* 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 lithium aluminium tetrahydride In diethyl ether at 20℃; for 3 h; Inert atmosphere
To a suspension of LiAihh (0.50 g . 13.2 mmol) in Ε2υ (30 ml) was added a solution of 18.4 (2.0? g . 1 1 mmoL) in E0 (30 ml.) dropwise under argon. The reaction mixture was stirred at r.t for 3 hr. The reaction was quenched with water (0.9 roU, filtered, and the filtrate was washed with E0 . The combined organic layers were dried and concentrated under reduced pressure to give 18.5 ( 1.56 g, 96percent) as a colorless oil. 1 H MR (400 MHz, DMSO~c δ 4.52 (i J=5.2H , 1 H), 3.81 (q, 2H), 3.60 (q, 2H), 3.38 (q, 2H). 1.70 (m, 1H), 1.29 (, 6H).
76%
Stage #1: With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 25℃; for 2.33333 h; Stage #2: With water; sodium sulfate In tetrahydrofuran; ethyl acetate at 25℃; for 1 h;
A solution of 2,2-dimethyl-[1,3]dioxane-5-carboxylic acid ethyl ester (7.03 g, 37.35 mmol) in tetrahydrofuran (20 ml) was added dropwise to a cooled to 0° C. suspension of lithium aluminum hydride (1.8 g, 48.55 mmol) in tetrahydrofuran (20 ml). The reaction was stirred at 0° C. for 20 min and at 25° C. for 2 h. After such time, ethyl acetate (1 ml) and a few crystals of sodium sulphate decahydrate were added with caution. After stirring at 25° C. for 1 h saturated sodium chloride solution was added and the product extracted with ethyl acetate (3.x.100 ml). The organics were washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to afford (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (4.09 g, 76percent) as a clear oil: 1H NMR (300 MHz, CDCl3) δ ppm 1.39 (s, 3 H, CH3), 1.44 (s, 3 H, CH3), 1.79-1.90 (m, 1 H, CH), 2.15-2.26 (brs, 1 H, OH), 3.69-3.81 (m, 2 H, 2.x.OCH of 2.x.OCH2), 3.74 (d, J=6.8 Hz, 2 H, OCH2), 3.96-4.05 (m, 2 H, 2.x.OCH of 2.x.OCH2).
75.2%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2.33333 h; Inert atmosphere
Under nitrogen, to a solution of LiAlH4 (1.39 g, 36.58 mmol) in THF (40 mL) which was cooled to 0° C., compound Ij″-1 (5.29 g, 28.0 mmol) (according to the synthesis procedure in the patent WO 2008/0021032) was added dropwise. The mixture was stirred for 20 minutes at 0° C. and 2 hours at room temperature. When the reaction finished, the mixture was diluted with Et2O (30 mL). With an ice bath, H2O (0.14 mL) was added dropwise to the mixture, followed with NaOH solution (15percent, 0.14 mL) and H2O (0.42 mL) in sequence. After the mixture was stirred for 20 minutes at room temperature, appropriate amount of MgSO4 was added to it and then another 20 minutes for stirring proceeded. After filtration, the filtrate was concentrated under vacuum to afford compound Ii″-1 (3.1 g, 75.2percent). [0138] 1HNMR (500MHz, CDCl3) δ: 3.93-3.96 (m, 2H), 3.65-3.72 (m, 4H), 1.73-1.79 (m, 1H), 1.35(d, J=25.0 HZ, 6H).
75.2%
With lithium aluminium tetrahydride In tetrahydrofuran at 0 - 20℃; for 2.33333 h; Inert atmosphere
Example 7: Preparation of compound Ii"-1: [0094] Under nitrogen, to a solution of LiAlH4 (1.39 g, 36.58 mmol) in THF (40 mL) which was cooled to 0°C, compoundIj"-1 (5.29 g, 28.0 mmol) (according to the synthesis procedure in the patent WO 2008/0021032) was added dropwise.The mixture was stirred for 20 minutes at 0°C and 2 hours at room temperature. When the reaction finished, the mixturewas diluted with Et2O (30 mL). With an ice bath, H2O (0.14 mL) was added dropwise to the mixture, followed with NaOHsolution (15percent, 0.14 mL) and H2O (0.42 mL) in sequence. After the mixture was stirred for 20 minutes at room temperature,appropriate amount of MgSO4 was added to it and then another 20 minutes for stirring proceeded. After filtration, thefiltrate was concentrated under vacuum to afford compound Ii"-1 (3.1 g, 75.2percent).1HNMR (500MHz, CDCl3) δ: 3.93-3.96 (m, 2H), 3.65-3.72 (m, 4H), 1.73-1.79 (m, 1H), 1.35 (d, J=25.0HZ, 6H).
