* 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 trichlorophosphate In acetone at 20℃; for 4 h;
To a magnetically stirred solution of AA (1.76 g, 10 mmol) in acetone (9 mL), phosphorus oxychloride (0.5 mL) was added and the reaction mixture was stirredfor 4 h at RT. Then it was filtered, washed with cold acetone–water and dried invacuo, leading to 5,6-O-isopropylidene-L-ascorbic acid 19 being obtained as colorless granules (1.92 g, 89percent). IR (KBr, cm-1): νmax 3242.6, 2993.3, 2907.6, 2741.6, 1755.5, 1665.4. 1H NMR (600 MHz, CD3COCD3): δ 4.71–4.73 (m, 1H, C4-H), 4.37–4.39 (m, 1H, C5-H), 4.16–4.21 (m, 1H, C6-H), 3.99–4.03 (m, 1H, C6-H), 1.29 (s, 6H, Me).
Reference：
[1] Research on Chemical Intermediates, 2017, vol. 43, # 10, p. 5901 - 5916
[2] Chemische Berichte, 1936, vol. 69, p. 879
[3] Nature (London, United Kingdom), 1932, vol. 130, p. 847
[4] Justus Liebigs Annalen der Chemie, 1947, vol. 558, p. 177,181
[5] Patent: US2002/156051, 2002, A1,
[6] Patent: US4999437, 1991, A,
[7] Patent: US4552888, 1985, A,
[8] Patent: EP411183, 1991, A1,
[9] Patent: EP411184, 1991, A1,
2
[ 77-76-9 ]
[ 50-81-7 ]
[ 15042-01-0 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 20 - 30℃; for 2 h; Inert atmosphere; Industry scale
i) 5,6-O-Isopropylidene-L-Ascorbic Acid To a mixture of L-ascorbic acid (65 kg, 369 mol), acetone (283 kg) and 2,2-dimethoxypropane (46 kg, 443 mol) was charged p-toluenesulfonic acid (1.1 kg, 5.5 mol). Temperature was adjusted to 25±5° C. The slurry was stirred for 2 hours, during which time nitrogen was frequently flushed through the bottom valve to prevent material from settling at the bottom of the reactor. NMR analysis (solvent: D2O) then showed 98.5percent conversion. Heptanes (222 kg) were charged and the temperature adjusted to 5±5° C. The reaction mixture was stirred for at least 30 minutes before filtering. Remains of the acetonide product in the reactor were rinsed onto the filter cake using the mother liquors. The filter cake was washed with heptanes (111 kg) and dried at 50° C. to give 5,6-O-isopropylidene-L-ascorbic acid (73 kg, 336 mol) as an almost white powder. Yield: 91percent. 1H NMR (400 MHz, d6-DMSO, with maleic acid and TFA) δ4.71 (d, J=3.0 Hz, 1H), 4.28 (m, 1H), 4.11 (dd, J=7.0, 8.4 Hz, 1H), 3.90 (dd, J=6.3, 8.4 Hz, 1H), 1.27 (s, 6H).
91%
With toluene-4-sulfonic acid In acetone at 25℃; for 2 h; Inert atmosphere; Large scale
To a mixture of L-ascorbic acid (65 kg, 369 mol), acetone (283 kg) and 2,2- dimethoxypropane (46 kg, 443 mol) was charged /?-toluenesulfonic acid (1.1 kg, 5.5 mol). Temperature was adjusted to 25±5°C. The slurry was stirred for 2 hours, during which time nitrogen was frequently flushed through the bottom valve to prevent material from settling at the bottom of the reactor. NMR analysis (solvent: D20) then showed 98.5 percent conversion. Heptanes (222 kg) were charged and the temperature adjusted to 5±5°C. The reaction mixture was stirred for at least 30 minutes before filtering. Remains of the acetonide product in the reactor were rinsed onto the filter cake using the mother liquors. The filter cake was washed with heptanes (111 kg) and dried at 50°C to give 5,6-O-isopropylidene-L-ascorbic acid (73 kg, 336 mol) as an almost white powder. Yield: 91percent. 1H NMR (400 MHz, d6-DMSO, with maleic acid and TFA) δ 4.71 (d, J= 3.0 Hz, 1H), 4.28 (m, 1H), 4.11 (dd, J= 7.0, 8.4 Hz, 1H), 3.90 (dd, J= 6.3, 8.4 Hz, 1H), 1.27 (s, 6H).
91%
With toluene-4-sulfonic acid In acetone at 20 - 30℃; for 2 h; Inert atmosphere; Industrial scale
To a mixture of L-ascorbic acid (65 kg, 369 mol), acetone (283 kg) and 2,2-dimethoxypropane (46 kg, 443 mol) was charged /p-toluenesulfonic acid (1.1 kg, 5.5 mol). Temperature was adjusted to 25±5°C. The slurry was stirred for 2 hours, during which time nitrogen was frequently flushed through the bottom valve to prevent material from settling at the bottom of the reactor. NMR analysis (solvent: D20) then showed 98.5 percent conversion. Heptanes (222 kg) were charged and the temperature adjusted to 5±5°C. The reaction mixture was stirred for at least 30 minutes before filtering. Remains of the acetonide product in the reactor were rinsed onto the filter cake using the mother liquors. The filter cake was washed with heptanes (111 kg) and dried at 50°C to give 5,6-O-isopropylidene-L-ascorbic acid (73 kg, 336 mol) as an almost white powder. Yield: 91percent. 1H NMR (400 MHz, d6-DMSO, with maleic acid and TFA) δ 4.71 (d, J= 3.0 Hz, 1H), 4.28 (m, 1H), 4.11 (dd, J= 7.0, 8.4 Hz, 1H), 3.90 (dd, J= 6.3, 8.4 Hz, 1H), 1.27 (s, 6H).
86%
With camphor-10-sulfonic acid In acetone at 20℃;
This material was prepared according to literature precedence (Bioorg. Med. Chem. 2003, vol. 11, 827). To a suspension of L-ascorbic acid (20.0 g, 114 mmol) in acetone (200 mL) was added 2,2-dimethoxypropane (20.4 g, 196 mmol) and 10- camphorsulfonic acid (1.32 g, 5.68 mmol). The resultant mixture was allowed to stir overnight at room temperature. To the resultant slurry was added approximately 0.6 g tri ethyl amine. A portion of hexane was added to the mixture, and the white precipitate was collected via vacuum filtration, washing with additional hexane. The material was dried under vacuum to afford the desired product (21.0 g, 86percent yield). NMR was consistent with the desired product.
82%
With tin(ll) chloride In acetone for 6 h; Reflux
A mixture of l-Ascorbic acid compound 1 g (2 mmol) and acetone(15 mL) was stirred for 15 min. 2,2-Dimethoxy propane(1.25 mL) and catalytic amount of tin chloride was added to thereaction mixture and it was refluxed for 6 h. Cooled the reactionmixture to 5-10 °C and stirred for 45 min at room temperature.The precipitated was filtered, washed with acetone and dried toget the compound 2A. Yield: 82percent; M.P: 206 C. TLC: 100 DCM: 20EA: 10 ethanol: 1 Acetic acid.
79%
With hydrogenchloride In methanol at 20 - 25℃; for 4 h;
To the solution of L-Ascorbic acid (100 g, 568 mmol) in 200 mL acetone was treated with 2,2-dimethoxypropane (118 g, 1.13 mmol), and Hydrochloric acid (4 M in methanol, 60 mL). The reaction mixture was stirred at room temperature for 4 h. the mixture was filtered and the filter cake was washed with 10 mL acetone and dried in vacuum to afford 37 (90 g, 79percent) as a white solid.
50 mg
With hydrogenchloride In acetone at 25 - 30℃; for 4 h;
A mixture of L-Ascorbic acid compound of formula-3 (50 gm) and acetone (250 ml) was stirred for 15 minutes. 2,2-Dimethoxy propane (62.5 ml) was added to the reaction mixture. Acidified the reaction mixture by using HCl gas and stirred for 4 hrs at 25-30°C. Cooled the reaction mixture to 5-10°C and stirred for 45 minutes at the same temperature. The precipitated solid was filtered, washed with acetone and dried to get the title compound. Yield: 50 gm; M.R: 205-210°C.
Reference：
[1] Tetrahedron Asymmetry, 1997, vol. 8, # 14, p. 2299 - 2302
[2] Tetrahedron Letters, 2002, vol. 43, # 2, p. 213 - 216
[3] Journal of Organic Chemistry, 1985, vol. 50, # 19, p. 3462 - 3467
[4] Tetrahedron: Asymmetry, 1991, vol. 2, # 5, p. 359 - 362
[5] Patent: US2012/15927, 2012, A1, . Location in patent: Page/Page column 8
[6] Patent: WO2013/8002, 2013, A1, . Location in patent: Page/Page column 39
[7] Patent: EP2740458, 2016, B1, . Location in patent: Paragraph 0045
[8] Tetrahedron, 2013, vol. 69, # 9, p. 2157 - 2166
[9] Patent: WO2017/95704, 2017, A1, . Location in patent: Page/Page column 53
[10] Bioorganic Chemistry, 2019, vol. 82, p. 178 - 191
[11] European Journal of Medicinal Chemistry, 2018, vol. 151, p. 98 - 109
[12] Tetrahedron Letters, 2004, vol. 45, # 28, p. 5395 - 5398
[13] Tetrahedron Letters, 1990, vol. 31, # 7, p. 1002 - 1006
[14] Synthesis, 1995, # 6, p. 687 - 692
[15] Patent: US4567282, 1986, A,
[16] Patent: US4502994, 1985, A,
[17] Carbohydrate Research, 2009, vol. 344, # 15, p. 2100 - 2104
[18] Bulletin of the Korean Chemical Society, 2012, vol. 33, # 7, p. 2213 - 2218
[19] Patent: WO2016/207907, 2016, A1, . Location in patent: Page/Page column 18
3
[ 75-36-5 ]
[ 50-81-7 ]
[ 15042-01-0 ]
Yield
Reaction Conditions
Operation in experiment
91%
at 5 - 20℃; for 22.5 h; Inert atmosphere
To a solution of L-ascorbic acid 5 (20.01 g, 113.6 mmol, 1.0 eq) in acetone (80 mL) was added acetyl chloride (2.1 mL, 29.9 mmol, 0.26 eq) at room temperature. After stirring for 3.5 h at room temperature, the reaction mixture was stored in the refrigerator (5 °C) for 19 h. The solid was then filtered off and washed with a small amount of cold acetone to afford 6 as a colorless solid (22.36 g, 103.4 mmol, 91percent)
Reference：
[1] Tetrahedron Letters, 2016, vol. 57, # 52, p. 5899 - 5901
[2] Patent: US6602906, 2003, B1,
[3] Patent: US5552520, 1996, A,
[4] Patent: US5607968, 1997, A,
4
[ 7778-85-0 ]
[ 50-81-7 ]
[ 15042-01-0 ]
Yield
Reaction Conditions
Operation in experiment
95%
With toluene-4-sulfonic acid In dimethyl sulfoxide; acetone at 50℃; for 5 h;
Example 1 Synthesis of 5,6-O-isopropylidene Ascorbic Acid To the mixed solvent composed of 100 mL of dimethylsulfoxide and 40 ml of acetone were added 17.6 g of L-ascorbic acid, 15.6 g of 1,2-dimethoxypropane and 1.2 g of p-tolusulfonic acid, followed by stirring for 5 hours at 50° C. The produced reaction mixture was vacuum-distillated at 20° C. to eliminate the remaining acetone and non-reacted 1,2-dimethoxypropane to give 20.5 g of the target compound (yield: 95percent).
