* 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.
Reference：
[1] Chemistry of Natural Compounds, 2004, vol. 40, # 5, p. 434 - 443
4
[ 1830-54-2 ]
[ 62935-72-2 ]
Reference：
[1] Chemistry of Natural Compounds, 2004, vol. 40, # 5, p. 434 - 443
5
[ 67-56-1 ]
[ 77-92-9 ]
[ 1830-54-2 ]
[ 100009-70-9 ]
[ 20820-77-3 ]
[ 1587-20-8 ]
[ 105-45-3 ]
Yield
Reaction Conditions
Operation in experiment
87.3%
Stage #1: With chlorosulfonic acid In dichloromethane at 10 - 15℃; for 5 - 6 h; Stage #2: at 3 - 35℃; for 2 h;
490 kg (370 1) of anhydrous methylene chloride are added to 1320 kg (753 1) of chlorosulphonic acid (the ratio of methylene chloride to chlorosulphonic acid is 0.5 : 1 by volume). The temperature of the mixture is adjusted to 10-15 oC, and 665.0 kg of citric acid monohydrate are added to it at a rate of 1.25 kg/minute, while the temperature of the reaction mixture is kept between 10 oC and 15 oC. When the addition has been completed the reaction mixture is stirred at a temperature between 10 oC and 15 oC until no more gas is liberated (at least 6 hours). The reaction mixture is then cooled to 3-5 oC and 640 kg (800 1) of anhydrous methanol are added to it at such a rate that the inner temperature does not exceed 25 oC. The reaction mixture is then warmed to 30-35 oC and stirred at the same temperature for 2 hours. The esterifying reaction is completed under this period. The reaction mixture is cooled to 10- 12 oC and 1300 1 of water are added to it at such a rate that the temperature does not exceed 15 oC. To the mixture 800 ml of methylene chloride are added and it is stirred for 15 minutes. The two-phase mixture is clarified for 30 minutes and the organic phase is separated. The aqueous layer is extracted three times with 400 ml each of methylene chloride. The organic phases are combined and washed first with 1000 1 of water, then with a solution of 75 kg of sodium hydrocarbonate in 1000 1 of water. The pH of the solution is adjusted to a value of about 7 by the addition of sodium hydrocarbonate. The organic phase is separated, washed twice with 750 ml each of water and evaporated in vacuo. Evaporation is carried out under a pressure of 3-5 kPa until the inner temperature rises at most to 75 oC. Thus 535 kg of dimethyl 3- OXOGLUTARATE are obtained, which can be used for the further reaction steps without purification. Qualification by gas chromatography: Purity by gas chromatography: Apparatus: gas chromatograph of HP-6850 type Method: Column : HP-1.25 m x 0. 32 MM, 0.17 URN of film thickness Carrier gas: hydrogen Program: 80 oC-5 MINUTES-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxoglutarate 5.77 minutes Enol ether 8.15 minutes Trimethyl aconitate 10. 00 minutes Trimethyl citrate 10. 42 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Result: Methyl acetoacetate: 0.31percent Dimethyl 3-oxoglutarate: 98.33percent Enol ether: 0. 81percent Trimethyl aconitate: 0. 28percent Trimethyl citrate : 0. 09percent Isoftalic acid derivative :- Other contamination (higher than 0,2 percent) Example 2 Into a mixture of 100.0 g (58 ml) of chlorosulphonic acid and 30 ml of methylene chloride 50.0 g of citric acid monohydrate are added within 30 minutes at a temperature between 10 oC and 15 oC. The mixture is stirred at the same temperature for 5 hours, cooled to 3-5 oC and 60 ml of methanol are introduced to it within 15 minutes at such a rate that the temperature does not exceed 25 oC. It is then stirred for 2 hours at a temperature between 30 oC and 35 oC, cooled to 15 oC and 100 ml of water are added to it within 15 minutes. The thus-obtained mixture is extracted three times with 50 ml each of methylene chloride; the organic phases are combined, washed successively with 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of water and evaporated in vacuo. Thus 40.8 g of dimethyl 3- OXOGLUTARATE are obtained. Yield: 98. 5 percent Apparatus : gas chromatograph of HP-6850 type Method : Column: HP-1.25 m x 0.32 mm, film thickness of 0. 17 Am Carrier gas: hydrogen Program: 80 oC-5 minutes-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxo- glutarate 5. 77 minutes Enol ether 8.15 minutes Trimethyl citrate 10.42 minutes Trimethyl aconitate 10.11 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Evaluation by gas chromatography (the method was carried out using the parameters specified in Example 1) : Result: Methyl acetoacetate: 0. 49percent Dimethyl 3-OXOGLUTARATE : 97. 62percent Enol ether: 0.98percent Trimethyl citrate: 0. 13percent Trimethyl aconitate: 0.29percent Isoftalic acid derivative: 0.07percent Other contamination (more than 0.2 percent) Example 3 (comparative example) Example 1 of the Belgian patent specification No. 879,537 A mixture of 212 ml of chlorosulphonic acid and 600 ml of methylene chloride is prepared (the ratio of methylene chloride to chlorosulphonic acid is 2.83 : 1 by volume). Then 200.0 g of citric acid are added to this mixture within 15-20 minutes, the addition rate of citric acid is 13.3 kg/minute, temperature = 20-22 oC. The reaction mixture is stirred at this temperature for 5 hours, cooled to a temperature between 3"C AND 5 C and 320 ml of methanol are added to it within 15 minutes at such a rate that the temperature remain below 25 oC. The reaction mixture is then stirred for 2 hours at a temperature between 30 oC and 35 oC, cooled to 15 oC, poured into 800 ml of water, stirred vigorously for 15 minutes, clarified for 15 minutes and the phases are separated. The aqueous phase is extracted three times with 150 ml each of methylene chloride. The organic phases are combined, washed once with 400 ml of saturated sodium hydrogen carbonate solution and twice with 200 ml each of water and evaporated in vacuo. Thus 158.2 g of dimethyl 3-oxoglutarate are obtained. Yield: 87. 3 percent. Evaluation by gas chromatography (the method was carried out using the parameters specified in Example 1) : Result: Methyl acetoacetate: 0.21percent Dimethyl 3-oxoglutarate: 91.07percent Enol ether: 4.78percent Trimethyl aconitate 0.46percent Trimethyl citrate : 2.27percent Isoftalic acid derivative: 0.53percent Other contamination (higher than 0. 2percent)
