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CAS No. : | 113583-35-0 | MDL No. : | MFCD00672151 |
Formula : | C7H10N2O4S | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ITDVJJVNAASTRS-UHFFFAOYSA-N |
M.W : | 218.23 g/mol | Pubchem ID : | 838363 |
Synonyms : |
|
Num. heavy atoms : | 14 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.43 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 48.11 |
TPSA : | 86.76 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.36 cm/s |
Log Po/w (iLOGP) : | 1.54 |
Log Po/w (XLOGP3) : | 0.38 |
Log Po/w (WLOGP) : | 0.98 |
Log Po/w (MLOGP) : | -0.9 |
Log Po/w (SILICOS-IT) : | 0.19 |
Consensus Log Po/w : | 0.44 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.55 |
Solubility : | 6.13 mg/ml ; 0.0281 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.77 |
Solubility : | 3.73 mg/ml ; 0.0171 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.23 |
Solubility : | 1.29 mg/ml ; 0.00592 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.23 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
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* 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 |
---|---|---|
84.5% | With sodium tungstate; dihydrogen peroxide; acetic acid In water at 40℃; | Example 10: Preparation of 4, 6-dimethoxy-2-(methylsulfonyl) pyrimidine To 200ml acetic acid was added 3mpercent sodium tungstate. To this, 1.0m 2-methylthio-4,6- dimethoxypyrimidine was added to obtain a mass (clear solution). The mass was heated to 40°C. To the heated mass 2.1m 30percent H202 was added in 4-8 hours and stirred at 40°c for 3-5 hours. Further, 0.05m 30 percent H202 was added and stirred at 40°C till complete conversion. Reaction was carried out at 40°c. Reaction mixture was cooled and solids were filtered. The obtained cake was washed with aqueous acetic acid followed by water. The cake was then dried. Yield = 83percent. The filtrate was extracted with ethylene dichloride. The obtained ethylene dichloride layer was concentrated, wt = 42g, yield of product was about 1-1.5percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tetrabutylammomium bromide; potassium carbonate In tolueneReflux | 0.04 mol of 2,6-dihydroxybenzoic acid was weighed separately,0.05 mol of 2-methanesulfonyl-4,6-dimethoxypyrimidine,0.004 mol of tetrabutylammonium bromide,0.08 mol of potassium carbonate was placed in a reaction vessel,Add 300mL toluene heated reflux reaction 8 ~ 1 Oh,The reaction is cooled and filtered,The filter cake was washed with toluene,dry,The resulting solid was mixed with 500 mL of water,Stir,Dropping 30percent HC1 to the system PH = 3 ~ 4,filter,dry,Was gray and solidbodyBispyribac15.7g,Purity 97percentYield 85percent. |
83% | Stage #1: With sodium hydride In N,N-dimethyl acetamide; toluene; paraffin oil at 100℃; for 5 h; Stage #2: at 20℃; for 1 h; |
Into a 500 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, 60percent sodium hydride (dispersed in liquid paraffin; 6.2 g, 0.155 mol) and Toluene (300 ml) was charged. Subsequently, a solution of 2,6-dihydroxybenzoic acid (7.7 g, 0.05 mol) dissolved in N, N-dimethylacetamide (DMAC; 10 ml) was slowly added dropwise thereto. While stirring the mixture at room temperature, 4,6-dimethoxy-2-methylsulfonylpyrimidine (21.8 g, 0.1 mol) was added in portions. Thereafter, the mixture was stirred at 100 ° C. for 5 hours. As a result, a reaction mixture containing sodium 2,6-bis (4,6-dimethoxypyrimidin-2-yloxy) benzoate was obtained. A small amount of the reaction mixture was sampled, acidified and analyzed by HPLC. The components other than solvent etc. in the reaction mixture were as follows. 82percent of 2- (4,6-dimethoxypyrimidin-2-yloxy) benzoic acid (target product), 2- (4,6- dimethoxypyrimidin-2-yloxy) -6-hydroxybenzoic acid: 2 percent, 4,6-dimethoxy-2-methylsulfonylpyrimidine (raw material): 8percent, 4,6-dimethoxy-2-hydroxypyrimidine (by- product): 3percent. After the reaction mixture was cooled to room temperature, a small amount of methanol was added thereto, and the mixture was stirred at room temperature for 1 hour. The mixture was poured into water and the resulting mixture was partitioned between organic and aqueous layers. The organic layer and the aqueous layer were separated, and an aqueous layer was obtained. Dilute hydrochloric acid was added to the obtained aqueous layer until the pH became 4. Precipitated crystals were collected by filtration, washed with water and dried to obtain 2, 6-bis (4,6-dimethoxypyrimidin-2-yloxy) benzoic acid (17.8 g) as white crystals. Yield: 83percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.5% | With sodium tungstate; dihydrogen peroxide; acetic acid; In water; at 40℃; | Example 10: Preparation of 4, 6-dimethoxy-2-(methylsulfonyl) pyrimidine To 200ml acetic acid was added 3m% sodium tungstate. To this, 1.0m 2-methylthio-4,6- dimethoxypyrimidine was added to obtain a mass (clear solution). The mass was heated to 40C. To the heated mass 2.1m 30% H202 was added in 4-8 hours and stirred at 40c for 3-5 hours. Further, 0.05m 30 % H202 was added and stirred at 40C till complete conversion. Reaction was carried out at 40c. Reaction mixture was cooled and solids were filtered. The obtained cake was washed with aqueous acetic acid followed by water. The cake was then dried. Yield = 83%. The filtrate was extracted with ethylene dichloride. The obtained ethylene dichloride layer was concentrated, wt = 42g, yield of product was about 1-1.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | 2.8 6 g (10 mmol) of <strong>[178306-47-3]methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate</strong> were dissolved in 40 ml of dimethylformamide,Then 0.3 g (12 mmol) sodium hydride was added.The mixture was stirred for 1 hour,Then 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added.After stirring at room temperature for 24 hours,Carefully hydrolyze with 10 ml of water,The pH was adjusted to 5 with acetic acid,The solvent was removed by distillation under high vacuum.The residue was placed in 100 ml of ethyl acetate,Wash with water,And dried over magnesium sulfate,The solvent was distilled off.The residue was mixed with 10 ml of ether,The resulting precipitate was collected by suction filtration.After drying, 3.48 g (82%) of a white powder remained. Melting point 81 C. | |
In N-methyl-acetamide; water; ethyl acetate; | Example 3 Methyl 2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate 2.86 g (10 mmol) of <strong>[178306-47-3]methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate</strong> were dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride was added. The mixture was stirred for 1 h and then 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine were added. After stirring at room temperature for 24 h, cautious hydrolysis was carried out with 10 ml of water, the pH was adjusted to 5 with acetic acid, and the solvent was removed by distillation under high vacuum. The residue was taken up in 100 ml of ethyl acetate, washed with water and dried over magnesium sulfate, and the solvent was distilled out. The residue was mixed with 10 ml of ether, and the resulting precipitate was filtered off with suction. After drying, 3.48 g (82%) of a white powder remained. Melting point 81 C. | |