With 1,2-dimethoxypropane; toluene-4-sulfonic acid In dimethyl sulfoxide at 50℃; for 5 h;
To the mixed solvent composed of 100 mL of dimethylsulfoxide and 40 ml of acetone were added 17.6 g of L- ascorbic acid, 15.6 g of 1, 2-dimethoxypropane and 1.2 g of p- tolusulfonic acid, followed by stirring for 5 hours at 50 °C The produced reaction mixture was vacuum-distillated at 20 °C to eliminate the remaining acetone and non-reacted 1,2- dimethoxypropane to give 20.5 g of the target compound (yield: 95percent) .
94.4%
for 4 h; Cooling with ice
To a 100 mL single flask was added 3.52 g of vitamin C, 2.76 g of p-toluenesulfonic acid, 15 mL of acetone, ice bath condition 4h, The filter cake was washed with ethyl acetate and dried in vacuo to give 4.08 g of 5,6-O-isopropylidene-L-ascorbic acid as a white solid in a yield of 94.4percent.
86%
at 20℃; for 3 h;
Preparation Example 1 : Preparation of ---5,6-O-isopropylidin-ascorbic acid; L-5,6-O-isopropylidin-ascorbic acid was prepared according to a method disclosed in Journal of the American Chemical Society, Vol. 102, No. 20, pp 6304,1980. That is, 100 g of ascorbic acid was added to 50 ml of acetone. While the reaction mixture was stirred at room temperature, 10 ml of acetyl chloride was <n="16"/>added to the mixture, which was then stirred for 3 hours. The mixture was cooled in ice bath and filtered to isolate a precipitate. The precipitate was washed with 500 ml of cold acetone and dried under reduced pressure to obtain 105 g of L-δ.e-O-isopropylidin-ascorbic acid (yield: 86percent, mp: 206-208 °C). 1H NMR (400MHz, CDCL3), Chemical shift; 5.50 (1 H, d), 5.18 (1 H1 m),4.20(2H, t), 2.52(2H, m), 2.51 (4H, t), 2.25-1.55 (12H, m)
85%
at 0℃; for 24 h;
FORMATION of one of the cholesterol absorption inhibitors described herein: Disodium ASCORBYL PHOSPHATE E RRE To a dry round bottom flask, acetone (150 ML) and L-ascorbic acid (50 g) were added at 0 °C. Acetyl chloride (7.5 ML was added dropwise through an addition funnel in 10 minutes. The reaction mixture was stirred at 0 °C for 24 hours. The precipitate was filtered off and washed with acetone (3X20 ML). The white product, 5, 6-ISOPROPYLIDINE ascorbic acid, was dried under vacuum for 1.5 hours to give a dry powder (52 g), yield 85percent. A dry three neck round bottom flask was fitted with a stirring bar, argon inlet and an addition funnel. A solution of dehydroisoandrosterone (1.73 g, 6 MMOL) in anhydrous THF (15 ml) and pyridine (2.4 ml) was added dropwise to the mixture of anhydrous THF (12 ml) and POCI3 (0.7 ML, 7.5 MMOL) at 0 °C over a period of 10 minutes. A white precipitate formed immediately. The suspension was stirred at 0 °C for 40 minutes, and at room temperature for 1 hour and 40 minutes. To the above suspension, a solution of 5, 6-ISOPROPYLIDINE ascorbic acid (3.6 g, 16.67 MMOL) in anhydrous pyridine (3 ml) and THF (30 ml) was added dropwise at 0 °C over a period of 20 minutes. The suspension was stirred at 0 °C for 30 minutes, and at room temperature for 1.5 hours. The formed pyridinium chloride was filtered out and washed with THF twice. The solvents were evaporated under reduced pressure at 40 °C to afford a residue. The residue was dissolved in THF (40 ML), and 2N HCI (30 ml) was added in one portion. The mixture was stirred at room temperature for 8 hours. THF was evaporated under a reduced pressure. The water layer was extracted with ethyl acetate (4X50 ML). The combined ethyl acetate solution was washed with brine (100 ML), and dried over NA2SO4. The solvent was evaporated to give a residue. The residue was dissolved in CHCI3, and then hexanes was added to precipitate the product. The precipitated solid was filtered out, washed with hexanes and dried under vacuum (2.43 g, crude product, yield : 77percent). The purification of phosphate ester was done by reverse phase C-18 chromatography (Waters, water/methanol = 90/10 to 60/40). Pure compound 4 (Figure 1,39 mg) was isolated from 50 mg of the crude product. The overall yield (base on dehydroisoandrosterone) was 60 percent. ASCORBYL phosphate ester of dehydroisoandrosterone (0.5 g, 0.95 MMOL) was dissolved in methanol (3 ml) at room temperature, and then sodium methoxide in methanol (1ML, 20percent) was added. The suspension was stirred at room temperature for 30 minutes. The precipitated solid was filtered out, washed with methanol, acetone and hexanes. The mother liquor was concentrated to 2 mi, acetone was added to precipitate the product. An additional white solid was obtained. The combined solid was dried under vacuum at room temperature. Disodium ascorbyl phosphate ester of dehydroisoandrosterone (0.49 G, yield 91 percent) was obtained.
85%
at 0℃; for 24 h;
To a dry round bottom flask, acetone (150 ml) and L-ascorbic acid (50 g) were added at 0 C. Acetyl chloride (7.5 ml) was added dropwise through an addition funnel in 10 minutes. The reaction mixture was stirred at 0 C. for 24 hours. The precipitate was filtered off and washed with acetone (3x20 ml). The white product, 5,6-isopropylidine ascorbic acid, was dried under vacuum for 1.5 hours to give a dry powder (52 g), yield 85percent.
80.6%
at 25℃;
250 ?l of acetyl chloride are added to a suspension of vitamin C, or ascorbic acid (3 g, 17 mmol) in 30 ml of acetone. The solution becomes clear and a white precipitate then forms. After reaction overnight, the precipitate is filtered off and then rinsed with ice-cold ethyl acetate. The powder obtained is then dried to give 2.96 g (13.7 mmol) of protected vitamin C (CV-100), i.e. an 80.6percent yield.
80%
at 25 - 30℃; for 5 h;
Methanesulfonic acid (13 mL, 0.200 mol) was dropwised to slurry of L-ascorbic acid (10 g, 0.568 mol) in acetone (400 mL). The mixture was stirred at 25-30° C. After 5 hours, the crystalline product separated. The crystals were collected by filtration, washed with cool acetone and dried in vacuum desiccators at 40° C. Gave 100 g of Formula I (0.463 mol; yield 80percent).
80.2%
at -5 - 20℃;
To a dried 1 L three-necked flask, 91.0 g of ascorbic acid and 450 mL of acetone were added. The temperature was cooled to -5° C. in an ice-salt bath; 200.0 g of concentrated sulfuric acid was dropped slowly for approximately 2.5 hours and the internal temperature of the solution was controlled to 0-5° C., stirred for 5.0 min, then the ice-salt bath was moved away; the temperature was increased naturally to room temperature, and the reaction was continued for 45 minutes; the reacting solution changed from colorless to pale yellow; then the reacting solution was subjected to vacuum filtration under reduced pressure and the filter cake was washed for several times with a small amount of acetone until the pH value was neutral; the filter cake was dried at 50° C. in a vacuum for 1-2 hours and 89.5 g of white solid powder was obtained the melting point of which is 215-217° C. The yield was 80.2percent.
74%
at 20℃;
5,6-Isopropylidene-L-ascorbic acid followed the procedure reported by Jung and Shaw (J. Am. Chem. Soc, 102 [1980] 6304). L-Ascorbic acid (10.01 g, 0.0568 mol) was added to a 125 mL Erlenmeyer flask with approximately 50 mL of acetone (0.681 mol). The slurry was stirred as 1 mL of acetyl chloride (0.0140 mol) was added. The mixture was corked, sealed with Parafilm and left to stir at room temperature for 2-3 hours. The flask was then stored in a refrigerator (7 °C) for 20-24 hours. The solid from this mixture was isolated by vacuum filtration, and was rinsed with cold acetone. After drying at room temperature, the solid weighed 9.09 g, (74percent). The identity of the solid as 5,6-isopropylidene-L-ascorbic acid was confirmed by NMR and a melting point of 202-205 °C (crude literature [J. Am. Chem. Soc, 102 (1980) 6304]: 195-200 °C); recrystallization from acetone/hexane did not improve the melting point (recrystallized literature [Can. J. Chem., 47 (1969) 2498]: 217-222 °C).1H NMR (Me2SO-d6) δ 1.255 (6H, s), 3.882 (1H, dd, J= 8.0, 6.8 Hz), 4.098 (1H, dd, J= 7.8, 8.0 Hz), 4.2615 (1H, td, J- 2.8, 6.6 Hz), 4.7095 (1H, d, 2.8 Hz), 8.482 (1H, s), 1 1.293 (1H, s).
