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CAS No. : | 91526-18-0 | MDL No. : | MFCD12165896 |
Formula : | C5H6O4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JEQSUJXHFAXJOW-UHFFFAOYSA-N |
M.W : | 130.10 | Pubchem ID : | 10510878 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: With formic acid; triethylamine In acetonitrile at 10 - 65℃; Stage #2: With hydrogenchloride In isopropyl alcoholReflux |
Example 4APreparation of 4-hydroxymethyl-5-methyl-l, 3-dioxol-2-oneTo a solution of 4-chloromethyl-5methyl-l ,3-dioxol-2-one (50 g) in acetonitrile (500 ml), formic acid (45 g) was added at 20-25°C and the reaction mass cool to 10-15°C followed by addition of triethylamine (95 g). Reaction mass was heated to 60-65 °C and stirred at the same temperature for about 5-6 hrs. Reaction mass was cooled to 15-20°C, filtered and washed by acetonitrile. Filtrate was taken and acetonitrile was distilled out under vacuum to concentrate the solution. Reaction mass was cooled to 25-30°C and ethyl acetate and water was added, followed by stirring for about 15-20 minutes at 25- 30°C. Aqueous layer extracted with ethyl acetate and combined organic layer were washed with brine solution. Organic layer was separated and evaporated completely under vacuum below 35-40°C. To the oily mass, methanol was added and heated to reflux temperature. A solution of HC1 in isopropyl alcohol was added and the resulting solution was refluxed for about 60-75 mins. Reaction mass was cooled to 30-35°C. Distilled out the solvent completely to obtain title compound as oily mass. (Yield: 34.6 g; 79percent) |
43% | Stage #1: With formic acid In acetonitrile at 20℃; for 0.0833333 h; Stage #2: With triethylamine In acetonitrile at 0 - 60℃; for 8 h; Stage #3: With hydrogenchloride In methanol at 20℃; for 2 h; |
4- (chloromethyl)-5-methyl-1,3-dioxol-2-one (400mg, 2.7mmol) was dissolved in acetonitrile 10ml) was added dropwise formic acid (496mg, 10.8mmol ), then the mixture was stirred at room temperature for 5 minutes. The reaction mixture was cooled to 0 deg.] C, thereto was added triethylamine (0.8ml, 5.4mmol), and the mixture was stirred at 60 8 hours, and then water is introduced, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in methanol (10ml), and thereto was added concentrated hydrochloric acid (1ml), then, the mixture was stirred at room temperature for 2 hours. To the reaction mixture, saturated aqueous sodium bicarbonate is introduced, the mixture was extracted with ethyl acetate, then washed with saturated brine and the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 (v / v)) for purification to prepare the title compound 150mg (43percent yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.6% | In dichloromethane; at 0 - 20℃; | 4-(Hydroxymethyl)-5-methyl-1,3-dioxol-2-one (3.00 g, 23.1 mmol) was dissolved in DCM (25 mL).Further, pyridine (2.01 g, 25.4 mmol) was added thereto.Stir at 0 C. A solution of (4-nitrophenyl)chloroformate (5.1 lg, 25.4 mmol) in DCM (25 mL)After reacting at 0 C for 10 min,Transfer to room temperature overnight.After the reaction, use 1% sodium hydroxide solution (50 mL)The reaction solution was washed with 1 M hydrochloric acid (50 mL).Let stand and layer, take the organic phase,Wash with saturated brine (50 mL),Dry over anhydrous sodium sulfate, filter,Concentrated under reduced pressure,The residue obtained is purified by silica gel column chromatography(RhoEpsilon/EpsilonAlpha(nu/nu) =10/1),An off-white solid was obtained.The resulting solid was added to toluene (40 mL).Stir at room temperature overnight.After suction filtration, the filter cake was rinsed with toluene (10 mL).Then spin dry at 60 C,The title compound was obtained as an off white solid (2.90 g, 42.6%). |
37% | prepared in Step 1 <strong>[91526-18-0]4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one</strong> (150mg, 1.2mmol) was dissolved in chloroform solution (2ml) and the mixture was cooled to 0 , was added dropwise pyridine (0.1ml, 1.3mmol). The reaction mixture was stirred at 0 5 minutes and then 4-nitrophenyl chloroformate is introduced (255mg, 1.3mmol), and the mixture was stirred at room temperature for 18 hours. To the reaction mixture, saturated aqueous sodium bicarbonate is introduced, the mixture was extracted with ethyl acetate, then washed with saturated brine and the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 (v / v)) for purification to prepare the title compound 138mg (37% yield). | |
With pyridine; In chloroform; at 0 - 20℃; | To 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (0.227g, 1.75mmol) (Alpegiani, M. et al, Syn. Com. 1992, 22 (9), 1277) in chloroforin-(5mL) at 0C was added pyridine (0.15mL) and 4-nitrophenyl chloroformate (0.387g, 1.9mmol). The reaction was allowed to warm to ambient temperature and was stirred 18h. The reaction mixture was washed with water,brine and dried (Na2SO4). The crude dioxolone was used in the next step. |
320 mg | With pyridine; In dichloromethane; at 0 - 20℃; for 16h; | 4-Nitrophenyl chloroformate10g And dichloromethane In 10 mlDissolve0 Followed by cooling and stirring.The reaction solution 4- (hydroxymethyl) -5-methyl-1,3-dioxol-2-on500 mg and pyridine223lAt room temperatureAnd stirred for 16 hours.After completion of the reaction, 10 wt% An aqueous citric acid solution and dichloromethaneBy additionThe reactants were extracted. The dichloromethane solution was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 320 mg of (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl (4-nitrophenyl) carbonate. |
3.7 g | With pyridine; In dichloromethane; at 0 - 20℃; for 18.5h; | To a stirred mixture of 4-nitrophenyl chloroformate (3.0 g, 14.9 mmol) in DCM (30 mL) at 0 C. was added pyridine (1.4 mL., 16.4 mmol). 4-(Hydroxymethyl)-5-methyl-1,3-dioxol-2-one (2.03 g, 15.6 mmol) in DCM (15 mL) was then added to the mixture. The mixture was stirred at 0 C. for 30 min, then allowed to warm to room temperature and stirred for 18 h. Additional DCM was added, and the mixture was washed with H2O (1*), 0.5 N NaOH (1*), H2O (2*), and brine (1*), then dried (Na2SO4). filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (40 g column) using EtOAc/hexanes as eluent (0:1 to 3:2) to give the title compound (5a) as an off-white solid (3.7 g). 1H-NMR (300 MHz, CDCl3) delta 8.30 (d, J=8.7 Hz, 2H), 7.40 (d, J=8.7 Hz, 2H), 5.03 (s, 2H), 2.22 (s, 3H); 13C-NMR (75 MHz, CDCl3), delta 155.1, 152.3, 151.7, 145.7, 141.5, 132.2, 125.4, 121.7, 58.1, 9.5. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; for 24h; | A mixture of 3-[6-(7-chloro-4-oxo-4H-1,3-benzothiazin-2-yl)-4-(methylsulfonyl)pyridin-2-yl]prop anoic acid (0.21 g, 0.5 mmol), (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl alcohol (0.13 g, 1.0 mmol), HOBt H2O (92 mg, 0.6 mmol), WSC (116 mg, 0.6 mmol), 4-dimethylaminopyridine (74 mg, 0.6 mmol) and DMF (3 ml) was stirred at room temperature for 24 hours. Water (20 ml) was added to the reaction mixture and the crystals formed were taken by filtration. The crystals were recrystallized from ethanol to give the title compound (0.24 g, 89%) as crystals. Melting point: 183.1-183.2C 1H-NMR (CDCl3) delta: 2.15 (3H, s), 3.09 (2H, t, J=6.9 Hz), 3.18 (3H, s), 3.40 (2H, t, J=6.9 Hz), 4.86 (2H, s), 7.61 (1H, dd, J=1.2 Hz, 8.7 Hz), 7.66 (1H, d, J=1.8 Hz), 7.97 (1H, d, J=1.2 Hz), 8.49 (1H, d, J=8.7 Hz), 8.80 (1H, d, J=0.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1H-imidazole; In N,N-dimethyl-formamide; at 25℃; for 24h; | [01658] A solution of 4,5-dimethyl-2-oxo-1,3-dioxolene (1 mmole) and selenium dioxide (2.5 mmole) in dioxane was heated at reflux for 1 h. Evaporation, extraction and chromatography gave 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene as a yellow oil. TLC: RPf=0.5, 5% MeOH-dichloromethane. [01659] A solution of 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene (1 mmole) in DMF was treated with tert-butyldimethylsilane (1.2 mmole) and imidazole (2.2 mmole) at 25 C. for 24 h. Extraction and chromatography gave 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-oxo-1,3-dioxolene. [01660] A solution of 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-oxo-1,3-dioxolene (1 mmole) and Lawesson's reagent (1.2 mmole) in toluene was heated to 120 C. for 12 h. Extraction and chromatography gave 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-thio-1,3-dioxolene. [01661] A solution of 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-thio-1,3-dioxolene in methanolic hydrogen chloride was stirred at 0 C. for 1 h and 25 C. for 12 h. Extraction and chromatography gave 5-methyl-4-hydroxymethyl-2-thio-1,3-dioxolene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With selenium(IV) oxide; In 1,4-dioxane; | Example 26 Preparation of 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene A mixture of <strong>[37830-90-3]4,5-dimethyl-2-oxo-1,3-dioxole</strong>ne (1 mmol) and selenium dioxide (2.5 mmol) in dioxane was heated at reflux for 1 h. Evaporation, extraction and chromatography gave 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene as a yellow oil. TLC: Rf=0.5, 5percent MeOH-dichloromethane. | |
With selenium(IV) oxide; In 1,4-dioxane; | Example 17 Preparation of 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene A solution of <strong>[37830-90-3]4,5-dimethyl-2-oxo-1,3-dioxole</strong>ne (1 mmol) and selenium dioxide (2.5 mmol) in dioxane was heated at reflux for 1 h. Evaporation, extraction and chromatography gave 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene as a yellow oil. TLC: Rf=0.5, 5percent MeOH-dichloromethane. | |
