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Structure of 22115-41-9 * Storage: {[proInfo.prStorage]}
* 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 N-Bromosuccinimide In tetrachloromethane at 90℃; for 2 h;
Azobisisobutyronitrile (AIBN, 29.25 mmol) is added to a solution of 2- methylbenzonitrile (325 mmol) and λ/-bromosuccinimide (NBS, 346 mmol) in carbontetrachloride (300 ml_). The reaction mixture is heated at 90 0C for 2 h and is allowed to cool to rt. The precipitated solids are removed by filtration and the filtrate is washed with saturated aqueous sodium bicarbonate (4 x 120 ml_), dried (sodium sulfate), and concentrated. The resulting solid is washed with hexane (4 x 500 ml_) and dried to provide 2-(bromomethyl)benzonitrile in 57percent yield as a yellow solid. A solution of 2-(bromomethyl)benzonitrile (214 mmol) in dimethylsulfoxide (40 ml_) is added over 90 min to a solution of ethyl 2-hydroxyacetate (431 mmol) and sodium ethoxide (215 mmol) in dimethylsulfoxide (14.5 ml_). The reaction mixture is maintained at rt for 1 h, is heated at 65 0C for 5 h, and is allowed to cool to rt. The reaction mixture is diluted with ice water (50 g) and extracted with ether (3 x 500 ml_) and the combined organic layers are dried (sodium sulfate), and concentrated. The residue is purified by chromatography (100/1 to 50/1 petroleum ether/ethyl acetate) to provide ethyl [(2- cyanobenzyl)oxy]acetate as a yellow oil.
57%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile) In tetrachloromethane for 5 h; Reflux
The synthesis procedure of (E)-2-(2-(1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)vinyl)benzonitrile (PY-oCN) was performed by the following steps (Fig. 3). At first 2-(bromomethyl)benzonitrile was synthesized also as an intermediate for the next pyrazoline derivative (PY-oCNCN). First 2-methylbenzonitrile (25 g, 0.21 mol) was dissolved in 150 cm3 of CCl4. Equimolar amount of NBS and 0.3 g of AIBN were added. The reaction mixture was refluxed for 5 h and after cooling to 40 °C it was filtered and the solvent was evaporated. The residue was chromatographed on silica gel with DCM as eluent. Only the first fraction was collected. The yield of reaction was 25 g (57 percent). According to the following procedure final compound – (E)-2-(2-(1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)vinyl)benzonitrile was obtained. The 2-(bromomethyl)benzonitrile from the first step of synthesis described above (0.4 g, 2 mmol) and triphenylphosphine (0.524 g, 2 mmol) were dissolved and boiled in dry benzene overnight. The resulting salt was filtered, washed with hot benzene and used without further purification. To the suspension of phosphonium salt in dry THF (25 cm3), under inert atmosphere at room temperature, sodium ethanolate (0.108 g, 2 mmol) was added. The color of the mixture became deep red and after that the solution was stirred for another 30min. After that time the solution of 1-phenyl-4,5-dihydro-1H-pyrazole-3-carbaldehyde (0.348 g, 2 mmol) in dry THF (10 cm3) was added drop wise and was stirred overnight at 50 °C. Next the solvent was evaporated and DCM was added to the orange residue until it became homogenous. The product was purified on silica gel with DCM as eluent. It was crystallized from heptane with yield of reaction 0.325 g (59.5 percent). To obtain – (E)-2-(1-cyano-2-(1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)vinyl)benzonitrile, which is a derivative of PY-oCN, it was necessary to synthesize another intermediate. The 2-(bromomethyl)benzonitrile (5 g, 25.5 mmol), which was obtained before, was dissolved in a mixture of ethanol (50 cm3) and water (10 cm3). Potassium cyanide (2.6 g, 40 mmol) was added to this solution. Then it was refluxed for 1.5 h and subsequently poured onto ice. Deep green-blue solution was extracted with DCM. The extract was dried with MgSO4 and passed on alumina (neutral) in DCM to give yellowish solution. The eluent was evaporated and the residue crystallized from methanol. The yield of the intermediate was 1.2 g (33 percent). The last step of (E)-2-(1-cyano-2-(1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)vinyl)benzonitrilesynthesis was as follows (cf. Fig. 3). Anhydrous sodium acetate was added (0.05 g) to the solution of 2-(cyanomethyl)benzonitrile (0.4 g, 2.8 mmol) and 1-phenyl-4,5-dihydro-1H-pyrazole-3-carbaldehyde (0.490 g, 2.8 mmol), in dry ethanol. Then it was stirred and refluxed overnight. The solvent was evaporated and oily residue was chromatographed on silica gel with DCM as eluent. After evaporation of DCM the oil was dissolved in boiling heptane. After cooling below 0 °C the orange solid precipitated from the solution and then it was filtered. The yield of this synthesis was 0.216 g (efficiency: 26 percent).