67.2%
at 20℃; for 2 h;
Ascorbic acid (4g, 22.7mmol) was suspended in 2.5ml of anhydrous acetone. A catalytic amount of acetyl chloride (1.76ml, 24.7mmol) was then added and the reaction mixture was stirred for 2 hours at room temperature using a calcium chloride drying tube. The slurry was cooled to O0C, filtered, washed with cold acetone and dried under vacuum to yield 5,6-O-isopropylidene-ascorbic acid (3.57g, yield: 67.2percent) as a white solid. <n="17"/>1H NMR (d6-DMSO) δ 1.23 (6 H, s, 2 CHJ), 3.86 - 3.88 (1 η, dd, -0-CHH-CH(O)-), 4.05 -4.09 (1 H, dd, -0-CHZZ-CH(O)-), 4.24 - 4.25 (1 H, td, -O-CH2 -CH(O)-CH-), 4.71 (1 H, d,CH2-CH(O)-CZZ(O)-), 8.43 (1 H, broad s, OH), 1 1.27 (1 η, broad s, OH).13C NMR (d6-DMS0) 6 25.53, 25.92, 64.97, 73.54, 74.36, 109.13, 1 18.28, 152.51 , 170.37MS-ESI mlz 234.09 [M + Nη4]+CHN: Found (C=49.36percent, 5.65percent), Theoretical (C=50.00percent, 5.59percent)
11.3 g
at 0 - 20℃; for 3 h;
To 10.1 g of ascorbic acid was added 50 ml of acetone, and the mixture was stirred. 0.85 g (0.011 mol) of acetyl chloride was added slowly at 0 °C, and the mixture was stirred at room temperature for 3 hours. The reaction solvent was removed and the residue was subjected to silica gel column chromatography with ethyl acetate and n-hexane (1: 3) to obtain 8.66 g of white solid title compound.
9.55 g
at 20℃; for 3 h;
As vitamin C, L-ascorbic acid (10 g, 55 mmol) manufactured by Wako Pure Chemical Industries, Ltd. was dissolved in acetone, acetyl chloride (1 ml, 15 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The solid was separated by filtration, and the obtained solid was washed with acetone and then dried to obtain 5,6-isopropylidene vitamin C (aka: 5,6-isopropylidene ascorbic acid) of the chemical formula 18 (9.55 g, 44.2 mmol) was obtained as a white solid.
19.6 g
With toluene-4-sulfonic acid In dimethyl sulfoxide at 25℃; for 5 h;
20.6 g of L-ascorbic acid and 1.7 g of p-toluenesulfonic acid were added to a mixed solution of 100 ml of dimethyl sulfoxide and 40 ml of acetone to prepare an ascorbic acid solution.And the mixture was stirred at 25 DEG C for 5 hours to synthesize 3-O-isopropylidene ascorbic acid in the solution. At this time, the termination time of the reaction is determined by thin layer chromatography (TLC)After the reaction was completed, the solution was dried to obtain 19.6 g of 3-O-isopropylidene ascorbic acid.
Reference：
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[2] Tetrahedron Letters, 2010, vol. 51, # 32, p. 4199 - 4201
[3] Tetrahedron, 2005, vol. 61, # 18, p. 4341 - 4346
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[14] Patent: US2004/236098, 2004, A1, . Location in patent: Page 6
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6
[ 78619-96-2 ]
[ 67-64-1 ]
[ 15042-01-0 ]
Reference：
[1] Patent: CN105367524, 2016, A, . Location in patent: Paragraph 0025; 0026
7
[ 50-81-7 ]
[ 15042-01-0 ]
Reference：
[1] Patent: EP411182, 1991, A1,
8
[ 75-36-5 ]
[ 50-81-7 ]
[ 15042-01-0 ]
Reference：
[1] Patent: US5536500, 1996, A,
9
[ 814-68-6 ]
[ 50-81-7 ]
[ 15042-01-0 ]
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10
[ 216872-53-6 ]
[ 15042-01-0 ]
Reference：
[1] Australian Journal of Chemistry, 1999, vol. 52, # 2, p. 137 - 142
11
[ 15042-01-0 ]
[ 23735-43-5 ]
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[1] Tetrahedron: Asymmetry, 1995, vol. 6, # 5, p. 1181 - 1190
[2] Tetrahedron: Asymmetry, 1995, vol. 6, # 5, p. 1181 - 1190
[3] Journal of the American Chemical Society, 1980, vol. 102, # 20, p. 6304 - 6311
12
[ 15042-01-0 ]
[ 137-66-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 20, p. 5313 - 5316
13
[ 15042-01-0 ]
[ 60456-21-5 ]
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[1] Synthesis, 1988, # 1, p. 54 - 56
14
[ 15042-01-0 ]
[ 86404-04-8 ]
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[1] Journal of Medicinal Chemistry, 1992, vol. 35, # 9, p. 1618 - 1623
[2] Patent: CN105367524, 2016, A,
With trichlorophosphate; In acetone; at 20℃; for 4h;
To a magnetically stirred solution of AA (1.76 g, 10 mmol) in acetone (9 mL), phosphorus oxychloride (0.5 mL) was added and the reaction mixture was stirredfor 4 h at RT. Then it was filtered, washed with cold acetone-water and dried invacuo, leading to 5,6-O-isopropylidene-L-ascorbic acid 19 being obtained as colorless granules (1.92 g, 89%). IR (KBr, cm-1): numax 3242.6, 2993.3, 2907.6, 2741.6, 1755.5, 1665.4. 1H NMR (600 MHz, CD3COCD3): delta 4.71-4.73 (m, 1H, C4-H), 4.37-4.39 (m, 1H, C5-H), 4.16-4.21 (m, 1H, C6-H), 3.99-4.03 (m, 1H, C6-H), 1.29 (s, 6H, Me).
In acetone;
Example 1 Protection of Ascorbic Acid Oleum (24%, 8.3 g) was added dropwise to acetone (50 ml). Ascorbic acid (12 g) was introduced to the mixture at 0 C. and the reaction mixture was stirred at 0 C. for 6 hours. The obtained crystals were filtered off under suction, the filtered cake was pressed to dryness and then washed with acetone (30 ml). The product, 5,6-isopropylidene ascorbic acid (14 g) was obtained.
In water; acetone;
EXAMPLE 3 Preparation of 5,6-isopropylidene-L-ascorbic acid 55 g of 24% strength oleum were added dropwise to 480 ml of acetone (water content about 1.4%) at -10 C. 120 g of L-ascorbic acid were introduced into the resulting mixture at about 0 C., and the reaction mixture was stirred for 6 h at 0 C. It was then cooled to -15 C. and the crystals formed were filtered off under suction. The resulting filter cake was pressed dry, washed with twice 100 ml of ice cold acetone and dried at room temperature under reduced pressure from a water pump.
Zinc chloride; In 1,4-dioxane; acetone;
EXAMPLE 5 Preparation of 5,6-O-(1-methylethylidene)-L-ascorbic acid A reaction mixture was prepared from 88 g. of L-ascorbic acid, 400 ml. of dioxane, 200 g. of zinc chloride and 750 ml. of acetone. The reaction mixture was stirred at ambient temperature overnight, and then was washed over a silica gel 60 column using a toluene-methanol (1:1) solution as the eluant. 600 ml. of wash were collected and the solvent removed therefrom in vacuo. Acetone was added and the solid product filtered. The collected crystals were washed with toluene. A yield of 35.6 g. of 5,6-O-(1-methylethylidene)-L-ascorbic acid was recovered. The compound had the following physical characteristics: Infrared spectrum: nu at 1670, 1760, 3000, 3250 cm-1. Titration: pKa=6.10 Mass spectrum: peaks at 216 (M+), 201.
In acetone;
(1) Synthesis of L-5,6-O-isopropylideneascorbic acid which is a starting material Ascorbic acid in an amount of 180 g was stirred in 750 ml of acetone and warmed to 40C. Acetyl chloride in a volume of 20 ml was added, and stirring was continued to form a slurry layer. After 3 hours, the slurry layer was cooled with ice to collect deposited precipitates by filtration. The resulting precipitates were washed with a mixture of cold acetone-n-hexane (3:7) on a funnel and dried with silica gel under reduced pressure. Recrystallization from acetone was then carried out to provide 190 g of L-5,6-O-isopropylidene-ascorbic acid (melting point: 206-208C).
In acetone;
(1) Synthesis of L-5,6-O-isopropylideneascorbic acid Ascorbic acid in an amount of 180 g was stirred in 750 ml of acetone and warmed to 40C. Acetyl chloride in a volume of 20 ml was added, and stirring was continued to form a slurry layer. After 3 hours, the slurry layer was cooled with ice to collect deposited precipitates by filtration. The resulting precipitates were washed with a mixture of cold acetone-n-hexane (3:7) on a funnel and dried with silica gel under reduced pressure. Recrystallization from acetone was then carried out to provide 190g of L-5,6-O-isopropylidene ascorbic acid (melting point: 206-208C).
With 1,2-dimethoxypropane; toluene-4-sulfonic acid; In dimethyl sulfoxide; at 50℃; for 5h;
To the mixed solvent composed of 100 mL of dimethylsulfoxide and 40 ml of acetone were added 17.6 g of L- ascorbic acid, 15.6 g of 1, 2-dimethoxypropane and 1.2 g of p- tolusulfonic acid, followed by stirring for 5 hours at 50 C The produced reaction mixture was vacuum-distillated at 20 C to eliminate the remaining acetone and non-reacted 1,2- dimethoxypropane to give 20.5 g of the target compound (yield: 95%) .
94.4%
With toluene-4-sulfonic acid; for 4h;Cooling with ice;
To a 100 mL single flask was added 3.52 g of vitamin C, 2.76 g of p-toluenesulfonic acid, 15 mL of acetone, ice bath condition 4h, The filter cake was washed with ethyl acetate and dried in vacuo to give 4.08 g of 5,6-O-isopropylidene-L-ascorbic acid as a white solid in a yield of 94.4%.