58%
With lithium aluminium tetrahydride In tetrahydrofuran for 2 h; Inert atmosphere; Reflux
LiAlH4 (60 g, 1.58 mol) was suspended in dry THF (500 mL) under inert atmosphere. The solution of 3 (188 g,1 mol) in THF (600 mL) was added dropwise and the mixture was refluxed for 2 hours. The mixture was quenched by 6M NaOH solution upon cooling and filtered; the precipitate was washed by ethyl acetate (300 mL). The solvents were evaporated and the residual oil was distilled yielding S3 (85 g, 58percent) as colorless liquid 1. 1H NMR (700 MHz, CDCl3, 300K): δ = 4.02 (dd, J = 4.3 Hz, 12.2 Hz, 2 H), 3.78 (dd, J = 5.8 Hz,12.2 Hz, 2 H), 3.76 (dd, J = 5.1 Hz, 6.6 Hz, 2 H), 1.83-1.87 (m, 1H), 1.66 (t, J = 5.1 Hz, 1 H),1.45 (s, 3 H), 1.41 (s, 3 H).
Reference：
[1] Tetrahedron, 1991, vol. 47, # 6, p. 1001 - 1012
[2] Patent: WO2013/170030, 2013, A1, . Location in patent: Page/Page column 56
[3] Journal of Organic Chemistry, 1986, vol. 51, # 14, p. 2637 - 2641
[4] Journal of the American Chemical Society, 1987, vol. 109, # 26, p. 8071 - 8081
[5] Patent: US2008/21032, 2008, A1, . Location in patent: Page/Page column 81
[6] Patent: US2013/324464, 2013, A1, . Location in patent: Paragraph 0137; 0138
[7] Patent: EP2676965, 2013, A1, . Location in patent: Paragraph 0093; 0094
[8] Synlett, 2017, vol. 28, # 5, p. 583 - 588
[9] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 2, p. 339 - 345
[10] Patent: US4336408, 1982, A,
[11] Collection of Czechoslovak Chemical Communications, 2007, vol. 72, # 7, p. 965 - 983
[12] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7358 - 7360
2
[ 51335-75-2 ]
[ 82962-54-7 ]
Yield
Reaction Conditions
Operation in experiment
78%
With water; sodium chloride In dimethyl sulfoxide for 20 h; Reflux
The mixture of 2,2-dimethyl-1,3-dioxane-5,5-dicarboxylate S2 (385 g, 1.5 mol), NaCl (105 g, 1.8 mol), water (58g, 3.2 mol) and dimethylsulfoxide (1500 mL) was refluxed for 20 hours. The solution was cooled to room temperature, the saturated solution of NaCl (750 mL) was added and the product was extracted with diethyl ether (4 x 600 mL). Combined organic extracts were washed by brine (2 x 150 mL) and dried over Na2SO4. The solvents were evaporated and the residual oil was distilled yielding 3 (220 g, 78percent) as colorless liquid 3. 1H NMR (700 MHz, CDCl3, 300K): δ = 4.16 (q, J = 7.3 Hz, 2H), 4.01-4.08 (m, 4H), 2.77-2.81(m, 1H), 1.43 (s, 3H), 1.40 (s, 3H), 1.26 (t, J = 7.3 Hz, 3H).
69%
Stage #1: With potassium hydroxide In ethanol; isopropyl alcohol at 20℃; for 5 h; Inert atmosphere Stage #2: With hydrogenchloride In ethanol; water; isopropyl alcohol at -4℃; Stage #3: at 90℃; for 16 h;
(4b) Synthesis of diethyl 2,2-dimethyl-l,3-dioxan-5-carboxylate (2). iPotassium hydroxide (15 g, 2.667 mol) was stirred in 1843 mL of anhydrous ethanol and 97 mL of isopropanol to produce a clear solution. To this clear solution was added 1 (527 g, 2.026 mol) in 184 mL of ethanol and 10 mL of isopropanol. The reaction was stirred at room temperature under nitrogen for 5 hours and then evaporated. Water (580 mL) was added and cooled to -4 °C. To this solution was added 58 mL of concentrated HC1 and 1.2 L of 1.0 M HC1 to reach a pH of 2.5 (followed by pH paper). The solution was extracted with ethyl acetate (4 χ 1 L, pH adjusted to 2.5 following each extraction). The combined organics were dried and evaporated to a colorless oil. After the addition of 1.35 L of pyridine, the solution was stirred at 90 °C overnight (16 hours). The solution was distilled at 80 °C (ca. 150 mmHg) to remove the pyridine, and the product was removed by distillation at 55-65 °C (1-2 mmHg), 261.7 g, in 69percent yield.