Reference：
[1] Chemical & Pharmaceutical Bulletin, 1981, vol. 29, # 10, p. 2762 - 2768
[2] Tetrahedron Letters, 1981, vol. 22, # 34, p. 3245 - 3246
7
[ 105-45-3 ]
[ 616-38-6 ]
[ 1830-54-2 ]
Reference：
[1] Recueil des Travaux Chimiques des Pays-Bas, 1989, vol. 108, # 2, p. 51 - 56
8
[ 77-92-9 ]
[ 1830-54-2 ]
Reference：
[1] Journal of Organic Chemistry, 1957, vol. 22, p. 1385,1388, 1392[2] Journal of Organic Chemistry, 1958, vol. 23, p. 391,393
[3] Patent: US2887508, 1958, ,
[4] Journal of the American Chemical Society, 1971, vol. 93, p. 3969 - 3977
9
[ 67-56-1 ]
[ 542-05-2 ]
[ 1830-54-2 ]
Reference：
[1] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1922, vol. 121, p. 146
[2] Annales de Chimie (Cachan, France), 1891, vol. <6> 23, p. 165
[3] Chemische Berichte, 1916, vol. 49, p. 2704[4] Chemische Berichte, 1920, vol. 53, p. 1917
[5] Hoppe-Seyler's Zeitschrift fuer Physiologische Chemie, 1922, vol. 121, p. 146
[6] Russian Journal of Organic Chemistry, 2010, vol. 46, # 4, p. 517 - 519
10
[ 67-56-1 ]
[ 77-92-9 ]
[ 1830-54-2 ]
Reference：
[1] Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1998, vol. 37, # 4, p. 397 - 398
11
[ 40018-26-6 ]
[ 1830-54-2 ]
[ 865187-80-0 ]
[ 53562-51-9 ]
Yield
Reaction Conditions
Operation in experiment
51%
With lithium bromide In 1,4-dioxane for 20 h; Reflux
A solution of dimethyl acetone-1,3-dicarboxylate (7) (51.4 g, 0.296 mol) in 1,4-dioxane (75 mL) and then LiBr (28.2 g, 0.325 mol) were added to a stirred suspension of 2,5-dihydroxy-1,4-dithiane (30.0 g, 0.197 mol) in 1,4-dioxane (300 mL). The mixture was stirred at reflux for 20 h. The mixture was filtered into a separating funnel and extracted with ethyl acetate (500 mL) and water (70 mL). The water layer was re-extracted with ethyl acetate (2.x.250 mL) and the combined organic layers were washed with aq HCl (500 mL, 1 M), aq NaHCO3 (5percent), aq NaOH (500 mL, percent10) and then with brine (500 mL). The solution was dried over MgSO4 and the solvent was evaporated. The crude product was purified by column chromatography (350 g) eluting with hexane/ethyl acetate (7:2) and then (5:2) to give monoester 10 as the first fraction. The desired diester 9 was isolated as the second fraction.
Reference：
[1] Journal of Organic Chemistry, 1957, vol. 22, p. 1385,1388, 1392[2] Journal of Organic Chemistry, 1958, vol. 23, p. 391,393
13
[ 1830-54-2 ]
[ 5164-76-1 ]
Reference：
[1] Journal of the American Chemical Society, 1969, vol. 91, p. 7359 - 7371
14
[ 1830-54-2 ]
[ 7250-55-7 ]
Yield
Reaction Conditions
Operation in experiment
94%
With sodium tetrahydroborate In methanol at 0 - 20℃; for 24 h;
To a stirred solution of dimethyl 3-oxoglutarate (17.7ml, 120.6mmol) in MeOH (315 mL) at 0 °C was added portion wise NaBH4 (3.9g, 102.5 mol). The reaction was allowed to reach room temperature. After 24 h, the reaction mixture was quenched by addition of solid citric acid until pH reached 5 to 6. To the reaction mixture was added silica gel (ca. 1g) and the solvent was distilled off. The residue was purified by column chromatography on silicagel (EtOAc:hexane, 1:1) to afford the dimethyl 3-hydroxyglutarate (19.98g, 94percent)as a colorless oil.
Reference：
[1] Journal of the Brazilian Chemical Society, 2011, vol. 22, # 1, p. 172 - 175
[2] Bioorganic and Medicinal Chemistry Letters, 2015, vol. 25, # 17, p. 3650 - 3653
[3] Journal of Organic Chemistry, 1988, vol. 53, # 7, p. 1567 - 1569
[4] RSC Advances, 2016, vol. 6, # 27, p. 22737 - 22748
[5] Journal of the American Chemical Society, 2009, vol. 131, # 49, p. 17980 - 17985
[6] Canadian Journal of Chemistry, 1988, vol. 66, # 6, p. 1422 - 1424
[7] Angewandte Chemie - International Edition, 2008, vol. 47, # 50, p. 9743 - 9746
[8] Journal of Organic Chemistry, 1997, vol. 62, # 15, p. 5057 - 5061
[9] Tetrahedron, 1997, vol. 53, # 40, p. 13757 - 13768
[10] Chemische Berichte, 1953, vol. 86, p. 186,188
[11] Zhurnal Obshchei Khimii, 1952, vol. 22, p. 1467[12] Chem.Abstr., 1953, vol. 47, p. 5949
[13] Chemische Berichte, 1953, vol. 86, p. 186,188
[14] Journal of the American Chemical Society, 1961, vol. 83, p. 4228 - 4233
[15] Journal of the American Chemical Society, 1969, vol. 91, p. 7359 - 7371
[16] Tetrahedron, 1987, vol. 43, # 1, p. 45 - 58
[17] Journal of Organic Chemistry, 1998, vol. 63, # 9, p. 3037 - 3040
[18] Il Farmaco; edizione scientifica, 1978, vol. 33, # 4, p. 237 - 252
15
[ 1830-54-2 ]
[ 106-95-6 ]
[ 7250-55-7 ]
[ 111086-20-5 ]
[ 147528-53-8 ]
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 8, p. 2260 - 2264
16
[ 1830-54-2 ]
[ 106-95-6 ]
[ 7250-55-7 ]
[ 111086-20-5 ]
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 8, p. 2260 - 2264
17
[ 1830-54-2 ]
[ 106-95-6 ]
[ 7250-55-7 ]
[ 147528-53-8 ]
Reference：
[1] Journal of Organic Chemistry, 1993, vol. 58, # 8, p. 2260 - 2264
18
[ 67-56-1 ]
[ 77-92-9 ]
[ 1830-54-2 ]
[ 100009-70-9 ]
[ 20820-77-3 ]
[ 1587-20-8 ]
[ 105-45-3 ]
Yield
Reaction Conditions
Operation in experiment
87.3%
Stage #1: With chlorosulfonic acid In dichloromethane at 10 - 15℃; for 5 - 6 h; Stage #2: at 3 - 35℃; for 2 h;