93%
With toluene-4-sulfonic acid; at 25℃; for 8h;
70 g of ascorbic acid, 22 g of p-toluenesulfonic acid, 700 ml of acetone were added to a 1.5-liter single-necked flask, and the reaction was performed at room temperature (25 C) for 8 hours. A large amount of crystals were formed in the reaction solution. After filtration, the filter cake was washed with acetone, and vacuum dried to obtain 80 g of 5,6-0-isopropylidene-L-ascorbic acid crystals in a yield of 93%. After replenishing acetone and ascorbic acid, the reaction can be repeated to obtain 5,6-0-isopropylidene-L-ascorbic acid.
86%
With acetyl chloride; at 20℃; for 3h;
Preparation Example 1 : Preparation of ---5,6-O-isopropylidin-ascorbic acid; L-5,6-O-isopropylidin-ascorbic acid was prepared according to a method disclosed in Journal of the American Chemical Society, Vol. 102, No. 20, pp 6304,1980. That is, 100 g of ascorbic acid was added to 50 ml of acetone. While the reaction mixture was stirred at room temperature, 10 ml of acetyl chloride was <n="16"/>added to the mixture, which was then stirred for 3 hours. The mixture was cooled in ice bath and filtered to isolate a precipitate. The precipitate was washed with 500 ml of cold acetone and dried under reduced pressure to obtain 105 g of L-delta.e-O-isopropylidin-ascorbic acid (yield: 86%, mp: 206-208 C). 1H NMR (400MHz, CDCL3), Chemical shift; 5.50 (1 H, d), 5.18 (1 H1 m),4.20(2H, t), 2.52(2H, m), 2.51 (4H, t), 2.25-1.55 (12H, m)
toluene-4-sulfonic acid; In acetone; at 20 - 30℃; for 2h;Inert atmosphere; Industry scale;
i) 5,6-O-Isopropylidene-L-Ascorbic Acid To a mixture of L-ascorbic acid (65 kg, 369 mol), acetone (283 kg) and 2,2-dimethoxypropane (46 kg, 443 mol) was charged p-toluenesulfonic acid (1.1 kg, 5.5 mol). Temperature was adjusted to 25±5 C. The slurry was stirred for 2 hours, during which time nitrogen was frequently flushed through the bottom valve to prevent material from settling at the bottom of the reactor. NMR analysis (solvent: D2O) then showed 98.5% conversion. Heptanes (222 kg) were charged and the temperature adjusted to 5±5 C. The reaction mixture was stirred for at least 30 minutes before filtering. Remains of the acetonide product in the reactor were rinsed onto the filter cake using the mother liquors. The filter cake was washed with heptanes (111 kg) and dried at 50 C. to give 5,6-O-isopropylidene-L-ascorbic acid (73 kg, 336 mol) as an almost white powder. Yield: 91%. 1H NMR (400 MHz, d6-DMSO, with maleic acid and TFA) delta4.71 (d, J=3.0 Hz, 1H), 4.28 (m, 1H), 4.11 (dd, J=7.0, 8.4 Hz, 1H), 3.90 (dd, J=6.3, 8.4 Hz, 1H), 1.27 (s, 6H).
91%
With toluene-4-sulfonic acid; In acetone; at 25℃; for 2h;Inert atmosphere; Large scale;
To a mixture of L-ascorbic acid (65 kg, 369 mol), acetone (283 kg) and 2,2- dimethoxypropane (46 kg, 443 mol) was charged /?-toluenesulfonic acid (1.1 kg, 5.5 mol). Temperature was adjusted to 25±5C. The slurry was stirred for 2 hours, during which time nitrogen was frequently flushed through the bottom valve to prevent material from settling at the bottom of the reactor. NMR analysis (solvent: D20) then showed 98.5 % conversion. Heptanes (222 kg) were charged and the temperature adjusted to 5±5C. The reaction mixture was stirred for at least 30 minutes before filtering. Remains of the acetonide product in the reactor were rinsed onto the filter cake using the mother liquors. The filter cake was washed with heptanes (111 kg) and dried at 50C to give 5,6-O-isopropylidene-L-ascorbic acid (73 kg, 336 mol) as an almost white powder. Yield: 91%. 1H NMR (400 MHz, d6-DMSO, with maleic acid and TFA) delta 4.71 (d, J= 3.0 Hz, 1H), 4.28 (m, 1H), 4.11 (dd, J= 7.0, 8.4 Hz, 1H), 3.90 (dd, J= 6.3, 8.4 Hz, 1H), 1.27 (s, 6H).
91%
With toluene-4-sulfonic acid; In acetone; at 20 - 30℃; for 2h;Inert atmosphere; Industrial scale;
To a mixture of L-ascorbic acid (65 kg, 369 mol), acetone (283 kg) and 2,2-dimethoxypropane (46 kg, 443 mol) was charged /p-toluenesulfonic acid (1.1 kg, 5.5 mol). Temperature was adjusted to 25±5C. The slurry was stirred for 2 hours, during which time nitrogen was frequently flushed through the bottom valve to prevent material from settling at the bottom of the reactor. NMR analysis (solvent: D20) then showed 98.5 % conversion. Heptanes (222 kg) were charged and the temperature adjusted to 5±5C. The reaction mixture was stirred for at least 30 minutes before filtering. Remains of the acetonide product in the reactor were rinsed onto the filter cake using the mother liquors. The filter cake was washed with heptanes (111 kg) and dried at 50C to give 5,6-O-isopropylidene-L-ascorbic acid (73 kg, 336 mol) as an almost white powder. Yield: 91%. 1H NMR (400 MHz, d6-DMSO, with maleic acid and TFA) delta 4.71 (d, J= 3.0 Hz, 1H), 4.28 (m, 1H), 4.11 (dd, J= 7.0, 8.4 Hz, 1H), 3.90 (dd, J= 6.3, 8.4 Hz, 1H), 1.27 (s, 6H).
86%
With camphor-10-sulfonic acid; In acetone; at 20℃;
This material was prepared according to literature precedence (Bioorg. Med. Chem. 2003, vol. 11, 827). To a suspension of L-ascorbic acid (20.0 g, 114 mmol) in acetone (200 mL) was added 2,2-dimethoxypropane (20.4 g, 196 mmol) and 10- camphorsulfonic acid (1.32 g, 5.68 mmol). The resultant mixture was allowed to stir overnight at room temperature. To the resultant slurry was added approximately 0.6 g tri ethyl amine. A portion of hexane was added to the mixture, and the white precipitate was collected via vacuum filtration, washing with additional hexane. The material was dried under vacuum to afford the desired product (21.0 g, 86% yield). NMR was consistent with the desired product.
82%
With tin(ll) chloride; In acetone; for 6h;Reflux;
A mixture of l-Ascorbic acid compound 1 g (2 mmol) and acetone(15 mL) was stirred for 15 min. 2,2-Dimethoxy propane(1.25 mL) and catalytic amount of tin chloride was added to thereaction mixture and it was refluxed for 6 h. Cooled the reactionmixture to 5-10 C and stirred for 45 min at room temperature.The precipitated was filtered, washed with acetone and dried toget the compound 2A. Yield: 82%; M.P: 206 C. TLC: 100 DCM: 20EA: 10 ethanol: 1 Acetic acid.
79%
With hydrogenchloride; In methanol; at 20 - 25℃; for 4h;
To the solution of L-Ascorbic acid (100 g, 568 mmol) in 200 mL acetone was treated with 2,2-dimethoxypropane (118 g, 1.13 mmol), and Hydrochloric acid (4 M in methanol, 60 mL). The reaction mixture was stirred at room temperature for 4 h. the mixture was filtered and the filter cake was washed with 10 mL acetone and dried in vacuum to afford 37 (90 g, 79%) as a white solid.
With hydrogenchloride; In acetone;
EXAMPLE 6 The mixture of 80 ml of acetone, 16 g of L-ascorbic acid and 18.8 ml of 2,2-dimethoxypropane was stirred for 15 minutes at room temperature. Hydrogen chloride was added slowly through bubbler to the reaction mixture over 5 minutes and the mixture was stirred for 1 hr at room temperature. Half volume of acetone was evaporated off under reduced pressure. The mixture was cooled in an ice bath, and the resulting precipitates were filtered and washed with 30 ml of cold acetone to give 15.2 g of 5,6-O-isopropylidene-L-ascorbic acid. Then mother liquor was concentrated to give 3.8 g of 5,6-O-isopropylidene-L-ascorbic acid.
With hydrogenchloride; In acetone;
EXAMPLE 1 5,6-O-isopropylidene L-ascorbic acid In a 12-L round bottom flask was placed 8,000 mL acetone, 1,600 g L-ascorbic acid, 1,880 mL 2,2-dimethoxypropane and the mixture was stirred for 1/4 hr; hydrogen chloride was added slowly through bubbler over 2-4 min (color of solution changed from colorless to dark yellow). The mixture was stirred for 1 hr and became very viscous. The product was filtered, washed with cold acetone and the solid was then air dried in hood to give 1,521 g of 1st crop of 5,6-O-isopropylidene-L-ascorbic acid. The mother liquor was concentrated to give 225 g of 2nd crop and 162 g of 3rd crop of 5,6-O-isopropylidene-L-ascorbic acid.
50 mg
With hydrogenchloride; In acetone; at 25 - 30℃; for 4h;
A mixture of L-Ascorbic acid compound of formula-3 (50 gm) and acetone (250 ml) was stirred for 15 minutes. 2,2-Dimethoxy propane (62.5 ml) was added to the reaction mixture. Acidified the reaction mixture by using HCl gas and stirred for 4 hrs at 25-30C. Cooled the reaction mixture to 5-10C and stirred for 45 minutes at the same temperature. The precipitated solid was filtered, washed with acetone and dried to get the title compound. Yield: 50 gm; M.R: 205-210C.
