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[ CAS No. 114861-22-2 ]

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CAS No. :114861-22-2 MDL No. :MFCD00010529
Formula : C8H14O5 Boiling Point : -
Linear Structure Formula :- InChI Key :N/A
M.W :190.19 g/mol Pubchem ID :10103984
Synonyms :

Safety of [ 114861-22-2 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P305+P351+P338 UN#:N/A
Hazard Statements:H302-H315-H319-H335 Packing Group:N/A
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  • Upstream synthesis route of [ 114861-22-2 ]
  • Downstream synthetic route of [ 114861-22-2 ]

[ 114861-22-2 ] Synthesis Path-Upstream   1~17

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YieldReaction ConditionsOperation in experiment
77% 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
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YieldReaction ConditionsOperation 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
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YieldReaction ConditionsOperation 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
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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
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Reference: [1] Patent: US2009/30198, 2009, A1, . Location in patent: Page/Page column 7
[2] Patent: US2010/16422, 2010, A1, . Location in patent: Page/Page column 4
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YieldReaction ConditionsOperation in experiment
52% at 20℃; for 12 h; 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] Patent: KR101770302, 2017, B1, . Location in patent: Paragraph 0331; 0332
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Reference: [1] Patent: US2012/172320, 2012, A1,
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Reference: [1] Collection of Czechoslovak Chemical Communications, 2006, vol. 71, # 7, p. 1063 - 1087
[2] Nucleosides, Nucleotides and Nucleic Acids, 2001, vol. 20, # 4-7, p. 703 - 706
[3] Helvetica Chimica Acta, 1938, vol. 21, p. 263,267
[4] Patent: WO2012/140596, 2012, A1,
[5] Patent: CN106892948, 2017, A,
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Reference: [1] Patent: EP2661256, 2018, B1,
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Reference: [1] Tetrahedron Asymmetry, 2003, vol. 14, # 1, p. 47 - 51
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Reference: [1] Collection of Czechoslovak Chemical Communications, 2011, vol. 76, # 5, p. 503 - 536
[2] RSC Advances, 2016, vol. 6, # 46, p. 39758 - 39761
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Reference: [1] Tetrahedron, 1988, vol. 44, # 15, p. 4721 - 4736
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Reference: [1] Patent: US2009/30198, 2009, A1, . Location in patent: Page/Page column 7
[2] Patent: US2010/16422, 2010, A1, . Location in patent: Page/Page column 4
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Reference: [1] Journal of Medicinal Chemistry, 1996, vol. 39, # 14, p. 2835 - 2843
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YieldReaction ConditionsOperation 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.

Reference: [1] Patent: US2009/30198, 2009, A1, . Location in patent: Page/Page column 7-8
[2] Patent: US2010/16422, 2010, A1, . Location in patent: Page/Page column 4
[3] Patent: EP2332947, 2011, A1, . Location in patent: Page/Page column 6-7
[4] Patent: EP2661256, 2018, B1, . Location in patent: Paragraph 0090
[5] Patent: CN106892948, 2017, A, . Location in patent: Paragraph 0192; 0193; 0194
[6] Patent: KR101770302, 2017, B1, . Location in patent: Paragraph 0334; 0335
[7] Patent: US2009/30198, 2009, A1, . Location in patent: Page/Page column 8
[8] Patent: WO2012/140596, 2012, A1, . Location in patent: Page/Page column 54-55
  • 16
  • [ 114861-22-2 ]
  • [ 1103738-19-7 ]
Reference: [1] Patent: EP2332947, 2011, A1,
[2] Patent: EP2332947, 2011, A1,
[3] Patent: CN106892948, 2017, A,
[4] Patent: KR101770302, 2017, B1,
[5] Patent: EP2661256, 2018, B1,
[6] Patent: EP2661256, 2018, B1,
  • 17
  • [ 114861-22-2 ]
  • [ 1103738-30-2 ]
Reference: [1] Patent: EP2332947, 2011, A1,
[2] Patent: EP2332947, 2011, A1,
[3] Patent: EP2661256, 2018, B1,
[4] Patent: EP2661256, 2018, B1,
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