was added NaHCO3 (33.0 g, 3.0 equiv), NaBr (2.8 g, 20 mol percent) and TEMPO (0.40 g, 2 mol percent) at 20° C. The mixture was cooled to 0-5° C. and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20° C. for 24h. Methanol (20 mL) was added and the mixture was stirred at 20° C. for 1 h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2.x.). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12.x. .x.3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5.x.) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0 g, 79percent). 1H NMR (methanol-d4), δ 6.00 (d, J=3.2 Hz, 1H), 4.72 d, J=3.2 Hz, 1H), 4.53 (d, J=3.2 Hz, 1H), 4.38 (d, J=3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H).
79%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide In water; acetone at 0 - 20℃;
To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0 g, 131 mmol) in acetone (375 mL, 15.x.) and H2O (125 mL, 5.x.) was added NaHCO3 (33.0 g, 3.0 equiv), NaBr (2.8 g, 20 mol percent) and TEMPO (0.40 g, 2 mol percent) at 20° C. The mixture was cooled to 0-5° C. and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20° C. for 24 h. Methanol (20 mL) was added and the mixture was stirred at 20° C. for 1 h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2.x.). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12.x. .x.3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5.x.) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0 g, 79percent). 1H NMR (methanol-d4), δ 6.00 (d, J=3.2 Hz, 1H), 4.72 d, J=3.2 Hz, 1H), 4.53 (d, J=3.2 Hz, 1H), 4.38 (d, J=3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H)
79%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide In water; acetone at 0 - 20℃;
6. EXAMPLES Aspects of this invention can be understood from the following examples.6.1. Synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro [2.3-d][13]dioxol-5-yl)(morpholino)methanone To a 12L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(-)-xylose (504.40 g, 3.360 mol), acetone (5L, reagent grade) and anhydrous MgSO4 powder (811.23g, 6.740 mol / 2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO4 (50 mL, 0.938 mol / 0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24°C over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all L-xylose had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH = 8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50percent w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wtpercent water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23g, 86percent yield, 96.7 areapercent pure by GC). 1H NMR (400 MHz, DMSO-d6)δ1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93 - 4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). 13C NMR (101MHz, DMSO-d6) δ26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73. To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H2O (125 mL, 5X) was added NaHC03 (33.0g, 3.0 equiv), NaBr (2.8g, 20 molpercent) and TEMPO (0.40g, 2 molpercent) at 20°C. The mixture was cooled to 0-5°C and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20°C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20°C for 1h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2X). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0g, 79percent). 1H NMR (methanol-d4), δ 6.00 (d, J= 3.2 Hz, 1H), 4.72 d, J= 3.2 Hz, 1H), 4.53 (d, J= 3.2 Hz, 1H), 4.38 (d, J= 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H). To a solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (5.0g, 24.5 mmol) in THF (100 mL, 20X) was added TBTU (11.8g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20°C for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20°C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64percent) as a white solid. 1H NMR (CDCl3), 8 6.02 (d, J= 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J= 3.2 Hz, 1H), 4.58 (d, J= 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
79%
Stage #1: With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium bromide In water; acetone at 0 - 5℃; Stage #2: With trichloroisocyanuric acid In water; acetone at 0 - 20℃; for 24 h;
To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H2O (125 mL, 5X) was added NaHCO3 (33.0g, 3.0 equiv), NaBr (2.8g, 20 molpercent) and TEMPO (0.40g, 2 molpercent) at 20°C. The mixture was cooled to 0-5°C and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20°C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20°C for 1h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2X). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0g, 79percent). 1H NMR (methanol-d4), δ 6.00 (d, J = 3.2 Hz, 1H), 4.72 d, J = 3.2 Hz, 1H), 4.53 (d, J = 3.2 Hz, 1H), 4.38 (d, J = 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H).