Reference：
[1] Organic Process Research and Development, 1998, vol. 2, # 4, p. 261 - 269
[2] Chemistry - A European Journal, 2002, vol. 8, # 9, p. 2000 - 2004
[3] Journal of Organic Chemistry, 2014, vol. 79, # 23, p. 11592 - 11608
[4] Patent: WO2009/55437, 2009, A2, . Location in patent: Page/Page column 61; 62
[5] Dyes and Pigments, 2014, vol. 102, p. 63 - 70
[6] Journal of the American Chemical Society, 1926, vol. 48, p. 834
[7] Chemische Berichte, 1891, vol. 24, p. 2572
[8] Israel Journal of Chemistry, 1971, vol. 9, p. 111 - 118
[9] Journal of the Indian Chemical Society, 1990, vol. 67, # 11, p. 909 - 911
[10] Journal of Medicinal Chemistry, 1989, vol. 32, # 4, p. 811 - 826
[11] Bulletin of the Chemical Society of Japan, 1994, vol. 67, # 6, p. 1769 - 1772
[12] Journal of Medicinal Chemistry, 2006, vol. 49, # 16, p. 4896 - 4911
[13] Beilstein Journal of Organic Chemistry, 2011, vol. 7, p. 1663 - 1670
[14] Chemical Communications, 2014, vol. 50, # 69, p. 9865 - 9868
Reference：
[1] Chemische Berichte, 1891, vol. 24, p. 2572
[2] Chemische Berichte, 1891, vol. 24, p. 2572
8
[ 529-19-1 ]
[ 655-63-0 ]
[ 22115-41-9 ]
Reference：
[1] Journal of the American Chemical Society, 1926, vol. 48, p. 834
9
[ 529-19-1 ]
[ 7726-95-6 ]
[ 22115-41-9 ]
Reference：
[1] Chemische Berichte, 1891, vol. 24, p. 2572
10
[ 22115-41-9 ]
[ 3759-28-2 ]
Yield
Reaction Conditions
Operation in experiment
33%
for 1.5 h; Reflux
The synthesis procedure of (E)-2-(2-(1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)vinyl)benzonitrile (PY-oCN) was performed by the following steps (Fig. 3). At first 2-(bromomethyl)benzonitrile was synthesized also as an intermediate for the next pyrazoline derivative (PY-oCNCN). First 2-methylbenzonitrile (25 g, 0.21 mol) was dissolved in 150 cm3 of CCl4. Equimolar amount of NBS and 0.3 g of AIBN were added. The reaction mixture was refluxed for 5 h and after cooling to 40 °C it was filtered and the solvent was evaporated. The residue was chromatographed on silica gel with DCM as eluent. Only the first fraction was collected. The yield of reaction was 25 g (57 percent). According to the following procedure final compound – (E)-2-(2-(1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)vinyl)benzonitrile was obtained. The 2-(bromomethyl)benzonitrile from the first step of synthesis described above (0.4 g, 2 mmol) and triphenylphosphine (0.524 g, 2 mmol) were dissolved and boiled in dry benzene overnight. The resulting salt was filtered, washed with hot benzene and used without further purification. To the suspension of phosphonium salt in dry THF (25 cm3), under inert atmosphere at room temperature, sodium ethanolate (0.108 g, 2 mmol) was added. The color of the mixture became deep red and after that the solution was stirred for another 30min. After that time the solution of 1-phenyl-4,5-dihydro-1H-pyrazole-3-carbaldehyde (0.348 g, 2 mmol) in dry THF (10 cm3) was added drop wise and was stirred overnight at 50 °C. Next the solvent was evaporated and DCM was added to the orange residue until it became homogenous. The product was purified on silica gel with DCM as eluent. It was crystallized from heptane with yield of reaction 0.325 g (59.5 percent). To obtain – (E)-2-(1-cyano-2-(1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)vinyl)benzonitrile, which is a derivative of PY-oCN, it was necessary to synthesize another intermediate. The 2-(bromomethyl)benzonitrile (5 g, 25.5 mmol), which was obtained before, was dissolved in a mixture of ethanol (50 cm3) and water (10 cm3). Potassium cyanide (2.6 g, 40 mmol) was added to this solution. Then it was refluxed for 1.5 h and subsequently poured onto ice. Deep green-blue solution was extracted with DCM. The extract was dried with MgSO4 and passed on alumina (neutral) in DCM to give yellowish solution. The eluent was evaporated and the residue crystallized from methanol. The yield of the intermediate was 1.2 g (33 percent). The last step of (E)-2-(1-cyano-2-(1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)vinyl)benzonitrilesynthesis was as follows (cf. Fig. 3). Anhydrous sodium acetate was added (0.05 g) to the solution of 2-(cyanomethyl)benzonitrile (0.4 g, 2.8 mmol) and 1-phenyl-4,5-dihydro-1H-pyrazole-3-carbaldehyde (0.490 g, 2.8 mmol), in dry ethanol. Then it was stirred and refluxed overnight. The solvent was evaporated and oily residue was chromatographed on silica gel with DCM as eluent. After evaporation of DCM the oil was dissolved in boiling heptane. After cooling below 0 °C the orange solid precipitated from the solution and then it was filtered. The yield of this synthesis was 0.216 g (efficiency: 26 percent).
Reference：
[1] Dyes and Pigments, 2014, vol. 102, p. 63 - 70
11
[ 143-33-9 ]
[ 22115-41-9 ]
[ 3759-28-2 ]
Reference：
[1] Israel Journal of Chemistry, 1971, vol. 9, p. 111 - 118
12
[ 151-50-8 ]
[ 22115-41-9 ]
[ 3759-28-2 ]
Reference：
[1] Journal of the Chemical Society, 1955, p. 2214,2216
13
[ 22115-41-9 ]
[ 89942-45-0 ]
Reference：
[1] Chemical Communications, 2014, vol. 50, # 69, p. 9865 - 9868
14
[ 64-19-7 ]
[ 22115-41-9 ]
[ 38866-59-0 ]
Reference：
[1] Chemical Communications, 2014, vol. 50, # 69, p. 9865 - 9868
15
[ 563-63-3 ]
[ 22115-41-9 ]
[ 38866-59-0 ]
Reference：
[1] Bulletin de l'Academie Polonaise des Sciences, Serie des Sciences Chimiques, 1972, vol. 20, p. 411 - 415
Stage #1: With dmap In acetonitrile at 80℃; for 6 h; Green chemistry Stage #2: for 8 h; Reflux; Green chemistry
A solution of 6-chloro-3-methyl uracil (20.0 g, 125 mmol), acetonitrile (200 mL), 2- cyanobenzyl bromide (27.0 g, 138 mmol), N, N- diisopropylethyl Amine (96.8 g, 750 mmol) and warmed to reflux (80 ° C) for 6 hours.(R) -3-Aminopiperidine dihydrochloride (23.6 g, 138 mmol) was added and reflux was continued for 8 hours.After the reaction was completed, the temperature was lowered to 30 ° C, added to 1000 mL of water, and then cooled to 5 ° C and stirred for 4 hours.Filter, filter cake washed twice with water, each 400 mL, pumpingdry. Get alogliptin 31.0 g. Yield 73percent, purity 99.8percent.
