* 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.
1,3-Dimethoxypropan-2-ol 1 was synthesized by treating epichlorohydrin with methanol and sodium hydroxide according to a modified procedure described in literature [15]. To a 250mL three-neck flask was added 165mL of absolute methanol, 11.4g of sodium hydroxide. The mixture was stirred and heated to reflux to form a solution. Epichlorohydrin (25.0g) was added dropwised within 1h. Refluxing of the reaction solution continued for another 6h. The mixture was then cooled to room temperature and its pH value was adjusted to 7 by the addition of concentrated hydrochloric acid. Sodium chloride, which has precipitated out, was filtered off and the filtrate was subjected to a fractional distillation under vacuum to obtain 1 (29.8g, yield 91.9percent). 1H NMR (300MHz, CDCl3): δ 3.92–3.99 (m, 1H, CH), 3.40–3.49 (m, 4H, CH2), 3.39 (s, 6H, CH3), 2.59 (s, 1H, OH, the shape, position and intensity of this peak vary with different sample concentration). 13C NMR (75MHz, CDCl3): δ 73.9 (CH2), 69.1 (CH), 59.0 (CH3). ESI-HRMS: m/z [M+Na]+ calcd. for [C5H12O3+Na]+: 143.0684; found: 143.0684. Elemental analysis: Calcd. for C5H12O3: C 49.98, H 10.07; Found: C 49.97, H 9.84.
50%
at 20 - 80℃; for 16 h; Cooling; Inert atmosphere
a) 1,3-dimethoxyglycerol, compound 12a [0285] Anhydrous methanol (100 mL) was treated with potassium hydroxide pellets(25 g, 0.446 mol) and the suspension was stirred at room temperature until all the base had dissolved. This solution was then cooled in an ice-bath and epichlorohydrin (0.223 mol, 20.6 g) was added drop wise. After completion of the addition, the reaction was warmed to room temperature and heated in an oil bath at 75-80°C under nitrogen for 16 hours. The reaction was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The recovered oil was dissolved in ethyl acetate (150 mL) and filtered again and then concentrated under reduced pressure. A colorless oil (21.5 g) was recovered that was purified by vacuum distillation to afford 12.9 g (50percent) of 1,3-dimethoxyglycerol, compound 12a.
Reference：
[1] Chinese Chemical Letters, 2013, vol. 24, # 12, p. 1106 - 1108
[2] Organic Letters, 2017, vol. 19, # 11, p. 2789 - 2792
[3] Patent: WO2011/60228, 2011, A1, . Location in patent: Page/Page column 69-70
[4] Atti della Accademia Nazionale dei Lincei, Classe di Scienze Fisiche, Matematiche e Naturali, Rendiconti, 1897, vol. <5> 6 II, p. 350
[5] Green Chemistry, 2015, vol. 17, # 8, p. 4326 - 4333
[6] Patent: CN103664614, 2016, B, . Location in patent: Paragraph 0027-0033
[7] Patent: CN103664615, 2016, B, . Location in patent: Paragraph 0030-0033
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[ 930-37-0 ]
[ 623-69-8 ]
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[ 67-56-1 ]
[ 56-81-5 ]
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[ 40453-77-8 ]
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[ 124-41-4 ]
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[2] Green Chemistry, 2010, vol. 12, # 3, p. 426 - 434
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[ 67-56-1 ]
[ 56-81-5 ]
[ 623-39-2 ]
[ 40453-77-8 ]
[ 623-69-8 ]
[ 20637-49-4 ]
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[ 96-23-1 ]
[ 124-41-4 ]
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[2] Journal of the American Chemical Society, 1939, vol. 61, p. 433
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[6] Journal of the Chemical Society, 1931, p. 449[7] Chemistry and Industry (London, United Kingdom), 1930, p. 1022
[8] Tetrahedron Letters, 1994, vol. 35, # 23, p. 3853 - 3856
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[ 96-13-9 ]
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[2] Journal of the Chemical Society, 1931, p. 449[3] Chemistry and Industry (London, United Kingdom), 1930, p. 1022
[4] Journal of the Chemical Society, 1929, p. 134
[5] Journal of the Chemical Society, 1925, vol. 127, p. 2739,2743
[6] Journal of the Chemical Society, 1929, p. 1152,2234[7] Journal of the Chemical Society, 1930, p. 374
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[ 124-41-4 ]
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[ 18664-32-9 ]
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With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 5h;