77.2%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide In methanol; water; acetone at 0 - 30℃; for 25 h;
in room temperature,(3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2,2-dimethyl-3a, 5,6,6a-tetrahydrofuro [2,3-d] [1,3] Oxepin-6-ol 1c (70.0 g, 368 mmol)Was dissolved in a mixed solvent of acetone and water (v / v = 5 / 2,1400 mL)Sodium bicarbonate (93 g, 1.11 mol),Sodium bromide (7.6 g, 74 mmol)And tetramethylpiperidine nitrogen oxide (1.2 g, 7.7 mmol) were successively added to the above solution.Cooling to 0 ,Sucralyl isocyanuric acid (86.0 g, 370 mmol) was added in portions,Stirred at room temperature for 24 hours,Then methanol (60 mL) was added,Stirring was continued for 1 hour.The solid was removed by filtration and washed with acetone (200 mL x 3). The filtrates were combined and the organic solvent was concentrated under reduced pressure. The residue was extracted with ethyl acetate (800 mL x 4). The solvent was concentrated under reduced pressure and acetone (400 mL) ,Filtration, vacuum concentration,The title compound was obtained as a reddish brown oil (58.0 g, 77.2percent).
58%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide In N,N-dimethyl-formamide at 20℃; for 12 h;
To a solution of ((3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2,2-dimethyltetrahydrofuro [3,2- d] [1 Was added TEMPO (0.24 g, 1.5 mmol) to a solutionof 3-bromopyridin-3-yl] The mixture was cooled to 0 [deg.] C and then trichloroisocyanuric acid (17.8 g, 76.7 mmol) was added in portions. The suspensionwas stirred at room temperature for 12 hours. Methanol (2.0 mL) was added and themixture was stirred at room temperature for 2 hours. The mixture was filtered andwashed with acetone (2 x 20 mL wash). The organic solvent was removed in vacuo, theaqueous layer was extracted with EtOAc and the organic layer was concentrated invacuo. Acetone was added and the mixture was filtered. The filtrate was concentrated togive the title compound (9.0 g, 58percent) as a light yellow solid.
With sulfuric acid; In methanol; water; at 20℃; for 6.0h;
To a stirred solution of the diacetonide (10.3 g, 44.7 mmol) in MeOH (120 mL) was added 3 M H2SO4 (120 mL) and the mixture was stirred for 6 h at r.t. (TLC monitoring). MeOH was removed in vacuo and the aqueous fraction was extracted with CHCl3 (3 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give 8.0 g (94%) of pure compound 8 as a colorless liquid. [alpha]D 29 -20.7 (c 0.3, CHCl3). IR (neat): 3423, 2986, 2937, 1380, 1216, 1073, 1014 cm-1. 1H NMR (300 MHz, CDCl3): delta = 6.00 (d, J = 3.5 Hz, 1 H, H-1), 4.54 (d, J = 3.5 Hz, 1 H, H-2), 4.34 (s, 1 H, OH), 4.23-4.01 (m, 3 H, H-3, H-4, H5), 3.95 (d, J = 2.6 Hz, 1 H, H-5?), 2.59-2.42 (m, 1 H, OH), 1.49 (s, 3 H, CH3), 1.33 (s, 3 H, CH3). 13C NMR (75 MHz, CDCl3): delta = 111.7, 104.7, 85.5, 78.7, 76.7, 61.0, 26.7, 26.1. MS (ESI): m/z = 213 [M + Na]+. HRMS (ESI): m/z [M + Na]+ calcd for C8H14O5Na: 213.07334; found: 213.07282.
86%
With sulfuric acid; In water; at 20 - 25℃; for 6.0h;
To an aqueous solution (1500 mL) of Compound 2 (500 g, 2170 mmol), 0.5 M sulfuric acid (30 mL) was slowly added at 20-25 C, and the mixture was stirred at 25 C for 6 hours.Mix the droplets with saturated sodium bicarbonate solution to adjust the pH to 6.5-7.5, distill the water under reduced pressure to concentrate the slurry, extract with ethyl acetate (1500 mL / time), stir for 40 minutes, filter, filter cake The mixture was washed three times with ethyl acetate (300 mL / EtOAc).A yellow transparent oil (355 g, 86%) was obtained.