490 kg (370 1) of anhydrous methylene chloride are added to 1320 kg (753 1) of chlorosulphonic acid (the ratio of methylene chloride to chlorosulphonic acid is 0.5 : 1 by volume). The temperature of the mixture is adjusted to 10-15 oC, and 665.0 kg of citric acid monohydrate are added to it at a rate of 1.25 kg/minute, while the temperature of the reaction mixture is kept between 10 oC and 15 oC. When the addition has been completed the reaction mixture is stirred at a temperature between 10 oC and 15 oC until no more gas is liberated (at least 6 hours). The reaction mixture is then cooled to 3-5 oC and 640 kg (800 1) of anhydrous methanol are added to it at such a rate that the inner temperature does not exceed 25 oC. The reaction mixture is then warmed to 30-35 oC and stirred at the same temperature for 2 hours. The esterifying reaction is completed under this period. The reaction mixture is cooled to 10- 12 oC and 1300 1 of water are added to it at such a rate that the temperature does not exceed 15 oC. To the mixture 800 ml of methylene chloride are added and it is stirred for 15 minutes. The two-phase mixture is clarified for 30 minutes and the organic phase is separated. The aqueous layer is extracted three times with 400 ml each of methylene chloride. The organic phases are combined and washed first with 1000 1 of water, then with a solution of 75 kg of sodium hydrocarbonate in 1000 1 of water. The pH of the solution is adjusted to a value of about 7 by the addition of sodium hydrocarbonate. The organic phase is separated, washed twice with 750 ml each of water and evaporated in vacuo. Evaporation is carried out under a pressure of 3-5 kPa until the inner temperature rises at most to 75 oC. Thus 535 kg of dimethyl 3- OXOGLUTARATE are obtained, which can be used for the further reaction steps without purification. Qualification by gas chromatography: Purity by gas chromatography: Apparatus: gas chromatograph of HP-6850 type Method: Column : HP-1.25 m x 0. 32 MM, 0.17 URN of film thickness Carrier gas: hydrogen Program: 80 oC-5 MINUTES-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxoglutarate 5.77 minutes Enol ether 8.15 minutes Trimethyl aconitate 10. 00 minutes Trimethyl citrate 10. 42 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Result: Methyl acetoacetate: 0.31percent Dimethyl 3-oxoglutarate: 98.33percent Enol ether: 0. 81percent Trimethyl aconitate: 0. 28percent Trimethyl citrate : 0. 09percent Isoftalic acid derivative :- Other contamination (higher than 0,2 percent) Example 2 Into a mixture of 100.0 g (58 ml) of chlorosulphonic acid and 30 ml of methylene chloride 50.0 g of citric acid monohydrate are added within 30 minutes at a temperature between 10 oC and 15 oC. The mixture is stirred at the same temperature for 5 hours, cooled to 3-5 oC and 60 ml of methanol are introduced to it within 15 minutes at such a rate that the temperature does not exceed 25 oC. It is then stirred for 2 hours at a temperature between 30 oC and 35 oC, cooled to 15 oC and 100 ml of water are added to it within 15 minutes. The thus-obtained mixture is extracted three times with 50 ml each of methylene chloride; the organic phases are combined, washed successively with 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of water and evaporated in vacuo. Thus 40.8 g of dimethyl 3- OXOGLUTARATE are obtained. Yield: 98. 5 percent Apparatus : gas chromatograph of HP-6850 type Method : Column: HP-1.25 m x 0.32 mm, film thickness of 0. 17 Am Carrier gas: hydrogen Program: 80 oC-5 minutes-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxo- glutarate 5. 77 minutes Enol ether 8.15 minutes Trimethyl citrate 10.42 minutes Trimethyl aconitate 10.11 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Evaluation by gas chromatography (the method was carried out using the parameters specified in Example 1) : Result: Methyl acetoacetate: 0. 49percent Dimethyl 3-OXOGLUTARATE : 97. 62percent Enol ether: 0.98percent Trimethyl citrate: 0. 13percent Trimethyl aconitate: 0.29percent Isoftalic acid derivative: 0.07percent Other contamination (more than 0.2 percent) Example 3 (comparative example) Example 1 of the Belgian patent specification No. 879,537 A mixture of 212 ml of chlorosulphonic acid and 600 ml of methylene chloride is prepared (the ratio of methylene chloride to chlorosulphonic acid is 2.83 : 1 by volume). Then 200.0 g of citric acid are added to this mixture within 15-20 minutes, the addition rate of citric acid is 13.3 kg/minute, temperature = 20-22 oC. The reaction mixture is stirred at this temperature for 5 hours, cooled to a temperature between 3"C AND 5 C and 320 ml of methanol are added to it within 15 minutes at such a rate that the temperature remain below 25 oC. The reaction mixture is then stirred for 2 hours at a temperature between 30 oC and 35 oC, cooled to 15 oC, poured into 800 ml of water, stirred vigorously for 15 minutes, clarified for 15 minutes and the phases are separated. The aqueous phase is extracted three times with 150 ml each of methylene chloride. The organic phases are combined, washed once with 400 ml of saturated sodium hydrogen carbonate solution and twice with 200 ml each of water and evaporated in vacuo. Thus 158.2 g of dimethyl 3-oxoglutarate are obtained. Yield: 87. 3 percent. Evaluation by gas chromatography (the method was carried out using the parameters specified in Example 1) : Result: Methyl acetoacetate: 0.21percent Dimethyl 3-oxoglutarate: 91.07percent Enol ether: 4.78percent Trimethyl aconitate 0.46percent Trimethyl citrate : 2.27percent Isoftalic acid derivative: 0.53percent Other contamination (higher than 0. 2percent)
Reference：
[1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1990, # 9, p. 2363 - 2369
22
[ 1830-54-2 ]
[ 122-51-0 ]
[ 79398-27-9 ]
Yield
Reaction Conditions
Operation in experiment
67%
Stage #1: at 120℃; for 1.5 h; Stage #2: With ammonia In water for 1 h; Cooling with ice Stage #3: With hydrogenchloride In water
3-Oxo-pentanedioic acid dimethyl ester (100 g, 575 mmol), (EtO)3CH (95 mL, 575 mmol), Ac2O (108 mL) and HOAc (108 mL) were mixed and heated at 120° C. for 1.5 hours, then allowed to cool to 25° C. The volatiles were removed under reduced pressure while maintaining the water bath around 85° C. To the crude liquid was added aqueous NH3 (25percent, 150 mL) in portions with swirling in an ice bath and the stirring was continued for 1 hour. The mixture was acidified by the addition of 6 N HCl. The yellow precipitate was collected by filtration, boiled in toluene, cooled and filtered to give 4,6-dihydroxy-nicotinic acid methyl ester as an orange solid. (Yield 65 g, 67percent). 1H NMR (300 MHz, d6-DMSO): δ 8.06 (s, 1H), 5.65 (s, 1H), 3.83 (s, 3H). LC-MS: [M+H]+ 170.