To 100 mL of DMF were added 20.5 g (0.095 mol) of 5, 6-O- isopropylidene ascorbic acid prepared in Example 1 and 1.0 g of the anion exchange resin absorbed with multi-iodine anions, to which 12.3 g (0.11 mol) of ethylbromide was slowly loaded at room temperature with stirring. Upon completion of the loading, stirring at room temperature was continued for 3 hours and then the anion exchange resin absorbed with multi-iodine anions was filtered from the reaction mixture. DMF and ethylbromide were eliminated by vacuum-distillation. Then, 180 ml of water and ethylacetate (120 ml x 2) were added to separate an organic layer, which was then collected. The organic layer was concentrated under the reduced pressure and the residue was re- crystallized in ethylacetate/hexane (1:1) to give 22.0 g of 3-0- <n="11"/>ethyl-isopropylidene ascorbic acid (yield: 95%) . mp : 105-1060C1H NMR(MeOH-d4) ppm, deltal.28(6H,S) 1.34 (3H,t) 4.12(3H,m) 4.51(2H,q) 4.65 (IH, d, 3Hz)
95%
With anion exchange resin with multi-iodide anions; In N,N-dimethyl-formamide; at 20℃;
Example 2 Synthesis of L-3-O-ethyl-isopropylidene Ascorbic Acid To 100 mL of DMF were added 20.5 g (0.095 mol) of 5,6-O-isopropylidene ascorbic acid prepared in Example 1 and 1.0 g of the anion exchange resin absorbed with multi-iodine anions, to which 12.3 g (0.11 mol) of ethylbromide was slowly loaded at room temperature with stirring. Upon completion of the loading, stirring at room temperature was continued for 3 hours and then the anion exchange resin absorbed with multi-iodine anions was filtered from the reaction mixture. DMF and ethylbromide were eliminated by vacuum-distillation. Then, 180 ml of water and ethylacetate (120 ml*2) were added to separate an organic layer, which was then collected. The organic layer was concentrated under the reduced pressure and the residue was re-crystallized in ethylacetate/hexane (1:1) to give 22.0 g of 3-O-ethyl-isopropylidene ascorbic acid (yield: 95%). mp: 105~106 C. 1H NMR (MeOH-d4) ppm, delta 1.28 (6H,S) 1.34 (3H, t) 4.12 (3H, m) 4.51 (2H, q) 4.65 (1H, d, 3 Hz)
62%
First, <strong>[15042-01-0](R)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxyfuran-2(5H)-one</strong> (4.32 g) was dissolved in dimethyl sulfoxide (25 mL), sodium bicarbonate (2.52 g) was added to the solution at room temperature, and the resulting mixture was stirred for 20 minutes. Subsequently, ethyl bromide (3.27 g) was added. The temperature of the thus obtained reaction mixture was raised to 50C, and the mixture was then stirred at that temperature for 17 hours. The reaction mixture was then cooled to room temperature, poured into water, acidified by addition of 1 N hydrochloric acid, and then extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The thus obtained concentrate was purified by silica gel column chromatography. (R)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-ethoxy-3-hydroxyfuran-2(5H)-one was obtained in an amount of 3.03 g, a yield of 62%.
16.2 g
With sodium hydrogencarbonate; In dimethyl sulfoxide; at 70℃; for 2h;
Weigh 30 grams of <strong>[15042-01-0]5,6-O-isopropylidene-L-ascorbic acid</strong>, dissolve in 120 ml of DMSO, add 7.6 grams of bromoethane, 11.6 grams of sodium bicarbonate, and then react at 70 C for 2 hours.After cooling to room temperature (25 C), it was extracted three times with 1000 ml of toluene. The extract was washed with water and concentrated to crystallize to obtain 16.2 g of 3-O-ethyl-5,6-O-isopropylidene ascorbic acid. The calculated yield is 95%.
To the equipped with mechanical stirrer, reflux condensation tube, thermometer of 100 ml is added to the three-mouth flask of 5, 6 - O - isopropylidene - L - anti-blood acid 2.16g, sodium carbonate 1.06g, benzyl bromide 1.20 ml, acetone 20 ml, backflow state reaction 4h, treat the above-mentioned solution is cooled to room temperature, the reaction liquid is washed by water, ethyl acetate (3 × 20 ml) extraction, salt wash with saturated sodium chloride solution, anhydrous magnesium sulfate drying, filtering, atmospheric evaporate ethyl acetate, column chromatography (petroleum ether: ethyl acetate=3:1) purification of a bright yellow oil of, to get the 3 - O - benzyl - 5, 6 - O - isopropylidene - L - anti-blood acid 1.89g, yield is 61.8%.
Acetonide protected ascorbic acid (5 g) was dissolved in 100 mL of DMSO / THF (9/8) mixed solvent, and anhydrous K 2 CO 3 (3.8 g) was added thereto and stirred for about 30 minutes.BnBr (3.3 mL) was added to the reaction mixture and stirred at room temperature for about 5 hours.The reaction solvent was removed using a rotary evaporator and extracted with water and ethyl acetate (EtOAc). The organic solvent was dried over anhydrous MgSO 4, filtered, and the solvent was removed. The resulting residue was purified by silica gel chromatography (Hexane: EtOAc = 3/1).
23.5 g
With sodium carbonate; In N,N-dimethyl-formamide; at 70℃; for 2h;
Weigh 30 grams of <strong>[15042-01-0]5,6-O-isopropylidene-L-ascorbic acid</strong>, dissolve in 120 ml of DMF, add 14.3 grams of bromobenzyl, 14.7 grams of sodium carbonate, and then react at 70 C for 2 hours.After cooling to room temperature (25 C), it was extracted three times with 1,000 ml of toluene. The extract was washed with water and concentrated to crystallize to obtain 23.5 g of 3-O-benzyl-5,6-O-isopropylidene ascorbic acid, calculated as benzyl bromide. The yield was 92%.
With potassium carbonate; In acetone; for 6h;Reflux;
a) (5R)-5-[(45)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-hydroxy-4-(methoxymethoxy)-2,5-dihydrofuran-2-one 3.86 g of anhydrous K2CO3 (28 mmol) is added to a solution of 5,6-isopropylidene ascorbic acid (6.0 g, 27.7 mmol) in acetone (145 mL) and the mixture is stirred vigorously. 2.1 mL of chloro(methoxy)methane (28 mmol) in acetone (10 mL) is added dropwise over a time of two hours. Stirring is continued under reflux for a further 4 h. After cooling, the solid is filtered and washed with acetone. The filtrate was concentrated under vacuum and the residue is purified by silica gel chromatography, eluting with cyclohexane/EtOAc/acetone 6:1:1 mixture to give the compound methoxymethyl ether in the form of a white solid (4.7 g, 65%). 1H NMR (CDCl3, 300 MHz) delta: 7.00-6.50 (broad s, 1H, OH), 5.33 (d, J=6.02 Hz, 1H, MeOCH2O), 5.31 (d, J=6.0 Hz, 1H, MeOCH2O), 4.56 (d, J=3.3 Hz, 1H, H-4), 4.26 (td, J=6.7 Hz, J=3.3 Hz, 1H, H-5), 4.10 (dd, J=8.5, 6.8 Hz, 1H, H-6), 3.98 (dd, J=8.5 Hz, J=6.7 Hz, 1H, H-6), 3.54 (s, 3H, CH3OCH2), 1.30 (s, 3H, OC(CH3)2O), 1.24 (s, 3H, OC(CH3)2O).
With dihydrogen peroxide; sodium hydrogencarbonate; sodium hydroxide; In water; at 35 - 60℃; for 3h;Large scale;
5,6-O-Isopropylidene-L-ascorbic acid (58.8 kg, 272 mol) was charged to sodium hydroxide solution (27.5 kg, 50%>, 340 mol) diluted with water (294 kg), and the temperature was adjusted to 30 ± 5C. Sodium bicarbonate (57 kg, 680 mol) was charged and the mixture was agitated for 15 minutes before the temperature was increased to 40 ± 5C. Hydrogen peroxide 35% (55 kg, 562 mol) was added to the mixture at 35 - 60C over a period of more than 60 minutes. The reaction mixture was agitated for two hours before NMR analysis (solvent: D20) showed Sodium sulfite (4.2 kg, 33 mol) was charged to the reactor and after stirring for 30 minutes, a test for peroxides was negative. After charging more sodium bicarbonate (34 kg, 408 mol), the mixture was heated to 70 ± 5C and agitated for at least one hour before NMR analysis (solvent: D20) showed 98.5% conversion to the next intermediate, (2i?)-[(45)-2,2-dimethyl-l,3-dioxolan-4- yl](hydroxy)ethanoic acid. Approximately 150 L of water was stripped off under reduced pressure before filtering off salts. The filter cake was washed with water (30 L). NMP (330 kg) was charged to the combined mother liquors/wash and the temperature was adjusted to 30 ± 5C. Methyl iodide (83 kg, 585 mol) was charged and the reactor closed. The temperature was adjusted to 55 ± 5C and the reaction mixture was left to react for at least 120 minutes before NMR analysis (solvent: D20) showed 6% of the residual hydroxy ethanoic acid intermediate. Sodium sulfite (56 kg, 446 mol) dissolved in water (147 kg) was charged and the mixture was agitated for 30 minutes. The solution was extracted four times for 10 minutes at 30 ± 10C using 406 kg toluene in each extraction. The combined organic phase was concentrated by stripping off solvent, under reduced pressure and a maximum temperature of 70C, until a residual volume of approximately 350 L was reached. The solution was cooled to below 30C and transferred to steel barrels over a Millipore filter to give (i?)-methyl 2-((S)- 2,2-dimethyl-l,3-dioxolan-4-yl)-2-hydroxyacetate solution in toluene (359 kg, 9.4%, 177 mol). Yield: 65%. 1H NMR consistent with commercially available sample of the sub-title product.