77%
With hydrogenchloride; In water; at 20 - 30℃; for 7.0h;
in room temperature,Hydrochloric acid (21 mL, 21 mmol, 1 M) was added(3aS, 3bR, 7aS, 8aS) -2,2,5,5-tetramethyltetrahydro-3aaH- [1,3] dioxolo [4 ', 5': 4,5] Furo [3,2-d] [1,3] dioxane 1b (110 g, 477.72 mmol)In aqueous solution (450 mL),The resulting reaction was stirred at room temperature for 7 hours.The mixture was adjusted to pH 7 with saturated aqueous sodium bicarbonate solution,And concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (600 mL)The insoluble matter was removed by filtration,The filter cake was washed with ethyl acetate (100 mL x 3), the filtrates were combined, concentrated under reduced pressure,To give the title compound 1c as a yellow oil (70.0 g, 77.0%).
With hydrogenchloride; In water; at 20℃; for 6.0h;pH 2;
To a 12 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(-)-xylose (504.40 g, 3.360 mol), acetone (5 L, reagent grade) and anhydrous MgSO4 powder (811.23 g, 6.740 mol/2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO4 (50 mL, 0.938 mol/0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24 C. over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all L-xylose had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH =8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142 mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5 S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25 L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wt % water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23 g, 86% yield, 96.7 area % pure by GC). 1H NMR (400 MHz, DMSO-d6) delta 1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93-4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). 3C NMR (101 MHz, DMSO-d6) delta 26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73.
With hydrogenchloride; water; at 20℃; for 6.0h;pH 9 - 2;
To a 12 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(-)-xylose (504.40 g, 3.360 mol), acetone (5 L, reagent grade) and anhydrous MgSO4 powder (811.23 g, 6.740 mol/2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO4 (50 mL, 0.938 mol/0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24 C. over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all L-xylose had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH=8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142 mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25 L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wt % water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23 g, 86% yield, 96.7 area % pure by GC). 1H NMR (400 MHz, DMSO-d6) delta 1.22 (s, 3H) 1.37 (s, 3H) 3.51 (dd, J=11.12, 5.81 Hz, 1H) 3.61 (dd, J=11.12, 5.05 Hz, 1H) 3.93-4.00 (m, 1H) 3.96 (s, 1H) 4.36 (d, J=3.79 Hz, 1H) 4.86 (br. s., 2H) 5.79 (d, J=3.54 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) delta 26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73
Step-ll: To a stirred solution of (3aS,3bR,7aS,8aS)-2,2,5,5-tetramethyl-tetrahydro- [1 ,3]dioxolo[4,5]furo[3,2-d][1 ,3]dioxine (78 g) in water (250 ml) was added 0.1 N HCI (20 ml) at ambient temperature. After stirring for 6 h, reaction was neutralized by the addition of 50% w/w aqueous K2HP04 (until pH =7). The solvent was evaporated under reduced pressure, ethyl acetate was added. The solid precipitated was filtered, the filtrate was concentrated to give 45 g of (3aS,5S,6R,6aS)-5-hydroxymethyl-2,2-dimethyl-tetrahydro- furo[2,3-d][1 ,3]dioxol-6-ol as an orange oil. 1H NMR (400 MHz, CD3OD): delta 1.29 (s, 3H), 1.44 (s, 3H), 3.73 (dd, J = 6.4, 1 1.6 Hz, 1 H), 3.79 (dd, J = 6.0, 1 1.6 Hz, 1 H), 4.08-4.17 (m, 2H), 4.45 (d, J = 4.0 Hz, 1 H), 5.87 (d, J = 4.0 Hz, 1 H).