In N-methyl-acetamide; water; ethyl acetate; | EXAMPLE 3 Methyl 2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate 2.86 g (10 mmol) of <strong>[178306-47-3]methyl 2-hydroxy-3-methoxy-3,3-diphenylpropionate</strong> were dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride was added. The mixture was stirred for 1 h. and then 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine were added. After stirring at room temperature for 24 h., cautious hydrolysis was carried out with 10 ml of water, the pH was adjusted to 5 with acetic acid, and the solvent was removed by distillation under high vacuum. The residue was taken up in 100 ml of ethyl acetate, washed with water and dried over magnesium sulfate, and the solvent was distilled out. The residue was mixed with 10 ml of ether, and the resulting precipitate was filtered off with suction. After drying, 3.48 g (82%) of a white powder remained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 16h; | Example 9 methyl 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3,3-diphenylbutyrate 1.2 g (4.4 mmol) of methyl 2-hydroxy-3,3-diphenylbutyrate were dissolved in 10 ml of absolute DMF and, under nitrogen, 1.2 g (8.8 mmol) of K2CO3 and 0.97 g (4.4 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added.. The mixture was stirred at room temperature for 16 hours.. It was then evaporated, and the residue was taken up in water and extracted three times with ethyl acetate.. The combined organic phases were dried over MgSO4 and concentrated. 1.8 g of crude product were obtained and were reacted further without purification. 1H-NMR [CDCl3], delta=2.0 (s, 3H); 3.25 (s, 3H); 3.9 (s, 6H)); 5.75 (d, 1H); 5.8 (s, 1H); 7.1-7.3 (m, 10H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 20℃; for 72h; | Example 14 2-(4,6-Dimethoxy-2-pyrimidinyloxy)-3,3-diphenylvaleronitrile 7.0 g (27.9 mmol) of 2-hydroxy-3,3-diphenylvaleronitrile were dissolved in 100 ml of DMF (abs.) and, under nitrogen, 7.57 g (55.7 mmol) of potassium carbonate and 6.1 g (27.9 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine were added, and the mixture was stirred at room temperature for 72 hours.. The mixture was concentrated under reduced pressure, and the residue was taken up in water and extracted three times with ethyl acetate.. The combined organic phases were dried over MgSO4, and the solvent was evaporated off.. The crude product was chromatographed on silica gel with n-heptane/ethyl acetate (20:1).. 8.8 g (81%) of product were obtained. 1H-NMR [CDCl3], delta=0.8 (t, 3H); 2.45 (dq, 2H); 3.95 (s, 6H), 5.8 (s, 1H); 6.25 (s, 1H); 7.2-7.4 (m, 10H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With potassium carbonate; In 1,4-dioxane; for 11h;Heating / reflux; | The resulting intermediate n-propyl 4-(2-hydroxy-benzylamino) benzamide (22.7 g, 0.08 mol), 17.44 g (0.08 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine are dissolved into 500 ml dioxane. 22 g (0.16 mol) of potassium carbonate is added at room temperature. The mixture is warm to reflux temperature for 11 hours, then suction filtered. The filter cake is washed with dioxane (50 ml*2) and the mother liquor is concentrated and recrystallized from ethyl acetate, giving 25.4 g of white solid product n-propyl 4-[2-(4,6-dimethoxy-2-pyrimidinyloxy)-benzylamino]-benzamide (I-78). The yield is 75%. m.p.: 96-97 C.; m/z: 423 (M+); 1H-NMR (CDCl3, delta): 7.14-7.88 (m, 8H), 6.51 (d, 1H), 5.78 (s, 1H), 4.45 (s, 2H), 4.19 (t, 2H), 3.80 (s, 6H), 1.77 (m, 2H), 1.03 (t, 3H) ppm |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate; In 1,4-dioxane; for 12h;Heating / reflux; | The resulting intermediate i-propyl 4-(2-hydroxy-benzylamino)benzamide (23.3 g, 0.082 mol), 18.0 g (0.083 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine are dissolved into 500 ml dioxane. 23 g (0.167 mol) of potassium carbonate is added at room temperature and the mixture is refluxed for 12 hours, then suction filtered. The filter cake is washed with dioxane (50 ml*2) and the mother liquor is concentrated and recrystallized from ethyl acetate, giving 27 g of white solid product i-propyl 4-[2-(4,6-dimethoxy-2-pyrimidinyloxy)-benzylamino]benzamide (I-79). The yield is 78%. m.p.: 83-84 C.; m/z: 423 (M+); 1H-NMR (CDCl3, delta): 7.11-7.86 (m, 6H), 6.52 (m, 2H), 5.77 (m, 1H), 5.22 (m, 1H), 4.43 (m, 2H), 3.80 (s, 6H), 3.70-3.90 (m, 1H), 1.35 (m, 6H)ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With potassium carbonate; In 1,4-dioxane; for 11h;Heating / reflux; | [0053] 2.190 g (7.66 mmol) of the resulting compound above, 1.670 g (7.66 mmol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine are dissolved into 30 ml of dioxane. 2.114 g (15.32 mmol) potassium carbonate is added at room temperature. The mixture is refluxed to react for 11 hours, and then suction filtered. The filter cake is washed with 20 ml dioxane and the mother liquor is concentrated. The residual product is added into 10 ml of ethanol while stirring, then suction filtered, to give 2.83 g of white solid product, N-{4-[2-(4,6-dimethoxy-2-pyrimidinyloxy)-3-methoxybenzyl amino]phenyl}acetamide. The yield is 87.0%. The product is purified by recrystallization from ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With acetic acid; In N-methyl-acetamide; water; | 2-(4,6-Dimethoxypyrimidin-2-yl)-oxy-3,3-dimethylbutyronitrile 29.5 g (0.14 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine were suspended in 180 ml of absolute dimethylformamide, and 20 g (0.18 mol) of 3,3-dimethyl-2-hydroxybutyronitrile were added. 5.2 g of 80% strength sodium hydride were then added a little at a time at 0 C., and the mixture was stirred for 3 hours at 60 C. After cooling, 10 g of acetic acid and 20 ml of water were added and the reaction mixture was poured onto 500 ml of water. The resulting precipitate was filtered off under suction and dried. 32.4 g of a white powder having a melting point of 88-89 C. were obtained (yield: 92% of theory). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate; In N,N-dimethyl-formamide; | EXAMPLE 1 Preparation of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-(1-pyrrolidinyl)picolinate (Compound No. 317) 1.55 g (7 mmol) of methyl 3-hydroxy-6-(1-pyrrolidinyl)picolinate, 1.83 g (8.4 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.96 g (7 mmol) of potassium carbonate were added to 50 ml of DMF and reacted at 100 C. for 3 hours. After completion of the reaction, the reaction product was poured into ice water, extracted with ethyl acetate, washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off, and the residue was crystallized from diisopropyl ether to obtain the desired product. Amount: 2.11 g (yield: 84%), melting point: 151-153 C. |
84% | With potassium carbonate; In N,N-dimethyl-formamide; | EXAMPLE 1 Preparation of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-(1-pyrrolidinyl)picolinate (Compound No. 317) 1.55 g (7 mmol) of methyl 3-hydroxy-6-(1-pyrrolidinyl)picolinate, 1.83 g (8.4 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.96 g (7 mmol) of potassium carbonate were added to 50 ml of DMF and reacted at 100C for 3 hours. After completion of the reaction, the reaction product was poured into ice water, extracted with ethyl acetate, washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was distilled off, and the residue was crystallized from diisopropyl ether to obtain the desired product. Amount: 2.11 g (yield: 84%), melting point: 151-153C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81.3% | With potassium carbonate; In N,N-dimethyl-formamide; | Preparation of methyl 6-amino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate A DMF suspension (50 ml) of 3.0 g (17.8 mmol) of methyl 6-amino-3-hydroxypicolinate, 3.9 g (17.8 mmol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine and 1.23 g (8.9 mmol) of potassium carbonate in a 100 ml round bottomed flask, was stirred at 80 C. for 4 hours. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic layer was washed with water, dried, concentrated and purified by silica gel chromatography (n-hexane/AcOEt=1/1+0.1 MeOH) to obtain 4.43 g (yield: 81.3%) of the desired product. Colorless prism crystals, melting point: 74-75 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With potassium carbonate; In N,N-dimethyl-formamide; | 0.78 g (3.7 mmol) of the obtained methyl 6-acetylamino-3-hydroxypicolinate, 0.81 g (3.7 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.51 g (3.7 mmol) of potassium carbonate were added to 50 ml of DMF, and the mixture was reacted at 80 C. for two hours. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried and concentrated. The oily product thereby obtained was purified by column chromatography to obtain methyl 6-acetylamino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate. Amount: 0.90 g (yield: 70%), melting point: 80-85 C. |