With selenium(IV) oxide; In 1,4-dioxane; for 1h;Heating / reflux; | [01658] A solution of <strong>[37830-90-3]4,5-dimethyl-2-oxo-1,3-dioxole</strong>ne (1 mmole) and selenium dioxide (2.5 mmole) in dioxane was heated at reflux for 1 h. Evaporation, extraction and chromatography gave 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene as a yellow oil. TLC: RPf=0.5, 5percent MeOH-dichloromethane. [01659] A solution of 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene (1 mmole) in DMF was treated with tert-butyldimethylsilane (1.2 mmole) and imidazole (2.2 mmole) at 25 C. for 24 h. Extraction and chromatography gave 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-oxo-1,3-dioxolene. [01660] A solution of 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-oxo-1,3-dioxolene (1 mmole) and Lawesson's reagent (1.2 mmole) in toluene was heated to 120 C. for 12 h. Extraction and chromatography gave 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-thio-1,3-dioxolene. [01661] A solution of 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-thio-1,3-dioxolene in methanolic hydrogen chloride was stirred at 0 C. for 1 h and 25 C. for 12 h. Extraction and chromatography gave 5-methyl-4-hydroxymethyl-2-thio-1,3-dioxolene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 48h; | To a solution of triacetate 75 (1.55 g, 3.50 mmol) in THF (50 mL) at 0 C. was added polymer supported-triphenylphosphine (4.95 g, 10.50 mmol, Argonaut). To this mixture was added <strong>[91526-18-0]4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one</strong> (0.91 g, 7.00 mmol), prepared according to the procedure of Alepegiani, Syn. Comm., 22(9), 1277-82 (1992) Diethyl azodicarboxylate (0.73 ml, 4.60 mmol) was then added dropwise. The resulting mixture was stirred at room temperature for 48 h, filtered and washed with MeOH and CHCl3. The filtrate was concentrated and purified by flash column chromatography (silica, acetone/CHCl3=10-20%) to afford dioxolone derivative 85 (1.38 g, 71%) as white solid: 1H (400 MHz, d6-DMSO);delta 7.06 (s, 2H), 6.00 (d, J=4.0 Hz, 1H), 5.92 (dd, J=6.6, 4.4 Hz, 1H), 5.56 (t, J=6.4 Hz, 1H), 5.30 (s, 2H), 4.38 (dd, J=11.6, 3.6 Hz, 1H), 4.25 (t, J=3.6 Hz, 1H), 4.10 (q, J=6.0 Hz, 1H), 2.23 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H); MS (+)-ES [M+H]+m/z 555.3. Elemental Analysis calc'd for C21H22N4O12S.Me2CO: C, 47.06; H, 4.61; N, 9.15; S, 5.23. Found: C, 47.25; H, 4.37; N, 9.53; S, 5.52. |
71% | With Argonaut PS-triphenylphosphine resin; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 48h; | To a solution of triacetate 25 (1.55 g, 3.50 mmol) in THF (50 mL) at 0 C was added polymer supported-triphenylphosphine (4.95 g, 10.50 mmol, Argonaut). To this mixture was added <strong>[91526-18-0]4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one</strong> (0.91 g, 7.00 mmol), prepared according to the procedure of Alepegiani, Syn. Comm. , 22(9), 1277-82 (1992) Diethyl azodicarboxylate (0.73 ml, 4.60 mmol) was then added dropwise. The resulting mixture was stirred at room temperature for 48 h, filtered and washed with MeOH and CHC13. The filtrate was concentrated and purified by flash column chromatography (silica, acetone/ends = 10-20%) to afford dioxolone derivative 66 (1.38 g, 71%) as white solid: H (400 MHz, d6-DMSO) 66; # 7.06 (s, 2H), 6.00 (d, J= 4.0 Hz, 1H), 5.92 (dd, J= 6.6, 4.4 Hz, 1H), 5.56 (t, J= 6.4 Hz, 1H), 5.30 (s, 2H), 4.38 (dd, J= 11.6, 3.6 Hz, 1H), 4.25 (t, J= 3.6 Hz, 1H), 4.10 (q, J= 6.0 Hz, 1H), 2.23 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H) ; MS (+) -ES [M+H]+ m/z 555.3. Elemental Analysis calc'd for C21H22N4O12S#Me2CO: C, 47.06; H, 4.61; N, 9.15; S, 5.23. Found: C, 47.25; H, 4.37; N, 9.53; S, 5.52 |
Yield | Reaction Conditions | Operation in experiment |
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95% | To a solution of 2-ethoxy-1-[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (9.0 g) and 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (3.08 g) in N,N-dimethylacetamide (100 mL) were added p-toluenesulfonyl chloride (4.13 g), N,N-dimethylaminopyridine (0.48 g) and potassium carbonate (3.54 g) under ice-cooling and the mixture was stirred at about 10 C. for 3 hrs. After adjusting the pH of the mixture to about 5, the mixture was crystallized by adding water (72 mL) to give crystals as a solvate. The isolated crystals were suspended in a mixture of water (63 mL) and acetone (27 mL) and the suspension was stirred at about 35 C. for 2 hrs. After stirring under ice-cooling for 2 hrs, the crystals were collected by filtration and the crystals were washed with water (18 mL) and dried under reduced pressure at 40 C. to give the title compound (10.6 g, 95%). 1H NMR (300 MHz, DMSO-d6) delta: 1.39 (3H, t, J=6.4 Hz), 2.17 (3H, s), 4.60 (2H, q, J=6.4 Hz), 5.12 (2H, s), 5.56 (2H, s), 7.00 (2H, d, J=7.0 Hz), 7.22-7.24 (3H, m), 7.46-7.57 (3H, m), 7.64-7.75 (3H, m). | |
81% | Example 5Preparation of (5-methyl-2-oxo-l, 3-dioxol-4yl) methyl 2-ethoxy-l-[[2'-(4, 5-dihydro- 5-oxo-4H-l, 2, 4-oxadiazoI-3-yl) biphenyl-4-yl] methyl]-2-ethoxy-lH-benzimidazole-7-carboxylate (<strong>[147403-03-0]Azilsartan</strong> medoxomi.) To a solution of l-[[2'-(4,5-dihydro-5-oxo-4H-l,2,4-oxadiazol-3-yl) biphenyl-4- yl] methyl]-2-ethoxy-lH-benzimidazole-7-carboxylic acid (5 g) in dimethylacetamide (55 ml), 4-hydroxymethyl-5-methyl-l,3-dioxol-2-one (2 g) was added at about 20-25C followed by cooling of the resulting solution to about -10 to -15C. To the resulting solution p-toluoyl sulfonylchloride (3 g), 4-dimethylaminopyridine (0.3 g) and K2C03 (2 g) was added at -10 to -15C. Temperature was. slowly raised to 10-15C in about 1-2 hrs followed by stirring at the same temperature for about 5-6 hrs. Water was added to the resulting solution at 15-20C. The pH of the solution was adjusted to 4-5 by using 0.5N HC1 solution followed by stirring for about 30 mins. The product was filtered, washed and dried to obtain title compound. (Yield: 5 g; 81%) | |
80.1% | With dmap; potassium carbonate; p-toluenesulfonyl chloride; In N,N-dimethyl acetamide; at 8 - 10℃; for 3h; | Example 1: Preparation of crude <strong>[147403-03-0]azilsartan</strong> medoxomil according to EP21 19715 4-toluenesulfonyl chloride (19 g), 4-dimethylaminopyridine (2.5 g), and potassium carbonate (18 g) were added to a solution of 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3- yl)bifenyl-4-yl)methyl)-lH-benzo[ ]-imidazole-7-carboxylic acid (42.8 g, 0.1 mol) and 4- hydroxymethyl-5-methyl-l,3-dioxol-2-one (16.3 g, 0.125 mol) in dimethylacetamide (450 ml) under cooling, and the mixture was stirred at a temperature of 8 - 10C for 3 hours. Then, pH of the mixture was adjusted to 4.5 - 5 by means of diluted hydrochloric acid and, after adding water, the precipitated insoluble portion was sucked off and washed with water. Then, the crude product was suspended in a water-acetone mixture and the mixture was stirred at 35C for 2 hours. After additional stirring in an ice bath for 2 hours, the insoluble portion was sucked off, washed with water, and dried under vacuum at 40C. 42.7 g of the substance (80.1%) was obtained. HPLC purity: 97.6%. |
80.1% | With dmap; potassium carbonate; p-toluenesulfonyl chloride; In N,N-dimethyl acetamide; at 8 - 10℃; for 3h;Cooling; | 4-Toluenesulfonyl chloride (19 g), 4-dimethyl aminopyridine (2.5 g) and potassium carbonate (18 g) were added too a solution of 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)-lH-benzo[i ]-imidazole-7-carboxylic acid (42.8 g, 0.1 mol) and 4- hydroxymethyl-5-methyl-l,3-dioxol-2-one (16.3 g, 0.125 mol) in dimethyl acetamide (450 ml) under cooling and the mixture was stirred at a temperature of 8-10C for 3 hours. Then, pH of the mixture was adjusted to 4.5-5 using diluted hydrochloric acid and the insoluble fraction, separated after addition of water, was aspirated and washed with water. After that, the crude product was suspended in a water-acetone mixture and the mixture was stirred at 35 C for 2 hours. After stirring for another 2 hours in an ice bath the insoluble fraction was aspirated, washed with water and dried in vacuo at 40C. 42.7 g of the substance (80.1 %) was obtained. HPLC purity: 97.6 %. |
3 g | With dmap; N,N-dimethyl acetamide; potassium carbonate; p-toluenesulfonyl chloride; at 0 - 5℃; for 2h; | To a mixture of 2-Ethoxy-l-[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid (5 gm) and N,N- dimethylacetamide (50 ml) were added to p-toluenesulfonyl chloride (3.5 gm), potassium carbonate (4 gm), N,N-dimethylaminopyridine (0.5 gm) and 4-hydroxymethyl-5-methyl- l,3-dioxol-2-one (3.5 gm) at 0 to 5C. The reaction mass was maintained for 2 hours at 0 to 5C and filtered through hi-flow bed. The pH of the filtrate thus obtained was adjusted to 2.0 with acetic acid and then added water (150 ml). The reaction mass was stirred for 30 minutes and filtered to provide a wet solid. To the wet solid was added acetone (15 ml) and water (35 ml) and maintained for 2 hours at room temperature. The contents were then cooled to 0 to 5C and maintained for 2 hours. The separated solid was filtered and then dried to provide 3 gm of <strong>[147403-03-0]azilsartan</strong> medoxomil crystalline Form I. |
92 g | With dmap; dicyclohexyl-carbodiimide; In ethyl acetate; at 15 - 20℃; | A mixture of <strong>[147403-03-0]azilsartan</strong> (I) (100 g), 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one (VII) (40.68 g ), Nu,Nu'- dicyclohexylcarbodiimide (45.20 g),dimethyl aminopyridine (1.0 g) in ethylacetate (1000 ml) was stirred at 15-20C for 18-20 hours. The reaction mixture was filtered. The filtrate was washed with 5% sodium bicarbonate (500 ml) and was concentrated under vacuum. Acetonitrile (230 ml) was added to the residue and heated at 78-80C for 30 minutes. The mixture was cooled to 5-10C and stirred for 30 minutes. The solid was filtered, washed with acetonitrile and dried under vacuum. Yield: 92 g; HPLC purity: 99.43%. |
202 g | With dmap; potassium carbonate; p-toluenesulfonyl chloride; In N,N-dimethyl acetamide; at 0 - 5℃; for 2h; | To a mixture of 2-Ethoxy-i-[2?-(5-oxo-4,5-dihy- dro-i ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-i H-benzimidazole-7-carboxylic acid (200 gm) and N,N-dimethylacetamide (2000 ml) were added to p-toluenesulfonyl chloride (140gm), potassium carbonate (159 gm), N,N-dimethylaminopyridine (20 gm) and 4-hydroxymethyl-5-methyl-i ,3-di- oxol-2-one (140 gm) at 0 to 5 C. The reaction mass was maintained for 2 hours at 0 to 5 C. and filtered through hi-flow bed. The solvent was distilled off under vacuum below 75 C. to obtain a residual mass. To the residual mass was added ethyl acetate (2000 ml) and water (2000 ml) and pH was adjusted to 5.4 with hydrochloric acid (iN). The layers were separated and aqueous layer was extracted with ethyl acetate. Combined organic layers were dried with sodium sulfate and then concentrated to provide a residual solid. To the residual solid was added acetone (600 ml) and water (1400 ml) at 45 C. and then heated to 65 C. for 30 minutes. The contents were then cooled to room temperature and maintained for 1 hour 30 minutes. The separated solid was filtered and then dried to provide 202 gm of <strong>[147403-03-0]azilsartan</strong> medoxomil crystalline Form Hi. |
Yield | Reaction Conditions | Operation in experiment |