Reference：
[1] Patent: CN106366068, 2017, A, . Location in patent: Paragraph 0016; 0017; 0018
18
[ 22115-41-9 ]
[ 850649-61-5 ]
Reference：
[1] Journal of Medicinal Chemistry, 2007, vol. 50, # 10, p. 2297 - 2300
[2] Patent: WO2013/46229, 2013, A1,
[3] European Journal of Medicinal Chemistry, 2014, vol. 83, p. 547 - 560
[4] Patent: WO2015/92807, 2015, A1,
[5] Patent: CN103980249, 2016, B,
[6] Patent: US2016/340333, 2016, A1,
[7] Patent: CN103524483, 2016, B,
[8] Patent: CN104193726, 2016, B,
[9] Patent: CN106608853, 2017, A,
[10] Patent: CN106336396, 2017, A,
[11] Patent: CN107954978, 2018, A,
With N-ethyl-N,N-diisopropylamine In dichloromethane at 40 - 45℃;
20.8 g of dichloromethane, 3.21 g of 6-chloro-3-methyluracil, 4.51 g of 2-cyanobenzyl bromide, and 5.16 g of DIPEA were successively added to the reaction flask with stirring, and the temperature was raised to reflux temperature. (40-45 °C), HPLC sampling was run until 3-methyl-6-chlorouracil disappeared. After completion of the reaction, the reaction system was cooled to 20 ~ 25 °C, dichloromethane was distilled off under reduced pressure, stirred with water after 1h was filtered, the filter cake was rinsed with water after adding ethanol, in the temperature 20 ~ 25 °C, stirred for 1h After filtration, the filter cake is washed with ethanol andfinally dried under reduced pressure at a temperature of 60 to 70 °C to obtain 5.28 g of a white crystalline solid 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)benzonitrile [hereinafter abbreviated as an intermediate], the yield was 95.8percent.
91.4%
With potassium carbonate In N,N-dimethyl-formamide at 100℃; for 12 h;
Methyl-6-chlorouracil And 117.6 g of α-bromo-o-methylbenzonitrile Dissolved in 400ml N, N-dimethylformamide, 103.5 g of potassium carbonate was added, Stirring and heating to 100 ° C, For 12 hours. Cooled to room temperature, filtered, 400 ml of water was added to the filtrate, Extracted three times with 400 ml of ethyl acetate, The organic layers were combined, The organic layer was washed with saturated brine, Dried over anhydrous sodium sulfate, The solvent was recovered to give the crude product, Recrystallization gave 125.9 g of an off-white solid, The yield was 91.4percent HPLC content 98.2percent
90%
With triethylamine In 1-methyl-pyrrolidin-2-one; toluene at 60 - 70℃; Large scale
Was added to the reaction kettle 50L 6-chloro-3-methyluracil 1.62Kg, o-cyanobenzyl bromide 1.98Kg and triethylamine 1.98Kg, N-methylpyrrolidone and toluene (4: 1) mixed solution of 12Kg,the reaction was heated to 60 ~ 70 deg. C. After incubation for 2 to 3 hours, cooled to 20 ~ 25 deg. C, 26.10Kg of purified water was added slowly, followed by stirring at 20 ~ 25 deg. C for 1 hour and filtered to obtain 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile crude product. At 50 ~ 60 deg. C blast drying 20 to 24 hours to give the product 2.52Kg, yield 90percent.
90.2%
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one; toluene at 70℃; for 1.5 h;
10.0 g (62.3 mmol) SM1 at 25°C40 mL of N-methylpyrrolidone, 12.1 g (93.6 mmol) of diisopropylethylamine were sequentially added to a 500 mL three-necked flask, and 40 mL of a toluene solution containing 13.4 g (68.4 mmol) of SM2 dissolved therein was added dropwise to the reaction flask while stirring. After completion of the dropwise addition, the temperature was raised to 70°C and the reaction was carried out for 1.5 hours. The reaction system was cooled to room temperature, 40 mL of water was added thereto, and the mixture was stirred at 25° C. for 30 minutes, cooled to 0° C., stirred for 1 hour, and suction-filtered. The filter cake was rinsed with 10 mL of isopropanol and dried to give 15.5 g of an off-white solid with a yield of 90.2percent.5.5 g (20 mmol, 1 eq) of TM1 was added to 100 mL of tert-butanol, and 50 g of an aqueous solution of 5.0 g (60 mmol, 3 eq) of sodium hydrogencarbonate was added dropwise at room temperature at 25C, and the mixture was stirred at 70C for 12 hours at room temperature.Concentrated hydrochloric acid was added dropwise to the system at 10 °C in a cold water bath, and the pH was adjusted to 5-6. The tert-butyl alcohol was removed by rotary evaporation in a water bath at 40°C. 100 mL of water and 100 mL of dichloromethane were added to separate the mixture. The aqueous phase was extracted with 100 mL of dichloromethane. Three times, the combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation in a 40° C. water bath to obtain a brown-red oil. 20 mL of methylene chloride was added to dissolve the oil, 80 mL of isopropyl ether was added, and frozen at −10° C. to precipitate a solid, which was filtered and blown at 40° C. to dry to obtain 2.7 g of a yellow solid with a content of 99.2percent and a yield of 44percent.
90.1%
With N-ethyl-N,N-diisopropylamine In ethyl acetate at 70 - 75℃; for 4 h; Large scale
In a 200L reactor with mechanical stirring and condenser, add 6-chloro-3-methyluracil (8kg,49.83 mol), 2-cyanobenzyl bromide (10.58 kg, 53.97 mol), ethyl acetate (6.4 kg),Diisopropylethylamine (10.2kg, 78.92mol) is controlled at a temperature of about 70-75°C for 4 hours and cooled to -5°C to 0°C.Stir for 3 hours, suction filtration, rinsing with a small amount of cold ethyl acetate to obtain a wet product, adding 800 g of purified water,The temperature was stirred at about 25°C for 20 minutes, suction filtered, and the wet product was dried at 50°C to obtain 12.38 kg of an off-white solid.Yield: 90.1percent, HPLC purity: 99.91percent.