6. EXAMPLES Aspects of this invention can be understood from the following examples.6.1. Synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro [2.3-d][13]dioxol-5-yl)(morpholino)methanone To a 12L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged <strong>[609-06-3]L-(-)-<strong>[609-06-3]xylose</strong></strong> (504.40 g, 3.360 mol), acetone (5L, reagent grade) and anhydrous MgSO4 powder (811.23g, 6.740 mol / 2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO4 (50 mL, 0.938 mol / 0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24C over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all <strong>[609-06-3]L-<strong>[609-06-3]xylose</strong></strong> had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH = 8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wt% water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23g, 86% yield, 96.7 area% pure by GC). 1H NMR (400 MHz, DMSO-d6)delta1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93 - 4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). 13C NMR (101MHz, DMSO-d6) delta26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73. To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H2O (125 mL, 5X) was added NaHC03 (33.0g, 3.0 equiv), NaBr (2.8g, 20 mol%) and TEMPO (0.40g, 2 mol%) at 20C. The mixture was cooled to 0-5C and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20C for 1h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2X). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0g, 79%). 1H NMR (methanol-d4), delta 6.00 (d, J= 3.2 Hz, 1H), 4.72 d, J= 3.2 Hz, 1H), 4.53 (d, J= 3.2 Hz, 1H), 4.38 (d, J= 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H). To a solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (5.0g, 24.5 mmol) in THF (100 mL, 20X) was added TBTU (11.8g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20C for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), 8 6.02 (d, J= 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J= 3.2 Hz, 1H), 4.58 (d, J= 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
86%
To a 12L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged 6 <strong>[609-06-3]L-(-)-<strong>[609-06-3]xylose</strong></strong> (504.40 g, 3.360 mol), 7 acetone (5L, reagent grade) and anhydrous 8 MgSO4 powder (811.23g, 6.740 mol /2.0 equiv). The suspension was set stirring at ambient and then 9 concentrated H2SO4 (50 mL, 0.938 mol / 0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24C over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all <strong>[609-06-3]L-<strong>[609-06-3]xylose</strong></strong> had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH = 8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L 10 water stirring in a 5L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142 mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to 11 (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange 13 oil which was dissolved in 1 L 14 methyl tert-butyl ether. This solution had 16 KF 0.23 wt% water and was concentrated to afford 11 (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23g, 86% yield, 96.7 area% pure by GC). 1H NMR (400 MHz, DMSO-d6) delta 1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93 - 4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). 13C NMR (101MHz, DMSO-d6) delta 26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73.
With sulfuric acid; magnesium sulfate; at 20 - 24℃; for 16.25h;
To a 12 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged <strong>[609-06-3]L-(-)-xylose</strong> (504.40 g, 3.360 mol), acetone (5 L, reagent grade) and anhydrous MgSO4 powder (811.23 g, 6.740 mol/2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO4 (50 mL, 0.938 mol/0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24 C. over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all <strong>[609-06-3]L-xylose</strong> had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH =8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142 mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5 S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25 L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wt % water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23 g, 86% yield, 96.7 area % pure by GC). 1H NMR (400 MHz, DMSO-d6) delta 1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93-4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). 3C NMR (101 MHz, DMSO-d6) delta 26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73.
With magnesium sulfate;sulfuric acid; at 20 - 24℃; for 16.25h;
To a 12 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged <strong>[609-06-3]L-(-)-xylose</strong> (504.40 g, 3.360 mol), acetone (5 L, reagent grade) and anhydrous MgSO4 powder (811.23 g, 6.740 mol/2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO4 (50 mL, 0.938 mol/0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24 C. over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all <strong>[609-06-3]L-xylose</strong> had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH=8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142 mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25 L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wt % water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23 g, 86% yield, 96.7 area % pure by GC). 1H NMR (400 MHz, DMSO-d6) delta 1.22 (s, 3H) 1.37 (s, 3H) 3.51 (dd, J=11.12, 5.81 Hz, 1H) 3.61 (dd, J=11.12, 5.05 Hz, 1H) 3.93-4.00 (m, 1H) 3.96 (s, 1H) 4.36 (d, J=3.79 Hz, 1H) 4.86 (br. s., 2H) 5.79 (d, J=3.54 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) delta 26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73
With trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide;2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In methanol; water; acetone; at 0 - 20℃; for 24h;
To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0 g, 131 mmol) in acetone (375 mL, 15×) and H2O (125 mL, 5×) was added NaHCO3 (33.0 g, 3.0 equiv), NaBr (2.8 g, 20 mol %) and TEMPO (0.40 g, 2 mol %) at 20 C. The mixture was cooled to 0-5 C. and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20 C. for 24h. Methanol (20 mL) was added and the mixture was stirred at 20 C. for 1 h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2×). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12× ×3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5×) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0 g, 79%). 1H NMR (methanol-d4), delta 6.00 (d, J=3.2 Hz, 1H), 4.72 d, J=3.2 Hz, 1H), 4.53 (d, J=3.2 Hz, 1H), 4.38 (d, J=3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H).
