* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium ethanolate In ethanol; water at 60 - 65℃; for 1 h;
The ethoxy oxime (II) (390 g; 851 mmol) is suspended in 3600 ml of diethyl carbonate. The suspension is heated up to 65°C. A solution of sodium ethoxide in ethanol (21 percent, 400 ml, 1072 mmol) is added dropwise to the reaction mixture at 65°C during 30 minutes. After completion of the addition the reaction mixture is agitated at 65°C for 30 minutes. The reaction mixture is cooled down to 60°C and water (1350 ml) is added. The resulting emulsionis agitated for at least 15 minutes. After separation of the layers the organic phase is extracted with water (1350 ml). The combined aqueous extracts are diluted with ethanol (1350 ml) and the temperature is adjusted to 40°C. Acetic acid (111 ml, 1940 mmcl) is added to the solution dropwise at 40°C during 30 minutes. The resuMing suspension is agitated at 40°C for 30 minutes and then cooled down to 20°C. The separated substance is aspirated and washed withwater (2 x 450 ml). The resulting product is then dried in a vacuum drier at 45°C. 397 g (86percent of the theoretical quantity, HPLC 95.8percent) of azilsartan ethyl ester (III) was obtained.
With potassium carbonate In dimethyl sulfoxide at 20℃; for 3 h;
Example 9Ethyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH- benzo[tf)imidazole-7-carboxylate of formula lbUsing the procedure described in Example 6 ethyl 2-ethoxy-l -((2'-(N'-(ethoxycarbonyloxy)- carbamimidoyl)biphenyl-4-yl)methyl)-lH-benz[i/]imidazole-7-carboxylate of formula VIbb; R' = Et) was converted to ethyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)-l H-benzo[t/]imidazole-7-carboxylate of formula lb. 93.0percent of a compound with the melting point of 179 to 182°C were obtained containing 97.8percent of a product of formula lb according to HPLC. NMR (500 MHz, DMSO) δ (ppm): 12.40 (s, lH, NH), 7.69 (dd, J = 7.9, 1.2 Hz, 1H, Ar), 7.50 (m, 1H, Ar), 7.44 (dd, J = 7.9, 1.2 Hz, 1H, Ar), 7.43-7.40 (m, 4H, Ar), 7.35 (d, J = 7.7 Hz, 1 H, Ar), 7.19 (t, J = 7.9 Hz, 1H, Ar), 6.95 (d, J = 8.3 Hz, 2H, Ar), 6.61 (bs, 2H, NH2), 5.57 (s, 2H, N-CH2-Ar), 4.60 (q, J = 7.1 Hz, 2H, COOCH2CH3), 4.18 (q, J = 7.1 Hz, 2H, OCH2CH3), 1.39 (t, J = 7.1 Hz, 3H, COOCH2CH3), 1.16 (t, J = 7.1 Hz, 3H, OCH2CH3).
4.3 g
at 110 - 115℃; for 2 h;
A mixture of ethyl 2-ethoxy-l-((2'-(N'-((ethoxycarbonyl)oxy)carbamimidoyl)-[biphenyl]- 4-yl)methyl)-lH-benzoimidazole-7-carboxylate (compound V; Ri= R2=ethyl) (5 g), and dibutyl amine (30 ml) was heated at 110-115°C for 2 hours. The reaction mixture cooled to 25-30°C and stirred for one hour. The solid was filtered, washed with ethyl acetate and dried. Yield: 4.3 g.