86%
With tributyl-amine In toluene at 80℃; for 5 h;
(1) At room temperature,6-Chloro-3-methyluracil (160 g, 1 mol),2-cyanobromobenzyl (243 g, 1.24 mol)And tri-n-butylamine (275 g, 1.5 mol)And toluene (800 mL) were successively added to the reaction kettle,Stirred for 10 minutes,Stirring was continued and the temperature was raised to 80 ° C.The reaction was carried out at 80 ° C for 5 h (the progress of the reaction was monitored by HPLC)After completion of the reaction, the reaction was cooled down to 5 ° C or lower, 320 g of purified water was added, and the mixture was stirred at 0 to 5 ° C for 40 minutes. A large amount of solid precipitated and was filtered off.The cake was dried at 80 ± 5 ° C to give a pale yellow solid2- (6-Chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1 (2H) -ylmethyl) -benzonitrile 236.5 g, HPLC purity: 98.5percent, yield: 86percent.
86.7%
With tributyl-amine In acetonitrile for 6 h; Reflux
1000ml three-necked flask by adding acetonitrile 600ml,O-bromomethylbenzonitrile 100.0 g,3-methyl-6-chlorouracil, 81.9 g,Tri-n-butylamine 113.5 g, stirred,The temperature was raised to reflux for 6 hours(TLC monitoring reaction end point,O-bromomethylbenzonitrile spots disappear),Cooling,After removing the solvent by steaming at 40 ° C,Add 500ml of anhydrous ethanol,Reflux stirring dissolved,Cooling to 10 below the crystallization,filter,The filter cake was washed with 100 ml of cyclohexane,And blasted at 60 ° C,Get 121.9g products,Yield 86.7percentHPLC purity 98.97percent.
86.77%
With triethylamine In dimethyl sulfoxide at 50℃; for 1 h;
7.71 g of 2-cyanobenzyl bromide (R1 is H and R2 is Br), 6.00 g of 3-methyl-6-chlorouracil and 4.20 g of triethylamine were dissolved in a mixed solution of 78 ml of DMSO and THF, and the temperature was raised The reaction was stirred at 50 ° C for 1 h, and the reaction was cooled to room temperature. 80 ml of ice water was slowly added dropwise, and the mixture was stirred for 1 h under ice-cooling. The crude product of compound III was 9.15 g. The yield was 88.81percent. The crude compound III was rinsed with ethyl acetate at 25 ° C, filtered, washed and dried to give pure Compound III 8.94. The purification yield was 97.90percent. The total yield of compound was 86.77percent and the purity was 89.70percent.
85%
With tributyl-amine In toluene at 80℃; for 3 h; Green chemistry
6-Chloro-3-methyl uracil 565.5g (3.5mol), 2- bromomethyl-benzonitrile 754.6g (3.85mol), tri-n-butylamine 1240ml (5.25mol) and toluene 3.65L, with inputs to mechanical stirring, 10L glass three-necked flask with a thermometer and a reflux tube.Oil bath was heated to 80 , heat the reaction was stirred 3h.Heating was stopped, the oil bath was removed, the water bath was cooled to room temperature, 1.2 L of water was added, stirring was cooled to ice bath change 0-5 , heat stirred 30min, filtered off with suction, washed with a small amount of solid was scraped into blast oven 50 and dried overnight to give a tan powdery solid 819.7g, a yield of 85.0percent, a purity of 98.04percent.
70%
Stage #1: With lithium bromide In dimethyl sulfoxide; N,N-dimethyl-formamide at 0℃; for 0.333333 h; Inert atmosphere Stage #2: at 20℃; for 1 h;
6-methyl-3-chlorouracil (200 g) was added to a 10 L three-necked flask at 0 ° C under N2 protection and dissolved in DMF / DMS0 (4.5 L, 5/1) LiBr (87 g, 1 mol) was added and stirring continued for 20 min. To which was then added dropwise a solution of o-nitrobenzyl bromide (244 g, 1. 25 mmol). After 1 hour reaction, the reaction was continued to room temperature. TLC was followed until complete reaction of the starting material. The solvent was distilled off under reduced pressure. The residue was subjected to extraction with CH2C12 (1LX 3 times). The organic phase was combined with The solvent was evaporated under reduced pressure to give 380 g of a reddish-brown residue which was refluxed for 1 hour with 3 times the absolute ethanol, cooled to room temperature, filtered and the cake was dried at 50 ° C for 3 hours. (3L), a large amount of solid precipitation, stirring at room temperature for 2h, filtration, 50 degrees for 3 hours drying to get 260. 7 light yellow solid. (2L) Yield: 70percent, m.p. 165-167 ° C).
Reference：
[1] Organic Letters, 2018, vol. 20, # 2, p. 473 - 476
[2] Patent: CN107954978, 2018, A, . Location in patent: Paragraph 0042; 0043; 0051
[3] Patent: CN103819450, 2016, B, . Location in patent: Paragraph 0034; 0038; 0039
[4] Patent: CN105367546, 2016, A, . Location in patent: Paragraph 0013
[5] Patent: CN107556249, 2018, A, . Location in patent: Paragraph 027; 0028
[6] Patent: CN107540656, 2018, A, . Location in patent: Paragraph 0039; 0059; 0060; 0062; 0063; 0064; 0078; 0080
[7] Patent: CN103980249, 2016, B, . Location in patent: Paragraph 0014; 0038-0039
[8] Patent: CN106632242, 2017, A, . Location in patent: Paragraph 0012; 0022
[9] Patent: CN106608853, 2017, A, . Location in patent: Paragraph 0024; 0026; 0031; 0032
[10] Patent: CN104193726, 2016, B, . Location in patent: Paragraph 0053-0055
[11] Patent: CN103524483, 2016, B, . Location in patent: Paragraph 0015-0017
[12] Patent: US2009/275750, 2009, A1, . Location in patent: Page/Page column 23
[13] Patent: EP2682110, 2014, A1, . Location in patent: Paragraph 0109-0112
[14] Patent: WO2015/92807, 2015, A1, . Location in patent: Sheet 8
21
[ 2565-47-1 ]
[ 22115-41-9 ]
[ 865758-96-9 ]
Yield
Reaction Conditions
Operation in experiment
40 g
Stage #1: With <i>N</i>,<i>N</i>-dimethyl-aniline; trichlorophosphate In toluene at 90 - 95℃; for 2 h; Stage #2: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 60 - 65℃;
In a dry flask charged toluene (150 ml), N-methylbarbituric acid (50 gm), phosphorous oxychloride (64.5 gm) and N,N-dimethylaniline (20 ml). Heated the reaction mass to 90°C - 95°C and maintained the reaction at this temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, cooled the reaction mass to 10°C - 15°C and charged methanol (150 ml) in the reaction mass and stirred at this temperature for 1 hour. The reaction mass was allowed to settle and the solvent was removed from the reaction mass. Charged again methanol (50 ml), stirred and separated the solvent from the reaction mixture to get the residual solid mass of the intermediate compound.To the solution of the intermediate compound charged solvent tetrahydrofuran (300 ml), 2-(bromomethyl)benzonitrile (67.3 gm) and dii sopropylethylamine (60.5 gm). Raised the temperature of the reaction mass to 60°C - 65°C and maintained at this temperature for 4 - 5 hours. The reaction progress was monitored by TLC. After the completion of the reaction the solvent was concentrated and to the residual mass charged water (300 ml) and stirred the reaction mass at 25°C - 30°C for 1 hour. Filtered the reaction mass and washed the solid mass with water (50 ml). The filtered wet solid mass was taken in solventisopropyl alcohol (150 ml) and stirred at 25°C - 30°C for 1 hour. Filtered the solid and washed with isopropyl alcohol (50 ml) and dried the compound to get 2-[(6- chloro-3 -methyl-2,4-dioxo-3 ,4-dihydropyrimidin- 1 -(2H)-yl)methyl]benzonitrile.Dry weight = 52 gm.