70% | With potassium carbonate; In N,N-dimethyl-formamide; | 0.78 g (3.7 mmol) of the obtained methyl 6-acetylamino-3-hydroxypicolinate, 0.81 g (3.7 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.51 g (3.7 mmol) of potassium carbonate were added to 50 ml of DMF, and the mixture was reacted at 80C for two hours. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried and concentrated. The oily product thereby obtained was purified by column chromatography to obtain methyl 6-acetylamino-3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate. Amount: 0.90 g (yield: 70%), melting point: 80-85C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.0% | With potassium hydroxide; potassium carbonate; citric acid; In water; dimethyl sulfoxide; | Process for producing 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-methylaminopicolinic acid (Second method) 10.5 mg (0.0576 mmol) of methyl 6-methylamino-3-hydroxypicolinate, 11.6 mg (0.0532 mmol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine, 8.8 mg (0.637 mmol) of potassium carbonate and 0.5 ml of dry dimethylsulfoxide were mixed. The mixture was stirred at room temperature for 5 hours, and then a 10% potassium hydroxide aqueous solution (corresponding to 90 mg, 0.160 mmol) was added thereto. The mixture was reacted at room temperature for one hour, and then 2.0 ml of water was added to the reaction mixture. Further, 1.0 ml of a 10% citric acid aqueous solution was added thereto, and the mixture was left to stand, whereby crystals precipitated. After being thoroughly precipitated, the crystals were filtered under suction and washed with water. The crystals were dried to obtain 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-methylaminopicolinic acid. Colorless prism crystals, 13.7 mg (yield: 84.0%) |
84.0% | With potassium hydroxide; potassium carbonate; citric acid; In water; dimethyl sulfoxide; | Process for producing 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-methylaminopicolinic acid (Second method) 10.5 mg (0.0576 mmol) of methyl 6-methylamino-3-hydroxypicolinate, 11.6 mg (0.0532 mmol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine, 8.8 mg (0.637 mmol) of potassium carbonate and 0.5 ml of dry dimethylsulfoxide were mixed. The mixture was stirred at room temperature for 5 hours, and then a 10% potassium hydroxide aqueous solution (corresponding to 90 mg, 0.160 mmol) was added thereto. The mixture was reacted at room temperature for one hour, and then 2.0 ml of water was added to the reaction mixture. Further, 1.0 ml of a 10% citric acid aqueous solution was added thereto, and the mixture was left to stand, whereby crystals precipitated. After being thoroughly precipitated, the crystals were filtered under suction and washed with water. The crystals were dried to obtain 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-methylaminopicolinic acid. Colorless prism crystals, 13.7 mg (yield: 84.0%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.6% | With potassium carbonate; In ethyl acetate; N,N-dimethyl-formamide; | EXAMPLE 1 Preparation of 2-trimethylsilylethyl 2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-6-(1-propenyl)benzoate (Compound No. 1) In a 50 ml round bottom-flask, there were charged 2-trimethylsilylethyl 6-(1-propenyl)salicylate (3.1 g, 11.0 mmol), 4,6-dimethoxy-2-methylsulfonylpyrimidine (2.4 g, 11.0 mmol), potassium carbonate (1.8 g, 13.0 mmol) and 10 ml of N,N-dimethylformamide (hereinafter referred to as "DMF"), and the resultant mixture was reacted for 1 hour at 80 C. After cooling the reaction mixture, DMF was distilled off under reduced pressure, and the residue thus obtained was dissolved in ethyl acetate, washed with water and a saturated salt water, dried with anhydrous sodium sulfate and concentrated. The resultant residue was purified by silica gel column chromatography to obtain 2.0 g (yield: 47.6%) of the aimed product (colorless transparent viscous liquid). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50.0% | With potassium carbonate; In N,N-dimethyl-formamide; | EXAMPLE 3 (Process A) Preparation of ethyl 4-(4,6-dimethoxypyrimidin-2-yloxy)-2-methylthiomethylthiophene-3-carboxylate (Compound No. 170) 50 ml of N,N-dimethylformamide was added to 3.5 g (15.1 mmol) of ethyl 4-hydroxy-2-methylthiomethylthiophene-3-carboxylate, 3.3 g (15.1 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 2.1 g (15.2 mmol) of potassium carbonate, and the mixture was heated and stirred at from 90 to 100 C. for 2 hours. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 2.8 g (yield: 50.0%) of the desired product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With potassium carbonate; In N,N-dimethyl-formamide; | EXAMPLE 1 Preparation of 5-(4,6-dimethoxypyrimidin-2-yl)oxy-4-formyl-3-methylbenzothiophene (Compound No. 104) A mixture comprising 2.1 g of 4-formyl-5-hydroxy-3-methylbenzothiophene, 2.4 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1.8 g of potassium carbonate in 30 ml of N,N-dimethylformamide, was heated and stirred at 70 C. for 3 hours. The mixture was returned to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. Then, it was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=10/1) to obtain 3.1 g (yield: 86%) of the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With potassium carbonate; In N,N-dimethyl-formamide; | EXAMPLE 8 Preparation of Methyl 5-(4,6-Dimethoxypyrimidin-2-yl)oxy-2-ethoxy-2,3-dihydrobenzofuran-4-carboxylate (Compound No. 507) A mixture comprising 1.0 g of methyl 2-ethoxy-5-hydroxy-2,3-dihydrobenzofuran-4-carboxylate, 1.0 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 0.78 g of potassium carbonate in 30 ml of N,N-dimethylformamide, was heated and stirred at 100 C. for two hours. The mixture was returned to room temperature, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to obtain 1.5 g (yield: 95%) of the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In N,N-dimethyl-formamide; | EXAMPLE 3 Preparation of Benzyl 5-(4,6-Dimethoxypyrimidin-2-yl)-oxy-3-ethoxycarbonyl-2-methylbenzofuran-4-carboxylate (Compound No. 1) A mixture comprising 12.88 g of benzyl 3-ethoxycarbonyl-5-hydroxy-2-methylbenzofuran-5carboxylate, 8.33 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 5.53 g of potassium carbonate in 150 ml of N,N-dimethylformamide, was heated and stirred at 70 C. for 3 hours. The mixture was returned to room temperature, then poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. It was