5,6-O-Isopropylidene-L-ascorbic acid (58.8 kg, 272 mol) was charged to sodium hydroxide solution (27.5 kg, 50%, 340 mol) diluted with water (294 kg), and the temperature was adjusted to 30 ± 5C. Sodium bicarbonate (57 kg, 680 mol) was charged and the mixture was agitated for 15 minutes before the temperature was increased to 40 ± 5C. Hydrogen peroxide 35% (55 kg, 562 mol) was added to the mixture at 35 - 60C over a period of more than 60 minutes. The reaction mixture was agitated for two hours before NMR analysis (solvent: D20) showed <1% residual starting material. Sodium sulfite (4.2 kg, 33 mol) was charged to the reactor and after stirring for 30 minutes, a test for peroxides was negative. After charging more sodium bicarbonate (34 kg, 408 mol), the mixture was heated to 70 ± 5C and agitated for at least one hour before NMR analysis (solvent: D20) showed 98.5% conversion to the next intermediate, (2R)-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl](hydroxy)ethanoic acid. Approximately 150 L of water was stripped off under reduced pressure before filtering off salts. The filter cake was washed with water (30 L). NMP (330 kg) was charged to the combined mother liquors/wash and the temperature was adjusted to 30 ± 5C. Methyl iodide (83 kg, 585 mol) was charged and the reactor closed. The temperature was adjusted to 55 ± 5C and the reaction mixture was leftto react for at least 120 minutes before NMR analysis (solvent: D20) showed 6% of the residual hydroxy ethanoic acid intermediate. Sodium sulfite (56 kg, 446 mol) dissolved in water (147 kg) was charged and the mixture was agitated for 30 minutes. The solution was extracted four times for 10 minutes at 30 ± 10C using 406 kg toluene in each extraction. The combined organic phase was concentrated by stripping off solvent, under reduced pressure and a maximum temperature of 70C, until a residual volume of approximately 350 L was reached. The solution was cooled to below 30C and transferred to steel barrels over a Millipore filter to give (R)-methyl 2-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-hydroxyacetate solution in toluene (359 kg, 9.4%, 177 mol). Yield: 65%. 1H NMR consistent with commercially available sample of the sub-title product.
50 g of L-5,6-O-isopropylidin-ascorbic acid prepared in Preparation Example1 was added to 70 ml of dimethylformamide. 64 g of calcium carbonate was added to the reaction mixture, which was then stirred for 30 minutes. 60 ml of benzyl bromide was gradually added to the reaction mixture, which was then stirred overnight at room temperature. The reaction mixture was distilled under reduced pressure to remove the solvent, and 300 ml of dichloromethane was added thereto. The reaction mixture was washed with water and further distilled under reduced pressure to obtain a brown solid. The obtained brown solid was added to methanol to remove un-reacted reactants and byproducts (i.e., a compound having a single benzyl group). The obtained reaction mixture was dried to obtain 65 g of L-5,6-O-isopropylidin-2,3-dibenzyl-ascorbic acid (yield: 71 %).
With potassium carbonate; acetic acid; In tetrahydrofuran; N,N-dimethyl-formamide;
(1) Synthesis of 2,3-O-dibenzyl-<strong>[15042-01-0]5,6-O-isopropylidene-L-ascorbic acid</strong> (known compound) In a mixture of N,N-dimethylformamide (300 ml) and tetrahydrofuran (250 ml) was dissolved 100 g of <strong>[15042-01-0]5,6-O-isopropylidene-L-ascorbic acid</strong> followed by addition of 128 g of potassium carbonate. While this mixture was held at a temperature not over 30 C. with stirring, 206 g of benzyl bromide was added dropwise. This reaction mixture was neutralized by adding 60 ml of acetic acid and 800 ml of purified water and extracted with 800 ml of dichloromethane. The extract was washed with 400 ml of saturated aqueous sodium hydrogen carbonate solution, dehydrated over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from 500 ml of ethyl acetate and 50 ml of isopropyl ether and the crystal crop was dried in vacuo to provide 80 g of 2,3-O-dibenzyl-<strong>[15042-01-0]5,6-O-isopropylidene-L-ascorbic acid</strong>.
With potassium carbonate; In acetone; for 4h;Reflux;
Compound 5 (6 g, 27.75 mmol) and K2CO3 powder (11.3 g, 81.5 mmol) were suspended in acetone (distilled, 100 ml). After reflux, benzyl bromide (8.74 ml?73.6 mmol) was added and the mixture was allowed to reflux for another 4 h. The solvent was removed under reduced pressure. The residue was treated with proper H2O and Et2O. After filtrated, the title compound 6 was afford as a white solid, which was used without purification. Yield (44.1%).
With pyridine; In dichloromethane;Cooling with ice;
5,6-Isopropylidene-2-O-acetyl-L-ascorbic acidThe synthesis of 5,6-isopropylidene-O-acetyl-L-ascorbic acid generally followed the synthesis of the other 2-O-acyl derivatives, but was slightly altered due to the increased reactivity of the starting material and suspected increased water solubility of the product. 5,6-Isopropylidene-L-ascorbic acid (1.00 g; 0.00463 mol) was added to a 150 mL round-bottom flask with acetyl chloride (0.38 g; 0.00484 mol) and approximately 20 mL of ice cold dichloromethane. The mixture was stirred as 0.76 mL of pyridine (0.00935 mol) dissolved in approximately 15 mL of cold dichloromethane was added. The reaction mixture was stirred overnight in an ice bath. The mixture was then diluted with approximately 100 mL of dichloromethane and washed with three 5 mL aliquots of 1 M HCl. The organic layer was dried over sodium sulfate for 1 hour before being concentrated in vacuo without heating to a white solid weighing 0.91 g (76.1%). Due to instability observed in the other 2-O-acyl derivatives, the crude product was moved forward to the next reaction. 1H NMR (CDCl3) delta 1.379 (3H, s), 1.406 (3H, s), 2.361 (3H, s), 4.102 (1H, dd, J= 6.8, 8.8 Hz), 4.208 (1H, dd, J = 7.0, 8.2 Hz), 4.439 (1H, td, J = 2.8, 6.8 Hz), 4.696 (1H, d, J= 2.4 Hz).
76.1%
With pyridine; In dichloromethane;Cooling with ice;
The synthesis of 2-O-acetyl-5,6-isopropylidene-L-ascorbic acid generally followed the synthetic procedure used for the other 2-O-acyl derivatives, but was slightly altered due to the increased reactivity of the acyl chloride (acetyl chloride) and suspected increased water solubility of the product. 5,6-Isopropylidene-L-ascorbic acid (1.00 g, 0.00463 mol) was added to a 150 mL round-bottom flask containing acetyl chloride (0.38 g, 0.00484 mol) in 20 mL of ice-cold dichloromethane. The mixture was stirred as 0.76 mL of pyridine (0.00935 mol) dissolved in 15 mL of cold dichloromethane was added. The reaction mixture was allowed to stir overnight in an ice bath. The mixture was then diluted with 100 mL of dichloromethane and quickly washed three times with 5 mL aliquots of 1 M HCl. The organic layer was dried over sodium sulfate for 1 hour before being concentrated in vacuo without heating to give a white solid weighing 0.91 g (76.1%). Due to the instability observed in the other 2-O-acyl derivatives, the crude product was moved forward without further purification to a 3-O-alkylation reaction as described below.
With dicyclohexyl-carbodiimide;dmap; In tetrahydrofuran; ethyl acetate; at 25℃; for 8h;
CV-104 prepared in example 1.1 (265 mg, 0.5 mmol) is dissolved in 10 ml of anhydrous EtOAc over about 15 minutes. In parallel, CV-100 prepared in example 3.1 (108 mg, 0.5 mmol, 1 eq) is dissolved in 2 ml of anhydrous tetrahydrofuran (THF) (or 0.2 ml of dimethylformamide, or DMF), followed by 5 ml of anhydrous ethyl acetate, and the solubility is checked after 5-10 minutes. The solution of CV-100 is added to that of CV-104, the solution remains clear, and DMAP (catalytic) and DCC (113 mg, 0.55 mmol, 1.1 eq) are added thereto. The precipitate forms immediately and the reaction is monitored by tlc (CH2Cl2/EtOAc/MeOH 8:1:1). The reaction is virtually complete after 8 hours. The mixture is filtered and washed very quickly with 0.1N HCl, and the organic phase is dried over MgSO4 and then evaporated to give CV-106 in the form of a white foam (386 mg). The coupling appears to take place mainly at C2 rather than at C3 of vitamin C. Specifically, the NMR data are more in accordance with the previously described C2 esters (Cabral J., J. Org. Chem. (1988), 53, 5742-50). The product is purified by HPLC (30 mg) column of silica 15-25, eluent CH2Cl2/EtOAc/NEt3 (9:1:0.5%) then CH2Cl2/EtOAc/NEt3/MeOH (9:1:0.5:2%). Appearance: white foamy powderRf (EtOAc/CH2Cl2/MeOH 1:8:1): 0.38; (EtOAc/CH2Cl2/MeOH 1:8:2): 0.48. 1H NMR (CDCl3, 250 MHz): 4.66 (d, 1H, C4 vitC) ; 4.39 (ddd, 1H, C5 vitC) ; 4.1 (td, 2H, C6 vitC, 3J6-5=7.2, 2J6-6?=19); 2.92, 2.76 (2t, 4H, H(Cac succ), 3J=6, 6); 2.58 (t, 2H, H(C4), 3J=6); 2.08, 2.0, 1.97 (3 s, 9H, CH3(C5), CH3(C7), CH3(C8)); 1.8-1.7 (m, 2H, H(C3)); 1.7-1.09 (broad multiplet, 23H, 10?CH2, 3?CH tocopherol); 0.87, 0.85 (2 s, 12H, 4?CH3 tocopherol). 13C NMR (CDCl3, 50 MHz): 171.65, 171.12 (s, 2?C=Oester) ; 159.12 (s, C3 vitC); 149.61 (s, C6); 140.46 (s, C8a); 126.58 (s, C7) ; 124.89 (s, C5) ; 123.16 (s, C8); 117.54 (s, C4a); 114.39 (s, C2 vitC) 110.57 (s, C7 vitc); 75.16 (s, C2); 75.10 (d, C4 vitC) ; 73.68 (d, C5 vitC); 65.32 (t, C6 vitC); 39.43 (t, C1?); 37.46 (t, C3); 32.84, 32.76, 29.00 (d, C8?+C4?+C12?); 31.09, 29.78, 28.99, 28.90, 28.70, 28.57, 24.88, 24.51, 21.09, 20.65 (t, C7?+C9?+C3?+C5?+C11?+C10?+C6?+C2?+C4+2?CH2 ac succ); 25.86, 25.61 (q, C8 and 8? vitC); 21.09, 20.65 (q, CH3(C2)+2?C13?); 22.81, 22.72, 13.00, 12.15, 11.89 (q, CH3(C8?+C4?)+CH3(C8+C7+C5)). IR (NaCl) : 3248, 2929, 2856, 1756, 1670, 1605, 1453, 1409, 1374, 1322, 1256, 1213, 1141, 1066, 885, 852, 820, 736, 700. MS (CI, NH3): 746 ([MNH4]+, 96); 728 ([M]+, 2.6); 612 (6.7); 548 [MNH4]+ of CV-104 (20.3); 423 (16); 234 [MNH4]+ of CV-100 (59). EA for C42H64O10 (728): calc. C, 69.20; H, 8.85; exp. C, 67.17; H, 8.83.