Reference Example 67 2-(Dimethylaminomethyl)benzonitrile Dimethylamine (7.7 ml) was added to a DMF solution (10 ml) of 2-(bromomethyl)benzonitrile (1.00 g), followed by stirring at room temperature for 10 hours. Water was added to the reaction solution, extracted with dichloromethane and dried over sodium sulfate. The solvent was evaporated, the thus obtained residue was purified by silica gel column chromatography, and the title compound (830 mg) was obtained as a yellowish brown oil from the elude of dichloromethane:methanol = 10:1. 1H-NMR (400 MHz, CDCl3) delta: 2.30 (6H, s), 3.63 (2H, s), 7.36 (1H, dt, J=2.3 and 7.8 Hz), 7.54-7.56 (2H, m), 7.64 (1H, d, J=7.8 Hz). ESI-MS m/z: 161 (M+H)+.
N-(diphenylmethylene)-ortho-cyanophenylalanine ethyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With tetrabutylammonium sulfate; sodium hydroxide; In dichloromethane; water; at 20℃;
2.2 Preparation of ethyl N-(diphenylmethylene)-alpha-(2-cyanophenyl)alaninate Aqueous sodium hydroxide solution NaOH (10% strength, 40 ml) was added to a solution of ethyl N-(diphenylmethylene)glycinate (5 g, 18.7 mmol; from Example 2.1), 2-cyanobenzyl bromide (4.1 g, 20.7 mmol) and tetrabutylammonium sulfate (320 m, 0.9 mmol) in dichloromethane (40 ml), and the mixture was stirred at room temperature overnight. The phases were separated, and the aqueous phase was then extracted with dichloromethane (2 times 50 ml). The organic phases obtained were combined, washed with water until the wash phase remained neutral, dried over MgSO4, filtered and freed from the solvent under reduced pressure. From the residue obtained, ethyl N-(diphenylmethylene)-alpha-(2-cyanophenyl)alaninate was isolated by flash chromatography (SiO2; cyclohexane/ethyl acetate) in a yield of 83%.
83%
With tetrabutylammonium sulfate; sodium hydroxide; In dichloromethane; water; at 20℃;
34.2 N-(Diphenylmethylene)-alpha-(2-cyanophenyl)ethylalaninate Aqueous sodium hydroxide solution NaOH (10% strength, 40 ml) was added to a solution of N-(diphenylmethylene)ethylglycinate (5 g, 18.7 mmol), 2-cyanobenzyl bromide (4.1 g, 20.7 mmol) and tetrabutylammonium sulfate (320 mg, 0.9 mmol) in dichloromethane (40 ml), and the mixture was stirred at room temperature overnight. The phases were separated, and the aqueous phase was then extracted with dichloromethane (2*50 ml). The organic phases obtained were combined, washed with water until the wash phase remained neutral, dried over MgSO4, filtered and freed from the solvent under reduced pressure. N-(Diphenyl-methylene)-alpha-(2-cyanophenyl)ethylalaninate was isolated from the residue obtained by flash chromatography (SiO2; cyclohexane/ethyl acetate) in a yield of 83%.
(1) To a solution of 0.49 g of sodium in 20 ml of ethanol was added dropwise a solution of 5.90 g of diethyl 2-N-t-butoxycarbonylaminomalonate in 10 ml of ethanol with stirring at room temperature. After stirring for 20 minutes, to the reaction solution was added a solution of 4.00 g of 2-cyanobenzyl bromide in 10 ml of ethanol, and the mixture was stirred at room temperature for 10 minutes and then at heating reflux for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the residue, after addition of ethyl acetate, was washed with water, 5% aqueous potassium bisulfate solution, a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography (silica gel; Wakogel C200 (manufactured by Wako Pure Chemicals), developing solvent; hexane-ethyl acetate=5:1) to give 7.86 g of diethyl 2-(2-cyanobenzyl)-2-N-t-butoxycarbonylaminomalonate as an oil.
2-((5,6-dimethylbenzimidazole-2-ylthio)methyl)benzenecarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
99%
With triethylamine; In N-methyl-acetamide; water;
Example 20 Preparation of Compound No. 952 To <strong>[3287-79-4]5,6-dimethylbenzimidazole-2-thiol</strong> (713 mg, 4 mmol) in dimethylformamide (10 ml), triethylamine (836 mul, 6 mmol) and 2-bromomethylbenzonitrile (1176 mg, 6 mmol) were added. After stirring at 80 C. overnight, water was added to the mixture, followed by extraction with ethyl acetate. After the ethyl acetate phase was dried with anhydrous sodium sulfate, it was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain 2-((5,6-dimethylbenzimidazole-2-ylthio)methyl)benzenecarbonitrile (1159 mg, yield 99%).