concentrated under reduced pressure, and the oily substance thereby obtained was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to obtain 14.45 g (yield: 81%) of the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With potassium carbonate; In N,N-dimethyl-formamide; | EXAMPLE 12 Preparation of Methyl 6-(4,6-Dimethoxypyrimidin-2-yl)oxy-3-methyl-benzisoxazol-7-carboxylate (Compound No. 487) A mixture comprising 1.3 g of methyl 6-hydroxy-3-methyl-benzisoxazol-7-carboxylate, 1.4 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1 g of potassium carbonate in 20 ml of N,N-dimethylformamide, was heated and stirred at 70 C. for two hours. The mixture was returned to room temperature, poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous sodium sulfate. Then, it was concentrated under reduced pressure, and the obtained crystals were thoroughly washed with isopropyl ether to obtain 1.6 g (yield: 73%) of the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In N,N-dimethyl-formamide; | EXAMPLE 25 Preparation of Benzyl 5-[(4,6-Dimethoxypyrimidin-2-yl)oxy]2-methylindol-4-carboxylate (Compound No. 664) A mixture comprising 2.2 g of benzyl 5-hydroxy-2-methylindol-4-carboxylate, 1.7 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1.3 g of potassium carbonate in 20 ml of N,N-dimethylformamide, was heated and stirred at a temperature of from 70 to 80 C. for two hours. The mixture was returned to room temperature, then poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure, was crystallized from isopropyl ether to obtain 2.8 g (yield: 85%) of the desired product. mp: 135-139 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In acetonitrile; | STR147 A mixture of 11.0 g (50 mmol) of 4,6-dimethoxy-2-methylsulphonyl-pyrimidine, 6.1 g (50 mmol) of 2-hydroxybenzaldehyde, 6.9 g of potassium carbonate and 170 ml of acetonitrile is refluxed for 5 hours and subsequently concentrated. The residue is shaken with water/ethyl acetate, and the organic phase is separated off, dried with sodium sulphate and filtered. The solvent is carefully removed from the filtrate by distillation under a water pump vacuum. 7.8 g (60% of theory) of 2-(4,6-dimethoxy-pyrimidin-2-yl-oxy)-benzaldehyde are obtained as a solid residue of melting point 81 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67.2% | With potassium carbonate; In water; N,N-dimethyl-formamide; | Example 2 Methyl 3-azido-3-phenyl-2-(4,6-dimethoxypyrimidin-2-yl)oxybutyrate 5.9 g (25 mmol) of methyl 3-azido-3-phenyl-2-hydroxybutyrate (Ex. 1) are dissolved in 80 ml of DMF, treated with 1.7 g (12.5 mmol) of potassium carbonate and 5.5 g (25 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine, and stirred for 6 hours at 50 C. and 12 hours at room temperature. The mixture is then poured onto 400 ml of water, and the precipitate formed is filtered off with suction, washed with water and dried. 6.3 g of a white powder are obtained. Yield: 67.2%, m.p.: 118-120 C. |
Yield | Reaction Conditions | Operation in experiment |
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61% | With acetic acid; In N-methyl-acetamide; water; ethyl acetate; | Example 3 Methyl 3-(2-thienyl)-3-fluoro-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]butyrate 2.2 g (10 mmol) of methyl 3-(2-thienyl)-3-fluoro-2-hydroxybutyrate (Compound 1.1) are dissolved in 40 ml of dimethylformamide, and 0.3 g (12 mmol) of sodium hydride is added. The mixture is stirred for 1 hour, and 2.2 g (10 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine are then added. After the mixture has been stirred at room temperature for 24 hours, it is hydrolyzed using 10 ml of water, the pH is brought to 5 using acetic acid, and the solvent is distilled off under a high vacuum. The residue is taken up in ethyl acetate, washed with water and dried over sodium sulfate, and the solvent is distilled off. The residue is treated with 10 ml of methyl t-butyl ether and the precipitate formed filtered off with suction. After drying, 1.8 g of a white powder remain. Yield: 61% (diastereomer mixture 1:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73.4% | With potassium carbonate; In water; N,N-dimethyl-formamide; | Example 8 Methyl 3-N-phenylamino-3-phenyl-2-(4,6-dimethoxypyrimidin-2-yl)oxybutyrate 2.1 g (7.4 mmol) of methyl 3-N-phenylamino-3-phenyl-2-hydroxybutyrate (Ex. 7) are dissolved in 50 ml of DMF, 0.5 g (3.7 mmol) of potassium carbonate and 1.6 g (7.4 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine are added and the mixture is stirred for 6 hours at 50 C., then for 12 hours at room temperature. It is poured onto 200 ml of water, and the resulting precipitate is filtered off with suction and washed with water. After drying, 2.3 g of a white powder remain. Yield: 73.4%, m.p.: 174-176 C. |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In water; acetonitrile; | STR394 A mixture of 4.0 g (0.04 mol) of <strong>[3069-67-8]5-methyl-1,3,4-oxadiazol-2(3H)-one</strong>, 8.8 g (0.047 mol) of 4,6-dimethoxy-2-methylsulphonyl-pyrimidine, 16.9 g (0.12 mol) of potassium carbonate and 100 ml of acetonitrile is stirred for 4 hours at 60 C. The cold mixture is concentrated under a waterpump vacuum, the residue is stirred with water, and the crystalline product is isolated by filtering off with suction. 4.8 g (50% of theory) of 3-(4,6-dimethoxypyrimidin-2-yl)-<strong>[3069-67-8]5-methyl-1,3,4-oxadiazol-2(3H)-one</strong> of melting point 158 C. are obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | EXAMPLE 5 Preparation of methyl 2-(4,6-dimethoxypyrimidin-2-yl)-oxy-6-fluorobenzoate (Compound No. 56) 4,6-Dimethoxy-2-methylsulfonylpyrimidine (4.0 g) was added to a solution in tetrahydrofuran (50 ml) of <strong>[72373-81-0]methyl 6-fluorosalicylate</strong> (3.5 g) and 60% sodium hydride (0.9 g), and the mixture was refluxed for 7 hours under heating. The reaction mixture was poured into water, and extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to obtain the above identified compound as a white crystal (3.8 g). (Melting point: 52-54 C.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | EXAMPLE 10 Preparation of 2,6-bis[(4,6-dimethoxypyrimidin-2-yl)oxy]benzoic acid (Compound No. 1) 60% sodium hydride (1.4 g) was suspended in THF. To the suspension, benzyl 2,6-dihydroxybenzoate (8.0 g) was added, and the mixture was stirred at room temperature for 15 minutes. Then, 4,6-dimethoxy-2-methylsulfonyl pyrimidine (7.8 g) was added thereto, and the mixture was reacted for 8 hours under reflux. After cooling, the reaction solution was poured into water and extracted with ethyl ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain benzyl 6-(4,6-dimethoxypyrimidin-2-yl)oxysalicylate (2.0 g) as white crystals. (Melting point: 63-65 C.