Reference：
[1] Patent: WO2012/139535, 2012, A1, . Location in patent: Page/Page column 16
[2] Journal of Heterocyclic Chemistry, 2013, vol. 50, # 4, p. 929 - 936
[3] Patent: WO2014/49512, 2014, A2, . Location in patent: Page/Page column 8
[4] Patent: CN108912109, 2018, A, . Location in patent: Paragraph 0094; 0096
[5] Patent: CN108640911, 2018, A, . Location in patent: Paragraph 0033; 0035; 0096-0233
3
[ 75-44-5 ]
[ 1397836-41-7 ]
[ 1403474-70-3 ]
Yield
Reaction Conditions
Operation in experiment
82.5%
With triethylamine In 1,4-dioxane; toluene at 50℃; for 8 h;
Example 20 Ethyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H- benzo[cf]imidazole-7-carboxylate of formula lbA 20 percent solution of phosgene in toluene (0.5 ml, 1 mmol) was added to a mixture of ethyl 2- ethoxy- l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[i/|imidazole-7- carboxylate (of formula Vb; 0.23 g, 0.5 mmol), dioxan (5 ml) and triethylamine (0.2 g, 2 mmol) and the mixture was stirred in a closed pressure tube at 50 °C for 8 hours. After cooling down, the solution was bubbled with nitrogen for 8 hours. After evaporation of the solvent the residue was triturated with water ( 10 ml), the resulting turbid solution was acidified with acetic acid and extracted with ethyl acetate (4 x 25 ml). After washing with brine the extract was dried with MgS04 and the obtained evaporation residue was crystallized from ethyl acetate. 0.20 g (82.5 percent) of a product was obtained containing 98.4 percent of the compound of formula lb according to HPLC
With sodium ethanolate In ethanol at 80℃; for 2 h;
The starting amidoxime (IV) was suspended in diethyl carbonate (30 g) and sodium ethoxide (21 percent in ethanol, 9 g) was added. The mixture was heated at 80°C for 2h, 20 ml of the solvent was removed by distillation, ethanol (20 ml), water (20 ml) and acetic acid (3 g) and more water (20 ml) were added. The suspension was stirred at 50°C for 1 h and cooled to 25°C. 8 g (76 percent) of the product was obtained.
With proton sponge In dimethyl sulfoxide at 20℃; for 3 h;
Example 6Ethyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH- benzo[c/]imidazole-7-carboxylate of formula lbThe corresponding base (0. 1 g) was added to a mixture of ethyl 2-ethoxy- l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l / -benzo[i ]imidazole-7-carboxylate (of formula Vb; 0.23 g, 0.5 mmol), DMSO (3 ml) and carbonyldiimidazole (0.1 g, 0,6 mmol) in a reaction vial under stirring and the mixture was stirred at the room temperature for 3 hours. Then, the content of the vial was poured into water (10 ml) and, after acidification with acetic acid, the separated solids were aspirated and washed with water. The yields and purity of the products are summarized in Table III. Table III - Yield and purity of the product of Example 6
Reference：
[1] Organic Process Research and Development, 2013, vol. 17, # 1, p. 77 - 86
[2] Patent: WO2012/139536, 2012, A1, . Location in patent: Page/Page column 13-14
6
[ 1397836-41-7 ]
[ 530-62-1 ]
[ 1403474-70-3 ]
Yield
Reaction Conditions
Operation in experiment
98.7 g
With 1,8-diazabicyclo[5.4.0]undec-7-ene In tetrahydrofuran at 20℃; for 2 h;
Example 1Prepared Synthesis of 2-ethoxy-3 - [[2 '- (N-benzyloxymethylidene) biphenyl-4-yl] methyl] benzimidazole-4-carboxylate,Into the reaction bottle,Add 209.8gCDI, 134ml DBU and 4.5L THF, room temperature reaction 2h, the reaction is completed. 4.5 L of water, 4.5 L of ethyl acetate was extracted and the organic phases were combined.Respectively, saturated NaHC03, saturated NaCl solution, dry anhydrous sodium sulfate organic phase, evaporated to dry organic solvent. Beaten with acetone, filtered and dried to obtain 98.7 g of a product.