79%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide; In water; acetone; at 0 - 20℃;Product distribution / selectivity;
To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0 g, 131 mmol) in acetone (375 mL, 15×) and H2O (125 mL, 5×) was added NaHCO3 (33.0 g, 3.0 equiv), NaBr (2.8 g, 20 mol %) and TEMPO (0.40 g, 2 mol %) at 20 C. The mixture was cooled to 0-5 C. and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20 C. for 24 h. Methanol (20 mL) was added and the mixture was stirred at 20 C. for 1 h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2×). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12× ×3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5×) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0 g, 79%). 1H NMR (methanol-d4), delta 6.00 (d, J=3.2 Hz, 1H), 4.72 d, J=3.2 Hz, 1H), 4.53 (d, J=3.2 Hz, 1H), 4.38 (d, J=3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H)
79%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide; In water; acetone; at 0 - 20℃;
6. EXAMPLES Aspects of this invention can be understood from the following examples.6.1. Synthesis of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro [2.3-d][13]dioxol-5-yl)(morpholino)methanone To a 12L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(-)-xylose (504.40 g, 3.360 mol), acetone (5L, reagent grade) and anhydrous MgSO4 powder (811.23g, 6.740 mol / 2.0 equiv). The suspension was set stirring at ambient and then concentrated H2SO4 (50 mL, 0.938 mol / 0.28 equiv) was added. A slow mild exotherm was noticed (temperature rose to 24C over about 1 hr) and the reaction was allowed to stir at ambient overnight. After 16.25 hours, TLC suggested all L-xylose had been consumed, with the major product being the bis-acetonide along with some (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction mixture was filtered and the collected solids were washed twice with acetone (500 mL per wash). The stirring yellow filtrate was neutralized with concentrated NH4OH solution (39 mL) to pH = 8.7. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford crude bis-acetonide intermediate as a yellow oil (725.23 g). The yellow oil was suspended in 2.5 L water stirring in a 5L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (142mL) and stirred at room temperature for 6 h until GC showed sufficient conversion of the bis-acetonide intermediate to (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol. The reaction was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (1.25L) was added to give a white suspension which was filtered. The filtrate was concentrated in vacuo to afford an orange oil which was dissolved in 1 L methyl tert-butyl ether. This solution had KF 0.23 wt% water and was concentrated to afford (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol as an orange oil (551.23g, 86% yield, 96.7 area% pure by GC). 1H NMR (400 MHz, DMSO-d6)delta1.22 (s, 3 H) 1.37 (s, 3 H) 3.51 (dd, J=11.12, 5.81 Hz, 1 H) 3.61 (dd, J=11.12, 5.05 Hz, 1 H) 3.93 - 4.00 (m, 1 H) 3.96 (s, 1 H) 4.36 (d, J=3.79 Hz, 1 H) 4.86 (br. s., 2 H) 5.79 (d, J=3.54 Hz, 1 H). 13C NMR (101MHz, DMSO-d6) delta26.48, 27.02, 59.30, 73.88, 81.71, 85.48, 104.69, 110.73. To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H2O (125 mL, 5X) was added NaHC03 (33.0g, 3.0 equiv), NaBr (2.8g, 20 mol%) and TEMPO (0.40g, 2 mol%) at 20C. The mixture was cooled to 0-5C and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20C for 1h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2X). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0g, 79%). 1H NMR (methanol-d4), delta 6.00 (d, J= 3.2 Hz, 1H), 4.72 d, J= 3.2 Hz, 1H), 4.53 (d, J= 3.2 Hz, 1H), 4.38 (d, J= 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H). To a solution of (3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid (5.0g, 24.5 mmol) in THF (100 mL, 20X) was added TBTU (11.8g, 1.5 equiv), N-methylmorpholine (NMM, 4.1 mL, 1.5 equiv) and the mixture was stirred at 20C for 30 min. Morpholine (3.2 mL, 1.5 equiv) was then added, and the reaction mixture was stirred at 20C for an additional 6h. The solid was filtered off by filtration and the cake was washed with THF (10 mL, 2X x2). The organic solution was concentrated under vacuum and the residue was purified by silica gel column chromatography (hexanes:EtOAc, from 1:4 to 4:1) to afford 4.3 g of the desired morpholine amide (64%) as a white solid. 1H NMR (CDCl3), 8 6.02 (d, J= 3.2 Hz, 1H), 5.11 (br s, 1H), 4.62 (d, J= 3.2 Hz, 1H), 4.58 (d, J= 3.2 Hz, 1H), 3.9-3.5 (m, 8H), 1.51 (s, 3H), 1.35 (s, 3H).