55%
Stage #1: at 150℃; for 4 h; Stage #2: at 100℃; for 1 h;
A (460.0 g, 2.64 mol) and triethyl orthoformate (586.5 g, 3.96 mol) were dissolved in 690 mL of acetic anhydride,After stirring at 150 ° C for 4 hours,The reaction mixture was volume-concentrated to 600 mL at 100 ° C.Slowly add 920 mL of NH3 · H2O with stirring, and after 1 hour,The reaction mixture was acidified with 2.3 L of 5 mol / L HCl.The precipitate was collected by filtration and dried to give 243.0 g of product B in 55percent yield.
46%
Stage #1: at 130℃; for 2 h; Stage #2: With ammonia In water for 0.5 h; Stage #3: With hydrogenchloride In water
A solution containing dimethyl-1, 3-acetonedicarboxylate (2000 g, 11.5 mol), ethyl orthoformate (1947 mL, 11.5 mol), and acetic anhydride (2168 mL, 23.0 mol) was heated at 130 °C for 2 h. The reaction was allowed to be cooled to room temperature then concentrated in vacuo to 1500 mL. The crude reaction was cooled in ice bath and aqueous ammonia (2 L) was added in portions with stirring. After 30 min, the mixture was acidified with concentrated HC1 (-300 mL) and the suspension was filtered. The crude product was dried under vacuum to give methyl 4,6- dihydroxynicotinate (900 g, 46percent) which was taken on directly into the next step.
Stage #1: at 130℃; for 1.5 h; Stage #2: With ammonia In water at 0℃; for 1 h;
Example 1 Synthesis of 2,4-dichloro-5-nitro-pyridine Dimethyl-1,3-acetonedicarboxylate (50.0 g, 287 mmol), triethylorthoformate (47.8 mL, 287 mmole), and acetic anhydride (54.2 mL, 102 mmol) were combined and heated to 130° C. for 1.5 h then allowed to cool to 25° C. The volatiles were removed in vacuo while maintaining the water bath around 85° C. until the volume of the reaction was reduced to about 25 mL. This crude liquid was poured into a 2000 mL flask and cooled in an ice bath. To this cooled flask was added 75 mL of concentrated aqueous NH3 in portions with swirling. After 1 hour the mixture was acidified by the addition of 6 N HCl (~250 mL). The yellow precipitate was collected by vacuum filtration and allowed to dry under a stream of air. The crude powder was boiled in 200 mL of benzene and allowed to cool and filtered to provide 4,6-dihydroxy-nicotinic acid methyl ester as an orange solid (25.7 g, 53percent).
Reference：
[1] Patent: US2006/217417, 2006, A1, . Location in patent: Page/Page column 12
[2] Journal of Heterocyclic Chemistry, 1983, vol. 20, p. 1363 - 1366
[3] Journal of the Chinese Chemical Society, 2016, vol. 63, # 9, p. 758 - 769
Stage #1: With Ni(acac)2 In 1,4-dioxane for 16 h; Reflux Stage #2: for 0.583333 h; Reflux
Example 63 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one A mixture of dimethyl acetone-1,3-dicarboxylate (200 g, 1.15 mol), cyanamide (48.3 g, 1.15 mol), and Ni(acac)2 (14.75 g, 0.0574 mol) in dioxane (200 mL) was heated to reflux for 16 h and then cooled to room temperature. The precipitate was filtered off, and the solid was mixed with methanol (200 mL) and stirred for 30 min and filtered again to give 93 g product (44percent yield). In a 1 L flask with a reflux condenser was added the product from step one (93.0 g, 0.505 mol) and POCl3 (425 mL) and the reaction mixture was heated to reflux for 35 min. POCl3 (300 mL) was evaporated under vacuum. The residue was poured into ice and water (400 mL), which was neutralized with KOH to pH 6-7. The precipitate was filtered off and extracted with ethyl acetate (2*300 mL). The organic solution was concentrated and purified by column chromatography to give methyl 2-amino-4,6-dichloropyridine-3-carboxylate (22.5 g, 20.1percent).
With hydrogenchloride; sulfuric acid; sodium chloride at 36℃; for 3.5h;
1.S2 S2: The esterification reaction yields dimethyl 1,3-acetone dicarboxylate (III), and the steps include
Methanol absorbs hydrogen chloride: 100.0 g of sodium chloride and 150 mL of concentrated sulfuric acid are sequentially added to a 500 mL three-necked flask, and concentrated sulfuric acid is slowly added dropwise while stirring. The generated hydrogen chloride gas is passed to a concentrated sulfuric acid reagent bottle to dry, and then passed to In the two-necked flask, the other bottle was connected to a drying tube, and the gas at the outlet of the drying tube was checked with a pH test paper. When the test paper became red, the hydrogen chloride methanol solution reached saturation.423 g of methanol (199 g of hydrogen chloride dissolved) was transferred into a flask equipped with a calcium chloride drying tube, and 65 g (0.445 mol) of 1,3-acetone dicarboxylic acid was added. The water bath was heated to 36 ° C, and after reacting for 3.5 hours, cooled to room temperature .First add 776 mL of water, separate the ester layer, and then add 689 mL of dichloromethane to take the organic phase. The aqueous phase was back-extracted with 242 mL of dichloromethane. After the organic phases were combined, the organic phase was washed with an aqueous sodium bicarbonate solution to pH = 7.0, and then washed twice with saturated brine, and dried over anhydrous magnesium sulfate. Concentrated at atmospheric pressure and vacuum rectified to obtain the product.
Example Fl: 2-(3-(l-(5-Ethylpyrimidin-2-yl)piperidin-4-yl)propoxy)-6- (methylsulfonyl)-5,6,7,8-tetrahydro- 1 ,6-naphthyridine.; Step A: To a solution of dimethyl 3-oxopentanedioate (4.8 g, 28.8 mmol) in water (5 rnL) is added saturated aqueous sodium carbonate until the pH is adjusted to 8-9. Then the mixture is cooled to 0C with an ice-bath. After addition of a solution of propiolamide (1.5 g, 21.7 mmol) in water (2 mL) the resulting mixture is stirred at 0C for 20 h. It is then extracted with CHCl3 (3 x 50 mL). The extracts are combined, washed with brine and dried over Na2SO4. Concentration and re-crystallization of the crude product from MeOH gave methyl 2-(2-methoxy-2-oxoethyl)-6-oxo-l,6- dihydropyridine-3-carboxylate 35. MS calculated for [M+H]+ C10H12NO5, 226.1; found: 226.1.