With sodium ethanolate In dimethyl sulfoxide at 20℃; for 4 h;
Example 5Ethyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1 H- benzo[c ]imidazole-7-carboxylate of formula lb0.05 g of the corresponding base was added to a mixture of 0.2 g of ethyl 2-ethoxy- l -((2'-(N'- (ethoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)- l -benz[(i]imidazole-7- carboxylate (of formula VIbb; R' = Et) and 4 ml of the respective solvent, stirred in a reaction vial, and the mixture was stirred at the room temperature for 4 h. The collected samples were acidified with acetic acid and analyzed with HPLC. Table II - Yield and purity of the product of Example 5
With sodium ethanolate; In dimethyl sulfoxide; at 20℃; for 4.0h;Product distribution / selectivity;
Example 5Ethyl 2-ethoxy- 1 -((2'-(5-oxo-4,5-dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- 1 H- benzo[c ]imidazole-7-carboxylate of formula lb0.05 g of the corresponding base was added to a mixture of 0.2 g of ethyl 2-ethoxy- l -((2'-(N'- (ethoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)- l -benz[(i]imidazole-7- carboxylate (of formula VIbb; R' = Et) and 4 ml of the respective solvent, stirred in a reaction vial, and the mixture was stirred at the room temperature for 4 h. The collected samples were acidified with acetic acid and analyzed with HPLC. Table II - Yield and purity of the product of Example 5
With potassium carbonate; In dimethyl sulfoxide; at 20℃; for 3.0h;Product distribution / selectivity;
Example 9Ethyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH- benzo[tf)imidazole-7-carboxylate of formula lbUsing the procedure described in Example 6 ethyl 2-ethoxy-l -((2'-(N'-(ethoxycarbonyloxy)- carbamimidoyl)biphenyl-4-yl)methyl)-lH-benz[i/]imidazole-7-carboxylate of formula VIbb; R' = Et) was converted to ethyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)-l H-benzo[t/]imidazole-7-carboxylate of formula lb. 93.0% of a compound with the melting point of 179 to 182C were obtained containing 97.8% of a product of formula lb according to HPLC. NMR (500 MHz, DMSO) delta (ppm): 12.40 (s, lH, NH), 7.69 (dd, J = 7.9, 1.2 Hz, 1H, Ar), 7.50 (m, 1H, Ar), 7.44 (dd, J = 7.9, 1.2 Hz, 1H, Ar), 7.43-7.40 (m, 4H, Ar), 7.35 (d, J = 7.7 Hz, 1 H, Ar), 7.19 (t, J = 7.9 Hz, 1H, Ar), 6.95 (d, J = 8.3 Hz, 2H, Ar), 6.61 (bs, 2H, NH2), 5.57 (s, 2H, N-CH2-Ar), 4.60 (q, J = 7.1 Hz, 2H, COOCH2CH3), 4.18 (q, J = 7.1 Hz, 2H, OCH2CH3), 1.39 (t, J = 7.1 Hz, 3H, COOCH2CH3), 1.16 (t, J = 7.1 Hz, 3H, OCH2CH3).
4.3 g
With dibutylamine; at 110 - 115℃; for 2.0h;
A mixture of ethyl 2-ethoxy-l-((2'-(N'-((ethoxycarbonyl)oxy)carbamimidoyl)-[biphenyl]- 4-yl)methyl)-lH-benzoimidazole-7-carboxylate (compound V; Ri= R2=ethyl) (5 g), and dibutyl amine (30 ml) was heated at 110-115C for 2 hours. The reaction mixture cooled to 25-30C and stirred for one hour. The solid was filtered, washed with ethyl acetate and dried. Yield: 4.3 g.
In isopropyl alcohol; at 80℃;
Add 120 g of toluene to the reaction flask.15 g of compound III-2, 12.5 g of triethanolamine,Stir well, slowly add 7.1 g of ethyl chloroformate at 30 C.After the addition is completed, the reaction is continued. After the reaction is completed, water is added to quench, and the liquid is allowed to stand for separation.The toluene layer is washed once with water and once with a saturated sodium chloride solution.Concentration under reduced pressure gave a solid V-2.The obtained solid V-2 and isopropanol were added to the reaction flask.Stirring to 70 C for the reaction, after the reaction is finished, cooling and crystallization,The crude compound II-2 was obtained by filtration. The obtained crude II-2 was added to ethyl acetate.Stirring at 70 C for 3 h, cooling to 30 C and stirring for 3 h,Filtration and drying to obtain the finished compound II-2,The yield was 73%.