Stage #1: 2-chloro-6-methoxy-3H-quinazolin-4-one With sodium hydride In 1,2-dimethoxyethane; N,N-dimethyl-formamide at 0℃; for 0.166667h;
Stage #2: With lithium bromide In 1,2-dimethoxyethane; N,N-dimethyl-formamide at 0 - 20℃; for 0.25h;
Stage #3: 2-(bromomethyl)benzonitrile In 1,2-dimethoxyethane; N,N-dimethyl-formamide at 65℃; Further stages.;
Stage #1: 2-(bromomethyl)benzonitrile; D-Prolin With potassium hydroxide In isopropyl alcohol at 40℃; for 6h;
Stage #2: With hydrogenchloride In dichloromethane; isopropyl alcohol at 20℃; for 1h;
1.A
To a solution of (D) -proline (4.9 g, 42.56 mmol) and KOH (7. 16 g, 127.6 mmol) in isopropanol (30 mL) was added 2-cyanobenzylbromide (10 g, 51.0 mmol). The reaction mixture was maintained at 40 C for 6 h. The reaction mixture was allowed to cool to room temperature and the pH was adjusted to 5 with concentrated HC1. Dichloromethane (12 mL) was added and stirring continued for 1 h. The precipitate was filtered and washed with CH2Cl2. The organic layers were combined and concentrated to a yellow gum which was purified by flash chromatography on silica gel eluting with 10% MeOH in CH2C12 to give the title compound (6.8 g, 69%) as a white solid (mp 130-133 C). MS (ES+) m/z 231 [M+H]. 1H NMR (500 MHz, CD30D) 1.90-2. 00 (m, 1H) ; 2.08-2. 18 (m, 2H); 2.42-2. 52 (m, lH) ; 3.20-3. 28 (m, lH) ; 3.54-3. 62 (m, lH) ; 3.92-4. 00 (m, lH); 4.50 (d, lH J=15.0 Hz) ; 4.70 (d, lH, J=15.0 Hz) ; 7.63 (dd, lH, J=10.0, 5.0 Hz); 7.79 (dd, lH, J=5.0, 10.0 Hz) ; 7.84 (d, LH, J= 10. 0 Hz); 7.94 (d, lH, J=10. OHZ). 3C NMR (125.65 MHz, CD30D) : 6 23.81 ; 29.68 ; 55.41 ; 56.70 ; 70. 03 ; 114. 69 ; 118. 19 ; 131.23 ; 133.21 ; 134.45 ; 134.72 ; 136.25 ; 174.13. [a] D : +15.57 (C = 0.92, MEOH).
9-fluorenyl-methoxycarbonyl-cyclohexyl alanine[ No CAS ]
[ 462-94-2 ]
[ 1458-98-6 ]
[ 78-77-3 ]
[ 1809-10-5 ]
[ 110-53-2 ]
[ 592-55-2 ]
[ 7328-91-8 ]
[ 871-76-1 ]
[ 105-83-9 ]
[ 144-48-9 ]
[ 929-59-9 ]
[ 107-59-5 ]
[ 5324-30-1 ]
[ 5428-54-6 ]
[ 27129-86-8 ]
[ 2417-72-3 ]
[ 2581-34-2 ]
[ 554-84-7 ]
[ 3385-21-5 ]
[ 126-38-5 ]
[ 636-93-1 ]
[ 88-30-2 ]
[ 620-13-3 ]
[ 823-78-9 ]
[ 5035-82-5 ]
[ 29022-11-5 ]
[ 539-48-0 ]
[ 35661-39-3 ]
[ 26759-46-6 ]
[ 20439-47-8 ]
[ 2615-25-0 ]
[ 6393-01-7 ]
[ 5372-81-6 ]
[ 35661-40-6 ]
[ 100-39-0 ]
[ 611-17-6 ]
[ 23915-07-3 ]
[ 71989-23-6 ]
[ 35737-15-6 ]
[ 2592-95-2 ]
[ 18880-00-7 ]
[ 88681-68-9 ]
[ 100063-22-7 ]
[ 75-03-6 ]
[ 106-94-5 ]
[ 104-81-4 ]
[ 589-10-6 ]
[ 107-15-3 ]
[ 109-76-2 ]
[ 110-60-1 ]
[ 7051-34-5 ]
[ 106-95-6 ]
[ 622-95-7 ]
[ 589-15-1 ]
[ 134-20-3 ]
[ 2550-36-9 ]
[ 89-92-9 ]
[ 456-41-7 ]
[ 766-80-3 ]
[ 459-46-1 ]
[ 874-98-6 ]
[ 402-49-3 ]
[ 870-63-3 ]
[ 85118-01-0 ]
[ 22115-41-9 ]
[ 3958-57-4 ]
[ 100-11-8 ]
[ 107-82-4 ]
[ 6482-24-2 ]
[ 3132-64-7 ]
[ 112883-41-7 ]
[ 3433-80-5 ]
[ 52727-57-8 ]
C18H15N2O3PolS[ No CAS ]
C20H20N3OPolS[ No CAS ]
C23H19N2O2PolS[ No CAS ]
C18H23ClN3OPolS[ No CAS ]
C22H26N3OPolS[ No CAS ]
C22H23N2O5PolS[ No CAS ]
C20H26ClN2O3PolS[ No CAS ]
C23H22ClN2O3PolS[ No CAS ]
C20H21FN3O3PolS[ No CAS ]
C22H29N2O3PolS[ No CAS ]
C21H28N3O3PolS[ No CAS ]
C19H26N3O4PolS2[ No CAS ]
C22H30N3OPolS[ No CAS ]
C21H28N3O4PolS[ No CAS ]
C26H26N3OPolS[ No CAS ]
C23H15ClF3N2O2PolS[ No CAS ]
C24H22N3O3PolS[ No CAS ]
C23H16ClF2N2O2PolS[ No CAS ]
C22H22Br2N3OPolS[ No CAS ]
C24H26FN2O5PolS[ No CAS ]
C25H22FN2O4PolS[ No CAS ]
C26H22N3O4PolS[ No CAS ]
C25H25ClN3O3PolS[ No CAS ]
C25H18ClF2N2O3PolS[ No CAS ]
C29H26N3O3PolS[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With piperidine; Carbonyldiimidazole; tin-2-ethylhexanoate dihydrate; potassium tert-butylate; water; N-ethyl-N,N-diisopropylamine; trifluoroacetic acid; diisopropyl-carbodiimide; dibromotriphenylphosphorane; In DMF (N,N-dimethyl-formamide); dichloromethane; N,N-dimethyl acetamide; 1,2-dichloro-ethane;Combinatorial reaction / High throughput screening (HTS);