56%
With water; sodium chloride In dimethyl sulfoxide at 180℃; for 48 h;
To a stirring solution o? 18.3 (32.0 g , 123,0 mmoL) in DMSO (350 ml) was added NaCi (7.20 g , 123,0 mmoL}: and H20 (4.43g ,246.0 mmoL) and the reaction mixture was heated to 180 C for 48 hour . The mixture was cooled to r.t , diluted with DCM (500 ml), and washed with water (3 x 500 ml) . The organic layer was dried over a-SC and concentrated under reduced pressure to give ISA (12.0 g: 56percent) as a red oil
53%
With sodium chloride In water; dimethyl sulfoxide for 7 h; Heating / reflux
To the solution of 2,2-dimethyl-[1,3]dioxane-5,5-dicarboxylic acid diethyl ester (19.75 g, 75.96 mmol) in dimethyl sulfoxide (80 ml) was added sodium chloride (4.4 g, 75.76 mmol) and water (2 ml). The reaction was refluxed for 7 h. After such time, it was poured into saturated sodium chloride solution (500 ml) and extracted with ether (4.x.200 ml). The combined organics were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residual oil was distilled under reduced pressure. Three fractions collected between 100° C. and 120° C. were combined to afford 2,2-dimethyl-[1,3]dioxane-5-carboxylic acid ethyl ester (7.58 g, 53percent) as a clear oil (J. Org. Chem. 1986, 51, 2637) 1H NMR (300 MHz, CDCl3) δ ppm 1.26 (t, J=7.1 Hz, 3 H, CH3), 1.41 (s, 3 H, CH3), 1.44 (s, 3 H, CH3), 2.74-2.85 (m, 1 H, CH), 3.96-4.30 (m, 6 H, 3.x.OCH2).
Reference：
[1] Synlett, 2017, vol. 28, # 5, p. 583 - 588
[2] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 2, p. 339 - 345
[3] Journal of the American Chemical Society, 1987, vol. 109, # 26, p. 8071 - 8081
[4] Journal of Organic Chemistry, 1986, vol. 51, # 14, p. 2637 - 2641
[5] Patent: WO2012/103279, 2012, A2, . Location in patent: Page/Page column 16-17
[6] Collection of Czechoslovak Chemical Communications, 2007, vol. 72, # 7, p. 965 - 983
[7] Angewandte Chemie - International Edition, 2018, vol. 57, # 2, p. 574 - 578[8] Angew. Chem., 2018, vol. 130, p. 583 - 587,5
[9] Patent: WO2013/170030, 2013, A1, . Location in patent: Page/Page column 56
[10] Patent: US2008/21032, 2008, A1, . Location in patent: Page/Page column 81
[11] Patent: US4336408, 1982, A,
[12] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 24, p. 7358 - 7360
[13] Organic Process Research and Development, 2012, vol. 16, # 9, p. 1527 - 1537
3
[ 20605-01-0 ]
[ 82962-54-7 ]
Reference：
[1] Chemical and Pharmaceutical Bulletin, 1993, vol. 41, # 2, p. 339 - 345
[2] Journal of the American Chemical Society, 1987, vol. 109, # 26, p. 8071 - 8081
[3] Journal of Organic Chemistry, 1986, vol. 51, # 14, p. 2637 - 2641
[4] Tetrahedron, 1991, vol. 47, # 6, p. 1001 - 1012
[5] Patent: WO2012/103279, 2012, A2,
[6] Organic Process Research and Development, 2012, vol. 16, # 9, p. 1527 - 1537
[7] Patent: WO2013/170030, 2013, A1,
[8] Synlett, 2017, vol. 28, # 5, p. 583 - 588
[9] Angewandte Chemie - International Edition, 2018, vol. 57, # 2, p. 574 - 578[10] Angew. Chem., 2018, vol. 130, p. 583 - 587,5
[11] Patent: US2008/21032, 2008, A1,
With water; sodium chloride; In dimethyl sulfoxide; for 20h;Reflux;
The mixture of 2,2-dimethyl-1,3-dioxane-5,5-dicarboxylate S2 (385 g, 1.5 mol), NaCl (105 g, 1.8 mol), water (58g, 3.2 mol) and dimethylsulfoxide (1500 mL) was refluxed for 20 hours. The solution was cooled to room temperature, the saturated solution of NaCl (750 mL) was added and the product was extracted with diethyl ether (4 x 600 mL). Combined organic extracts were washed by brine (2 x 150 mL) and dried over Na2SO4. The solvents were evaporated and the residual oil was distilled yielding 3 (220 g, 78%) as colorless liquid 3. 1H NMR (700 MHz, CDCl3, 300K): delta = 4.16 (q, J = 7.3 Hz, 2H), 4.01-4.08 (m, 4H), 2.77-2.81(m, 1H), 1.43 (s, 3H), 1.40 (s, 3H), 1.26 (t, J = 7.3 Hz, 3H).