Example 1 Synthesis of 2,4-dichloro-5-nitro-pyridine Dimethyl-1,3-acetonedicarboxylate (50.0 g, 287 mmol), triethylorthoformate (47.8 mL, 287 mmole), and acetic anhydride (54.2 mL, 102 mmol) were combined and heated to 130 C. for 1.5 h then allowed to cool to 25 C. The volatiles were removed in vacuo while maintaining the water bath around 85 C. until the volume of the reaction was reduced to about 25 mL. This crude liquid was poured into a 2000 mL flask and cooled in an ice bath. To this cooled flask was added 75 mL of concentrated aqueous NH3 in portions with swirling. After 1 hour the mixture was acidified by the addition of 6 N HCl (~250 mL). The yellow precipitate was collected by vacuum filtration and allowed to dry under a stream of air. The crude powder was boiled in 200 mL of benzene and allowed to cool and filtered to provide 4,6-dihydroxy-nicotinic acid methyl ester as an orange solid (25.7 g, 53%).
7 Methyl 8-hydroxy-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylate (7a)
Methyl 8-hydroxy-6-oxo-2,3,4,6-tetrahydro-1H-quinolizine-9-carboxylate (7a) Dimethyl-1,3-acetonedicarboxylate (8.1 g, 46.6 mmol) was added to a mixture of triethylamine (0.26 mL, 1.86 mmol) and o-methylvalerolactin (4.8 g, 42.4 mmol) and the reaction was stirred at room temperature for 48 h. The solution was concentrated in vacuo and the resulting crystals were filtered and washed with diethyl ether to give 5.35 g (52%) of compound 7a as a white solid. 1H NMR (400 MHz,DMSO-d6): δ 10.89 (s, 1H), 5.59 (s, 1H), 3.80 (t, 2H, J=6.2 Hz), 3.75 (s, 3H), 2.74 (t, 2H, J=6.7 Hz), 2.45-2.57 (m, 2H), 1.65-1.69 (m, 2H). MS (ES) [m+H] calc'd for C11H13NO4 224; found 224.
490 kg (370 1) of anhydrous methylene chloride are added to 1320 kg (753 1) of chlorosulphonic acid (the ratio of methylene chloride to chlorosulphonic acid is 0.5 : 1 by volume). The temperature of the mixture is adjusted to 10-15 oC, and 665.0 kg of citric acid monohydrate are added to it at a rate of 1.25 kg/minute, while the temperature of the reaction mixture is kept between 10 oC and 15 oC. When the addition has been completed the reaction mixture is stirred at a temperature between 10 oC and 15 oC until no more gas is liberated (at least 6 hours). The reaction mixture is then cooled to 3-5 oC and 640 kg (800 1) of anhydrous methanol are added to it at such a rate that the inner temperature does not exceed 25 oC. The reaction mixture is then warmed to 30-35 oC and stirred at the same temperature for 2 hours. The esterifying reaction is completed under this period. The reaction mixture is cooled to 10- 12 oC and 1300 1 of water are added to it at such a rate that the temperature does not exceed 15 oC. To the mixture 800 ml of methylene chloride are added and it is stirred for 15 minutes. The two-phase mixture is clarified for 30 minutes and the organic phase is separated. The aqueous layer is extracted three times with 400 ml each of methylene chloride. The organic phases are combined and washed first with 1000 1 of water, then with a solution of 75 kg of sodium hydrocarbonate in 1000 1 of water. The pH of the solution is adjusted to a value of about 7 by the addition of sodium hydrocarbonate. The organic phase is separated, washed twice with 750 ml each of water and evaporated in vacuo. Evaporation is carried out under a pressure of 3-5 kPa until the inner temperature rises at most to 75 oC. Thus 535 kg of dimethyl 3- OXOGLUTARATE are obtained, which can be used for the further reaction steps without purification. Qualification by gas chromatography: Purity by gas chromatography: Apparatus: gas chromatograph of HP-6850 type Method: Column : HP-1.25 m x 0. 32 MM, 0.17 URN of film thickness Carrier gas: hydrogen Program: 80 oC-5 MINUTES-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxoglutarate 5.77 minutes Enol ether 8.15 minutes Trimethyl aconitate 10. 00 minutes Trimethyl citrate 10. 42 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Result: Methyl acetoacetate: 0.31% Dimethyl 3-oxoglutarate: 98.33% Enol ether: 0. 81% Trimethyl aconitate: 0. 28% Trimethyl citrate : 0. 09% Isoftalic acid derivative :- Other contamination (higher than 0,2 %) Example 2 Into a mixture of 100.0 g (58 ml) of chlorosulphonic acid and 30 ml of methylene chloride 50.0 g of citric acid monohydrate are added within 30 minutes at a temperature between 10 oC and 15 oC. The mixture is stirred at the same temperature for 5 hours, cooled to 3-5 oC and 60 ml of methanol are introduced to it within 15 minutes at such a rate that the temperature does not exceed 25 oC. It is then stirred for 2 hours at a temperature between 30 oC and 35 oC, cooled to 15 oC and 100 ml of water are added to it within 15 minutes. The thus-obtained mixture is extracted three times with 50 ml each of methylene chloride; the organic phases are combined, washed successively with 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of water and evaporated in vacuo. Thus 40.8 g of dimethyl 3- OXOGLUTARATE are obtained. Yield: 98. 5 % Apparatus : gas chromatograph of HP-6850 type Method : Column: HP-1.25 m x 0.32 mm, film thickness of 0. 17 Am Carrier gas: hydrogen Program: 80 oC-5 minutes-10 oC/MINUTE-200 oC-8 minutes Detector: FID 280 oC Injector: 200 oC. Expected retention times: Methyl acetoacetate 1.18 minutes Dimethyl 3-oxo- glutarate 5. 77 minutes Enol ether 8.15 minutes Trimethyl citrate 10.42 minutes Trimethyl aconitate 10.11 minutes Isoftalic acid derivative 18.76 minutes Evaluation: by area normalization Evaluation by gas chromatography (the method was carried out using the parameters specified in Example 1) : Result: Methyl acetoacetate: 0. 49% Dimethyl 3-OXOGLUTARATE : 97. 62% Enol ether: 0.98% Trimethyl citrate: 0. 13% Trimethyl aconitate: 0.29% Isoftalic acid derivative: 0.07% Other contamination (more than 0.2 %) Example 3 (comparative example) Example 1 of the Belgian patent specification No. 879,537 A mixture of 212 ml of chlorosulphonic acid and 600 ml of methylene chloride is prepared (the ratio of methylene chloride to chlorosulphonic acid is 2.83 : 1 by volume). Then 200.0 g of citric acid are added to this mixture within 15-20 minutes, the addition rate of citric acid is 13.3 kg/minute, temperature = 20-22 oC. The reaction mixture is stirred at this temperature for 5 hours, cooled to a temperature between 3"C AND 5 C and 320 ml of methanol are added to it within 15 minutes at such a rate that the temperature remain below 25 oC. The reaction mixture is then stirred for 2 hours at a temperature between 30...