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In butanone; | EXAMPLE 3 Preparation of methyl 3-(4,5-dimethoxypyrimidin-2-yloxy)thiophene-2-carboxylate 2.2 g (0.01 mol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1.6 g (0.01 mol) of methyl 3-hydroxythiophene-2-carboxylate are dissolved in 50 ml of ethyl methyl ketone, and 13.8 g (0.1 mol) of potassium carbonate are added. The mixture is refluxed for 4 hours, cooled down, diluted with water and extracted with methylene chloride. The extract is dried over sodium sulfate and concentrated under reduced pressure. The residue is stirred up with n-hephtane, filtered off and dried under reduced pressure, leaving 1.8 g of methyl 3-(4,5-dimethoxypyrimidin-2-yloxy)thiophene-2-carboxylate of m.p. 107-109 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N-methyl-acetamide; | Step E Synthesis of 6-chloro-2-(4,6-dimethoxypyrimidin-2-yloxy)benzaldehyde as an intermediate Under a nitrogen atmosphere a solution of 2.0 grams (0.013 mole) of 6-chlorosalicylaldehyde in 10 mL of dimethylformamide was stirred, and 1.94 grams (0.0141 mole) of potassium carbonate was added. The reaction mixture was then stirred for 10 minutes, and a solution of 2.6 grams (0.013 mole) of 4,6-dimethoxy-2-methylsulfonylpyrimidine (prepared in Steps A-C) in 15 mL of dimethylformamide was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was warmed to 60° C. where it was stirred for 18 hours. The reaction mixture was poured into 150 mL of water, cooled, and the pH was adjusted to 12 with aqueous 50percent sodium hydroxide, with stirring. The mixture was stirred for 15 minutes, and the resultant solid was collected by filtration to yield 1.62 grams of 6-chloro-2-(4,6-dimethoxypyrimidin-2-yloxy)benzaldehyde. The nmr spectrum was consistent with the proposed structure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In dichloromethane; acetonitrile; | STR21 54.5 g (0.25 mol) of 2-methylsulphonyl-4,6-dimethoxy-pyrimidine, 69 g (0.5 mol) of potassium carbonate and 1500 ml of acetonitrile are mixed with stirring. 33.85 g (0.1375 mol) of O-methyl-isourea sulphate are then added and the mixture is heated to boiling for 17 hours. After cooling, the solution is filtered off with suction and the mother liquor is concentrated. After taking up the residue in methylene chloride, the solution is washed three times with water, dried and concentrated again. 49.9 g of N-(4,6-dimethoxy-pyrimidin-2-yl)-O-methylisourea are obtained in the form of yellow crystals of melting point 91-95 C. (90% purity; yield 85% of theory). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium iodide; potassium carbonate; In N-methyl-acetamide; | EXAMPLE 1 Preparation of methyl 3-(4,6-dimethoxypyrimidin-2-yl)oxy picolinate (Compound No. 1) To a solution of 30.0 g of methyl 3-hydroxypicolinate in 250 ml of dimethylformamide, 42.7 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine, 32.5 g of potassium carbonate and 16.3 g of potassium iodide, were added, and the mixture was heated and stirred at a reaction temperature of from 100 to 110 C. for 1.5 hours. After cooling, the reaction solution was poured into water, and extracted with ethyl acetate. The extract was washed with water, and dried over magnesium sulfate. Ethyl acetate was distilled off under reduced pressure, and the residue was recrystallized from a solvent mixture of hexane, diisopropyl ether and toluene, to obtain 37.2 g of methyl 3-(4,6-dimethoxypyrimidin-2-yl)oxy picolinate. (Yield: 65%, white crystal, melting point: 65-66 C.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With potassium carbonate; In N-methyl-acetamide; | EXAMPLE 8 Preparation of phenyl 2-chloro-6-(4,6-dimethoxypyrimidin-2-yl)oxy benzoate (Compound No. 81) A suspension in dimethylformamide (20 ml) of 3.8 g of phenyl 6-chlorosalicylate (3.8 g), 4,6-dimethoxy-2-methylsulfonylpyrimidine (3.4 g) and potassium carbonate (2.1 g) was heated and stirred at a temperature of from 100 to 110 C. for 30 minutes. The mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and dried. Then, the solvent was distilled off, and the residue thereby obtained was purified by silica gel column chromatography to obtain phenyl 2-chloro-6-(4,6-dimethoxypyrimidin-2-yl)oxy benzoate (2.5 g). Yield: 42%, white crystals, Melting point: 119-121 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With potassium carbonate; In methanol; chloroform; butanone; | EXAMPLE 164 Methyl 2-(4,6-dimethoxypyrimidin-2-yl)oxybut-2-enoate A mixture of methyl 2-hydroxybut-3-enoate (0.80g, 6.9mmol), 4,6-dimethoxy-2-methanesulphonylpyrimidine (1.50g, 6.9mmol) and potassium carbonate (1.04g, 7.6mmol) in methyl ethyl ketone (100ml) was refluxed for 12 hours. The reaction mixture was filtered and the filtrate evaporated in vacuo. Flash column chromatography (silica, 1.5% methanol in chloroform) of the residue gave the title compound (1.37g, 78% yield by weight). Melting point: 71.0 C. Analysis (%): Calc. C 52.0. H 5.5. N 11.0. Found C 50.6. H 5.8. N 10.5. Examination of the product by nmr spectroscopic analysis confirms the structure as methyl 2-(4,6-dimethoxypyrimidin-2-yl)oxybut-2-enoate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | General procedure: The intermediate 2-3 (30 mmol), anhydrous potassium carbonate (60 mmol) was dissolved in 50 mL of N, N-dimethylformamide in a 250 mL reaction flask and stirred at 25 C for 1 h. The compound (total 30 mmol) shown in the formula (2-4) was added to the reaction system 3 times, the temperature was raised to 100 C, the TLC was tracked until the reaction was complete, the reaction was stopped, and the reaction system was poured into ice water when the reaction system was cooled to 25 C. A large amount of white solid precipitated, and the white powder intermediate 2-5 was filtered off. Specifically, when R1, R3 and R4 are both H, the yield of the obtained intermediate 2-5 is 90%. When R1 is CH3, and both R3 and R4 are H, the yield of the obtained intermediate 2-5 is 87%. | |
In tetrahydrofuran; | Reference Example 7 A solution of 2,2-dimethyl-5-hydroxy-4-oxo-benzo-1,3-dioxin (8.0 g) in tetrahydrofuran was added dropwise during 0.25 hour to a stirred suspension of sodium hydride (1.75 g of 60%) under nitrogen. After 0.25 hour 4,6-dimethoxy-2-methylsulphonylpyrimidine (9.68 g) was added during 5 minutes and the mixture heated at reflux overnight. The cooled mixture was diluted with water, extracted (ether), dried (magnesium sulphate), evaporated and purified by chromatography on silica gel eluding with isohexane/ethyl acetate to give 5-(4,6-dimethoxypyrimidin-2-yl)oxy-2,2-dimethyl-4-oxo-benzo-1,3-dioxin (2.64 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With ammonium chloride; In N-methyl-acetamide; | Preparation 1 Synthesis of 6-hydroxy-2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoic acid allyl ester (VII) 2.0g of allyl 2,6-dihydroxybenzoate (V) was added to the suspension of 0.4g of sodium hydride in 50ml of dimethylformamide and the mixture was stirred for 10 minutes. To this mixture was added 2.2g of 4,6-dimethoxy-2-methylsulfonylpyrimidine. The reaction mixture was stirred for 5 hours and 50ml of saturated ammonium chloride solution was added thereto. The reaction solution was then extracted with 200ml of ethylacetate. The extract was dried over anhydrous sodium sulfate and then distilled under reduced pressure to remove the solvent. The residue was subjected to column chromatography (hexane:ethylacetate= 2:1 v/v) on silica gel to obtain 3.0g (Yield 90%) of the title compound. 1H NMR (CDCl3, delta): 3. 