In isopropyl alcohol;Reflux;
(3) Mixing Intermediate 2 and isopropanol in a reaction vessel, the molar ratio of the intermediate 2 to the isopropanol is 1:1, heating under reflux, after completion of the reaction, cooling to room temperature, and distilling off under reduced pressure. Solvent, then add acetone to reflux, add activated carbon, stir, filter, cool to 10 C, crystallize, then filter, dry, to obtain intermediate 3;
With proton sponge; In dimethyl sulfoxide; at 20℃; for 3.0h;Product distribution / selectivity;
Example 6Ethyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- lH- benzo[c/]imidazole-7-carboxylate of formula lbThe corresponding base (0. 1 g) was added to a mixture of ethyl 2-ethoxy- l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l / -benzo[i ]imidazole-7-carboxylate (of formula Vb; 0.23 g, 0.5 mmol), DMSO (3 ml) and carbonyldiimidazole (0.1 g, 0,6 mmol) in a reaction vial under stirring and the mixture was stirred at the room temperature for 3 hours. Then, the content of the vial was poured into water (10 ml) and, after acidification with acetic acid, the separated solids were aspirated and washed with water. The yields and purity of the products are summarized in Table III. Table III - Yield and purity of the product of Example 6
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20 - 25℃; for 2.0h;
Put 20 g of AQST-1 intermediate and 200 ml of tetrahydrofuran into the flask, stir well, and slowly add 11.9 g of DBU (1,8-diazabicycloundec-7-ene) dropwise at 20-25 C. , Add 17.5g of CDI (carbonyldiimidazole), and keep the reaction at 20-25 C for about 2 hours to TLC the plate until the reaction is complete (the AQST-1 spots have basically disappeared);After the reaction, 160 ml of water was added dropwise to terminate the reaction. 160 ml of dichloromethane was added, and the layers were stirred and separated. The aqueous layer was extracted with dichloromethane (160 ml * 2). The organic layers were combined and saturated sodium bicarbonate solution and saturated sodium chloride were separately used. The solution was washed, and the organic layer was separated, dried with about 40 g of anhydrous sodium sulfate, filtered, and the filter cake was rinsed with dichloromethane. The dichloromethane feed solution was concentrated to dryness, and 60 ml of acetone was added for hot beating for about 1 hour. Rinse and suction filter to dry, collect AQST-3 wet product;Put the wet product of AQST-3 into the flask, add 60ml of acetone, heat to 55 C, beat for 1 hour, and filter; repeat the above purification process twice for the filter cake, and collect the purified wet product of AQST-3Dry at 50 under vacuum to constant weight;
With triethylamine; In 1,4-dioxane; toluene; at 50℃; for 8.0h;
Example 20 Ethyl 2-ethoxy-l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H- benzo[cf]imidazole-7-carboxylate of formula lbA 20 % solution of phosgene in toluene (0.5 ml, 1 mmol) was added to a mixture of ethyl 2- ethoxy- l -((2'-((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[i/|imidazole-7- carboxylate (of formula Vb; 0.23 g, 0.5 mmol), dioxan (5 ml) and triethylamine (0.2 g, 2 mmol) and the mixture was stirred in a closed pressure tube at 50 C for 8 hours. After cooling down, the solution was bubbled with nitrogen for 8 hours. After evaporation of the solvent the residue was triturated with water ( 10 ml), the resulting turbid solution was acidified with acetic acid and extracted with ethyl acetate (4 x 25 ml). After washing with brine the extract was dried with MgS04 and the obtained evaporation residue was crystallized from ethyl acetate. 0.20 g (82.5 %) of a product was obtained containing 98.4 % of the compound of formula lb according to HPLC
With sodium ethanolate; In ethanol; water; at 60 - 65℃; for 1.0h;
The ethoxy oxime (II) (390 g; 851 mmol) is suspended in 3600 ml of diethyl carbonate. The suspension is heated up to 65C. A solution of sodium ethoxide in ethanol (21 %, 400 ml, 1072 mmol) is added dropwise to the reaction mixture at 65C during 30 minutes. After completion of the addition the reaction mixture is agitated at 65C for 30 minutes. The reaction mixture is cooled down to 60C and water (1350 ml) is added. The resulting emulsionis agitated for at least 15 minutes. After separation of the layers the organic phase is extracted with water (1350 ml). The combined aqueous extracts are diluted with ethanol (1350 ml) and the temperature is adjusted to 40C. Acetic acid (111 ml, 1940 mmcl) is added to the solution dropwise at 40C during 30 minutes. The resuMing suspension is agitated at 40C for 30 minutes and then cooled down to 20C. The separated substance is aspirated and washed withwater (2 x 450 ml). The resulting product is then dried in a vacuum drier at 45C. 397 g (86% of the theoretical quantity, HPLC 95.8%) of azilsartan ethyl ester (III) was obtained.