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With dmap; In dichloromethane; at 20℃; for 4h; | To a solution of 2-ethoxy-1-[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (5.0 g) and triethylamine (1.69 mL) in THF (50 mL) was added dropwise 2,4,6-trichlorobenzoyl chloride (1.81 mL) under ice-cooling. After stirring the mixture at room temperature for 12 hrs, insoluble material was filtered off and the filtrate was concentrated. The residue was dissolved in methylene chloride (50 mL), and 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (1.72 g) and N,N-dimethylaminopyridine (1.61 g) were added under ice-cooling. After stirring the mixture at room temperature for 4 hrs, the reaction mixture was diluted with chloroform (150 mL), washed with water, saturated aqueous sodium hydrogen carbonate, 1N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was crystallized from diisopropyl ether to give crude crystals. The crude crystals were dissolved in ethanol (18 mL) with refluxing. Activated carbon (0.1 g) was added to the solution and the mixture was stirred with refluxing for 30 min. Insoluble material was filtered off and the filtrate was allowed to cool to room temperature. After 12 hrs., the precipitated crystals were collected by filtration and the crystals were washed with ice-cooled ethanol and dried under reduced pressure at room temperature to give the title compound (3.0 g, 50%). 4-Hydroxymethyl-5-methyl-1,3-dioxol-2-one was synthesised by the method described in Alpegiani, M.; Zarini, F.; Perrone, E. Synthetic Communication, Vol. 22, pp. 1277-1282 (1992). 1H NMR (300 MHz, DMSO-d6) delta: 1.37 (3H, t, J=7.2 Hz), 2.14 (3H, s), 4.58 (2H, q, J=7.2 Hz), 5.10 (2H, s), 5.53 (2H, s), 6.97 (2H, d, J=7.8 Hz), 7.17-7.22 (3H, m), 7.44-7.53 (3H, m), 7.61-7.73 (3H, m). |
Yield | Reaction Conditions | Operation in experiment |
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93% | EXAMPLE 4 Preparation of 4-hydroxymethyl-5-methyl-1,3-dioxolene-2-one STR15 The above formuyloxymethyldioxolenone (7.6 g) was dissolved in methanol (100 mL) and 0.3 mL of 36% hydrochloric acid was added. After stirring one hour at room temperature the methanol was evaporated off. The residue was applied to a column of silica gel (100 g) and eluted with ethyl acetate. The pure 4-hydroxymethyl-5-methyl-1,3-dioxolen-2-one (5.59 g, 93%) was obtained as a colorless oil; 1 H NMR (CDCl3) delta2.14 (s, 3H), 3.35 (bs, 1H), 4.40 (s, 2H); IR (film), 3428, 1825, 1735, 1222, 1180, 1006 cm-1. | |
43% | Example 11 Synthesis of 4-Hydroxymethyl-5-methyl-1,3-dioxol-2-one To a solution of the crude formate (19.9 g) and 80% methanol (250 mL) at room temperature was added conc. HCl (1 mL) and stirred for 6 h. Methanol was evaporated off in rotavap at 30 C. under reduced pressure and the residue was extracted with ethyl acetate. Passage through a short pad of silica gel and concentration gave 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one as a colorless oil (7.0 g, 43%), 1H NMR (CDCl3) delta 4.37 (s, 2H, CH2OH), 2.80 (s, 1H, OH, D2O exchangeable), 2.11 (s, 3H, CH3); 13C NMR (CDCl3) delta 152.94 (OCOO), 137.63 (=CCH2OH), 135.01 (=CCH3), 53.32 (CH2OH), 9.33 (CH3). | |
Step E: 4-Hydroxymethyl-5-Methyl-2-Oxo-1,3-Dioxol-4-ene (122) To a solution of the acid (121) (1.62 g, 11.10 mmol) and anhydrous DMF (112 muL) in dry dichloromethane (50 mL) at 0 C. was dropwise added oxalyl chloride (6.1 mL of 2M solution, 12.2 mmol). After stirring for 30 min at 0 C. and 1 h at room temperature, the solvent was removed under reduced pressure. The residue was dissolved in anhydrous dichloromethane (65 mL) and cooled to -78 C. To this solution was dropwise added a solution of Bu4NBH4 (3.14 g, 12.2 mmol, in 20 mL dichloromethane) over 10 min. After stirring for 1 h at -78 C., the mixture was cautiously quenched with 0.1N HCl (30 mL) and allowed to warm to room temperature. The aqueous layer was separated and was extracted with EtOAc (3*50 mL) and the combined organic extract was washed with brine and dried over Na2SO4. After removing the solvent under reduced pressure, column chromatography on silica gel, eluding with 50% EtOAc-in dichloromethane provided 767 mg of the title compound. 1H-NMR (CD3OD, 400 MHz): delta 2.09 (s, 3H), 4.34 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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With silver nitrate; acetic acid; In acetonitrile; | EXAMPLE 3 4-hydroxymethyl-5-methyl-1,3-dioxolen-2-one A solution of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one (960 mg) in dry CH3 CN (15 ml) was treated with silver nitrate (830 mg). The mixture was stirred 15 minutes at r.t. diluted with benzene (20 ml) and filtered. The filtrate was heated at reflux for 2.5 h, then cooled to 20 C. and treated with acetic acid (10 ml) and excess zinc powder. Stirring was continued for few hours at r.t. (until completion of the reaction: TLC monitoring: ethyl acetate-cyclohexane 1:1, detection with aqueous KMnO4). Removal of the solvent in vacuo and flash chromatography of the residue afforded a light yellow oil (470 mg). Alternatively the mixture was filtered, concentrated, and the residue purified by distillation under reduced pressure (108 C./0.5 mmHg) IR (CHCl3)numax 3300-3600, 1810 (strong), 1740 cm-1 NMR (CDCl3, 90 MHZ)delta: 2.13 (3H, s) 2.6 (1H, br.s, exch.D2 O) 4.30 (2H, S) |
Yield | Reaction Conditions | Operation in experiment |
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In toluene;Heating / reflux; | A suspension of the alcohol (122) (767 mg, 5.9 mmol) and benzyl 1-isocyanatomethyl-1-cyclohexane acetate (5.9 mmol) in toluene was refluxed overnight. After removing the solvent under reduced pressure, the residue was purified by flash column chromatography, eluting with 30% EtOAc in hexane to provide 510 mg of the title compound. 1H-NMR (CD3OD, 400 MHz): delta 1.58-1.30 (m, 10H), 2.18 (s, 3H), 2.35 (s, 2H), 3.17 (d, J=6.8 Hz, 2H), 4.80 (s, 2H), 5.11 (s, 2H), 5.44 (t, J=6.8 Hz, 1H), 7.36 (m, 5H). |
Yield | Reaction Conditions | Operation in experiment |
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80 - 84% | Example 4 crystal of (5-methyl-2-oxo-l,3-dioxol-4-yl) methyl 2-cyclopropyl- l-{ [2'-(5-oxo-4,5-dihydro-lr2,4-oxadiazol-3-yl)biphenyl-4- yl]methyl}-lH-benzimidazole-7-carboxylate2-Cyclopropyl-l-{ [2 '- (5-oxo-4 , 5-dihydro-l ,2 ,4-oxadiazol-3- yl)biphenyl-4-yl]methyl}-lH-benzimidazole-7-carboxylic acid (1 EPO <DP n="43"/>kg) was dissolved in N,N-dimethylacetamide (10 L) , and 4- hydroxymethyl-5-methyl-l , 3-dioxol-2-one (345 g) was added.After cooling to not more than 100C, p-toluenesulfonyl chloride (463 g) , 4-dimethylaminopyridine (54 g) and potassium carbonate (397 g) were added, and the mixture was stirred at not more than 20C for about 3 hrs . 0.5N Hydrochloric acid was added to adjust pH to 4, and water (10 L) was added to allow crystallization. The precipitated crystals were collected by filtration under reduced pressure, and washed successively with N,N- dimethylacetamide (2 L) and 70% water-containing acetone (2 L) . The isolated crystals were suspended in 14% water-containing acetone (6 L) , and the suspension was dissolved by heating to500C. Activated carbon (30 g) was added, and the mixture was stirred for 10 min. The activated carbon was removed by filtration, and washed with 14% water-containing acetone (1 L) . The filtrate was cooled to about 25C to allow precipitation of crystals, and the mixture was stirred at the same temperature for 1 hr. Water (13 L) was added and the mixture was further stirred for 1 hr. The mixture was cooled to not more than 100C and further stirred for 1 hr. The precipitated crystals were isolated and washed with 70% water-containing acetone (6 L) to give a solvate crystal containing acetone. The crystal was dried at 900C under reduced pressure to give Form A crystal (903 g, yield: 80%) . Example 5 crystal of (5-methyl-2-oxo-l,3-dioxol-4-yl) methyl 2-cyclopropyl- 1-{ [2 '- (5-OXO-4 , 5-dihydro-l ,2 ,4-oxadiazol-3-yl) biphenyl-4- yl]methyl}-lH-benzimidazole-7-carboxylate2-Cyclopropyl-l-{ [2 '- (5-oxo-4 ,5-dihydro-l ,2 ,4-oxadiazol-3- yl) biphenyl-4-yl]methyl J-lH-benzoimidazole-7-carboxylic acid (15.00 kg) was dissolved in N,N-dimethylacetamide (150 L), and 4-hydroxymethyl-5-methyl-l,3-dioxol-2-one (5.18 kg) was added. After cooling to not more than 100C, p-toluenesulfonyl chloride (6.95 kg), 4-dimethylaminopyridine (0.81 kg) and potassium carbonate (5.96 kg) were added, and the mixture was stirred at EPO <DP n="44"/>not more than 200C for about 3 hrs. 0.5N Hydrochloric acid was added to adjust pH to 4, and water (150 L) was added to allow crystallization. The crystallized solvate crystals were collected by filtration under reduced pressure, and washed successively with N,N-dimethylacetamide (30 L) and 70% water- containing acetone (30 L) . The isolated crystals were suspended in 40% water-containing acetone (225 L) , and the suspension was dissolved by heating to 50C. The solution was decontaminated by filtration, and washed with 50% water-containing acetone (30 L) . The filtrate was cooled to about 25C to allow precipitation of crystals, and the mixture was stirred at the same temperature for 1 hr. Water (45 L) was added and the mixture was further stirred for 1 hr. The mixture was cooled to not more than 100C and further stirred for 1 hr. The precipitated crystals were isolated and washed with 50% water-containing acetone (30 L) to give a solvate crystal containing acetone. The crystal was dried at 950C under reduced pressure to give Form A crystal (15.73 kg, yield: 84%) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; In dichloromethane; for 12h; | Example 1(5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-cyclopropyl-l-{ [2 '- (5- oxo-4 , 5-dihydro-l,2 ,4-oxadiazol-3-yl) biphenyl-4-yl]methyl}-IH- benzimidazole-7-carboxylateThe compound (4.20 g) obtained in Reference Example 3 was dissolved in THF (42 ml), and triethylamine (1.42 ml) and 2,4,6- trichlorobenzoyl chloride (1.52 ml) were added, and the mixture was stirred for 12 hrs. The insoluble materials were removed by filtration, and the filtrate was concentrated. The residue was dissolved in dichloromethane (42 ml) , and medoxomil alcohol (1.45 g) and DMAP (1.36 g) were added, and the mixture was EPO <DP n="41"/>stirred for 12 hrs. The reaction mixture was diluted with chloroform, washed successively with IN hydrochloric acid, saturated aqueous sodium hydrogencarbonate and saturated brine. The organic layer was dried over magnesium sulfate and concentrated to give the title compound (3.08 g, 59%).IH NMR (300 MHz, DMSO-d6) delta ppm 0.97 - 1.10 (m, 4 H), 2.14 (s, 3 H), 2.18 - 2.31 (m, 1 H), 5.11 (s, 2 H), 5.89 (s, 2 H), 6.96 (d, J=8.29 Hz, 2 H), 7.18 - 7.31 (m, 3 H), 7.44 - 7.71 (m, 5 H), 7.82 (dd, J=8.01, 1.04 Hz, 1 H), 12.38 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