81(s, 6H), 4.58(d, 2H), 5.11-5.29(d, 2H), 5.51-5.70(m, 1H), 5.73(s, 1H), 6.68-7.47(m, 3H), 11.12(s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | To (R)-2-mercapto-3-methylbutanoic acid (2.10 g, 15.6 mmol) was added aqueous NaOH (1.0 M in H2O, 37.6 mL, 37.6 mmol). The mixture was stirred at rt for 10 min. The resulting solution was cooled to 0 C., diluted with DMF (20 mL), and 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine (3.42 g, 15.6 mmol) in DMF (10 mL) was added (a slightly modified procedure of Fukuda, S.; Akiyoshi, Y.; Hori, K. J. Org. Chem. 1999, 64, 4768; 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine is commercially available from Aldrich). The mixture was warmed to rt and stirred for 1 h. The resulting solution was quenched with 2 M HCl and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4) and concentrated. Purification by silica gel chromatography (gradient column, ethyl acetate-hexanes, 1:5?1:1?1:0) afforded (R)-compound Y as white crystals (3.77 g, 88%); 1H NMR (300 MHz, CDCl3) delta 1.15 (d, J=6.4 Hz, 3H), 1.17 (J=6.4 Hz, 3H), 2.41 (m, 1H), 3.89 (s, 6H), 4.16 (d, J=5.9 Hz, 1H), 5.78 (s, 1H); 13C NMR (75 MHz, CDCl3) delta 20.1, 20.9, 30.1, 54.4, 54.9, 86.5, 169.4, 170.9, 177.9; IR (neat) 3050, 2964, 1710, 1581, 1557 cm-1; [alpha]D22=+127.2 (c 1, CH2Cl2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | To (S)-2-mercapto-3-methylbutanoic acid (2.00 g, 14.9 mmol) was added aqueous NaOH (1.0 M in H2O, 35.8 mL, 35.8 mmol). The mixture was stirred at rt for 10 min. The resulting solution was cooled to 0 C., diluted with DMF (20 mL), and 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine2,3 (3.25 g, 14.9 mmol) in DMF (10 mL) was added. The mixture was warmed to rt and stirred for 1 h. The resulting solution was quenched with 2 M HCl and extracted with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4) and concentrated. Purification by silica gel chromatography (gradient column, ethyl acetate-hexanes, 1:5?1:1?1:0) afforded (S)-compound Y as white crystals (3.65 g, 90%); 1H NMR (300 MHz, CDCl3) delta 1.15 (d, J=6.4 Hz, 3H), 1.17 (J=6.4 Hz, 3H), 2.41 (m, 1H), 3.89 (s, 6H), 4.16 (d, J=5.9 Hz, 1H), 5.78 (s, 1H); 13C NMR (75 MHz, CDCl3) delta 20.1, 20.9, 30.1, 54.4, 54.9, 86.5, 169.4, 170.9, 177.9; IR (neat) 3050, 2964, 1710, 1581, 1557 cm-1; [alpha]D22=-127.3 (c 1, CH2Cl2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66.1% | With potassium carbonate; In N,N-dimethyl-formamide; at 90 - 92℃; for 1.5h;Inert atmosphere; | Example 6:Preparation of (S)-methyl-2-(4,6-dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3- diphenylpropionate (compound II; R' = methyl, R= methoxy)To a stirred solution of (S)-methyl-2-hydroxy-3-methoxy-3,3-diphenylpropionate (compound IV;50 gms/0.174 moles) and potassium carbonate (26.36gms /0.191moles) in DMF (500 ml) was added 4,6-Dimethoxy-2-(methyl sulfonyl) pyrimidine (compound III; R= methoxy) (41.42 gms /0.191 moles) in a dry flask under nitrogen at 25-30C. The reaction mass was heated to 90-92C and further stirred for 1.5 hour. The reaction mass was charged with ethyl acetate (1.5 lit) .The organic layer was washed with 2N citric acid (500 ml) followed by water and treated with charcoal. The clear filtrate was distilled completely under vacuum. The residue was stirred with n-heptane (200 ml), filtered, washed with n-heptane (120 ml) and dried to obtain 56 gms of compound (II).The compound (II) was dissolved in acetonitrile (1.12 lit) and isolated in water (2.8 lit). The solid was isolated by filtration and dried to obtain 49 gms of compound (II).Efficiency: 66.10 %Purity by HPLC:99.1%Chiral purity: 99.4% |
Example-16: Preparation of (+)-(2S)-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-3- methoxy- 3,3-diphenylpropanoic acid methyl ester compound of formula-lOb:Mixture of (S)-2-hydroxy-3~methoxy-3,3-diphenylprorhoionic acid methyl ester compound of formula-8a (50 grams), acetone (500 ml) and potassium carbonate (12 grams) was stirred for 40 minutes at 25-35C. 4,6-dimethoxy-2-(methylsulphonyl) pyrimidine (29.25 grams) was added to the above reaction mixture, heated to 55-600C and stirred for 10 hours. The reaction mixture was cooled to 25-35C, filtered and washed with acetone. The filtrate was distilled off under reduced pressure at 5O0C. The reaction mixture was cooled to 25-35C and quenched with water. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was distilled off completely under reduced pressure at 600C. The reaction mixture cooled to 45C and methanol was added then distilled off methanol. Methanol (100 ml) was added to the obtained residue and heated to 55-600C and stirred for 30 minutes. The reaction mixture was cooled to 20-250C and stirred for 45 minutes. The obtained solid was filtered off and washed with methanol. The solid was dried at 50-600C to get the title compound. Yield: 41 grams M.R: 108-1120C; S.O.R: + 115 (C= 0.5; MeOH) | ||
Preparation of (+)-(2S)-2-[(4,6-dimethoxypyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid methyl ester compound of formula-10b Mixture of (S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester compound of formula-8a (50 grams), acetone (500 ml) and potassium carbonate (12 grams) was stirred for 40 minutes at 25-35 C. 4,6-dimethoxy-2-(methylsulphonyl)pyrimidine (29.25 grams) was added to the above reaction mixture, heated to 55-60 C. and stirred for 10 hours. The reaction mixture was cooled to 25-35 C., filtered and washed with acetone. The filtrate was distilled off under reduced pressure at 50 C. The reaction mixture was cooled to 25-35 C. and quenched with water. The reaction mixture was extracted with ethyl acetate. The ethyl acetate layer was distilled off completely under reduced pressure at 60 C. The reaction mixture cooled to 45 C. and methanol was added then distilled off methanol. Methanol (100 ml) was added to the obtained residue and heated to 55-60 C. and stirred for 30 minutes. The reaction mixture was cooled to 20-25 C. and stirred for 45 minutes. The obtained solid was filtered off and washed with methanol. The solid was dried at 50-60 C. to get the title compound.Yield: 41 gramsM.R: 108-112 C.; S.O.R: +115 (C=0.5; MeOH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide;Heating; | 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine (0.02 mol, 4.36g) and methyl 2-hydroxybenzoate (0.02 mol, 4.36 g) were mixed, then anhydrous K2CO3 (0.04 mol, 5.52 g) and DMF (40 mL) were added. The reaction mixture was heated at 65 oC, which was monitored by TLC until the disappearance of starting materials. The mixture was poured into water (100 mL) quickly, and then filtered. The crude solid was washed by water some times and dried to give white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With potassium carbonate; In N,N-dimethyl-formamide; at 60 - 70℃; for 6h;Inert atmosphere; | Example 1 A: Production of tert-butyl 2-cyano-2-(4,6-dimethoxypyrimidin-2-yl)acetate Into a 100-ml eggplant-shaped flask equipped with a magnetic stirrer and a reflux condenser were added 6.08g (44 mmol) of potassium carbonate, 4.36 g (20 mmol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine, 3.11 g (22 mmol) of tert-butyl cyanoacetate and 10 ml of N,N-dimethylformamide. The system inside was purged with nitrogen and stirred for 2 hours at 60C and for 4 hours at 70C. The reaction slurry was cooled to room temperature and poured into 30 ml of a 5% aqueous hydrochloric acid solution. Thereto was added 50 ml of water, and concentrated hydrochloric acid was dropped until the system became acidic, followed by sufficient stirring. Then, filtration and washing with 30 ml of water were conducted. The crystals obtained were dried to obtain tert-butyl 2-cyano-2-(4,6-dimethoxypyrimidin-2-yl)acetate as white crystal of 5.4 g. HPLC purity: 99.3% Yield: 97% Decomposition point: 188C 1H-NMR (300 MHz, CDCl3) delta: 13.24 (br, 1H), 5.35 (d, J=2.1 Hz, 1H), 4.04 (s, 3H), 3.94 (s, 3H), 1.53 (s, 9H) ppm LC-MS (M+1)+ = 280.1 |