79%
To a solution of (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (25.0g, 131 mmol) in acetone (375 mL, 15X) and H2O (125 mL, 5X) was added NaHCO3 (33.0g, 3.0 equiv), NaBr (2.8g, 20 mol%) and TEMPO (0.40g, 2 mol%) at 20C. The mixture was cooled to 0-5C and solid trichloroisocyanuric acid (TCCA, 30.5 g, 1.0 equiv) was then added in portions. The suspension was stirred at 20C for 24h. Methanol (20 mL) was added and the mixture was stirred at 20C for 1h. A white suspension was formed at this point. The mixture was filtered, washed with acetone (50 mL, 2X). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (300 mL, 12X x3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (125 mL, 5X) was added and the mixture was filtered. The acetone solution was then concentrated to afford the desired acid ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid) as a yellow solid (21.0g, 79%). 1H NMR (methanol-d4), delta 6.00 (d, J = 3.2 Hz, 1H), 4.72 d, J = 3.2 Hz, 1H), 4.53 (d, J = 3.2 Hz, 1H), 4.38 (d, J = 3.2 Hz, 1H), 1.44 (s, 3H), 1.32 (s, 3H).
77.2%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide; In methanol; water; acetone; at 0 - 30℃; for 25h;
in room temperature,(3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2,2-dimethyl-3a, 5,6,6a-tetrahydrofuro [2,3-d] [1,3] Oxepin-6-ol 1c (70.0 g, 368 mmol)Was dissolved in a mixed solvent of acetone and water (v / v = 5 / 2,1400 mL)Sodium bicarbonate (93 g, 1.11 mol),Sodium bromide (7.6 g, 74 mmol)And tetramethylpiperidine nitrogen oxide (1.2 g, 7.7 mmol) were successively added to the above solution.Cooling to 0 ,Sucralyl isocyanuric acid (86.0 g, 370 mmol) was added in portions,Stirred at room temperature for 24 hours,Then methanol (60 mL) was added,Stirring was continued for 1 hour.The solid was removed by filtration and washed with acetone (200 mL x 3). The filtrates were combined and the organic solvent was concentrated under reduced pressure. The residue was extracted with ethyl acetate (800 mL x 4). The solvent was concentrated under reduced pressure and acetone (400 mL) ,Filtration, vacuum concentration,The title compound was obtained as a reddish brown oil (58.0 g, 77.2%).
58%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide; In N,N-dimethyl-formamide; at 20℃; for 12h;
To a solution of ((3aS, 5S, 6R, 6aS) -5- (hydroxymethyl) -2,2-dimethyltetrahydrofuro [3,2- d] [1 Was added TEMPO (0.24 g, 1.5 mmol) to a solutionof 3-bromopyridin-3-yl] The mixture was cooled to 0 [deg.] C and then trichloroisocyanuric acid (17.8 g, 76.7 mmol) was added in portions. The suspensionwas stirred at room temperature for 12 hours. Methanol (2.0 mL) was added and themixture was stirred at room temperature for 2 hours. The mixture was filtered andwashed with acetone (2 x 20 mL wash). The organic solvent was removed in vacuo, theaqueous layer was extracted with EtOAc and the organic layer was concentrated invacuo. Acetone was added and the mixture was filtered. The filtrate was concentrated togive the title compound (9.0 g, 58%) as a light yellow solid.