69%
(4b) Synthesis of diethyl 2,2-dimethyl-l,3-dioxan-5-carboxylate (2). iPotassium hydroxide (15 g, 2.667 mol) was stirred in 1843 mL of anhydrous ethanol and 97 mL of isopropanol to produce a clear solution. To this clear solution was added 1 (527 g, 2.026 mol) in 184 mL of ethanol and 10 mL of isopropanol. The reaction was stirred at room temperature under nitrogen for 5 hours and then evaporated. Water (580 mL) was added and cooled to -4 C. To this solution was added 58 mL of concentrated HC1 and 1.2 L of 1.0 M HC1 to reach a pH of 2.5 (followed by pH paper). The solution was extracted with ethyl acetate (4 chi 1 L, pH adjusted to 2.5 following each extraction). The combined organics were dried and evaporated to a colorless oil. After the addition of 1.35 L of pyridine, the solution was stirred at 90 C overnight (16 hours). The solution was distilled at 80 C (ca. 150 mmHg) to remove the pyridine, and the product was removed by distillation at 55-65 C (1-2 mmHg), 261.7 g, in 69% yield.
56%
With water; sodium chloride; In dimethyl sulfoxide; at 180℃; for 48h;
To a stirring solution o? 18.3 (32.0 g , 123,0 mmoL) in DMSO (350 ml) was added NaCi (7.20 g , 123,0 mmoL}: and H20 (4.43g ,246.0 mmoL) and the reaction mixture was heated to 180 C for 48 hour . The mixture was cooled to r.t , diluted with DCM (500 ml), and washed with water (3 x 500 ml) . The organic layer was dried over a-SC and concentrated under reduced pressure to give ISA (12.0 g: 56%) as a red oil
53%
With sodium chloride; In water; dimethyl sulfoxide; for 7h;Heating / reflux;
To the solution of 2,2-dimethyl-[1,3]dioxane-5,5-dicarboxylic acid diethyl ester (19.75 g, 75.96 mmol) in dimethyl sulfoxide (80 ml) was added sodium chloride (4.4 g, 75.76 mmol) and water (2 ml). The reaction was refluxed for 7 h. After such time, it was poured into saturated sodium chloride solution (500 ml) and extracted with ether (4×200 ml). The combined organics were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residual oil was distilled under reduced pressure. Three fractions collected between 100 C. and 120 C. were combined to afford 2,2-dimethyl-[1,3]dioxane-5-carboxylic acid ethyl ester (7.58 g, 53%) as a clear oil (J. Org. Chem. 1986, 51, 2637) 1H NMR (300 MHz, CDCl3) delta ppm 1.26 (t, J=7.1 Hz, 3 H, CH3), 1.41 (s, 3 H, CH3), 1.44 (s, 3 H, CH3), 2.74-2.85 (m, 1 H, CH), 3.96-4.30 (m, 6 H, 3×OCH2).
With sodium chloride; In water; dimethyl sulfoxide;
EXAMPLE 3 2,2-Dimethyl-5-Carbethoxy-1,3-Dioxane To a solution of the product of Example 2 (65 g) in dimethyl sulfoxide (65 g) is added sodium chloride (1 g). The mixture is stirred while warming at about 180 C., and water is added in small portions while maintaining the temperature between 170 and 180. Ethanol and water are evolved and are removed by distillation until about 60 ml of liquid has been collected. The mixture is cooled, ether (200 ml) added, and the mixture partitioned with 3 portions of water (50 ml). The organic phase is dried over sodium sulfate and evaporated to a residue. Distillation of the residue gives the title product (25 g) (57%) B.P. 38 (0.01 mm) nD26 1.4400.