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71% | In tetrahydrofuran; | EXAMPLE 32 5-Amino-7-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxy)-3-(2',3',5'-tri-O-acetyl-beta-D-ribofuranosyl)-thiazolo[4,5-d]pyrimidin-2-one (66) To a solution of triacetate 25 (1.55 g, 3.50 mmol) in THF (50 mL) at 0 C. was added polymer supported-triphenylphosphine (4.95 g, 10.50 mmol, Argonaut). To this mixture was added <strong>[91526-18-0]4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one</strong> (0.91 g, 7.00 mmol), prepared according to the procedure of Alepegiani, Syn. Comm., 22(9), 1277-82 (1992) Diethyl azodicarboxylate (0.73 ml, 4.60 mmol) was then added dropwise. The resulting mixture was stirred at room temperature for 48 h, filtered and washed with MeOH and CHCl3. The filtrate was concentrated and purified by flash column chromatography (silica, acetone/CHCl3=10-20%) to afford dioxolone derivative 66 (1.38 g, 71%) as white solid: 1H (400 MHz, d6-DMSO) 66; delta 7.06 (s, 2H), 6.00 (d, J=4.0 Hz, 1H), 5.92 (dd, J=6.6, 4.4 Hz, 1H), 5.56 (t, J=6.4 Hz, 1H), 5.30 (s, 2H), 4.38 (dd, J=11.6, 3.6 Hz, 1H), 4.25 (t, J=3.6 Hz, 1H), 4.10 (q, J=6.0 Hz, 1H), 2.23 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H); MS (+)-ES [M+H]+ m/z 555.3. Elemental Analysis calc'd for C21H22N4O12S.Me2CO: C, 47.06; H, 4.61; N, 9.15; S, 5.23. Found: C, 47.25; H, 4.37; N, 9.53; S, 5.52. |
Yield | Reaction Conditions | Operation in experiment |
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77% | With pyridine; In diethyl ether; at 0 - 20℃; for 19h; | 2,5-Dioxopyrrolidin-l-yl-((5-methyl-2-oxo-l,3-dioxol-4-yl)methyl carbonate (12). 4-(Hydroxymethy 7.89 mmol, 1 eq.) the solution was c pyridine (608 mg, and finally the solution of S-ethyl carbonochloridothionate (1.04 g, 874 mu, 8.38 mmol, 1.09 eq.) in dry Et^O (8 mL) was added by dropwise. The mixture was stirred for 1 h at 0 C and overnight at rt (18 h). Et^O was removed by vacuo and DCM (70 mL) was added. The reaction mixture was washed with sat. NaHC03 (40 mL) and with water (3x40 mL), dried with MgS04 and DCM was removed by rotavap. The crude product was purified by column chromatography (hexane/EtOAc 5: 1, Rf 0.24). A light yellow liquid (1.29 g) was obtained in 77 % yield. S-Ethyl 0-((5-methyl-2- oxo-1, 3-dioxol-4-yl)methyl) carbonothioate (800 mg, 3.67 mmol, 1 eq.) and N- hydroxysuccinimide (844 mg, 7.33 mmol, 2 eq.) were suspended in dry DCM (8 mL). The solution was cooled to 0 C and peracetic acid (836 mg (100 %), 2.32 g (36 %), 11.00 mmol, 3 eq., 36 % solution in acetic acid) was added by dropwise in 10 minutes. The final mixture was stirred for 30 minutes at 0 C and 2 h at rt. DCM (20 mL) was added and the organic phase was washed with water (2x35 mL) and sat. NaCl (35 mL). DCM was evaporated and the product 12 was obtained as a colorless solid compound (750 mg) in 76 % yield. *H NMR (400 MHz, CDC13): 2.20 (3H, s), 2.86 (4H, s), 5.05 (2H, s). 13C NMR (101 MHz, CDC13): 9.67, 25.58, 59.89, 131.61, 142.20, 151.65, 168.39. IR (CHC13): 1842 m, 1824 s, 1819 s, 1792 s, 1749 vs, 1431 w, 1386 w, 1309 m, 1195 s, 935 w, 900 w, 811 vw cm"1. ESI MS: 294 ([M + Na]+). HR ESI MS: calcd for Ci0H9O8NNa 294.02204; found 294.02213 |
With pyridine; In diethyl ether; at 0 - 20℃; | Step 1: Thiocarbonic Acid S-ethyl Ester O-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl) Ester To an ice cold solution of 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (see J. Med. Chem., 1999, 42, 3994-4000 for preparation, 3.0 g, 23.07 mmol) in anhydrous ether (120 mL), were added pyridine (1.83 mL, 23.07 mmol) followed by a preformed solution of ethylchlorothiolate (2.7 mL, 25.4 mmol) in ether (25 mL). The reaction mixture was stirred overnight at room temperature, filtered and concentrated in vacuo. The residue was taken up in dichloromethane (200 mL) and washed with sat aq. NaHCO3, water (3*100 mL). The organic fraction was dried over sodium sulfate. Solvent was evaporated to give the target compound as brown oil (3.2 g). |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 45℃; for 18h; | Example 101: 4-((R)-3-[Bis-(5-methyl-2-oxo-[l,3]dioxol-4-ylmethoxy)-phosphoryl]-2- [6-((S)-3-methoxy-pyrrolidin-l-yl)-2-phenyl-pyrimidine-4-carbonyl]-amino}-propionyl)- piperazine-1-carboxylic acid butyl ester. To a solution of intermediate 2.6 (100 mg), 4-hydroxymethyl-5-methyl-[l,3]dioxol-2-one (0.14 mL; prepared as described in Synthetic Communications (1984), 22(9), 1277-1282) and PyBOP (421 mg) in anh. DMF (0.32 mL) was added DIPEA (0.22 mL) and the solution was stirred for 18h at 45C under argon. The mixture was diluted with DCM, washed with 10% aq. solution of citric acid, sat.-NaHCO3 and brine, dried (Na2SO^ and evaporated off. The crude was purified by CC (solvent A: EA, solvent B: EA:MeOH (8:2), gradient: 10 to 100%B/15CV, 100%B/2CV; then reverse phase, solvent A: H2O, solvent B: MeCN, gradient: 5 to 95%B/15CV, 95%B/2CV) to give the title product as a white powder after freeze-drying (45 mg). LC-MS (A): tR = 1.07 min; [M+H]+: 842.93. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | 0.40 g (1.07 mmol; 1 eq.) of (S) 2-methylamino-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate is placed under nitrogen then placed in solution in 53 ml of dichloromethane. Then 1.3 ml (2.53 mmol; 2.36 eq.) of a solution at 20% of phosgene in toluene is added, then 0.16 ml (1.18 mmol; 1.1 eq.) of triethylamine. Stirring is maintained for 22 hours at ambient temperature. 0.69 g (5.35 mmol; 5 eq.) of <strong>[91526-18-0]4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one</strong> is then added. After an additional 24 hours at ambient temperature, the reaction mixture is washed with 2×40 ml water and 1×40 ml of 1M HCl. The organic phase is dried over Na2SO4, filtered then evaporated to dryness.The residue obtained is purified by 2 flash chromatographies on silica gel (dichloromethane then ethyl acetate/cyclohexane gradient 1:9 to 3:7, v/v) in order to produce 0.085 g (15%) of the expected product (S) 2-(5-methyl-1,3-dioxol-2-one-4-yl methyl amino)-2-phenyl-n-butyl 3,4,5-trimethoxybenzoate in the form of a colourless oil.1H-NMR (CDCl3, 400 MHz):delta(ppm)=0.78 (t, J=7.2 Hz, 3H, CH3); 1.94 (s, 3H, CH3); 2.02 (m, 1H, diastereotopic CH2); 2.32 (m, 1H, diastereotopic CH2); 3.02 (s(b), 3H, NCH3); 3.80 (s, 6H, 2×OCH3); 3.82 (s, 3H, OCH3); 4.64 (s(b), 2H, OCH2Csp2); 4.80 (m, 1H, diastereotopic OCH2); 4.93 (m, 1H, diastereotopic OCH2); 7.10-7.27 (m, 7H, ArH).MS (CI, NH3): m/z (%)=547 [(M+NH4)+, 5], 479 [80], 260 [100].Rf (SiO2, dichloromethane/methanol, 98:2): 0.16. |
Yield | Reaction Conditions | Operation in experiment |
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With dmap; potassium carbonate; p-toluenesulfonyl chloride; In ISOPROPYLAMIDE; at 35℃;Cooling with ice; | Example 7(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (3R,5S)-5-[[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylate dihydrochloride (3R,5S)-1-(tert-Butoxycarbonyl)-5-[[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (0.3 g) and <strong>[91526-18-0]4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one</strong> (0.09 g) were dissolved in DMA (3.0 ml), toluenesulfonyl chloride (0.13 g), DMAP (0.014 g) and potassium carbonate (0.1 g) were added with stirring under ice-cooling, and the mixture was stirred for 6 hr under ice-cooling, and further at room temperature overnight. The reaction mixture was neutralized with 1N aqueous hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with aqueous sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (0:10?1:1) was concentrated under reduced pressure, and a fraction eluted with ethyl acetate was concentrated under reduced pressure. The residue was dissolved in 2N hydrochloric acid-ethyl acetate solution, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated to give the object product (186 mg).MS (ESI+, m/e) 543 (M+1) |
Yield | Reaction Conditions | Operation in experiment |
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8% | Step 3: (S)-2-(benzyloxycarbonylamino)-6-(N-(((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)sulfamoylamino)hexanoic acid N-(4-phenylthiazol-2-yl)amide (268) To a solution of chlorosulfonyl isocyanate (143 uL, 1.65 mmol) in dichloromethane (2 mL) at 0 C. was added <strong>[91526-18-0]4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one</strong> (215 mg, 1.65 mmol). The mixture was stirred at 0 C. for 10 min, and then for 10 min at room temperature. That intermediate was added dropwise to a mixture of 267 (658 mg, 1.5 mmol) in dichloromethane (4 mL) at 0 C. The mixture was stirred at room temperature for 2 h. Solvent was evaporated, and the residue was purified by silica gel column chromatography with ethyl acetate (80%) in hexanes. The material was purified again by silica gel column chromatography with ethyl acetate (60%) in hexanes, followed by prep-hplc using aquasil C18 column, with acetonitrile (10-95%) in water to afford 268 (80 mg, 8%) as a white solid. (DMSO-d6) delta (ppm) 1H, 12.40 (s, 1H), 11.33 (s, 1H), 7.89 (d, J=7.4 Hz, 2H), 7.82 (bs, 1H), 7.68 (d, J=7.4 Hz, 1H), 7.63 (s, 1H), 7.42 (t, J=7.4 Hz, 2H), 7.36-7.12 (m, 6H), 5.02 (d, J=2.0 Hz, 2H), 4.97 (s, 2H), 4.25 (q, J=3.5 Hz, 1H), 2.86 (q, J=6.3 Hz, 2H), 2.13 (s, 3H), 1.72-1.54 (m, 2H), 1.52-1.22 (m, 4H). LRMS (ESI): (calc.) 673.2; (found) 674.2 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
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(R)-3-[N'-t-Butoxycarbonyl-N-(3'-chlorobiphenyl-4-ylmethyl)-hydrazino]-2-hydroxy-propionic acid (150 mg, 356 mumol), HOBt (140 mg, 1.1 mmol), EDC (0.19 mL, 1.1 mmol) were dissolved into DCM. The mixture was stirred for 10 minutes, then <strong>[91526-18-0]4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one</strong> (370 mg, 2.8 mmol) and 4-methylmorpholine (160 muL, 1.4 mmol) were added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and purified (combiflash. 10-95% EtOAc in hexanes with 0.01% Et3N). The clean fractions were combined and concentrated. MeCN (10 mL, 200 mmol) and 4 M HCl in dioxane (3 mL, 10 mmol) was added and the mixture was stirred at room temperature for 3 hours. The solvent was removed to yield an intermediate HCl salt. 3-hydroxyisoxazole-5-carboxylic acid (55 mg, 430 mumol) and HATU (160 mg, 430 mumol) were combined in DMF (5 mL, 60 mmol). The resulting mixture was stirred for 5 minutes followed by the addition of DIPEA (120 muL, 710 mumol) and the intermediate HCl salt. The mixture was stirred for 30 minutes then evaporated under reduced pressure and purified by preparative HPLC to yield the title compound as a TFA salt (37 mg; purity 95%). MS m/z [M+H]+calc'd for C25H22ClN3O9, 544.10. found 544.4. |