With sodium ethanolate; In ethanol; at 100℃; for 48.0h;
Example 16Ethyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H- benzo[if|imidazole-7-carboxylate of formula lbEtONa (0.12 g, 1.8 mmol) was added to a suspension of ethyl 2-ethoxy-l -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- l H-benzo[cflimidazoIe-7-carboxyIate (of formula Vb; 0.46 g, 1 mmol) in dry ethanol (20 ml) and the mixture was stirred at the room temperature for 10 minutes. After adding diethyl carbonate (DEC; 0.6 g, 5.0 mmol) the mixture was stirred in a pressure flask at the temperature of 100 C for 24 hours. The mixture contained 48.3% of the starting compound of formula Vb and 33.1 % of the compound of formula lb according to HPLC. After stirring in a pressure flash at 100 C for another 24 hours the mixture contained 1 1.3 % of the starting compound of formula Vb and 77.1 % of the compound of formula lb according to HPLC. After evaporation the residue was dissolved in water (20 ml) and the solids separated after acidification with 5% HCl were aspirated and washed with water. 0.32 g (66.0 %) of the product containing 92.7 % of the compound of formula lb according to HPLC was obtained.
1-[{2’-(2,5-dihydro-5-oxo-1,2,4-oxodiazol-3-yl)(1,1’-biphenyl)-4-yl}methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester potassium salt[ No CAS ]
The starting <strong>[1403474-70-3]ethyl ester of azilsartan</strong> (V, 250 g) was suspended in a solution of sodium hydroxide in water (56 g/800ml). The suspension was heated at 50C for 4 h, after pH adjustment to 4-5, the product crystallized providing 232 g (98.5 %).
93.4%
With sodium hydroxide; In water; at 70 - 75℃; for 1.5h;
15g of AQST-3 intermediate was put into the flask, and 232g of the prepared 0.4mol / L sodium hydroxide solution was added. The temperature was raised to 70-75 C and the reaction was kept for about 1.5 hours. The reaction was monitored by TLC for completeness (no spots of AQST-3);After the reaction, drop to room temperature, filter, rinse the filter cake with a small amount of water, add 100ml of absolute ethanol to the filtrate, lower the temperature to 20-25 C and adjust the pH to 2 ~ 3 with 2mol / L diluted hydrochloric acid, and stir for about 1 hour. Filter and rinse to get crude AQST;
91%
With pyrographite; sodium hydroxide; In water; at 55℃; for 2.0h;
20 g of compound II-2 was added to a 15% aqueous NaOH solution.Stir the mixture to a temperature of 55 C for 2 h, add activated carbon and continue to stir.Filter and collect the filtrate. Cool down to 15 C, adjust the pH to 3 with hydrochloric acid,Filtration, washing with water, drying to obtain the finished compound I,The yield is 91%,
89.3%
With sodium hydroxide; In ethanol; at 73 - 75℃; for 1.6h;
Compound (5B) 5 g, placed in a reaction flask, adding ethanol 30ml, was added dropwise 2.5mol / L sodium hydroxide 13ml, 73-75 1.6 hours the reaction.After completion of the reaction, cooled to room temperature, the solution was added dropwise to the acidic water pH = 3-4, to precipitate a white solid 4.2g, 89.3%.