87.3% | With potassium carbonate; In acetonitrile; for 24h;Reflux; | 5g 4,6-dimethoxy-2-methylsulfonylpyrimidine (23mmol),3.56g t-Butyl cyanoacetate (25.2mmol) and 3.88 potassium carbonate (27.5 mmol) was refluxed in 100 ml of acetonitrile for 24 h. . After the reaction was cooled to room temperature, the reaction mixture was poured into 500 ml of ice-water mixture. The pH value was adjusted to 3 to 4 with 1 N diluted hydrochloric acid, and a large amount of solid precipitated. The solid was filtered and dried to give 5.6 g of t-butyl 2-cyano- (4,6-dimethoxy-2-pyrimidinyl) acetate in 87.3% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 3h; | Comparative Example 2; Production of 2-cyanomethyl-4,6-dimethoxypyrimidine (the production method of Patent Literature 1); 436 g (2 mol) of 2-methanesulfonyl-4,6-dimethoxypyrimidine and 218 g (2.2 mol) of methyl cyanoacetate were dissolved in 2.0 liters of N,N-dimethylformamide. Thereto was gradually added 304 g (2.2 mol) potassium carbonate at 80C, followed by stirring for 3 hours at the same temperature. The reaction mixture was poured into ice water and the whole mixture was made acidic (pH = 1) using concentrated hydrochloric acid, followed by stirring for 1 hour. The precipitate (crystals) was separated by filtration and washed by water. The hydrated methyl 2-cyano-2-(4,6-dimethoxypyrimidin-2-yl)acetate obtained was suspended in 1.5 liters of dimethyl sulfoxide, followed by stirring for 3 hours at 150C. The reaction mixture was cooled to room temperature and poured into water. The precipitate (crystals) was separated by filtration, water-washed, and dried. 2-Cyanomethyl-4,6-dimethoxypyrimidine was obtained at a 60% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With potassium carbonate; In N,N-dimethyl-formamide; at 95℃; | 4-Hydroxypyridine 1.88g (0.02 mol) and 4,6-dimethoxypyrimidine-2-yl methyl sulfone 4.36g (0.02 mol) were dissolved in DMF 100 ml, and K2CO3 3.3g (1.2 eq) was added thereto. Then, the temperature was maintained at 95C while the mixture was stirred over night. The reacted solution was added to water 100 ml, extracted with diethyl ether, dried with MgSO4, and distilled under reduced pressure to obtain residue. Through purification with silica gel column chromatography, a solid material 3.73g (80%) was obtained: 1H NMR (CDCl3); 3.73 (s, 6H), 5.49 (s, 1H), 6.85-8.42 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With potassium carbonate; In N,N-dimethyl-formamide; at 95℃; | methyl 2-hydrtoxy-3-methylbutanoate 2.62g (0.02 mol) and 4,6-dimethoxypyrimidine-2-yl methyl sulfone 4.36g (0.02 mol) were dissolved in DMF 100 ml, and K2CO3 3.3g (1.2 eq) was added thereto. Then, the temperature was maintained at 95C while the mixture was stirred over night. The reacted solution was added to water 100 ml, extracted with diethyl ether, dried with MgSO4, and distilled under reduced pressure to obtain residue. Through purification with silica gel column chromatography, a solid material 3.40g (63%) was obtained: 1H NMR (CDCl3); 1.01 (d, 6H), 2.97 (m, 1H), 3.67 (s, 3H), 3.73 (s, 6H), 4.51 (d, 1H), 6.13 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In N,N-dimethyl-formamide; at 95℃; | 2-chlorobenyl alcohol 2.85g (0.02 mol) and <strong>[113583-35-0]4,6-dimethoxypyrimidin-2-yl methyl sulfone</strong> 4.36g (0.02 mol) were dissolved in DMF (N,N-dimethylformamide) 100 ml, and K2CO3 3.3g (1.2 eq) was added thereto. Then, the temperature was maintained at 95C while the mixture was stirred over night. The reacted solution was added to water 100 ml, extracted with diethyl ether, dried with MgSO4, and distilled under reduced pressure to obtain residue. Through purification with Silica gel column chromatography, a yellow solid material 4.7g (81%) was obtained: 1H NMR (CDCl3); 3.73 (s, 6H), 5.20 (s, 2H), 6.22 (s, 1H), 7,07-7.20 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With potassium carbonate; In N,N-dimethyl-formamide; at 95℃; | (S)-methyl 2-hydrtoxy-3-methylbutanoate 2.62g (0.02 mol) and 4,6-dimethoxypyrimidine-2-yl methyl sulfone 4.36g (0.02 mol) were dissolved in DMF 100 ml, and K2CO3 3.3 g (1.2 eq) was added thereto. Then, the temperature was maintained at 95C while the mixture was stirred over night. The reacted solution was added to water 100 ml, extracted with diethyl ether, dried with MgSO4, and distilled under reduced pressure to obtain residue. Through purification with silica gel column chromatography, a colorless solid material 3.51g (65%) was obtained: 1H NMR (CDCl3); 1.01 (d, 6H), 2.97 (m, 1H), 3.67 (s, 3H), 3.73 (s, 6H), 4.51 (d, 1H), 6.13 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With potassium carbonate; In N,N-dimethyl-formamide; at 95℃; | 3-amino-4-hydroxypyridine 2.18g (0.02 mol) and 4,6-dimethoxypyrimidine-2-yl methyl sulfone g (0.02 mol) were dissolved in DMF 100 ml, and K2CO3 3.3g (1.2 eq) was added thereto. Then, the temperature was maintained at 95C while the mixture was stirred over night. The reacted solution was added to water 100 ml, extracted with diethyl ether, dried with MgSO4, and distilled under reduced pressure to obtain residue. Through purification with silica gel column chromatography, a solid material 4.02g (81%) was obtained: 1H NMR (CDCl3); 3.73 (s, 6H), 5.49 (s, 1H), 6.51 (s, 2H), 6.75-7.50 (m, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step g: Preparation of 1 -[4-chloro-2-(3-pyridyl)thiazol-5-yl]-N-(4,6-dimethoxypyrimidin-2- yl)oxy-ethanimine (compound 1.058):To a suspension of sodium hydride (NaH, 60 % dispersion in mineral oil: 48 mg, 1.2 mmol) in DMF (2 ml) was added a solution of 1 -[4-chloro-2-(3-pyridyl)thiazol-5-yl]ethanone oxime (253.7 mg, 1 mmol) in DMF (3 ml), and the resulting frothy mixture was stirred for 1 hour. After that, 4,6-dimethoxy-2-methylsulfonyl-pyrimidine (218 mg, 1 mmol) was added into the above solution. The homogeneous, dark-red solution was stirred at ambient temperature for 18 hours. The precipitated brown solid was filtered and washed with water and dried under vacuum to afford the brown solid of 1 -[4-chloro-2-(3-pyridyl)thiazol-5-yl]-N-(4,6- dimethoxypyrimidin-2-yl)oxy-ethanimine in a mixture of Z and E-isomers. 1H NMR (300 Mz, CDCIs): delta: 9.16(s, 1 H), 8.70(d, 1 H, J=4.8Hz), 8.24(m, 1 H), 7.41 (m, 1 H), 5.84(m, 1 H), 3.97(m, 6 H), 2.79(m, 2 H). MS(ESI): 392(M+1 ), 414(M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In n-heptane; water; ethyl acetate; N,N-dimethyl-formamide; acetonitrile; | EXAMPLE 6 Preparation of (S)-methyl-2-(4,6-dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionate (Compound II; R'=ethyl, R=methoxy) To a stirred solution of (S)-methyl-2-hydroxy-3-methoxy-3,3-diphenylpropionate (compound IV;50 gms/0.174 moles) and potassium carbonate (26.36 gms/0.191 moles) in DMF (500 ml) was added 4,6-Dimethoxy-2-(methyl sulfonyl)pyrimidine (compound III; R=methoxy) (41.42 gms/0.191 moles) in a dry flask under nitrogen at 25-30 C. The reaction mass was heated to 90-92 C. and further stirred for 1.5 hour. The reaction mass was charged with ethyl acetate (1.5 lit).The organic layer was washed with 2N citric acid (500 ml) followed by water and treated with charcoal. The clear filtrate was distilled completely under vacuum. The residue was stirred with n-heptane (200 ml), filtered, washed with n-heptane (120 ml) and dried to obtain 56 gms of compound (II). The compound (II) was dissolved in acetonitrile (1.12 lit) and isolated in water (2.8 lit). The solid was isolated by filtration and dried to obtain 49 gms of compound (II). Efficiency: 66.10% Purity by HPLC:99.1% Chiral purity: 99.4% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