Example 254; In 2.5 ml of tetrahydrofuran were dissolved 390 mg of the compound represented by the formula (IIa-1) and 250 mg of 1, 3-dimethoxy-2-propanol, 70 mg of sodium hydride (60percent oily) and 0.5 ml of tetrahydrofuran were added under ice- cooling, and the mixture was stirred at room temperature for .5 hours. Thereafter, an aqueous saturated ammonium chloride solution was added to the reaction mixture, followed by extraction with t-butyl methyl ether. The Organic layer was dried with sodium sulfate, and concentrated under reduced pressure. The residue was subjected to medium pressure preparative liquid <n="295"/>chromatography to obtain 390 mg of a compound represented by the formula (254) :(hereinafter, referred to as present compound (254)). 1H-NMR (CDCl3, TMS) delta (ppm) : 5.36-5.31 (IH, m) , 3.77-3.70 (4H, m) , 3.39 (6H, s) , 3.04 (6H, br)
(-)-(3S,4R)-6-cyano-4-[(1-(2,2,2-trifluoroethyl)-1,6-dihydro-6-oxo-3-pyridazinyl)amino]-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran-3-ol[ No CAS ]
(-)-(3S,4R)-6-cyano-3,4-dihydro-4-[(1,6-dihydro-1-(methoxycarbonylmethyl)-6-oxo-3-pyridazinyl)amino]-2,2-bis-(methoxymethyl)-2H-1-benzopyran-3-ol[ No CAS ]
With triethylamine; In dichloromethane; at 5 - 20℃; for 24h;
To a solution of 1, 3-dimethoxy-2-hydroxypropane (3.84g, 0. 032mol) in DCM (70ml) cooled at 5 C was added triethylamine (Sml, 0. 036mol) followed by slow addition of methanesulphonyl chloride (2. 72ml, 0. 035mol). The mixture was then stirred at ambient temperature for 24 hours. The mixture was then absorbed onto silica gel and purified by flash silica chromatography DCM: isohexane (3: 1) to give the title compound (3.74g, 59percent). NMR 3.15 (s, 3H), 3.28 (s, 6H), 3.52 (d, 4H), 4.78 (q, 1H).
With triethylamine; In dichloromethane;
61c. Methanesulfonic acid 2-methoxy-1-methoxymethyl-ethyl ester 4.3 mL of methanesulfonyl chloride was added dropwise at 5° C. to a stirred solution of 6.0 g of 1,3-dimethoxy-propan-2-ol and 9.0 mL of triethylamine in 60 mL of dichloromethane. Stirring was continued for 72 hours at room temperature, followed by extraction with water. The combined organic extracts were dried (sodium sulfate) and concentrated and the residue purified by silica chromatography (isohexane/ethyl acetate=9/1, 8/2, 7/3, 6/4 v/v) yielding 2.5 g of methanesulfonic acid 2-methoxy-1-methoxymethyl-ethyl ester as an oil. EI-MS: 198 (M+).
61b. 1.3-Dimethoxy-propan-2-ol To a stirred solution of 13.2 g of 2-methoxymethyl-oxirane in 75 mL of methanol was added 0.1 mL of boron trifluoride etherate while stirring at 5° C. Stirring was continued for 24 hours at room temperature, followed by removal of the solvent. Distillation afforded 7.0 g of 1,3-dimethoxy-propan-2-ol as a liquid. B.p. 75-80° C./12 Torr (reference: Gilchrist, Purves, J. Chem. Soc. 1925, 127, 2739, 2743: b.p. 69.5-70.5/15 Torr); (+)-FAB-MS: 121 (MH+).
2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-methoxy-1-methoxymethyl-ethoxy)-pyridin-3-yl]-N-methyl-isobutyramide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
63%
With sodium hydroxide; cetyltrimethylammonim bromide; In water; toluene; at 130℃; for 0.5h;Microwave irradiation;
A mixture of 0.15 g (0.28 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.17 g (1.4 mmol) <strong>[623-69-8]1,3-dimethoxy-2-propanol</strong>, 5 mg (0.01 mmol) cetyltrimethylammonium bromide, 0.1 ml NaOH 50percent and 1 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under microwave irradiation at 130° C. for 30 min. After cooling to room temperature the mixture was diluted with water and extracted with two portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 0.11 g (63percent) of the title compound as an off-white solid. MS m/e (percent): 619 (M+H+, 100).
With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 16h;
A solution of <strong>[623-69-8]1,3-dimethoxy-2-propanol</strong> (361.5 mg, Tyger) in tetrahydrofuran (4 ml) was added with sodium iodoacetate (624.6 mg, Spectrum), and successively added with sodium hydride (198 mg, Wako Pure Chemical Industries) as several portions at 0° C., and the mixture was stirred at the same temperature for 30 minutes, and then further stirred at room temperature for 15.5 hours. The reaction mixture was cooled again to 0° C., and then carefully added with water and then with chloroform, and the organic layer was separated. The aqueous layer was acidified (pH 4) with 1 N hydrochloric acid, and extracted three times with chloroform, and the combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure to obtain the title compound (206.5 mg).