With N-ethyl-N,N-diisopropylamine; In toluene; for 18h;Reflux;
Example 1: Formation of 2-benzyl-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione (1)(Compound Ia, Scheme 1); [Show Image] a) methyl (1-benzyl-5-hydroxy-1H-pyrazol-3-yl)acetate (Compound of Formula (IV), Scheme 1).; To a suspension of benzylamine dihydrochloride (1.000 g, 5.126 mmol, 1 equiv.) in anhydrous toluene (25 ml) were added successively diisopropylethylamine (1.32 ml, 10.252 mmol, 2 equiv) and dimethyl 3-oxopentanedioate (0.893 g, 5.126 mmol, 1 equiv.). The resulting mixture was heated at reflux for 18h before being concentrated in vacuo. The resulting brown oil was purified by flash chromatography over SiO2 (CH2Cl2:MeOH, 97:3). 0.810 g of pure methyl (1-benzyl-5-hydroxy-1H-pyrazol-3-yl)acetate was obtained as a white solid. Yield 64%. MS(ESI+): 247.1; MS(ESI-): 245.1.
Into a 500 mL round-bottomed flask were added acetondimethylacetate (6.97 g, 40 mmol), acetic anhydride (7.55 ml, 80 mmol), and trimethylorthformate (4.24 g, 40 mmol). The resulted reaction mixture was stirred and heated at 120 0C for two hours, and then was cooled down to room temperature. After removing all volatile material in-vacuo, the residue was dissolved with THF (100 mL), [(4-bromo-2-fluorophenyl)methyl] amine (8.16 g, 40 mmol) was added slowly. The reaction mixture was stirred at room temperature overnight. Sodium hydride (1.92 g, 80 mmol) was added portionwise. The reaction was stirred at room temperature for 30 minutes. LCMS showed that the reaction was complete. The reaction mixture was concentrated, cooled down to 0 0C, and added ethyl acetate (100 mL) and 30 ml of 10percent HCl solution (to adjuste pH of aqueous layer around 2). Two layers were separated, and aqueous layer was extracted with ethyl acetate (75mL x 2). Combined organic layers were dried and concentrated to yield desired product (1.2 g, 8 percent), which was used for next step without further purification.
Stage #1: 3-oxopentanedioic acid dimethyl ester; trimethyl orthoformate With acetic anhydride at 120℃; for 2h;
Stage #2: 2-fluoro-4-(trifluoromethyl)benzylamine In tetrahydrofuran at 20℃;
Stage #3: With sodium hydride In tetrahydrofuran at 20℃;
123.123a
Into a 250 mL round-bottomed flask were added acetondimethylacetate (1.74 g, 10 mmol), acetic anhydride (1.9 ml, 20 mmol), and trimethylorthformate (1.06 g, 10 mmol). The resulted reaction mixture was stirred and heated at 120 0C for two hours, and cooled down to room temperature. After removing all volatile material in-vacuo, the residue was dissolved with THF (100 mL). [2-fluoro-4- (trifluoromethyl)phenyl]methyl} amine (1.93 g, 10 mmol) was added slowly. The resulted reaction mixture was stirred at room temperature overnight. Sodium hydride (0.48 g, 20 mmol) was added portionwise. Reaction mixture was stirred at room temperature for 30 minutes. LCMS showed that the reaction was complete. Solvent was removed. The reaction mixture was cooled down to 0 0C, and added ethyl acetate (100 mL) and 30 ml of 10% HCl (to adjust pH of aqueous layer around 2). Two layers were separated, and the aqueous layer was extracted with ethyl acetate (75 mL x2). Combined organic layers were dried and solvent was removed. Crude product (1.55 g) was obtained and used without further purification.
With tetrabutylammomium bromide; sodium hydrogencarbonate; In dichloromethane; water; at 40℃; for 16h;Inert atmosphere;
General procedure (b), reaction with methyl acetonedicarboxylate (6): A solution of 1,2-bis-bromomethylaryle 5a-e,h (10 mmol) and 6 (1.7 ml, 12 mmol, 1.2 equiv) in CH2Cl2 (25-40 mL) was added dropwise to a solution of NBu4Br (2.0 g, 6 mmol, 0.6 equiv) in 1 N aqueous NaHCO3 (50-80 mL) and CH2Cl2 (25-40 mL). The biphasic mixture was vigorously stirred at 40 C under Argon for 6 h to overnight. The layers were separated, the aqueous layer was extracted with CH2Cl2 (2 × 50 mL) and the combined organic solutions were evaporated. The residue was dissolved in AcOEt and washed with brine (3 × 50 mL), dried over MgSO4 and evaporated to give a yellowish resin which was used without further purification (quantitative).
With tetrabutylammomium bromide; sodium hydrogencarbonate; In dichloromethane; water; at 40℃; for 6h;Inert atmosphere;
General procedure (b), reaction with methyl acetonedicarboxylate (6): A solution of 1,2-bis-bromomethylaryle 5a-e,h (10 mmol) and 6 (1.7 ml, 12 mmol, 1.2 equiv) in CH2Cl2 (25-40 mL) was added dropwise to a solution of NBu4Br (2.0 g, 6 mmol, 0.6 equiv) in 1 N aqueous NaHCO3 (50-80 mL) and CH2Cl2 (25-40 mL). The biphasic mixture was vigorously stirred at 40 C under Argon for 6 h to overnight. The layers were separated, the aqueous layer was extracted with CH2Cl2 (2 × 50 mL) and the combined organic solutions were evaporated. The residue was dissolved in AcOEt and washed with brine (3 × 50 mL), dried over MgSO4 and evaporated to give a yellowish resin which was used without further purification (quantitative).