58%
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide; In water; acetone; at 0 - 20℃; for 12h;
To a solution of (178 (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,2-d][1,3]dioxol-6-ol (14.6 g, 76.7 mmol), 39 NaHCO3 (19.3 g, 230.3 mmol), and 180 NaBr (1.6 g, 15.4 mmol) in 42 acetone/9 water (120 mL/40 mL) was added 181 TEMPO (0.24 g, 1.5 mmol) at room temperature. The mixture was cooled to 0 C., and then 182 trichloroisocyanuric acid (17.8 g, 76.7 mmol) was added in small portions. The suspension was stirred at room temperature for 12 hours. 170 Methanol (2.0 mL) was added and the mixture was stirred at room temperature for 2 hours. The mixture was filtered and washed with acetone (twice, 20 mL per wash). The organic solvent was removed in vacuo, the aqueous layer was extracted with EtOAc, and the organic layer was concentrated in vacuo. Acetone was added thereto and the mixture was filtered. The filtrate was concentrated to obtain the desired 183 acid (9.0 g, 58%) as a light yellow solid. 1H NMR (400 MHz, CD3OD) delta 5.98 (d, J=3.6 Hz, 1H), 4.71 (d, J=3.2 Hz, 1H), 4.51 (d, J=3.6 Hz, 1H), 4.36 (d, J=3.6 Hz, 1H), 1.45 (s, 3H), 1.31 (s, 3H).
With sodium hypochlorite; sodium chlorite; dipotassium hydrogenphosphate; potassium dihydrogenphosphate;2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; In water; acetonitrile; at 15 - 25℃;Industry scale;Product distribution / selectivity;
A solution of the diol (3aS,5S,6R,6aS)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol in acetonitrile (5.38 kg, 65% w/w, 3.50 kg active, 18.40 mol), acetonitrile (10.5 L) and TEMPO (28.4 g, 1 mol %) were added to a solution of K2HPO4 (0.32 kg, 1.84 mol) and KH2PO4 (1.25 kg, 9.20 mol) in water (10.5 L). A solution of NaClO2 (3.12 kg, 80% w/w, 27.6 mole, 1.50 eq) in water (7.0 L) and a solution of K2HPO4 (2.89 kg, 0.90 eq) in water (3.0 L) were prepared with cooling. Bleach (3.0 L, approximate 6% household grade) was mixed with the K2HPO4 solution. Approximately 20% of the NaClO2 solution (1.6 L) and bleach/K2HPO4 solution (400 mL, 1 mol %) were added. The remainders of the two solutions were added simultaneously. The reaction mixture turned dark red brown and slow exotherm was observed. The addition rate of the NaClO2 solution was about 40 mL/min (3-4 h addition) and the addition rate for the bleach/K2HPO4 solution was about 10-12 mL/min (10 hr addition) while maintaining the batch at 15-25 C. Additional charges of TEMPO (14.3 g, 0.5 mol %) were performed every 5-6 hr until the reaction went to completion (usually two charges are sufficient). Nitrogen sweep of the headspace to a scrubber with aqueous was performed to keep the green-yellowish gas from accumulating in the vessel. The reaction mixture was cooled to <10 C. and quenched with Na2SO3 (1.4 kg, 0.6 eq) in three portions over 1 hr. The reaction mixture was then acidified with H3PO4 until pH reached 2.0-2.1 (2.5-2.7 L) at 5-15 C. The layers were separated and the aqueous layer was extracted with acetonitrile (10.5 L ×3). The combined organic layer was concentrated under vacuo (100-120 torr) at <35 C. (28-32 C. vapor, 45-50 C. bath) to low volume (6-7 L) and then flushed with acetonitrile (40 L) until KF of the solution reached <1% when diluted to volume of about 12-15Lwith acetonitrile. Morpholine (1.61 L, 18.4 mol, 1.0 eq) was added over 4-6 h and the slurry was aged overnight under nitrogen. The mixture was cooled to 0-5 C. and aged for 3 hours then filtered. The filter cake was washed with acetonitrile (10 L). Drying under flowing nitrogen gave 4.13 kg of the morpholine salt of ((3aS,5R,6S,6aS)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid as a white solid (92-94% pure based on 1H NMR with 1,4-dimethoxybenzene as the internal standard), 72-75% yield corrected for purity. 1H NMR (D2O) delta 5.96 (d, J=3.6 Hz, 1H), 4.58 (d, J=3.6 Hz, 1H), 4.53 (d, J=3.2 Hz, 1H), 4.30 (d, J=3.2 Hz, 1H), 3.84 (m, 2H), 3.18 (m, 2H), 1.40 (s, 1H), 1.25 (s, 1H). 13H NMR (D2O) delta 174.5, 112.5, 104.6, 84.2, 81.7, 75.0, 63.6, 43.1, 25.6, 25.1.