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at 50℃; for 40h;
A mixture of methyl 7-hydroxy-5-{ [5-(methylsulfonyl) pyridin-2-yl] oxy} -lH-indole-2-carboxylate (2.75 g) , tributylphosphine (3.7 mL) , 1,1'- (azodicarbonyl) dipiperidine (3.8 g) , 1, 3-dimethoxypropan-2-ol (1.8 g) and tetrahydrofuran (50 mL) was stirred at 50°C for 8 h. Tributylphosphine (1.9 mL) , 1, 1' - (azodicarbonyl) dipiperidine (1.9 g) and 1, 3-dimethoxypropan-2-ol (0.9 g) were added to the mixture again, and the mixture was stirred at 5O0C for 8 h. Furthermore, tributylphosphine (3.7 mL), 1,1'-(azodicarbonyl) dipiperidine (3.8 g) and 1, 3-dimethoxypropan-2- ol (1.8 g) were added to the mixture. After stirring at 500C for 24 h, the mixture was cooled to O0C and a precipitate was removed by filtration. The filtrate was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90 to 80/20, volume ratio) twice, <n="156"/>followed by basic silica gel column chromatography (ethyl acetate/hexane 20/80 to 85/15) to give the crude title compound (3.42 g) as a yellow oil. MS 465 (MH+).
With tributylphosphine; 1,1'-azodicarbonyl-dipiperidine; In tetrahydrofuran; at 50 - 70℃; for 21h;
A mixture of ethyl 7-hydroxy-5- [4-(methylsulfonyl) phenoxy] -lH-indole-2-carboxylate (1.2 g) , tributylphosphine (1.6 mL) , 1, 1' - (azodicarbonyl) dipiperidine (1.7 g), 1, 3-dimethoxypropan-2-ol (0.8 g) and tetrahydrofuran (20 mL) was stirred at 5O0C for 13 h. Tributylphosphine (0.82 mL) , 1, 1'- (azodicarbonyl) dipiperidine (0.83 g) and 1,3- dimethoxypropan-2-ol (0.4 g) were added to the mixture again and the mixture was stirred at 7O0C for 5 h. Furthermore, <n="145"/>tributylphosphine (1.64 mL) , 1, V - (azodicarbonyl) dipiperidine (1.66 g) and 1, 3-dimethoxypropan-2-ol (0.8 g) were added to the mixture. After stirring at 70°C for 3 h, the mixture was cooled to 00C and insoluble materials were removed by filtration. The filtrate was concentrated and the residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=20/80 to 85/15, volume ratio) to give the title compound (1.79 g, 84percent) as an orange oil. MS 463 (MH").
With dmap; In pyridine; at 20℃; for 72h;Inert atmosphere;
b Compound 12b[0287] A solution of 1,3-dimethoxyglycerol, compound 12a (1 g, 8.3 mmoles) in anhydrous pyridine (20 mL) was treated with p-toluenesulfonyl chloride (2.38 g, 1.5 equivalents) and 4-dimethylaminopyridine (0.253 g, 0.25 equivalent). The reaction was stirred at room temperature under nitrogen for 3 days. The solvent was then removed under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and IN HCl (50 mL). The ethyl acetate layer was separated and washed once with In HCl (50 mL), followed by aqueous sodium bicarbonate (3 x 50 mL). It was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product (2.5 g) was purified by flash chromatography on silica using 20percent ethyl acetate in hexanes as eluent. Yield = 1.79 g (65percent).
Step 1; To NaH (0.366 g, 9.16 mmol) in THF (12 mL) at 0° C. was added <strong>[623-69-8]1,3-dimethoxy-2-propanol</strong> (1 g, 8.32 mmol) in THF (8 mL) solution. The mixture was warmed to ambient temperature and stirred for 0.5 hour. To this was added tosyl chloride (1.587 g, 8.32 mmol) in one portion. The resulting white cloudy mixture then was stirred at ambient temperature for 16 hours. LC/MS showed complete conversion to 1,3-dimethoxypropan-2-yl 4-methylbenzenesulfonate. The reaction mixture mixture was poured into water and extracted with EtOAc. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo to yield 2 g of a colorless oil. The crude mixture was purified by Analogix system (silica gel column 80 g, gradient: 0 min, 100percent n-heptane; 5-12 min, 20percent EtOAc in Heptane; 12-15 min. 30percent EtOAc in Heptane and hold until 30 min). The pure fractions were combined and concentrated in vacuo to yield 1.25 g of the tosylate product 1,3-dimethoxypropan-2-yl 4-methylbenzenesulfonate as a colorless oil, which solidified upon standing.