With lithium bromide; In 1,4-dioxane; for 20.0h;Reflux;
A solution of dimethyl acetone-1,3-dicarboxylate (7) (51.4 g, 0.296 mol) in 1,4-dioxane (75 mL) and then LiBr (28.2 g, 0.325 mol) were added to a stirred suspension of 2,5-dihydroxy-1,4-dithiane (30.0 g, 0.197 mol) in 1,4-dioxane (300 mL). The mixture was stirred at reflux for 20 h. The mixture was filtered into a separating funnel and extracted with ethyl acetate (500 mL) and water (70 mL). The water layer was re-extracted with ethyl acetate (2×250 mL) and the combined organic layers were washed with aq HCl (500 mL, 1 M), aq NaHCO3 (5%), aq NaOH (500 mL, %10) and then with brine (500 mL). The solution was dried over MgSO4 and the solvent was evaporated. The crude product was purified by column chromatography (350 g) eluting with hexane/ethyl acetate (7:2) and then (5:2) to give monoester 10 as the first fraction. The desired diester 9 was isolated as the second fraction.
3-Oxo-pentanedioic acid dimethyl ester (100 g, 575 mmol), (EtO)3CH (95 mL, 575 mmol), Ac2O (108 mL) and HOAc (108 mL) were mixed and heated at 120 C. for 1.5 hours, then allowed to cool to 25 C. The volatiles were removed under reduced pressure while maintaining the water bath around 85 C. To the crude liquid was added aqueous NH3 (25%, 150 mL) in portions with swirling in an ice bath and the stirring was continued for 1 hour. The mixture was acidified by the addition of 6 N HCl. The yellow precipitate was collected by filtration, boiled in toluene, cooled and filtered to give 4,6-dihydroxy-nicotinic acid methyl ester as an orange solid. (Yield 65 g, 67%). 1H NMR (300 MHz, d6-DMSO): delta 8.06 (s, 1H), 5.65 (s, 1H), 3.83 (s, 3H). LC-MS: [M+H]+ 170.
55%
A (460.0 g, 2.64 mol) and triethyl orthoformate (586.5 g, 3.96 mol) were dissolved in 690 mL of acetic anhydride,After stirring at 150 C for 4 hours,The reaction mixture was volume-concentrated to 600 mL at 100 C.Slowly add 920 mL of NH3 · H2O with stirring, and after 1 hour,The reaction mixture was acidified with 2.3 L of 5 mol / L HCl.The precipitate was collected by filtration and dried to give 243.0 g of product B in 55% yield.
46%
A solution containing dimethyl-1, 3-acetonedicarboxylate (2000 g, 11.5 mol), ethyl orthoformate (1947 mL, 11.5 mol), and acetic anhydride (2168 mL, 23.0 mol) was heated at 130 C for 2 h. The reaction was allowed to be cooled to room temperature then concentrated in vacuo to 1500 mL. The crude reaction was cooled in ice bath and aqueous ammonia (2 L) was added in portions with stirring. After 30 min, the mixture was acidified with concentrated HC1 (-300 mL) and the suspension was filtered. The crude product was dried under vacuum to give methyl 4,6- dihydroxynicotinate (900 g, 46%) which was taken on directly into the next step.
Preparation of methyl 4,6-dihydroxypyridine-3-carboxylateA mixture of dimethyl 3-oxopentanedioate (5.0 g, 28.735 mmol), tri ethyl ortho formate (4.25 g, 28.71 mmol) and acetic anhydride was stirred at 130C for 2 h. The reaction mass was allowed to cool at RT. Excess of solvent was removed under vaccum at 85C. The obtained compound was cooled at 0C and liquid ammonia (10 mL) was added. The reaction mass was stirred at 0C for 1 h. The reaction mass was acidified with 6 N HC1 and again stirred at RT for 20 mins. The obtained crude product was stirred in benzene at 60C. The reaction mass was filtered to afford 2.5 g of desired product. .HNMR (DMSO- d6): delta 1.78 (s, 3H), 5.20 (s, 1H), 5.85 (br hump, 2H), 7.81 (s, 1H); [M+H]+ : 170.14.
To a solution of starting compound C (2-methoxy phenyl hydrazine hydrochloride, Aldrich) (350 g, 1 eq.) in MeOH (2 L) was al-3-yl]dded 3-oxo-pentanedioic acid dimethyl ester (Aldrich) (1.2 eq.) under N2, this solution was been refluxing for 1h, TLC showed there was no STM. The solvent was removed by evaporation and the residue was purified by silica column (DCM/MeOH 200:1?50:1) to give desired intermediate D as white solid. (360 g, yield 68%).
With acetic acid; In water; at 200℃; for 0.05h;Microwave irradiation;
General procedure: Acetonedicarboxylate (1.5mmol), 1,2-aryldiamine 1 (1.0mmol), water (5mL) and two drops of acetic acid were mixed thoroughly and were irradiated in a Biotage Initiator 2.0 microwave oven at 200C for 3min. The crude product was filtered by Gooch funnel, washed on the funnel with diethyl ether and recrystallized from ethanol.
With acetic acid In water at 200℃; for 0.05h; Microwave irradiation;
5.2.1 General procedure for the synthesis of 2-methoxycarbonylmethylene-4-oxo-1,5-benzodiazepines 3 under microwave irradiation
General procedure: Acetonedicarboxylate (1.5mmol), 1,2-aryldiamine 1 (1.0mmol), water (5mL) and two drops of acetic acid were mixed thoroughly and were irradiated in a Biotage Initiator 2.0 microwave oven at 200°C for 3min. The crude product was filtered by Gooch funnel, washed on the funnel with diethyl ether and recrystallized from ethanol.
Example 63 2-(4-hydroxy-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one A mixture of dimethyl acetone-1,3-dicarboxylate (200 g, 1.15 mol), cyanamide (48.3 g, 1.15 mol), and Ni(acac)2 (14.75 g, 0.0574 mol) in dioxane (200 mL) was heated to reflux for 16 h and then cooled to room temperature. The precipitate was filtered off, and the solid was mixed with methanol (200 mL) and stirred for 30 min and filtered again to give 93 g product (44% yield). In a 1 L flask with a reflux condenser was added the product from step one (93.0 g, 0.505 mol) and POCl3 (425 mL) and the reaction mixture was heated to reflux for 35 min. POCl3 (300 mL) was evaporated under vacuum. The residue was poured into ice and water (400 mL), which was neutralized with KOH to pH 6-7. The precipitate was filtered off and extracted with ethyl acetate (2*300 mL). The organic solution was concentrated and purified by column chromatography to give methyl 2-amino-4,6-dichloropyridine-3-carboxylate (22.5 g, 20.1%).
methyl 3-(7-methoxy-2-oxo-2H-chromen-3-yl)-3-oxopropanoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
With piperidine In ethanol at 20℃; for 24h;
General procedure for the synthesis of compounds 3aa-3ca
General procedure: To a stirred solution of the appropriate β-ketoester 2 (10 mmol) and the corresponding salicylaldehyde 1 (10 mmol) in EtOH was added piperidine (2.5 mmol) dropwise. The mixture was stirred at room temperature for 24 h, and after completion of the reaction (monitored by TLC), the precipitate was filtered and washed with cold EtOH to afford the desired compound.