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 14.5h;
- H 1) TBS-CI, DIPEA HO H 900 THF, rt HO > / - HO OH 2) BF3-Et2, propanedithiol HO OTBS CH2CI2 HPLC: Alltech Rocket, PLATINUM-C18, 100A, 3 URN, 7 x 53 mm, PN 50523; Temperature: 25C ; Mobile phase: (A = 0.025 % TFA in water; B = 0.025% TFA in acetonitrile), 90% A/10% B (start); linear gradient to 30% B over 3 min; linear gradient to 90% B over 3 min, hold for 2 min; linear gradient to 90% A/10% B over 1 min, then hold for 1 min; Flow rate: 2.5 ML/MIN ; Detector wavelength: 256 NM. To a stirring solution of 5,6-isopropyledine ascorbic acid (100.0 g, 463 mmol) in 1.00 L THF was added tert-butyldimethylsilyl chloride (TBSC1) (76.7 g, 509 mmol) at rt followed by addition OF N, N- diisopropylethylamine (DIPEA) (161 mL, 925 mmol) over 30 min. The reaction was stirred 14 h at rt, then concentrated under vacuum. The mixture was dissolved in methyl tert-butyl ether (MTBE) (1.00 L) and extracted with 1 M potassium carbonate (1.00 L) in a separatory funnel. The aqueous layer was extracted one more time with MTBE (1.00 L), and the pH of the aqueous layer was adjusted to pH 6 using 2 N HC1. The aqueous layer was extracted twice with isopropyl acetate (IPAC) (1.00 L) and concentrated to afford an off white solid (150.4 g, 98% yield) : H-NMR (DMSO d6) 8 11.3 (1 H, s), 4.78 (1 H, d, J=2.0 Hz), 4.41-4. 36 (1 H, m), 4.11 (1 H, dd, J=8.4, 7.4 Hz), 3.92 (1 H, dd, J=8.4, 6.0), 1.24 (3 H, s), 1.23 (3 H, s), 0.92 (9 H, s), 0.14 (6H, s); HPLC 5. 9 min [91.6% (AUC) ]; Mass spectroscopy-ESI, m/z=329.2 (M-H-).
In acetone; at 5 - 20℃; for 22.5h;Inert atmosphere;
To a solution of L-ascorbic acid 5 (20.01 g, 113.6 mmol, 1.0 eq) in acetone (80 mL) was added acetyl chloride (2.1 mL, 29.9 mmol, 0.26 eq) at room temperature. After stirring for 3.5 h at room temperature, the reaction mixture was stored in the refrigerator (5 C) for 19 h. The solid was then filtered off and washed with a small amount of cold acetone to afford 6 as a colorless solid (22.36 g, 103.4 mmol, 91%)
77%
In potassium hydroxide; acetone;
EXAMPLE 1 5,6-O-isopropylidene-L-ascorbic acid was synthesised by the addition of acetyl chloride (124.9 mL) to a slurry of L-ascorbic acid USP (1000 g) in acetone (4.5 L). The mixture was stirred vigorously at 35-30 C. After two hours, the crystalline product separated. The crystals were collected by filtration, washed with cold acetone, and dried in a vacuum desciccator over potassium hydroxide pellets. The product, produced in 77% yield, consisted of needle-shaped crystals with a melting point of 217-223 C.
In acetone;
EXAMPLE 1 Synthesis of Lauryl-2-O-L-Ascorbyl-Phosphate Initially, 5,6-O-isopropylidene-L-ascorbic acid (IAA) was prepared by adding L-ascorbic acid (100 gm, 0.57 mole) into a three-necked 1-liter flask equipped with a mechanical stirrer and a thermometer. The L-ascorbic acid was followed by acetone (450 ml) and acetyl chloride (12.5 ml), and the whole mixture was stirred vigorously at 30-40 C. for 2 hours.
In acetone; at 20℃; for 16h;
Specifically, Compound 1 Vitamin C (5 g) was added to a 100 mL round bottom flask.Then 40 mL of acetone was added and stirring was started.Acetyl chloride (1.0 eq.) was uniformly added to the flask at room temperature.The reaction was stirred at room temperature for 16 hours.Filter and filter cake was washed with a small amount of acetone (10 mL).Solid drying gave Compound 2.
In acetone;
5,6-0-Isopropylideneascorbic acid Acetylchloride (0.67 ml)was added to a rapidly stirred suspension of ascorbic acid (8.0 g) in acetone (80 ml) and the mixture was stirred at room temperature overnight. The precipitate was collected by filtration, washed with ethyl acetate, and dried at reduced pressure to afford 8.29 g of 5,6-0-Isopropylideneascorbic acid as a colorless solid. TLC (silica gel: CHCl3 /MeOH/HOAC [3:1:0.1], Rf=0.54).
L-5,6-0-isopropyliden-2,3-di-α-lipoyl-ascorbic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
76%
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; at 20℃;
3 g of L-delta^-O-isopropylidin-ascorbic acid prepared in Preparation Example 1 and 6.01 g of alpha-lipoic acid were added to 100 ml of dichloromethane. While stirring the reaction mixture, 5.59 g of 3-dimethyl-aminopropyl-N-ethyl carbodiimide was gradually added to the reaction mixture over the period of 30 minutes. 500 mg of N,N'-dimethylaminopyridine was added to the reaction mixture, which was then stirred overnight at room temperature. The reaction mixture was distilled under reduced pressure and 100 ml of ethyl acetate was added to the resulting residue. Then, the resultant was washed three times with 1 N hydrochloric acid and water. The resultant was distilled under reduced pressure to remove the solvent and dried in vacuo to obtain 6.25 g of L-5,6-0-isopropylidin-2,3-di-alpha-lipoyl-ascorbic acid as a solid (yield: 76 %).
L-5,6-O-isopropyliden-2-α-lipoyl-ascorbic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
92%
With pyridine; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃;
Example 1 and 20 g of alpha-lipoic acid were added to 200 ml of pyridine. While stirring the reaction mixture, a solution of 24 g of dicyclohexyl carbodiimide in 50 ml of dichloromethane was gradually added to the reaction mixture, which was then stirred at room temperature overnight. The resultant was distilled under reduced pressure, and then extracted by adding 200 ml of ethyl acetate thereto. The obtained organic layer was washed three times with a saturated aqueous solution of sodium carbonate. The resultant was concentrated under reduced pressure, and 300 ml of a mixed solvent of ether and hexane (1 :1 , v/v) was added thereto. The resultant was cooled to -10C and then filtered. The filtrate was dried to obtain 32 g of L-5,6-O-isopropylidin-2-alpha-lipoyl-ascorbic acid (yield: 92%).
With toluene-4-sulfonic acid; In dimethyl sulfoxide; acetone; at 50℃; for 5h;
Example 1 Synthesis of 5,6-O-isopropylidene Ascorbic Acid To the mixed solvent composed of 100 mL of dimethylsulfoxide and 40 ml of acetone were added 17.6 g of L-ascorbic acid, 15.6 g of 1,2-dimethoxypropane and 1.2 g of p-tolusulfonic acid, followed by stirring for 5 hours at 50 C. The produced reaction mixture was vacuum-distillated at 20 C. to eliminate the remaining acetone and non-reacted 1,2-dimethoxypropane to give 20.5 g of the target compound (yield: 95%).