To NaH (0.366 g, 9.16 mmol) in THF (12 mL) at 0 °C was added l,3-dimethoxy-2-propanol (1 g, 8.32 mmol) in THF (8 mL) solution. The mixture was warmed to room temperature and stirred for 0.5 hour. To this was added tosyl chloride (1.587 g, 8.32 mmol) in one portion. The white cloudy mixture was stirred at room temperature for 16 hours. LC/MS showed complete conversion. The reaction mixture was poured into water and extracted with EtOAc. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo to give 2 g of colorless oil. The crude mixture was purified by column chromatography (silica gel column 80 g, gradient: 0 min, 100percentn-heptane; 5-12 min, 20percent EtOAc in Heptane; 12-15 min. 30percent EtOAc in Heptane and hold until 30 min). The pure fractions were combined and concentrated under reduced pressure to give 1.25 g of product as colorless oil which solidified upon standing.
To NaH (0.366 g, 9.16 mmol) in THF (12 mL) at 0 °C was added 1 ,3- dimethoxy-2-propanol (1 g, 8.32 mmol) in THF (8 mL) solution. The mixture was warmed to room temperature and stirred for 0.5 hour. To this was added tosyl chloride (1.587 g, 8.32 mmol) in one portion. The white cloudy mixture was stirred at room temperature for 16 hours. LC/MS showed complete conversion. The reaction mixture was poured into water and extracted with EtOAc. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo to give 2 g of colorless oil. The crude mixture was purified by Analogix system (silica gel column 80 g, gradient: 0 min, 100percentn-heptane; 5-12 min, 20percent EtOAc in Heptane; 12-15 min. 30percent EtOAc in Heptane and hold until 30 min). The pure fractions were combined and concentrated in vacuo to give 1.25 g of product as colorless oil which solidified upon standing.
To NaH (0.366 g, 9.16 mmol) in THF (12 mL) at 0 °C was added 1 ,3-dimethoxy-2- propanol (1 g, 8.32 mmol) in THF (8 mL) solution. The mixture was warmed to room temperature and stirred for 0.5 hour. To this was added tosyl chloride (1.587 g, 8.32 mmol) in one portion. The white cloudy mixture was stirred at room temperature for 16 hours. LC/MS showed complete conversion. The reaction mixture was poured into water and extracted with EtOAc. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo to give 2 g of colorless oil. The crude mixture was purified by column chromatography (silica gel column 80 g, gradient: 0 min, 100percentn-heptane; 5-12 min, 20percent EtOAc in Heptane; 12-15 min. 30percent EtOAc in Heptane and hold until 30 min). The pure fractions were combined and concentrated under reduced pressure to give 1.25 g of product as colorless oil which solidified upon standing
Synthesis of trans-N 1 -(1 ,3-dimethoxypropan-2-yl)cyclohexane-1 ,4-diamine (IntermediateStep 1 . To NaH (0.366 g, 9.16 mmol) in THF (12 mL) at 0 °C was added 1 ,3- dimethoxy-2-propanol (1 g, 8.32 mmol) in THF (8 mL) solution. The mixture was warmed to ambient temperature and stirred for 0.5 hour. To this was added tosyl chloride (1.587 g, 8.32 mmol) in one portion. The resulting white cloudy mixture then was stirred at ambient temperature for 16 hours. LC/MS showed complete conversion to 1 ,3- dimethoxypropan-2-yl 4-methylbenzenesulfonate. The reaction mixture was poured into water and extracted with EtOAc. The organic extracts were combined, washed with brine, dried with sodium sulfate and concentrated in vacuo to yield 2 g of a colorless oil. The crude mixture was purified by Analogix system (silica gel column 80 g, gradient: 0 min, 100percentn-heptane; 5-12 min, 20percent EtOAc in Heptane; 12-15 min. 30percent EtOAc in Heptane and hold until 30 min). The pure fractions were combined and concentrated in vacuo to yield 1.25 g of the tosylate product 1 ,3-dimethoxypropan-2-yl 4- methylbenzenesulfonate as a colorless oil, which solidified upon standing.
1,3-Dimethoxypropan-2-ol (12.96 ml) was initially charged in DMF (25 ml), admixed under argon with sodium hydride (681 mg) and stirred at 40° C. for 1 h. Subsequently, 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.002; 1.5 g), dissolved in DMF (25 ml), was added dropwise within 20 min. After 1 h, the mixture was admixed with water and extracted by shaking four times with dichloromethane. The combined organic phases were dried over magnesium sulfate and concentrated by rotary evaporation. The residue was triturated with MtB ether, filtered off with suction and dried. 764 mg of the title compound were isolated. LC-MS rt: 0.74 min [M+H]+: 268.1 (met. a)
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