EXAMPLE 1 [0213] This example shows the synthesis of a combinatorial library of thioquinazolinone derivatives. [0214] Step 1a: Preparation of Wang Bromide Resin [0215] 40 tea bags containing 2 g each of Wang resin (80 g, 120 mmol) was taken in a 5 L PP container. A solution of triphenylphosphine dibromide (152 g, 0.15 M, 3 eq., 360 mmol) in 2000 ml DCM was added and the solution was shaken at room temperature overnight. The resin was sequentially washed with DCM (4×, 1.5 L each) and diethylether (6×, 1.5 L each) and dried under vacuum, to give the bromo wang resin. [0216] Step 1b: Loading of the Nitrophenol on Bromo Wang [0217] 20 g of the Bromo wang resin (1.5 meq/g) was taken in a 2 L wide-mouthed glass container and 1000 mL DMA was addded to it followed by the addition of the nitro phenol (10 eq., 0.3M, 300 mmol). Potasium t-butoxide (33.46 g, 10 eq., 300 mmol) was then added to it and the bottles were heated at 50 C. overnight. The bags were washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The tea bags were then dried overnight in air. The following nitrophenols were used: [0218] 2-METHYL-5-NITROPHENOL [0219] 5-HYDROXY-2-NITROBENZOTRIFLUORIDE [0220] 3-METHYL-4-NITROPHENOL [0221] 2-METHOXY-5-NITROPHENOL [0222] M-NITROPHENOL [0223] Step 1c: Reduction of the Nitro Group to Amine [0224] A 2.0 M solution of tin-2-ethylhexanoate dihydrate was prepared in DMF containing 0.5% H2O. The tea bags were added and the solution is heated at 50 C. for 40 hours. After cooling the bags are washed with DMF/10% HOAc (3×), DMF (3×), 5% DIEA/DCM (2×), DCM (2×) and MeOH (2×) and dried in air overnight. [0225] Step 1d: Coupling N-FMOC Protected Amino Acid to Wang Resin. [0226] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL plastic bottle. DMF (300 mL), DCM (300 mL), FMOC-Cyclohexyl alanine (70.82 g, 6 eq., 0.3M, 180 mmol), DIC (22.71 g, 6 eq., 180 mmol), HOBt (24.32 g, 6 eq., 180 mmol) were added sequentially. After shaking for 12 hours, the packet was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried overnight in air. The tea bags containing the amino acids were then treated with 20% piperidine/DMF for 2 h at room temperature to deblock the FMOC group. The following amino acids were used: [0227] FMOC-GLY-OH [0228] FMOC-ALA-OH [0229] FMOC-L-ISOLEUCINE [0230] FMOC-L-PHENYLALANINE [0231] FMOC-D-NLE-OH [0232] FMOC-CHA-OH [0233] FMOC-L-TRYPTOPHAN [0234] Step 1e: Coupling of the Diamines to Wang Resin [0235] 20 g of Wang resin (1.5 meq/g) was placed in a porous polypropylene packet (Tea-bag, 60 mm×60 mm, 65mu) and taken in a 1000 mL Nalgene bottle. 600 mL of DCM was added followed by the addition of the carbonyl diimidazole (29.9 g, 6 eq., 0.3M, 180 mmol) and the flasks were shaken at room temperature for 3 hours after which they were decanted and washed with DCM (2×, 600 mL). To these Nalgene bottles were added the diamines (6 eq., 0.4M, 180 mmol) in 450 mL of DCM (0.4M) and they were shaken at room temperature overnight. The diamines used were as follows: [0236] 2,2-DIMETHYL-1,3-PROPANEDIAMINE [0237] 1,3-CYCLOHEXANEDIAMINE [0238] (1R,2R)-(-)-1,2-DIAMINOCYCLOHEXANE [0239] TRANS-1,4-DIAMINOCYCLOHEXANE [0240] P-XYLYLENEDIAMINE [0241] 1,4-BIS(3-AMINOPROPYL)PIPERAZINE [0242] ETHYLENEDIAMINE [0243] 1,3-DIAMINOPROPANE [0244] 1,8-DIAMINO-3,6-DIOXAOCTANE [0245] 1,4-DIAMINOBUTANE [0246] 1,5-DIAMINOPENTANE [0247] 1,6-HEXANEDIAMINE [0248] N,N-BIS(3-AMINOPROPYL)METHYLAMINE [0249] 2,2'-THIOBIS(ETHYLAMINE) [0250] 2,5-DIMETHYL-1,4-PHENYLENEDIAMINE [0251] After shaking overnight, the packets was washed alternatively with DMF (500 mL) and DCM (500 mL) 3 cycles followed by 6 cycles of MeOH (500 mL). The packet was then dried in air. [0252] Step 2: Formation of the Isothiocyanate [0253] The o-amino benzoate ester (136 g, 10 eq., 900 mmol) was taken in a 5 L wide-mouthed glass bottle and 2.7 L of dichloroethane was added to it (0.3M). The following esters were used: [0254] METHYL ANTHRANILATE [0255] METHYL 2-AMINO-4-CHLOROBENZOATE [0256] 2-AMINO-4,5-DIMETHOXYBENZOIC ACID [0257] METHYL ESTER [0258] METHYL 3,4,5-TRIMETHOXYANTHRANILATE [0259] DIMETHYL AMINOTEREPHTHALATE [0260] METHYL 2-AMINO-5-BROMOBENZOATE [0261] METHYL 3-AMINOTHIOPHENE-2-CARBOXYLATE [0262] METHYL 3-AMINO-5-PHENYLTHIOPHENE-2-CARBOXYLATE [0263] Thiocarbonyl diimidazole (160 g, 10 eq., 900 mmol) was added to it and the solution was heated at 55 C. overnight to form the isothiocyanate. [0264] Step 3: Formation of the Thioquinazolinone [0265] The next day the tea bags containing the amino acids, diamines and the amino phenols on wang resin (90 mmol) was added to the isothiocyanate solution from reaction 2 and the glass bottles were heated at 55 C. overnight. After cooling the bags was washed alternatively with DMF (2000 mL) and DCM (2000 mL) 3 cycles followed by 6 cycles of MeOH...