Yield | Reaction Conditions | Operation in experiment |
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79% | Example 4APreparation of 4-hydroxymethyl-5-methyl-l, 3-dioxol-2-oneTo a solution of 4-chloromethyl-5methyl-l ,3-dioxol-2-one (50 g) in acetonitrile (500 ml), formic acid (45 g) was added at 20-25C and the reaction mass cool to 10-15C followed by addition of triethylamine (95 g). Reaction mass was heated to 60-65 C and stirred at the same temperature for about 5-6 hrs. Reaction mass was cooled to 15-20C, filtered and washed by acetonitrile. Filtrate was taken and acetonitrile was distilled out under vacuum to concentrate the solution. Reaction mass was cooled to 25-30C and ethyl acetate and water was added, followed by stirring for about 15-20 minutes at 25- 30C. Aqueous layer extracted with ethyl acetate and combined organic layer were washed with brine solution. Organic layer was separated and evaporated completely under vacuum below 35-40C. To the oily mass, methanol was added and heated to reflux temperature. A solution of HC1 in isopropyl alcohol was added and the resulting solution was refluxed for about 60-75 mins. Reaction mass was cooled to 30-35C. Distilled out the solvent completely to obtain title compound as oily mass. (Yield: 34.6 g; 79%) | |
43% | 4- (chloromethyl)-5-methyl-1,3-dioxol-2-one (400mg, 2.7mmol) was dissolved in acetonitrile 10ml) was added dropwise formic acid (496mg, 10.8mmol ), then the mixture was stirred at room temperature for 5 minutes. The reaction mixture was cooled to 0 deg.] C, thereto was added triethylamine (0.8ml, 5.4mmol), and the mixture was stirred at 60 8 hours, and then water is introduced, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was dissolved in methanol (10ml), and thereto was added concentrated hydrochloric acid (1ml), then, the mixture was stirred at room temperature for 2 hours. To the reaction mixture, saturated aqueous sodium bicarbonate is introduced, the mixture was extracted with ethyl acetate, then washed with saturated brine and the organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 1: 2 (v / v)) for purification to prepare the title compound 150mg (43% yield). | |
With formic acid; triethylamine; In acetonitrile; at 0 - 65℃; for 3h; | Formic acid (0.750 mL, 19.6 mmol) and triethylamine (2.62 mL, 18.8 mmol) were added to a solution of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (1.00 g, 6.73 mmol) in acetonitrile (10.0 mL) at 0 C., the temperature of the reaction liquid was raised to 65 C., and the reaction liquid was stirred for 3 hours. The precipitate was filtered through Celite, and the filtrate was concentrated under reduced pressure. Distilled water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Methanol (10.0 mL) was added to the obtained residue at room temperature and the obtained residue was dissolved. Distilled water (3.0 mL) and concentrated hydrochloric acid (0.120 mL, 3.95 mmol) were added to the reaction liquid at room temperature, and the resulting mixture was stirred at the same temperature for 3 hours. Distilled water was added to the reaction liquid, and the reaction liquid was concentrated under reduced pressure. Distilled water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one. |
Reference Example 25 Synthesis of crude 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (0413) (0414) Formic acid (0.750 mL, 19.6 mmol) and triethylamine (2.62 mL, 18.8 mmol) were added to a solution of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (1.00 g, 6.73 mmol) in acetonitrile (10.0 mL) at 0 C., the temperature of the reaction liquid was raised to 65 C., and the reaction liquid was stirred for 3 hours. The precipitate was filtered through Celite, and the filtrate was concentrated under reduced pressure. Distilled water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Methanol (10.0 mL) was added to the obtained residue at room temperature and the obtained residue was dissolved. Distilled water (3.0 mL) and concentrated hydrochloric acid (0.120 mL, 3.95 mmol) were added to the reaction liquid at room temperature, and the resulting mixture was stirred at the same temperature for 3 hours. Distilled water was added to the reaction liquid, and the reaction liquid was concentrated under reduced pressure. Distilled water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product of 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one. |
Yield | Reaction Conditions | Operation in experiment |
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With 4-methyl-morpholine; benzotriazol-1-ol; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; at 20℃;Inert atmosphere; | C. (2S,4S)-5-Biphenyl-4-yl-2-hydroxymethyl-4-[(3H-[1,2,3]-triazole-4-carbonyl)-amino]-pentanoic acid 5-methyl-2-oxo-[1,3]-dioxol-4-ylmethyl ester (R7=-CH2-5-methyl-[1,3]-dioxol-2-one) (2S,4S)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-pentanoic acid (75 mg, 190 mumol, 1.0 eq.), HOBt (76 mg, 560 mumol, 3.0 eq.), and EDCI (100 muL, 560 mumol, 3.0 eq.) were dissolved in DCM (2 mL). After stirring for 10 minutes, <strong>[91526-18-0]4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one</strong> (0.2 g, 1.5 mmol, 8.0 eq.) and 4-methylmorpholine (82 muL, 4.0 eq.) were added. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with DCM, and washed with water and saturated aqueous NaCl. The organic layer was collected and concentrated. MeCN (1.9 mL) and 4 M of HCl in dioxane (190 muL, 4.0 eq.) were added and the resulting mixture was stirred at room temperature for 2 hours. The solvent was removed to provide the intermediate HCl salt, which was used in the following coupling step. 1,2,3-Triazole-4-carboxylic acid (25 mg, 220 mumol, 1.2 eq.) and HATU (71 mg, 190 mumol, 1.0 eq.) were dissolved in DMF (1.5 mL), and the resulting solution was stirred for 5 minutes, followed by the addition of DIPEA (650 muL) and the intermediate HCl salt. The reaction was monitored and after 1 hour an additional equivalent of 1,2,3-triazole-4-carboxylic acid, HATU, and DIPEA was added. The reaction was quenched with water and the product purified by preparative HPLC to yield the title compound (39.5 mg; purity 95%). MS m/z [M+H]+ calc'd for C26H26N4O7, 507.18. found 507.4. |
Yield | Reaction Conditions | Operation in experiment |
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C. (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid 5-methyl-2-oxo-[1,3]-dioxol-4-ylmethyl ester (R4=H; R7=-CH2-5-methyl-[1,3]dioxol-2-one) (2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (100 mg, 245 mumol, 1.0 eq.), EDCI (52 muL, 294 mumol, 1.2 eq.) and HOBt (39.7 mg, 294 mumol, 1.2 eq.) were dissolved in DCM (5 mL). After stirring for 10 minutes, <strong>[91526-18-0]4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one</strong> (127 mg, 979 mumol, 4.0 eq.) was added. The mixture was stirred for 1 hour and 4-methylmorpholine (40.4 muL, 1.5 eq.) was added. After 1 hour, the crude material was dissolved in AcOH and purified by preparative HPLC to yield the title compound (20 mg). MS m/z [M+H]+ calc'd for C27H28N4O7, 521.20. found 521.4. |
Yield | Reaction Conditions | Operation in experiment |
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19.1 mg | E. (2R,4R)-5-(3'-Chlorobiphenyl-4-yl)-2-hydroxy-4-[(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxyoxalyl)amino]pentanoic Acid 5-methyl-2-oxo-[1,3]-dioxol-4-ylmethyl Ester Oxalyl chloride (22.4 muL, 264 mumol) was added to a solution of <strong>[91526-18-0]4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one</strong> (29.1 mg, 224 mumol) in ether (1.5 mL) and the mixture was stirred at room temperature for 2 hours. The ether was removed under vacuum and the residue was dissolved in DMF (1.5 mL). The resulting solution was added to a solution of (2R,4R)-4-amino-5-(3'-chloro-biphenyl-4-yl)-2-hydroxy-pentanoic acid (65.0 mg, 203 mumol) and NaHCO3 (51.2 mg) at 0 C. The resulting mixture was stirred at room temperature for 3 hours, then concentrated under vacuum. The residue was then purified by reverse phase preparative HPLC (30%-90% MeCN/H2O) to yield compound 1 (19.1 mg) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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5.1 mg | 1-Hydroxybenzotriazole (7.7 mg, 56.8 mumol) and N-(3-dimethylaminopropyl)-N?-ethylcarbodiimide hydrochloride (10.9 mg, 56.8 mumol) were added to a solution of compound 1 (19.1 mg, 37.9 mumol) in DCM (1.0 mL) and the mixture was stirred at room temperature for 10 minutes. 4-Hydroxymethyl-5-methyl-[1,3]dioxol-2-one (14.8 mg, 114 mumol) and 4-methylmorpholine (7.7 mg, 75.8 mumol) were added and the resulting mixture was stirred at room temperature for 6 hours. Water was added and the mixture was extracted with DCM (3×1.5 mL). The DCM layers were combined, dried over Na2SO4, and concentrated to yield a yellow liquid. The crude liquid was purified by reverse phase preparative HPLC to yield the title compound as a white solid (5.1 mg). MS m/z [M+H]+ calc'd for C29H26ClNO12, 616.11; found 616.1. |
Yield | Reaction Conditions | Operation in experiment |
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6.5 g | Example 3 : Preparation of <strong>[147403-03-0]Azilsartan</strong> MedoxomilDichloromethane (50 mL) was added to <strong>[147403-03-0]azilsartan</strong> (5 g) at 20C to 30C. The reaction mixture was cooled to 0C to 5C.4-Dimethylaminopyridine (0.27 g) was added to the reaction mixture at 5C. Triethylamine (2.33 g) was slowly added to the reaction mixture at 5C. A solution of 4-nitrobenzenesulfonyl chloride (2.91 g) in dichloromethane (25 mL) was slowly added to the reaction mixture at 0C to 5C. The temperature of the reaction mixture was raised to 20C to 30C and it was stirred for 1 hour. 4- Hydroxymethyl-5-methyl- l,3-dioxol-2-one (1.71 g) and N,N-dimethylaminopyridine (1.41 g) were added to the reaction mixture at 20C to 30C. The temperature of the reaction mixture was raised to 35C to 40C and it was stirred for 1 hour. The reaction mixture was cooled to 20C to 30C and washed with IN hydrochloric acid (25 mL). The organic layer was washed with 5% sodium bicarbonate solution (25 mL). The organic layer was further washed with 25% sodium chloride solution (25 mL). The organic layer was recovered under vacuum at 25C to 30C. The solid obtained was recrystallized from diisopropylether (50 mL) and the solid obtained was filtered and washed withdiisopropylether (2 x 5 mL). The solid obtained was dried under vacuum at 25C to 30C to obtain the title compound having an X-ray powder diffraction pattern as depicted in Figure 1.Yield: 6.5 g |