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid; sodium hydrogencarbonate; sodium bromide; In water; acetone; at 0 - 20℃; for 24h;
Step-Ill: To a stirred solution of (3aS,5S,6R,6aS)-5-hydroxymethyl-2,2-dimethyl- tetrahydro-furo[2,3-d][1 ,3]dioxol-6-ol (30 g, 157 mmol) in acetone (450 ml) and water (150 ml) was added sodium bicarbonate (39.8 g, 473 mmol), sodium bromide (3.25 g, 31 mmol) and TEMPO (490 mg, 3.1 mmol) at 20 C. The mixture was cooled to 0-5 C and solid trichloroisocyanuric acid (TCCA, 36.69 g, 157 mmol) was then added in portions. After stirring for 24 h at room temperature, methanol (25 ml) was added stirred for additional 1 h. The white suspension was formed. This was filtered, washed with acetone (50 ml X 2). The volatiles were evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate (300 ml X 3) and combined organic layers were concentrated to thick oily mixture with some solid residue. This was taken in acetone and filtered. The filtrate was concentrated to give 25 g of (3aS,5R,6S,6aS)-6- hydroxy-2,2-dimethyl-tetrahydro-furo[2,3-d][1 ,3]dioxole-5-carboxylic acid as a yellow solid. 1H NMR (400 MHz, CD3OD): delta 1.30 (s, 3H), 1.44 (s, 3H), 4.35 (d, J = 2.8 Hz, 1 H), 4.50 (d, J = 2.0 Hz, 1 H), 4.69 (d, J = 3.6 Hz, 1 H), 5.97 (d, J = 3.2 Hz, 1 H).
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene; In water; acetonitrile; at 30 - 50℃;
Compound 3 (100 g, 525.8 mmol) was dissolved in a mixed solution of acetonitrile (380 mL) and water (190 mL), and 2,2,6,6-tetramethylpiperidine oxide (0.2-0.7 eq) was added.And iodobenzene diacetate (1.0-5.0 eq),The reaction mixture was stirred at 30-50 120-180 minutes, and extracted three times with ethyl acetate (500mL / times) and concentrated under reduced pressure to give a brown oily crude product (93.6g, 87%) ethyl acetate solution was concentrated.
2.1. Synthesis and crystallization
The title compound was synthesized in eight synthetic stepsaccording to the procedure described by Goodwin et al.(2009), starting from commercially available (3aS,5S,6R,6aS)-5-hydroxymethyl-2,2-dimethyltetrahydrofuro[2,3-d]-1,3-dioxol-6-ol. Dissolving sotagliflozin in propan-2-ol at reflux temperature (80 mg ml1) and slow cooling of the solution yielde dsingle crystals of (I). Single crystals of (II) were extracted froma mixture of (I) and (II) obtained after the slow addition ofwater to a methanol solution of sotagliflozin (80 mg ml1) atroom temperature. The powder X-ray diffractogram (seeFig. S1 of the supporting information), as well as the meltingpoint of (I) (396 K), correspond with the data of form 1disclosed by De Paul et al. (2010). The existence of themonohydrate (II) has not been reported previously. Thisphase has a melting point of 344 K and the experimentalpowder pattern is shown in Fig. S2 of the supporting information.