7-(tert-Butyl-diphenyl-silanyloxy)-6-(tert-butyl-diphenyl-silanyloxymethyl)-1-(2,2-dimethyl-[1,3]dioxan-5-yl)-2-((R)-toluene-4-sulfinyl)-heptan-3-one[ No CAS ]
5-aminocarbonyl-2,2-dimethyl-1,3-dioxane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
98%
With ammonium hydroxide;
EXAMPLE 1 Preparation of 5-aminocarbonyl-2,2-dimethyl-1,3-dioxane A mixture of <strong>[82962-54-7]2,2-dimethyl-5-ethoxycarbonyl-1,3-dioxane</strong> (4.1 g; 21.8 moles) and aqueous ammonia at 30% (10 ml) was kept under vigorous stirring for 20 hours. At the end of the reaction the water was evaporated at reduced pressure; 3.4 g of crude 5-aminocarbonyl-2,2-dimethyl-1,3-dioxane (98% yield) were obtained, which could be used as such in the subsequent rearrangement reaction. By crystallization from toluene 2.76 g of pure product (80% yield) were obtained. 1 H-NMR (DMSO-d,), delta (ppm), J (Hz): 1.27 (3H, s); 1.35 (3H, s); 2.6 (1H, m); 3.85 (4H, m); 7.0 (1H, bs); 7.3 (1H, bs). 13 C-NMR (DMSO-d6), delta (ppm): 19.9 (q); 27.7 (q); 40.6 (d); 60.8 (t); 97.1 (s); 172.11 (s). IR (KBr): cm-1 3360, 3200, 1665, 1635 Mass (m/e): 160 (M+1)+
98%
With ammonium hydroxide;
Example 1 Preparation of 5-aminocarbonyl-2,2-dimethyl-1,3-dioxane A mixture of <strong>[82962-54-7]2,2-dimethyl-5-ethoxycarbonyl-1,3-dioxane</strong> (4.1 g; 21.8 mmoles) and aqueous ammonia at 30% (10 ml) was kept under vigorous stirring for 20 hours. At the end of the reaction the water was evaporated at reduced pressure; 3.4 g of crude 5-aminocarbonyl-2,2-dimethyl-1,3-dioxane (98% yield) were obtained, which could be used as such in the subsequent rearrangement reaction. By crystallization from toluene 2.76 g of pure product (80% yield) were obtained. 1H-NMR (DMSO-d6), delta (ppm), J (Hz): 1.27 (3H, s); 1.35 (3H, s); 2.6 (1H, m); 3.85 (4H, m); 7.0 (1H, bs); 7.3 (1H, bs). 13C-NMR (DMSO-d6), delta (ppm): 19.9 (q); 27.7 (q); 40.6 (d); 60.8 (t); 97.1 (s); 172.11 (s). IR (KBr): cmmin1 3360, 3200, 1665, 1635 Mass (m/e): 160 (M+1)+
5-aminocarbonyl-2,2-dimethyl-1,3-dioxane[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
Example 3 Preparation of 5-aminocarbonyl-2,2-dimethyl-1,3-dioxane A mixture of 2,2-dimethyl-5-methoxycarbonyl-1,3-dioxane and <strong>[82962-54-7]2,2-dimethyl-5-ethoxycarbonyl-1,3-dioxane</strong> having a GC titre of 77% and 18%, respectively (850 g; 3.76 moles and 0.814 moles, respectively) and aqueous ammonia at 30% (940 ml) was kept under vigorous stirring at room temperature and under nitrogen atmosphere for 24 hours. At the end, the reaction mixture was cooled at 0C and kept under stirring for 60 minutes. A solid was obtained which was filtered, washed with water (100 ml) and dried under vacuum at 70C affording 5-aminocarbonyl-2,2-dimeth yl-1,3-dioxane (541 g; 74% yield) which was used as such in the subsequent rearrangement reaction. m.p. 132-134C.
74%.
EXAMPLE 3 Preparation of 5-aminocarbonyl2,2-dimethyl-1,3-dioxane A mixture of 2,2-dimethyl-5-methoxycarbonyl-1,3-dioxane and <strong>[82962-54-7]2,2-dimethyl-5-ethoxycarbonyl-1,3-dioxane</strong> having a GC titre of 77% and 18%, respectively (850 g; 3.76 moles and 0.814 moles, respectively) and aqueous ammonia at 30% (940 ml) was kept under vigorous stirring at room temperature and under nitrogen atmosphere for 24 hours. At the end, the reaction mixture was cooled at 0 C. and kept under stirring for 60 minutes. A solid was obtained which was filtered, washed with water (100 ml) and dried under vacuum at 70 C. affording 5-aminocarbonyl-2,2-dimethyl-1,3-dioxane (541 g; 74%. yield) which was used as such in the subsequent rearrangement reaction. m.p. 132-134 C.
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