Yield | Reaction Conditions | Operation in experiment |
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5.1 g | Example 2: Preparation of Azilsartan MedoxomilDichloromethane (50 mL) was added to the(2-ethoxy-l- [2'-(5-oxo-4,5-dihydro- l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-lH-benzimidazol-7-yl)-carboxyl-4- nitrophenyl sulfonate (6.5 g) obtained in Example 1 at 20C to 30C and stirred for 5 minutes. 4-Hydroxymethyl-5-methyl-l,3-dioxol-2-one (1.71 g) and 4- dimethylaminopyridine(1.41 g) were added to the reaction mixture at 20C to 30C. The temperature of the reaction mixture was raised to 40C to 45C and it was stirred for 2 hours. The reaction mixture was cooled to 20C to 30C and was washed with saturated sodium bicarbonate solution (50 mL). The reaction mixture was washed with 2N hydrochloric acid solution (25 mL). The organic layer was recovered under vacuum at 25C to 30C. The solution was recrystallized from diisopropylether (50 mL) to obtain the title compound.Yield: 5.1 g |
Yield | Reaction Conditions | Operation in experiment |
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20 mg | Compound 6 (100 mg, 245 mumol, 1.0 eq.), EDCI (52 muL, 294 mumol, 1.2 eq.) and HOBt (39.7 mg, 294 mumol, 1.2 eq.) were dissolved in DCM (5 mL). After stirring for 10 minutes, <strong>[91526-18-0]4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one</strong> (127 mg, 979 mumol, 4.0 eq.) was added. The mixture was stirred for 1 hour and 4-methylmorpholine (40.4 muL, 1.5 eq.) was added. After 1 hour, the crude material was dissolved in AcOH and purified by preparative HPLC to yield the title compound as a TFA salt (20 mg). MS m/z [M+H]+ calc'd for C27H28N4O7, 521.20. found 521.4. |
Yield | Reaction Conditions | Operation in experiment |
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Example 6E (R)-3-[N'-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic Acid 5-Methyl-2-oxo-[1,3]-dioxol-4-ylmethyl Ester (R)-3-[N'-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5'-chloro-2'-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (30.0 mg, 63 mmol), HOBt (26 mg, 190 mumol) and EDC (34 muL, 190 mumol) were combined in DCM (243 muL, 3.8 mmol) and stirred for 10 minutes. 4-Hydroxymethyl-5-methyl-[1,3]dioxol-2-one (66 mg, 0.5 mmol) and 4-methylmorpholine (28 muL, 250 mumol) were added and the resulting mixture was stirred at room temperature for 3 hours. The mixture was evaporated under reduced pressure, yielding a brown oil, which was purified by preparative HPLC to yield the title compound (4.6 mg, purity 97%) as a TFA salt. MS m/z [M+H]+ calc'd for C27H24ClFN4O8, 587.13. found 587.1. |
Yield | Reaction Conditions | Operation in experiment |
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50% | (2SAS) odo-4-((S)-3-methoxy-2-((S)-3-methoxy-2-(2-methylthiazole-5- carboxamido)propanamido)propanamido)-2-methyl-3-oxo-5-phenylpentan-2-yl ((5- methyl-2-oxo-l,3-dioxol-4-yl)methyl) carbonate A solution of N-((S)-l-(((S)-l -(((2S,4S)-4-hydroxy-5-iodo-4-methyl-3-oxo-l- phenylpentan-2-yl)amino)-3 -methoxy- 1 -oxopropan-2-yl)amino)-3 -methoxy- 1 - oxopropan-2-yl)-2-methylthiazole-5-carboxamide (500 mg, 0.76 mmol) and DMAP (180 mg, 1.5 mmol) in dichloromethane (7.5 mL) was kept at 0 C in an ice-water bath. A solution of triphosgene (150 mg, 1.5 mmol) in toluene (7.5 mL) was added. The solution was stirred 10 min, then DMAP (90 mg, 0.75 mmol) was added. The solution was stirred another 10 min, then another portion of DMAP (180 mg, 1.5 mmol) was added. The reaction mixture was stirred 10 min, then 4-(hydroxymethyl)-5-methyl-l ,3-dioxol-2-one (1 g, 7.6 mmol) was added. The mixture was allowed to stirred over night, then diluted with water (20 mL) and dichloromethane (50 mL). The dichloromethane layer was separated and washed with IN HCl (10 mL) and brine (10 mL). It was dried over sodium sulfate then concentrated to dryness. Three similar batches were combined, and the residue was purified on reverse-phase prep-HPLC to give product as a white powder (75 mg) as white powder; NMR (300 MHz, CDC13): delta 8.12 (s, 1H), 7.29-7.10 (m, 6H), 6.95 (m, 2H), 5.48-5.37 (m, 1H), 4.93 (m, 2H), 4.78-4.69 (m, 1H), 4.51-4.42 (m, 1H), 3.87-3.82 (m, 2H), 3.79-3.73 (m, 1H), 3.66-3.55 (m, 2H), 3.48 (s, 3H), 3.47-3.44 (m, 1H), 3.28 (s, 3H), 3.18-3.11 (m, 1H), 2.90-2.82 (m, 1H), 2.77 (s, 3H), 2.22 (s, 3H), 1.48 (s, 3H); MS for C3iH37lN4012S m/z: 817 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
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86.4% | With dmap; potassium carbonate; p-toluenesulfonyl chloride; at 30℃; for 3h;Cooling; | 4-Toluenesulfonyl chloride (22 g), 4-dimethyl aminopyridine (1,6 g) and potassium carbonate (18.4 g) were added to a solution of 2-ethoxy-l-((2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3- yl)biphenyl-4-yl)memyl)-lH-benzo[i^-irnidazole-7-carboxylic acid (40 g) and 4- hydroxymethyl-5-methyl-l,3-dioxol-2-one (15 g) in dimethyl acetamide (400 ml) under cooling and the mixture was stirred at 30C 3 for 3 hours. Then, pH of the mixture was adjusted to 4.5-5 with the use of acetic acid and, after addition of water (210 ml), a product, 49.7 g (86.4 %) precipitated as a solvate with dimethyl acetamide. HPLC 97.3 %. |
Yield | Reaction Conditions | Operation in experiment |
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60.0 mg | (1) (1S,2S,3S,5R,6S)-Diallyl 3-fluoro-2-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate (D-15-1) To a solution of triphosgene (35 mg) in chloroform (4 mL), <strong>[91526-18-0]4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one</strong> (45.9 mg) and a solution of N,N-diisopropylethylamine (0.18 mL) in tetrahydrofuran (4 mL) were added at room temperature. After the mixture was stirred at the same temperature for 30 minutes, a solution of (1S,2S,3S,5R,6S)-diallyl 2-amino-3-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylate (D-13-3, 100 mg) in chloroform (4 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for 3 hours. To the reaction mixture, ethyl acetate was added, and the organic layer was washed once with water and once with brine, sequentially. After the organic layer was dried over anhydrous sodium sulfate, the insoluble was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel cartridge, hexane:ethyl acetate = 90:10 - 70:30) to give (1S,2S,3S,5R,6S)-diallyl 3-fluoro-2-((((5-methyl-2-oxo-1,3-dioxol-4-yl)methoxy)carbonyl)amino)bicyclo[3.1.0]hexane-2,6-dicarboxylate (D-15-1, 60.0 mg) as a colorless amorphous. |
Yield | Reaction Conditions | Operation in experiment |
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84% | Dibenzyl 2-((diethoxyphosphoryl)methyl)pentanedioate (2.31 g,5.0 mmol) was hydrogenated in anhydrous THF (100ml) in the presence of catalytic amount of 10 % Pd/Cat room temperature and 1 atm overnight. The catalystwas filtered off and <strong>[91526-18-0]4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one</strong> (1.49 g, 11.0 mmol), HOBt (1.49 g, 11.0 mmol) were added. A solution of EDC.HCl (2.11 g, 11.0 mmol) and DMAP (1.34 g, 11.0 mmol) in DMF (60 ml) was added and the mixture was stirred at roomtemperature overnight. Solvents were evaporated and the residue was partitioned between EtOAc - H2O (1:1, 200 ml). The aqueous solution was extracted with EtOAc (100 ml) again and combined organic extracts were dried (MgSO4) and evaporated. The residue was chromatographed on a silica gel column in EtOAc - 2 % MeOH/EtOAc. Yield 2.13 g (84 %) of oil. 1H NMR (400 MHz, CDCl3): 1.30- 1.33 (m, 6H, CH3(Et)), 1.87 (ddd, 1H, Jlb-p=18.6, Jgem = 15.4, Jlb-2 5.5, H-ib), 1.96-2.08 (m, 2H, H-3), 2.18,2.19(2 x s,2 x3H, 4?CH3), 2.21 (ddd,Jiap i8.i,Jgem 15.4, J1a2 8.5, H-ia), 2.32-2.44 (m, 2H,H-4), 2.84 (m, 1H, H-2), 4.05 - 4.13 (m, 4H, CH2 (Et)), 4.82 - 4.93 (m, 4H, 3 ?-CH2). 13C NMR (101 MHz, CDCl3): 9.35, 9.37 (4?-CH3), 16.36, 16.37 (2 x d, JCH3-P 5.9,CH3(Et)), 27.72 (d, J1p= 143.2, C-i), 27.86 (d, J3p= 12.6, C-3), 30.88 (C-4), 38.96(d, J2p= 3.5, C-2), 53.84, 54.22 (3?-CH2), 61.91 -62.00 (m, CH2 (Et)), 133.15,133.30 (C-3?), 140.17, 140.30 (C-4?), 152.01, 152.05 (C-i?), 171.72 (C-5), 173.29 (d,JC-2-l-P = 8.6, COO). ESI MS: 529 ([M + Na]j. HR ESI MS: calcd for C20H27O13NaP 529. 10815; found 529.10819. |
Yield | Reaction Conditions | Operation in experiment |
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91% | With dmap; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 20℃; | To a solution of 2-((diethoxyphosphoryl)methyl)-5-oxo-5-(2-(trimethylsilyl)ethoxy)pentanoic acid (1.49 g, 3.90 mmol), <strong>[91526-18-0]4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one</strong> (663 mg, 5.1 mmol) and HOBt (690 mg, 5.1 mmol) in anhydrous DMF (10 ml) a solution of EDC.HCl (980 mg, 5.1 mmol) and DMAP (623 mg, 5.1 mmol) in DMF (10 ml) was added. The mixture was stirred at RT overnight. The solvent was evaporated and the residue was extractedwith EtOAc - H2O mixture (1:1, 200 ml). Aqueous portion was extracted with EtOAc(50 ml) again. Organic extracts were dried with MgSO4 and evaporated. The residuewas chromatographed on a silica gel column in EtOAc - 1 % MeOH/EtOAc. Yield1.75 g of oil (91 %). 1H NMR (400 MHz, CDCl3): 0.04 (s, 9H, S1-CH3); 0.98 (m, 2H, Si-CH2); 1.29 - 1.33 (m, 6H, CH3(Et)), 1.88 (ddd, 1H, Jlb_P = 18.7, Jgem = 15.4, Jlb_2 = 5.0, H-lb), 1.95 - 2.03 (m, 2H, H-3), 2.19 (t, 3H, JCH3-CH2 = 0.5, 4'-CH3), 2.21 (ddd, Jla_P = 17.8, Jgem = 15.4, Jia-2 = 8.9, H-la), 2.27 - 2.35 (m, 2H, H-4), 2.84 (m, 1H, H-2), 4.05 - 4.12 (m, 4H, CH2 (Et)), 4.16 (m, 2H, OCH2 (TMSE)), 4.84 (dq, 1H, Jgem = 13.9, Jcm-cro = 0.5, 3 '-CH2b), 4.89 (dq, 1H, Jgem = 13.9, Jcm-cro = 0.5, 3 '-CH2a).13C NMR (101 MHz, CDCl3): -1.55 (S1-CH3), 9.37 (4'-CH3), 16.37 (d, JCH3-p = 6.0, CH3(Et)), 17.26 (Si-CH2), 27.69 (d, Ji_P = 128.7, C-l), 28.31 (C-3), 31.41 (C-4), 39.15 (d, J2_p = 3.7, C-2), 54.17 (3 '-CH2), 61.81 - 61.92 (m, CH2 (Et)), 62.90 (OCH2 (TMSE)), 133.24 (C-3 '), 140.20 (C-4'), 152.01 (C-l '), 171.40 (C-5), 173.48 (d, JC-2-i- P = 7.7, COO).ESI MS: 517 ([M + Na]+).HR ESI MS: calcd for C2oH350io aPSi 517.16293; found 517.16306. |
Yield | Reaction Conditions | Operation in experiment |