With piperidine In ethanol at 25℃;
4.2 General procedure for the β-dicarbonyl compounds (3a-c)
General procedure: To a stirred solution of 2,4-dihydroxy benzaldehyde 1a or 4-methoxy-2-hydroxy benzaldehyde 1b or 4-(diethylamino) salicylaldehyde 1c (3 mmol) and dimethyl 3-oxopentanedioate 2 (3 mmol) in 10 mL EtOH, piperidine (0.77 mmol) was added dropwise. The reaction was stirred at room temperature for 15 min - 6 h. The precipitate formed was filtrated out and washed with cold EtOH.
methyl 2-[3-methyl-1-(4-chlorophenyl)-6(1H)-oxopyrano[2,3-c]pyrazole-4-yl]acetate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
82%
Stage #1: ethyl acetoacetate; N-4-chlorophenylhydrazine In ethanol at 80℃; Green chemistry;
Stage #2: 3-oxopentanedioic acid dimethyl ester With urea In ethanol at 80℃; for 5h; Green chemistry;
4.3 General procedure for the three-component one-pot synthesis of multi-substituted 6(1H)-oxo-pyrano[2,3-c]pyrazole derivatives (6a-6d)
Ethyl acetoacetate (1, 0.5 mmol), substituted hydrazine (2, 0.5 mmol), and 80 % EtOH (10 mL) were stirred at 80 °C for 5-10 min. 3-Oxo-pentanedioic acid dimethyl ester (3, 0.5 mmol) and urea (20 mol %) were added to the reaction mixture, which was heated at the same temperature for 4-5 h. After the reaction was complete (monitored by TLC), the mixture was cooled to room temperature. The mixture was allowed to stand and large amounts of precipitate formed. The precipitate was filtered and washed thoroughly with 70 % EtOH. The crude product was recrystallized from 95 % EtOH. Characterization data for compounds 6 are given below.
85 Synthesis of compound 85.1
Example 85. Synthesis of 3-fluoro-2-(4-(3-(4-hydroxy-2,6-dimethylpiperidin-l- yl)- lH-pyrazol- l-yl)-5-oxo-6,7-dihydro-5H-pyrrolo [3,4-b] pyridin-2-yl)benzonitrile, 1-85 Synthesis of compound 85.1. To a solution of 1.1 (2.5g, 14.3mmol, l.Oeq) in DCM (lOmL) was added dimethyl 3-oxopentanedioate (5 g, 28mmol, 2eq) and acetaldehyde (1.6mL, 36.0mmol, 2. leq) at -30 °C. Reaction mixture was stirred at room temperature for 16 h. Upon completion of reaction; concentrated under reduced pressure to obtained crude material. This was purified by column chromatography and the compound was eluted in 5% ethyl acetate in hexane to get pure 85.1. (0.9 g, 15.6 %). MS(ES): m/z 400.35 [M+H]+.
dimethyl 2-(2-bromoprop-2-en-1-yl)-3-oxopentanedioate[ No CAS ]
[ 95314-71-9 ]
Yield
Reaction Conditions
Operation in experiment
1: 31%
2: 14%
With potassium carbonate In dimethyl sulfoxide at 20 - 70℃; for 8h;
Alkylation of dimethyl 3-oxopentanedioate (1) (general procedure).
General procedure: 1,2-Dibromoethane or 1,2,3-tribromopropane, 0.05 mol, was added with stirring to a mixture of 0.05 mol of diester 1 and 0.05 mol of calcined potassium carbonate in 100 mL of DMSO. The mixture was stirred for 3 h at 20 °C and for 5 h at 70 °C, cooled, and treated with water and diethyl ether (3 × 100 mL). The combined extracts were dried over anhydrous MgSO4, the solvent was distilled off, and the residue was distilled under reduced pressure
Equimolar amounts of 1,3,5 <strong>[290-87-9]triazine</strong> (3.15 g, 38.5 mmol) and dimethyl-1,3-acetonedicarboxylate(6.70 g, 38.5 mmol) were slowly added under magnetic stirring and at roomtemperature to a freshly prepared sodium ethoxide solution in anhydrous ethanol. Thesolution was always maintained under magnetic stirring and nitrogen gas flow. During the addition, the solution became yellow and a white precipitate was formed. After theaddition, the solution was allowed to react under reflux for 2 h. The resulting orangesolution, after cooling, was slowly acidified to ca. pH = 4 with HCl solution
methyl 6,7-difluoro-2,4-dihydroxy-1-naphthoate[ No CAS ]
methyl 6,7-difluoro-1,3-dihydroxy-2-naphthoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
1: 10%
2: 51%
With cesium fluoride In tetrahydrofuran at 100℃; for 12h; Sealed tube; Inert atmosphere; regioselective reaction;
4.3 Representative general procedure for the preparation of naphthoresorcinols
General procedure: (Note: All the reagents and solvents were added in an Ace pressure tube inside the glove box and it was sealed with cap before heating). An oven dried 15mL Ace pressure tube (Sigma-Aldrich) was charged with aryne precursor silyl aryl triflate 1a (0.33mmol) and Dimethyl-1,3-acetonedicarboxylate 2a (0.3mmol) to which anhydrous THF (5mL) and CsF (0.6mmol) were added the tube was sealed with the cap and was placed in a pre-heated oil bath at 100°C and was stirred for 12h. The reaction mixture was cooled to room temperature and filtered through celite with the aid of EtOAc, volatile components were removed under reduced pressure using rotary evaporator and the resulted crude compound was purified by silica gel flash column chromatography to afford the substituted naphthoresorcinols 3a-e, 4a-e and 16, 17.
methyl 7-(2-methoxy-2-oxoethyl)-2-phenyl[1,2,4]-triazolo[1,5-a]pyrimidine-6-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
58%
In acetonitrile; for 6h;Reflux;
General procedure: A mixture of the corresponding aminotriazole 1a-d (1.5 mmol), β-ketoglutaric acid dimethyl ester (2) (313 mg, 1.8 mmol), DMADMF (3) (214 mg, 1.8 mmol) in MeCN (3 ml) was heated under reflux for 6 h. After the completion of the reaction (TLC control), the solvent was removed under reduced pressure, i-PrOH (6 ml) was added to the residue, the precipitate was filtered off and washed with i-PrOH.
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