22 g
With water; sodium hydroxide; at 70 - 75℃; for 1.5h;
A mixture of azilsartan ester (VI; Ri= Et) (25 g) and 0.4 N NaOH solution (380 ml) was heated at 70-75C for 90 minutes. The reaction mixture was cooled to 10-15C and the pH was adjusted to 2.5-3.0 with 2 N HC1. The mixture was stirred for 30 minutes at 10- 15C. The solid was filtered, washed with water (100 ml) and dried under vacuum. Yield: 22.0 g;X-ray powder diffraction pattern as depicted in figure 1.
50.6 g
With sodium hydroxide; at 75℃;
Example 2 Preparation of the product 2-Ethoxy-3- [2 '- (5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl) 4-ylmethyl] -3H-benzimidazole-4-carboxylate 55.1 g,0.4 MN NaOH into the reaction bottle,75 C stirring reaction to the raw material reaction is completed. The reaction solution was cooled to room temperature. The filtrate was added with 820ml of absolute ethanol, filtered and kept at 20 C. The pH was adjusted to 1 with 2M HC1 solution. A large amount of solid was precipitated, stirred for 1 hour, filtered and washed with water. 50.6 g,HPL (^ i ^ S 98.6%
With ethanol; sodium hydroxide; at 75℃;
(4) Intermediate 3, 0.4 N NaOH solution, ethanol was added to the reaction kettle, the molar ratio of intermediate 3 to NaOH was 1:1.05, and the volume ratio of NaOH solution to ethanol was 1:1 at 75 C. Stirring, after completion of the reaction, cooling to room temperature, filtration, pH adjustment with 1N hydrochloric acid solution, to precipitate solids, stirring, filtration, adding ethanol to be beaten, filtering, and drying the filter cake to obtain crude azilsartan;
With sodium ethanolate; In ethanol; at 80℃; for 2.0h;
The starting amidoxime (IV) was suspended in diethyl carbonate (30 g) and sodium ethoxide (21 % in ethanol, 9 g) was added. The mixture was heated at 80C for 2h, 20 ml of the solvent was removed by distillation, ethanol (20 ml), water (20 ml) and acetic acid (3 g) and more water (20 ml) were added. The suspension was stirred at 50C for 1 h and cooled to 25C. 8 g (76 %) of the product was obtained.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In tetrahydrofuran; at 20℃; for 2.0h;
Example 1Prepared Synthesis of 2-ethoxy-3 - [[2 '- (N-benzyloxymethylidene) biphenyl-4-yl] methyl] benzimidazole-4-carboxylate,Into the reaction bottle,Add 209.8gCDI, 134ml DBU and 4.5L THF, room temperature reaction 2h, the reaction is completed. 4.5 L of water, 4.5 L of ethyl acetate was extracted and the organic phases were combined.Respectively, saturated NaHC03, saturated NaCl solution, dry anhydrous sodium sulfate organic phase, evaporated to dry organic solvent. Beaten with acetone, filtered and dried to obtain 98.7 g of a product.
Compound (4B, R = isopropyl) 9 grams, placed in a reaction flask, 60ml of ethanol was refluxed for 15 hours, cooling crystallization to give a solid 6.5, yield 81.2%.
Compound (4B, R = methyl) 9 grams, placed in a reaction flask, 60ml of ethanol was refluxed for 15 hours, cooling crystallization to give a solid 7.2, yield 85.7%.
Compound (4B, R = ethyl) 9 grams, placed in a reaction flask, 60ml of ethanol was refluxed for 15 hours, cooling crystallization to give a solid 7.3, yield 89.0%.
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