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48% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 20℃; for 6h; | A solution of bis((5-methyl-2-oxo-1,3-dioxol-4-yl)methyl) 2-((diethoxyphosphoryl)methyl)pentanedioate (250 mg, 0.494 mmol) inanhydrous acetonitrile (5 ml) was treated withMe3SiBr (530 mul, 4.0 mmol) at 0 C. Thesolution was kept at 0 C overnight. Thevolatiles were evaporated and the residue wascodistilled with MeCN, dissolved in dioxane (5 ml) and treated with water (36 jil, 2.0 mmol). The solution was stirred 30 min at room temperature then toluene (5 ml) wasadded and the solvents were evaporated. To a solution of resulting phosphonic acid, triphenylphosphine (777 mg, 2.96 mmol) and <strong>[91526-18-0]4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one</strong> (386 mg, 2.96 mmol) in THF (10 ml, DIAD (583 mul, 2.96 mmol) was added dropwise. The mixture was stirred 6 h at room temperature. The solvent was removed in vacuo and the residue was chromatographed on a silica gel column in EtOAc - 4 % MeOH/EtOAc. Yield 160 mg (48 %). 1H NMR (400 MHz, CDCl3): 1.93 -2.01 (m, 3H, H-3, H-lb), 2.19, 2.20 (3 x s, 3H,6H, 3H, 4 x CH3), 2.24-2.45 (m, 3H, H-4, H-la), 2.82 (m, 1H, H-2), 4.77-4.96 (m,8H, O-CH2). 13C NMR (101 MHz, CDCl3): 9.24, 9.27, 9.29 (4 x CH3), 27.90 (d, J3-P = 14.0, C-3),28.07 (d, Jl-P = 141.8, C-l), 30.67 (C-4), 38.51 (d, J2-P = 3.7, C-2), 53.88, 54.40 (2 xOCH2), 55.23, 55.37 (2 x d, JCH2-O-P = 6.0 and 5.8, CH2-O-P), 132.89-133.30 (m,C-3?), 140.23, 140.34, 140.51 (C-4?), 151.72, 151.75, 152.05, 152.07 (C-F), 171.49(C-5), 172.74 (d, JC-P = 7.4, COO). ESI MS: 697 ([M + Na]j. HR ESI MS: calcd for C26H27O19NaP 697.07764; found 697.07752. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | The 2-methyl-2-[[5-methoxy-1-(4-cyanonaphthalene-1-yl)-1H-benzo[d]imidazol-2-yl]thio]propionic acid (100 mg, 0 . 240mmol) dissolved in 5 ml dry methylene chloride, added oxalyl chloride (61 mg, 0 . 480mmol) and 1 drop catalytic DMF, room temperature stirring 1h, TLC detection without raw residual, concentrated under reduced pressure to dry, the residue is dissolved in 5 ml dry dichloromethane, by adding 4 -(hydroxymethyl)-5-methyl[1,3]dioxol-2-one (62 mg, 0 . 480mmol) and triethylamine (71 mg, 0 . 702mmol), under the protection of nitrogen, heating to 40 C, reaction 3 hours. Concentrating the reaction system, the separation and purification of the residue by silica gel column (eluant, petroleum ether: ethyl acetate = 10 the [...] 1, v v), shall be 83 mg white solid, yield is 65%, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With dmap; potassium carbonate; p-toluenesulfonyl chloride; In N,N-dimethyl-formamide; at 0 - 15℃; for 12h; | The 206g2--ethoxy-7-carboxylate and 195g4- (hydroxymethyl) -5-methyl - [l, 3] dioxol-2-one of Formula IV was dissolved 2LN, N - dimethyl formamide, the mixture was cooled to 0 ~ 5 , followed by adding 207g of potassium carbonate, and 230g p-toluenesulfonyl chloride 35g4- dimethylaminopyridine. after the addition, the reaction at 0 ~ 5 1h, the temperature was raised to 15 deg.] C to continue the reaction was stirred 12h, the reaction was complete by TLC detection by 0.5mol / L hydrochloric acid to pH 5 mediation, 2L of ethyl acetate was added water and delamination 2L, 1L ethyl acetate layer was washed with water washed 2 times, the organic phase was concentrated to give a solid was slurried with 500mL of methanol was refluxed for 4h, cooled to room temperature and filtered, the filter cake slurried and then 500mL of methanol was refluxed for 4h, cooled to room temperature, filtered, and dried to give compound 50 deg.] C V267g, yield 84.0%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.0501 g | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In chloroform; at 20℃; for 16h; | Diisopropylethylamine (0.113 mL, 0.649 mmol), HBTU (0.184 g, 0.486 mmol), and crude <strong>[91526-18-0]4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one</strong> (0.0840 g, 0.649 mmol) were added to a solution of 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetic acid (0.100 g, 0.324 mmol) in chloroform (3.0 mL) at room temperature, and the reaction liquid was stirred at the same temperature for 16 hours. Hydrochloric acid (1.0 N) was added to the reaction liquid, and then the reaction liquid was back-extracted. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained aqueous layer for neutralization, and then the resulting mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate (0.0501 g, 0.119 mmol, 37%) (hereinafter referred to as a ?compound of Example 59?) as a colorless oil. |
0.0501 g | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In chloroform; at 20℃; for 16h; | Example 59 Synthesis of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate (0668) (0669) Diisopropylethylamine (0.113 mL, 0.649 mmol), HBTU (0.184 g, 0.486 mmol), and crude <strong>[91526-18-0]4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one</strong> (0.0840 g, 0.649 mmol) were added to a solution of 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetic acid (0.100 g, 0.324 mmol) in chloroform (3.0 mL) at room temperature, and the reaction liquid was stirred at the same temperature for 16 hours. Hydrochloric acid (1.0 N) was added to the reaction liquid, and then the reaction liquid was back-extracted. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained aqueous layer for neutralization, and then the resulting mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-(2-(3-(4-(dimethylamino)piperidin-1-yl)-3-oxopropyl)-1H-imidazol-1-yl)acetate (0.0501 g, 0.119 mmol, 37%) (hereinafter referred to as a ?compound of Example 59?) as a colorless oil. (0670) 1H-NMR (400 MHz, CDCl3) delta: 1.16-1.44 (2H, m), 1.77-1.90 (2H, m), 2.16 (3H, s), 2.20-2.42 (7H, m), 2.52-2.62 (1H, m), 2.86-3.04 (5H, m), 3.92-4.04 (1H, m), 4.50-4.62 (1H, m), 4.84 (2H, s), 4.92 (2H, s), 6.78-6.83 (1H, m), 6.95-6.98 (1H, m). (0671) ESI-MS: m/z=421 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.6% | The 45g2-ethoxy -1H-benzimidazole-7-carboxylic acid and 500 ml by adding dichloromethane for added to a reaction flask, stirring cooling to 20 °C the following, to-drop 50.7g triethylamine, the drop finishes, drop by adding 54.0g to toluene sulfonyl chloride and 100 ml dichloromethane mixed solution, drop Bi Yu 10-20 °C stirring reaction 3h, for 10-20 °C adding 39.7g4-hydroxymethyl-5-methyl -1,3-dioxol-2-one, the temperature rising to adding 30-40 °C stirring reaction, with used in HPLC. After the reaction is complete, cooling to 15-25°C, by adding 400 ml purified water stirring, layered, with 30g drying by anhydrous sodium sulfate. Decompression jeung dry dichloromethane, by adding 300 ml methyl tert-butyl ether refined, cooling to 0-5 °C stirring crystallization 3h, filtering, with 20 ml cool to 0-5 °C methyl tert-butyl ether washing, for 40-50 °C reduced-pressure drying to the job (5-methyl-2-oxo -1,3-dioxol-4-yl) methyl 2-ethoxy -1H-benzo[d] imidazol-7-carboxylic acid ester 63.6 g. The yield of 91.6percent, purity 98.1percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
650 mg | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 60℃; for 16h; | 2 g of the dabigatranethexylate sodium salt prepared in Step 1, 4- (hydroxymethyl) -5-methyl-1,3-dioxol-2-one460.4 mg,740.2 mg of N- (3-dimethylaminopropyl) -N-ethylcarbamoide hydrochloride, 1-hydroxybenzotriazole521.7 mg of hydrate and 1.4 ml of N, N-diisopropylethylamine were dissolved in 20 ml of N, N-dimethylformamide,And stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 100 ml of ethyl acetate and 100 ml of a supersaturated aqueous ammonium chloride solutionWas added to extract the reaction product. To the extracted ethyl acetate was added two 100 ml portions of water, followed by washing and adding anhydrous sodium sulfateLt; / RTI & gt; and concentrated. The residue was purified by column chromatography to give 650 mg of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; toluene; for 24h; | To 0.1 mmole of the methyl ester of DFMO in DCM (10 mL) cooled to 0C is added a 20% solution of phosgene in toluene (0.21 mmole) in the presence of triethylamine (3 eq). After stirring for 24 hours to form the intermediate 3A, 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one ( 0.5 mmole) is then added. Stirring is continued for 24 hours. To the reaction is then added water (5 mL) and then 1 N HCI (5 mL). The organic layer is then separated, dried with sodium sulfate and then concentrated under vacuum to afford Prodrug 3 (Formula (II) where Q1 and Q3 are -C(=O)OCH2-5-methyl-l,3-dioxol-2-one, Q2 and Q4 are H and Q5 is -CH3). | |
In dichloromethane; toluene; for 24h; | To 0.1 mmole of the methyl ester of DFMO in DCM (10 mL) cooled to 0oC is added a 20% solution of phosgene in toluene (0.21 mmole) in the presence of triethylamine (3 eq). After stirring for 24 hours to form the intermediate 3A, <strong>[91526-18-0]4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one</strong> ( 0.5 mmole) is then added. Stirring is continued for 24 hours. To the reaction is then added water (5 mL) and then 1 N HCl (5 mL). The organic layer is then separated, dried with sodium sulfate and then concentrated under vacuum to afford Prodrug 3 (Formula (II) where Q1and Q3are-C(=O)OCH2-5-methyl-1,3- dioxol-2-one, Q2and Q4are H and Q5is-CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1. Preparation of Methyl Vinyl Carbonate Bonded to a Methyl Sulfite Group Through a Methylene Bridge. (0182) 4-Chloromethyl-5-methyl vinylene carbonate (Sigma Aldrich) is reacted with sodium sulfite to prepare the corresponding 4-sulfite-methyl salt. The salt is reacted with methyl trifluromethane sulfonate (methyl triflate) to prepare the product: thionyl chloride is reacted with methanol to prepare methyl chlorosulfinate. Methyl chlorosulfinate is reacted with 4-hydroxymethyl ethylene carbonate (Sigma Aldrich) to prepare the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | A solution of 8- (4-cyanonaphthalen-1-yl) -2-methyl-3,4-dihydro-2H-thiopyran [3,2-c] pyridine-2-carboxylic acid (100 mg, 0.277 mmol )Was dissolved in 5 mL of dry dichloromethane,Oxalyl chloride (45 mg, 0.351 mmol)And 1 drop of DMF catalyzed,Stirred at room temperature for 1 h,TLC detection without raw material remaining,Concentrated under reduced pressure to dry,The residue was dissolved in 5 mL of dry dichloromethane,A solution of 4- (hydroxymethyl) -5-methyl- [1,3] dioxol-2-one (46 mg, 0.351 mmol)And triethylamine (71 mg, 0.702 mmol)Under nitrogen protection,Heated to 40 C,Reaction for 3 hours.The reaction system was concentrated under reduced pressure,The residue was purified by silica gel column chromatography (eluent,Petroleum ether: ethyl acetate = 10: 1, v: v),To give 85 mg of a white solid,The yield was 67% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | at 0 - 20℃; for 6h; | To the solution containing the afore synthesized acid chloride cooled to 0 C was added 4- (hydroxymethyl)-5-methyl-2H-1,3-dioxol-2-one (323 .il, 2.48 mmol). The reaction mixture waswarmed to room temperature and stirred for 6 hours, after which time the reaction mixture was diluted with DCM (10 mL) and quenched with water (10 mL). The organic layer was isolated and the aqueous layer was re-extracted with DCM (3 x 10 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by silica gel chromatography eluting with heptanes: ethyl acetate (0 - 80%) toafford the title compound as a pale yellow oil (92 mg, 20 % yield). LC-MS tR = 1.06 mi [M+Naj =576. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | A solution of 2-[[3-(4-cyanonaphthalen-1-yl)-3H-imidazo[4,5-c]pyridin-2-yl]mercapto]-2-methylpropionic acid (100 mg, 0.257 mmol) was dissolved in 5 mL of dry dichloromethane, and oxalyl chloride (45 mg, 0.351 mmol) and 1 drop of DMF were added and stirred at room temperature for 1 h. TLC was tested for the remainder of the starting material, concentrated to dryness under reduced pressure, and the residue was dissolved in 5 mL of dry dichloromethane. A solution of <strong>[91526-18-0]4-(hydroxymethyl)-5-methyl-[1,3]dioxol-2-one</strong> (46 mg, 0.351 mmol) and triethylamine (71 mg, 0.702 mmol) was added under nitrogen, heated to 40 C and reacted for 3 hours. The reaction was concentrated under reduced pressure and the residue was purified by silica gel column eluting (eluent, petroleum ether: ethyl acetate = 5: 1, v: v) to give 77 mg of a white solid in 60% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.924 g | With pyridine; In dichloromethane; at 20℃;Cooling with ice; | 4-light methyl-5-methyl-1,3-dioxazol-2-one (2.6 g, 20 mmol) dissolved in 10 ml of dry dichloromethane,Add 5 ml of pyridine,Ice water cooling under stirring, A solution of chloromethyl chloroformate (0.645 g, 5 mm & lt; 0 & gt;The reaction was stirred overnight at room temperature, The reaction was quenched by the addition of 30 ml of saturated aqueous sodium bicarbonate solution, The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness on a rotary evaporator. The residue was purified by column chromatography to give a pale yellow liquid (0.924 g) |
0.924 g | With pyridine; In dichloromethane; at 20℃;Cooling; | Compound 5 (2.6 g, 20 mmol) was dissolved in 10 mldried dichloromethane. Afier adding 5 ml pyridine, the mixture was stirred under the cooling condition with the drops of Compound 4 (0.645 g, 5 mmol) and then being incubated overnight with stirring at room temperature. The next day, 30 ml saturated sodium bicarbonate was added to quench the reaction. The organic phase was separated, dried by anhydrous sodium sulfate and then being filtered. Rotary evaporators was used to treat the filtrate. The residue was purified by column chromatography and finally got compound (111-3) (0.924 g, light yellow liquid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.804 g | With pyridine; In dichloromethane; at 20℃;Cooling with ice; | 4-hydroxymethyl-5-methyl-1,3-dioxazol-2-one (2.6 g, 20 mmol) dissolved in 10 ml of dry dichloromethane, add 5 ml of pyridine,Ice water cooling under stirring, a solution of chloroethyl chloroformate (0.715 g, 5 mmol) the reaction was stirred overnight at room temperature, the reaction was quenched by the addition of 30 ml of saturated aqueous sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness on a rotary evaporator. The residue was purified by column chromatography to give a pale yellow liquid (0.804 g) |
0.804 g | With pyridine; In dichloromethane; at 20℃; | Compound 5 (2.6 g, 20 mmol) was dissolved in 10 ml dried dichloromethane. Afier adding 5 ml pyridine, themixture was stirred under the cooling condition with thedrops of Compound 6 (0.715 g, 5 mmol) and then beingincubated overnight with stirring at room temperature. The next day, 30 ml saturated sodium bicarbonate was added to quench the reaction. The organic phase was separated, dried by anhydrous sodium sulfate and then being filtered. Rotaryevaporators was used to treat the filtrate. The residue waspurified by column chromatography and finally got compound (111-4) (0.804 g, light yellow liquid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
147 mg | With triethylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; at 20℃; for 3h; | (R) -3-tert-butoxycarbonylamino-4- (5-fluoro-2'-difluoromethoxy-biphenyl-4-yl) butanoate (150 mg, 0.34 mmol)And 4-hydroxymethyl-5-methyl- [1,3] dioxazol-2-one (75 mg) were dissolved in 5 ml of dichloromethane,HATU (250 mg) was added,Adding 0.5 ml of triethylamine,Stirred at room temperature for 3 hours,Evaporated solvent,The residue was purified by column chromatography to give a pale yellow oily liquid (147 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7.8 g | With dmap; p-toluenesulfonyl chloride; In N,N-dimethyl acetamide; at 10℃; for 3h;Cooling with ice; | To a reaction vessel placed in an ice bath was added <strong>[147403-03-0]azilsartan</strong>(8.59 g, 18.84 mmol), DMAc (80 ml), DMAP (0.5 g), TsCl (3.9 g) 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (2.4 g) was dissolved with stirring, Add the base in Table 1,After completion of the dropwise addition, the mixture was warmed to 10 C and stirred for 3 hours. The reaction was complete. 0.3 N HCl was added dropwise to the reaction solution, the pH was adjusted to 5, and then 60 ml of water was slowly added dropwise, The solid was precipitated, filtered, and 80 ml of acetone / water (VV: 1: 3) was added dropwise to the resulting solid, After stirring at 35 C for 2 hours, the mixture was stirred in an ice bath for 3 hours, filtered, 50C vacuum drying 10h <strong>[147403-03-0]Azilsartan</strong> tetramer 7.8g, Aztastamate HP LC purity and <strong>[147403-03-0]Azilsartan</strong> tetramer impurity content as shown in Table 1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
18.42% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 18h; | l-((6'-(2H-tetrazol-5-yl)-[l,l':3',l"-terphenyl]-4-yl)methyl)-2-butyl-4-chloro-lH- imidazole-5-carboxylic acid, TFA salt (Example 384, 15 mg, 0.024 mmol) was dissolved in DCM (2 niL) along with 4-(hydroxymethyl)-5-methyl-l,3-dioxol-2-one (15.56 mg, 0.120 mmol). DMAP (14.61 mg, 0.120 mmol) was added followed by EDC (22.93 mg, 0.120 mmol). The reaction mixture was allowed to stir at RT for 18 h. The reaction mixture was concentrated and purified by ISCO (0-30% MeOH/DCM) to afford the title compound (Example 411, 2.9 mg, 4.41 muiotaetaomicron, 18.42 % yield). LC-MS (Method A2): 1.09 min, [M + H]+=625.1. H NMR (500MHz, CDC13) delta 8.16 (d, 7=8.0 Hz, 1H), 7.81 (dd, 7=8.1, 1.8 Hz, 1H), 7.77 - 7.73 (m, 1H), 7.71 - 7.64 (m, 3H), 7.53 - 7.48 (m, 2H), 7.45 (d, 7=7.4 Hz, 1H), 7.02 (d, 7=8.3 Hz, 2H), 5.57 (s, 2H), 5.07 (s, 2H), 2.73 - 2.61 (m, 2H), 1.79 - 1.69 (m, 2H), 1.39 (q, 7=7.2 Hz, 2H), 1.28 (s, 3H), 0.92 (t, 7=7.3 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; N-(3-dimethylaminopropyl)-N-ethylcarbodiimide; In dichloromethane; N,N-dimethyl-formamide; at 20℃; | General procedure: Ester prodrugs of BEX and RA were synthesised by adding2.87 mmol of the desired alcohol to 0.287 mmol of BEX or RA. 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (0.431 mmol) and 4-dimethylaminopyridine(0.057 mmol) were added, and dichloromethane(15 mL) was used as the solvent. The mixture was stirred magneticallyovernight at room temperature. Purification was performed by flashchromatography using a 200-400 mesh silica gel-packed glass columnsand hexane-ethyl acetate 50:2 (v/v) as the mobile phase. Specific detailsfor compounds that were obtained by different synthetic schemesare described in Supplementary Material 1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(2) adding azilsartan chloride, a first organic solvent, an acid binding agent, DMAP to the reactor, and stirring for 0.5-1 h,Cool down to 0-5 C, slowly add p-toluenesulfonyl chloride, control the temperature during the dropwise addition 0-5 C, after the completion of the addition, the incubation reaction 0.5h;Then 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one was added in portions, and the reaction was incubated at 0-5 C for 1 h.The temperature is raised to 5-10 C, and the reaction is kept for 16 h. After the reaction is finished, the temperature is lowered to -5-0 C, and the reaction is kept for 16 h.Filtered, acetone was added to the filtration cake, stirred at room temperature 2h, filtered, 25-30 dried under reduced pressure to give azilsartan medoxomil;The first organic solvent is selected from the group consisting of dichloromethane; the acid binding agent is triethylamine;The azilsartin chloride and the acid binding agent, the DMAP, the p-toluenesulfonyl chloride,The molar ratio of 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one is 1:2:0.2:1.1:1.2; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; | To a stirred solution of 3-hydroxy-2,2-dimethylpropanoic acid (4.0 g, 33.9 mmol) and potassium carbonate (4.68 g, 33.9 mmol) in DMF (45 mL) at 0 C. was added 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (5.03 g, 33.9 mmol) in DMF (5 mL) dropwise over 1 h. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography using EtOAc/ hexane (1:4 to 2:3) as eluent to give the product (25a) as a yellow liquid (1.6 g, yield 21%). 1H NMR (300 MHz, CDCl3): delta 4.86 (s, 2H), 3.58 (s, 2H), 2.18 (s, 3H), 1.20 (s, 6H). |
21% | With potassium carbonate; In N,N-dimethyl-formamide; at 0 - 20℃; | To a stirred solution of 99 3-hydroxy-2,2-dimethylpropanoic acid (4.0 g, 33.9 mmol) and 280 potassium carbonate (4.68 g, 33.9 mmol) in 143 DMF (45 mL) at 0° C. was added 281 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (5.03 g, 33.9 mmol) in DMF (5 mL) dropwise over 1 h. The reaction was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to give a crude residue. The residue was purified by silica gel column chromatography using 21 EtOAc/282 hexane (1:4 to 2:3) as eluent to give the 283 product (42a) as a yellow liquid (1.6 g, yield 21percent). 1H-NMR (300 MHz, CDCl3): delta 4.86 (s, 2H), 3.58 (s, 2H), 2.18 (s, 3H), 1.20 (s, 6H). |
Tags: 91526-18-0 synthesis path| 91526-18-0 SDS| 91526-18-0 COA| 91526-18-0 purity| 91526-18-0 application| 91526-18-0 NMR| 91526-18-0 COA| 91526-18-0 structure
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P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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