With sodium hydrogencarbonate; In N,N-dimethyl-formamide; at 60℃; for 10h;Inert atmosphere;
Formula I (10 g, 0.465 mol) was dissolved in 172 mL of dimethylformamide and then sodium bicarbonate (102 g, 1.605 mol) was added, followed by addition of <strong>[80-40-0]ethyl tosylate</strong> (81 g, 0.404 mol), nitrogen was in purged. The reaction mixture was stirred at 60 C. for 10 hours. After cooled to the room temperature, sodium bicarbonate and salt were filtered and evaporated. After evaporation, 5% sodium bicarbonate (100 mL) was added into crude and extracted for twice with Toluene. The organic phase was washed with water and evaporated. Crystallization from n-heptane gave 55 g formula II (0.225 mol; yield=65%). Intermediate was dissolved in n-propanol (60 mL) and then added 2N HCl (16.9 mL), heat to 60 C., after 2 hours, the solvent was evaporated. re-crystallization from Toluene and n-propanol gave 35 g of formula (III). (0.172 mol; yield 56%)
4
The 10 g (0.046 mol) of Formula (I) was dissolved in 120 g dichloromethane. 15.5 g (0.154 mol) of triethylamine was added. The temperature was set at 5-10° C. Azelaoyl chloride (5 g, 0.022 mol) was dropwise into reactor and than was stirred at 5-10° C. 1 hr. The mixture solution was extracted by 10 mL triethylamine/50 mL H2O. The organic layer was discarded. Add 6 mL TFA/H2O solution to water layer to adjust pH to 3-4 and than water layer was extracted by dichloromethane twice. Dichloromethane was evaporated at 40° C. to give white solid intermediate I. (Purity=90.6%, weight=10.76 g). Intermediate I (10 g, 0.018 mol) of was dissolved in 50 mL dichloromethane. Trifluoroacetic acid (1 mL, 0.019 mol) was slowly dropped into the mixture. The mixture was stirred at 25° C. overnight and then the crude mixture was evaporated by vacuum. The product was purified on a silica gel column to yield 4.5 g (8.929 mmol; yield=40.9%).The compound was characterized by Mass: mw.504
Multi-step reaction with 3 steps
1.1: sodium hydrogencarbonate; sodium hydroxide / water / 35 - 45 °C / Industry scale
1.2: 3 h / 30 - 60 °C / Industry scale
2.1: sodium hydrogencarbonate; sodium hydroxide / 1-methyl-pyrrolidin-2-one; water / 2 h / 30 - 60 °C / Industry scale
3.1: dmap; triethylamine / acetonitrile / 3.5 h / 20 - 30 °C / Industry scale
Multi-step reaction with 3 steps
1: sodium hydroxide; sodium hydrogencarbonate; dihydrogen peroxide / water / 3 h / 35 - 60 °C / Large scale
2: sodium hydrogencarbonate / water; 1-methyl-pyrrolidin-2-one / 3 h / 35 - 60 °C / Large scale
3: triethylamine; dmap / acetonitrile / 3.5 h / 25 °C / Large scale
Multi-step reaction with 3 steps
1.1: sodium hydroxide; sodium hydrogencarbonate; water / 0.25 h / 25 - 35 °C / Industrial scale
1.2: 35 - 60 °C / Industrial scale
2.1: water; 1-methyl-pyrrolidin-2-one / 2 h / 25 - 60 °C / Industrial scale
3.1: triethylamine; dmap / acetonitrile / 3.5 h / 20 - 30 °C / Industrial scale
5,6-isopropylidene-2-O-(propyloxycarbonyl)-L-ascorbic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
79%
With pyridine; In dichloromethane;
5,6-Isopropylidene-2-O-(propyloxycarbonyl)-L-ascorbic acid and other 2-O-acyl derivatives5,6-Isopropylidene-L-ascorbic acid (1.51 g, 0.00698 mol) and propyl chloroformate (0.86 g, 0.00702 mol) were added to a 150 mL round-bottom flask with approximately 50 mL of dichloromethane. The mixture was stirred and 1.2 mL of pyridine (0.0148 mol) in approximately 20 mL of dichloromethane was added. The flask was corked and the contents were left to stir for 20-24 hours. The orange-tinted solution was then rinsed with dichloromethane into a 250 mL separatory funnel and washed three times with 10 mL aliquots of 1 M HCl. The washed dichloromethane layer was dried over sodium sulfate for 1 hour, then concentrated in vacuo without heating to give 1.67 g (79%) of 5,6-isopropylidene-2-O-(propyloxycarbonyl)-L-ascorbic acid. The product could be somewhat purified by trituration in hexane, but due to observed instability the product was usually moved forward to the next reaction. 1H NMR (CDCl3) delta 1.006 (3H, t, J = 7.6 Hz), 1.381 (3H, s), 1.406 (3H, s), 1.773 (2H, q, J= 7.2 Hz), 4.103 (1H, dd, J = 6.8, 8.8 Hz), 4.207 (1H, dd, J= 6.8, 8.2 Hz), 4.268 (2H, t, J= 6.6 Hz), 4.441 (1 H, td, J= 2.8, 6.7 Hz). 4.700 (1H, d, J= 2.4 Hz).
77.9%
With pyridine; In dichloromethane; at 20℃;
5,6-Isopropylidene-L-ascorbic acid (1.51 g, 0.00698 mol) and propyl chloroformate (0.86 g, 0.00702 mol) were added to a 150 mL round-bottom flask with 50 mL of dichloromethane. The mixture was stirred and 1.2 mL of pyridine (0.0148 mol) in 20 mL of dichloromethane was added. The flask was corked and the contents were left to stir for 20-24 hours. The orange-tinted solution was then rinsed with dichloromethane into a 250 mL separatory funnel and quickly washed three times with 10 mL aliquots of 1 M HCl. The organic layer was dried over sodium sulfate for 1 hour, then concentrated in vacuo without heating to give 1.67 g (79%) of 2-O-propyloxycarbonyl-5,6-isopropylidene-L-ascorbic acid, 5.
(R)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl pivalate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
95%
Imidazole was dissolved in dichloromethane (27 mL), and a dichloromethane solution (21 mL) containing pivaloyl chloride (1.37 g) was added dropwise at room temperature. The resulting mixture was then stirred at the same temperature for one hour. Subsequently, a dichloromethane solution (11 mL) containing <strong>[15042-01-0](R)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3,4-dihydroxyfuran-2(5H)-one</strong> (2.17 g) was added, and the resulting mixture was stirred overnight at room temperature. Next, the reaction mixture was poured into 1 N hydrochloric acid, and then extracted with dichloromethane. The organic phase was dried over anhydrous magnesium sulfate, filtered, and then concentrated under reduced pressure. The thus obtained concentrate was purified by recrystallization using dichloromethane and hexane. (R)-5-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl pivalate (compound 2-46) was obtained in an amount of 2.84 g, a yield of 95%.
(R)-2,5,7,8-tetramethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman-6-yl 2-bromoacetate[ No CAS ]
[ 15042-01-0 ]
3-(α-tocopheryl acetyl)-5,6-isopropylidene-L-ascorbic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
A 500 mL three-necked round flask equipped with a dropping funnel was charged with Ar gas, and then 26.5 g (0.123 mol) of 5,6-isopropylidene-L-ascorbic acid was taken and dissolved in 100 mL of DMSO. Under normal temperature, 10.34 g (0.123 mol) of NaHCO3 was slowly added and stirred vigorously. Stirring was continued until the outflow of the CO2 gas generated by interrupting the inflow of the Ar gas was almost eliminated. After 1 hour, the solution was kept at a low temperature and a solution of 56.1 g (0.102 mol) of alpha -Tocopheryl bromoacetate dissolved in 120 mL of DMSO was transferred to a dropping funnel and slowly added dropwise with vigorous stirring. After the addition is complete, warm the reaction temperature to about 40 and while flowing Ar gas again was the reaction with vigorous stirring for 4 hours. After completion of the reaction, 150 mL of cold distilled water was added to neutralize the solution with 1M HCl solution while measuring the pH, and the mixture was stirred at room temperature for 30 minutes. The organic layer was recovered using ethyl acetate (300 mL), washed again with 1M HCl and distilled water, and dehydrated with MgSO4. The filtrate from which the desiccant was removed was concentrated and purified by silica gel column chromatography (ethyl acetate: hexane = 4: 6) to obtain 50.4 g (yield: 72%) of the title compound as a clear pale yellow viscous liquid.
1.06 g
With potassium hydrogencarbonate; In N,N-dimethyl-formamide; at 20℃;
5,6-isopropylidene ascorbic acid (0.726 g, 3.36 mmol) and bromoacetyl D-alpha-tocopherol (1.56 g, 2.8 mmol) were dissolved in DMF (10 ml), potassium hydrogen carbonate (0.336 g, 3.36 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtering the sodium sulfate, the solvent was distilled off, and the obtained residue was purified by column chromatography (hexane: ethyl acetate = 5:1) to obtain a vitamin C derivative of the present invention of Chemical Formula 20 5,6-isopropylidene ascorbic acid-3-acetyl diester-D-alpha-tocopherol (1.06 g, 1.54 mmol) was obtained as a white solid.
With dicyclohexyl-carbodiimide; In tetrahydrofuran; at 40℃; for 24.0h;
5 g of Compound A, 5.8 g of dicyclocarbamoylimide (C6H11N=C=NC6H11) and 6 g of 5,6-O-isopropylidene ascorbic acid were dissolved in 100 mL of tetrahydrofuran, and the mixture was stirred at 40C for 24 hours . After stirring is completed,The crude filtrate was concentrated to 75 mL, filtered again, and concentrated. The resulting concentrate was recrystallized from 400 mL of diethyl ether, filtered 5,6-O-isopropylidene ascorbic nicotinic acid (Compound B)3.7 g was obtained as a pale yellow solid [Fig. 2].
Potassium carbonate (2.07 g, 15.0 mmol) was added to a solution of p-AA (3.24 g, 15.0 mmol) in 50 ml of 1 : 1 THF/DMSO. The resultant mixture was allowed to stir for 30 min. A solution of l-(bromomethyl)-4,5-dimethoxy-2-nitrobenzene (prepared as in PE-8; 4.14 g, 15.0 mmol) in 50 mL of 1 : 1 THF/DMSO was then added dropwise via addition funnel over 10 min. The resultant mixture was allowed to stir under nitrogen atmosphere overnight, during which time it became dark orange in color. Approximately 200 mL of H2O was added to the mixture, which was then extracted with EtOAc (3x). The combined organic layers were washed with sat. aq. NaCl, dried over MgS04, filtered, and concentrated to an orange oil. This material was purified via suction filter chromatography (S1O2, ramp eluent from 2: 1 to 1 : 1 hexane/EtOAc) to afford 3.50 g of product as a yellow oil which foams under vacuum (57% yield). NMR was consistent with the desired product.
To a solution of 5,6 isopropylidine ascorbic acid (4.0 g, 1 mmol)in 10 mL of dry DCM were added triethylamine (1.46 g, 1.1 mmol),and a catalytic amount of DMAP. The reaction mixture was stirredat room temperature for 15 min. The solution of O-Amino ethyl-[N,O-(hydroxyethyl), N methyl] benzene sulfonate-a-tocopherol(2.12 g, 18 mmol), in dry DCM were added drop wise about20 min. The reaction mixture is dissolved in 25 mL of ethyl acetateand washed twice with 2 30 mL of 1 N HCl solution to removeany excess triethylamine. The organic layer was dried on anhydrousmagnesium sulphate, the solvent was evaporated, and thesample was purified by column chromatography, eluting with 5-8% (v/v) ethyl acetate in n-hexane to obtain 4.0 g of O-Aminoethyl-[N,O-(hydroxyethyl), N methyl] 5, 6 isopropylidine ascorbicacid -a-tocopherol. (Yield 85.10%, Rf = 0.3, Ethyl acetate in hexane,1:9 v/v).1H NMR (400 MHz, CDCl3) d/ppm 0.8-0.90 (m, 12H), 1.00-1.5(m, 25H), 1.77-1.88 (m, 14H), 2.08 (s, 3H, -NCH3), 2.14 (s, 3H),2.17 (s, 3H), 2.18 (s, 3H), 2.56-2.82 (t, 2H), 3.84 (t, 4H), 4.33 (t,7H), 4.99 (m, 1H); ESI-MS; Calculated 730; found [M+] 730.
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