385 g | Preparation of Bispyribac sodium (Examples 1-5) Example-1 : A clear solution of 154 gm of 2,6-dihydroxy benzoic acid in 500 ml Dimethyl sulfoxide is added over 2-3 hr into a mixture of commercial available (60% emulsion in oil) 130 gm of Sodium hydride in 2 lit. of Dimethyl sulfoxide at 30-32C . Mass is further stirred for 2 hr at 30-32C and 480 gm of 4,6-Dimethoxy-2-(Methyl Sulfonyl)-pyrimidine is added into it over 2 hr. Reaction is maintained at 30-32C till completion to get Bispyribac sodium. The reaction was monitored by HPLC. Mass is filtered, washed with DMSO. Wet solids were reslurried into 1000 ml of methanol & then in 1000 ml of 75% aq. Methanol. Wet solids were dried in oven to get 435 gm of Bispyribac sodium. This Bispyribac sodium is reslurried into 1200 ml of Toluene at reflux temperature, cooled, filtered & dried to give 385 gm of Bispyribac sodium ( purity 98.7% HPLC). | |
With sodium hydride; In 1-methyl-pyrrolidin-2-one; paraffin oil; at 25 - 60℃; for 1h; | Into a 200 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, 65% sodium hydride (dispersed in liquid paraffin; 2.3 g, 0.061 mol) and N-methylpyrrolidone (NMP; 27 ml) was charged. While stirring at 25 C., a solution of 2,6-dihydroxybenzoic acid (3.1 g, 0.020 mol -1) dissolved in N-methylpyrrolidone (NMP; 31 ml) was added dropwise thereto. While stirring the mixture at room temperature, 4,6-dimethoxy-2-methylsulfonylpyrimidine (8.8 g, 0.041 mol) was added. Thereafter, the mixture was stirred at 60 C. for 1 hour. In this way, a reaction mixture containing the target product sodium 2,6-bis (4,6-dimethoxypyrimidin-2-yloxy) benzoate was obtained. As a result of HPLC of the reaction mixture, the reaction mixture contained 77% of the desired product in an area percentage excluding the solvent and the like. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 3h; | To 2.4 g intermediate (2S)-2-hydroxyl-3-methoxy-3,3-diphenylethyl propionate obtained in step (2), 11 mL of N,N-dimethyl methanamide and 0.66 g of potassium carbonate were added, after stirring for half an hour, 4,6-dimethoxy-2-methylsulfonyl pyrimidine was added to conduct nucleophilic substitution reaction in 90 C. oil bath, wherein the molar ratio of (2S)-2-hydroxyl-3-methoxy-3,3-diphenylethyl propionate, 4,6-dimethoxy-2-methylsulfonyl pyrimidine and potassium carbonate is 1:1.2:0.6; after about 3 hours when monitoring the accomplishment of the material consumption using the nuclear magnetism, ethyl acetate and water were added to extract the reaction liquid, the ethyl acetate was concentrated to obtain 2.38 g intermediate (2S)-2-(4,6-dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenylethyl propionate with crude product yield of 68%. 1H NMR [400 MHz, CDCl3] delta 7.45 (d, J=8.0 Hz, 2H), 7.39-7.21 (m, 8H), 6.02 (s, 1H), 5.72 (s, 1H), 3.90 (q, J=7.2 Hz, 2H), 3.86 (s, 3H) 3.42 (s, 3H), 0.91 (t, J=7.2 Hz, 3H); 13C NMR [100 MHz, CDCl3] delta 172.93, 168.60, 163.36, 142.12, 141.12, 128.69, 128.24, 127.99, 127.88, 127.57, 84.40, 83.69, 79.31, 60.78, 54.39, 53.69. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | This example is used to describe the pyrimidine salicylic acid compounds of the present invention and processes for their preparation.1 mmol of Compound A was dissolved in 30 mL of re-evaporated toluene, 2 mmol of potassium carbonate was added, reacted at 20 C for 2 hours, 4,6-dimethoxy-2-methylsulfonylpyrimidine (1 mmol) was added and reacted at 120C for 12 h. The solvent was distilled off under reduced pressure, and a small amount of water was added to completely dissolve the solid. The aqueous layer was washed with ether several times. The aqueous layer was acidified with concentrated hydrochloric acid to pH=1, extracted with dichloromethane, dried over anhydrous sodium sulfate, Acid compound A1. The yield of compound A1 from compound A was 78% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | This example is used to describe the pyrimidine salicylic acid compounds of the present invention and processes for their preparation. 1 mmol of compound B was dissolved in 30 mL of re-evaporated toluene, 2 mmol of potassium carbonate was added, reacted at 23 C for 1.5 hours, A solution of 4,6-dimethoxy-2-methylsulfonylpyrimidine(1 mmol) was added and reacted at 118 C for 16 h. The solvent was distilled off under reduced pressure, and a small amount of water was added to completely dissolve the solid. The aqueous layer was washed with ether several times. The aqueous layer was acidified with concentrated hydrochloric acid to POH = 1, extracted with dichloromethane, dried over anhydrous sodium sulfate, Acid compound B1. The yield of compound B1 from compound B was 65% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tetrabutylammomium bromide; potassium carbonate; In toluene;Reflux; | 0.04 mol of 2,6-dihydroxybenzoic acid was weighed separately,0.05 mol of 2-methanesulfonyl-4,6-dimethoxypyrimidine,0.004 mol of tetrabutylammonium bromide,0.08 mol of potassium carbonate was placed in a reaction vessel,Add 300mL toluene heated reflux reaction 8 ~ 1 Oh,The reaction is cooled and filtered,The filter cake was washed with toluene,dry,The resulting solid was mixed with 500 mL of water,Stir,Dropping 30% HC1 to the system PH = 3 ~ 4,filter,dry,Was gray and solidbodyBispyribac15.7g,Purity 97%Yield 85%. |
83% | Into a 500 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, 60% sodium hydride (dispersed in liquid paraffin; 6.2 g, 0.155 mol) and Toluene (300 ml) was charged. Subsequently, a solution of 2,6-dihydroxybenzoic acid (7.7 g, 0.05 mol) dissolved in N, N-dimethylacetamide (DMAC; 10 ml) was slowly added dropwise thereto. While stirring the mixture at room temperature, 4,6-dimethoxy-2-methylsulfonylpyrimidine (21.8 g, 0.1 mol) was added in portions. Thereafter, the mixture was stirred at 100 C. for 5 hours. As a result, a reaction mixture containing sodium 2,6-bis (4,6-dimethoxypyrimidin-2-yloxy) benzoate was obtained. A small amount of the reaction mixture was sampled, acidified and analyzed by HPLC. The components other than solvent etc. in the reaction mixture were as follows. 82% of 2- (4,6-dimethoxypyrimidin-2-yloxy) benzoic acid (target product), 2- (4,6- dimethoxypyrimidin-2-yloxy) -6-hydroxybenzoic acid: 2 %, 4,6-dimethoxy-2-methylsulfonylpyrimidine (raw material): 8%, 4,6-dimethoxy-2-hydroxypyrimidine (by- product): 3%. After the reaction mixture was cooled to room temperature, a small amount of methanol was added thereto, and the mixture was stirred at room temperature for 1 hour. The mixture was poured into water and the resulting mixture was partitioned between organic and aqueous layers. The organic layer and the aqueous layer were separated, and an aqueous layer was obtained. Dilute hydrochloric acid was added to the obtained aqueous layer until the pH became 4. Precipitated crystals were collected by filtration, washed with water and dried to obtain 2, 6-bis (4,6-dimethoxypyrimidin-2-yloxy) benzoic acid (17.8 g) as white crystals. Yield: 83%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.5% | With potassium carbonate; In acetone; for 2.5h;Reflux; | Add 3,6-dihydroxybenzoic acid methyl ester 0.3g (1.78 mmol) to a 100 mL two-necked flask and add potassium carbonate.0.616 g (4.46 mmol), adding acetone 20 mL, refluxing for 0.5 h, adding 4,6-dimethoxy-2-methanesulfonylpyrimidine0.779 g (3.573 mmol), refluxing for 2 h. Filtration, desolvation to remove acetone, crude product recrystallized from ethanol to obtain white crystals0.725 g, yield 91.5%, |
Tags: 113583-35-0 synthesis path| 113583-35-0 SDS| 113583-35-0 COA| 113583-35-0 purity| 113583-35-0 application| 113583-35-0 NMR| 113583-35-0 COA| 113583-35-0 structure
[ 89466-55-7 ]
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