With sodium ethanolate In ethanol; N,N-dimethyl-formamide at 90℃; for 3h;
1 Example 1
Compound 2 (25.04 g, 184 mmol) was dissolved in N,N-dimethylformamide (180 mL) and ethanol (90 mL).At room temperature then successively added sodium ethoxide (10.8 g, 199 mmol) and Compound 1 (35 g, 179 mmol,), stirred under a nitrogen atmosphere,Then, the reaction was performed at 90 °C for 3 hours, and TLC (volume ether / ethyl acetate volume ratio = 5/1) showed that the reaction was completed.Then, the ethanol in the solvent was removed by concentration.Water (90 mL) was added to the mixture, and then filtered to obtain a crude product.The crude product was separated by column chromatography (gradient elution: petroleum ether ~ petroleum ether / ethyl acetate volume ratio = 100/1 ~ 20/1) to obtain pure compound 3 (25 g, 107 mmol). The yield was 60.3%
With sodium methylate In <i>N</i>-methyl-acetamide; methanol; ethanol; water
1.K Step K:
Step K: 2-(2-Cyanophenyl)-5-methylbenzofuran A 500 mL 3-neck round bottom flask equipped with a magnetic stirrer, dropping funnel, thermometer and nitrogen bubbler was charged with 10.7 g (108 mmol) of sodium methoxide and 75 mL of absolute ethanol. A solution of 24.9 g (183 mmol) of 2-hydroxy-5-methylbenzaldehyde in 75 mL of dry dimethylformamide was added dropwise over 15 minutes. The mixture was stirred for 20 minutes then treated dropwise over 20 minutes with a solution of 34.8 g (177 mmol) of α-bromo-o-tolunitrile in 75 mL of dry dimethylformamide. The mixture was heated at 75° C. for 30 minutes, then allowed to cool for one hour. A suspension of 10.7 g (188 mmol) of sodium methoxide in 20 mL of dry dimethylformamide was added and the resulting mixture heated at 90° C. for 1.5 hours. The reaction mixture was concentrated under vacuum at 50° C. to give a brown solid that was slurried in 100-200 mL of cold water and filtered. The solids were triturated with 200 mL of methanol, filtered, washed with additional methanol, then air dried. After drying in a dessicator under high vacuum, 26.1 g (112 mmol,63%) of the product was isolated as a beige solid. 1 H NMR (200 MHz,CDCl3): 2.45 (s,3H), 7.17 (d,8 Hz,1H), 7.4 (m,3H), 7.6-7.8 (m,3H), 8.10 (d,8 Hz,1H).
With sodium hexamethyldisilazane; In tetrahydrofuran;
Step A t-Butyl (2S,3R,5R)-5-(2-cyanobenzyl)-6-oxo-2,3-diphenyl-4-morpholine carboxylate To a stirred solution of 9.68 g (27.4 mmol) of t-butyl (2S,3R)-(+)-6-oxo-2,3-diphenyl-4-morpholine carboxylate (Aldrich Chemical Company) and 5.91 g (30.1 mmol, 1.1 eq) of alpha-bromo-o-tolunitrile in 140 mL of tetrahydrofuran at -78 C. was added dropwise 28.8 mL of a 1.0M THF solution of sodium hexamethyldisilazide (28.8 mmol) over 15 min. The mixture was stirred at -78 C. for 3 h, then quenched with saturated aqueous ammonium chloride, extracted with ethyl acetate (5*150 mL) and the combined organic extracts washed with water, saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated under reduced pressure. Chromatography on silica gel (elution with 20% ethyl acetate-hexanes) gave the product as a white solid (8.01 g, 63%). 1 H NMR indicates this compound exists as an approximately 5:1 mixture of rotamers. 1 H NMR (400 MHz, CDCl3): major rotamer--delta0.92 (s, 9H), 3.52 (dd; 10, 14 Hz; 1H), 3.62 (dd; 5, 14 Hz; 1H), 5.08 (d, 3 Hz, 1H), 5.40 (dd; 5, 10 Hz; 1H); 5.79 (d, 3 Hz, 1H), 6.52 (d, 8 Hz, 2H), 6.92 (d, 8 Hz, 2H), 7.00-7.70 (m, 1 OH). FAB-MS: calculated for C29 H28 N2 O4 468; found 469 (M+H,30%), 369 (M-BOC, 100%).
3-(2-cyanophenylmethyl)-2-thiazolidinone[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With potassium carbonate; In ethanol; water; 4-methyl-2-pentanone;
EXAMPLE 1 Preparation of 3-(2-cyanophenylmethyl)-2-thiazolidinone A mixture containing 3.09 g (0.03 mol) of 2-thiazolidinone, 11.2 g (0.081 mol) of potassium carbonate, 1.8 g (0.018 mol) of potassium hydrogen carbonate, 0.5 ml (0.027 mol) of water and 6.47 g (0.033 mol) of 2-bromomethylbenzonitrile in 30 ml of methyl isobutyl ketone is refluxed for 5 hours, then cooled down. After adding 30 ml of water the mixture is stirred for 30 minutes, the insoluble precipitate is filtered off, washed twice with 10 ml of water each and dried. After recrystallizing 4.71 g of crude product from 20 ml of ethanol under simultaneous clarification with activated carbon 3.39 g (51.8%) of white, crystalline title compound are obtained, m.p.: 116-117 C.
2-(3,5-di-t-butylphenoxymethyl)-1-benzenecarbonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
EXAMPLE 5 Preparation of 2-(3,5-di-t-butylphenoxymethyl)-1-benzenecarbonitrile Using the method of Example 1, 20.6 g (0.10 mole) of alpha-bromo-o-tolunitrile was reacted with 3,5-di-t-butylphenol to give 9.9 g of white crystalline 2-(3,5-di-t-butylphenoxymethyl)-1-benzenecarbonitrile.
In methanol; hexane; ethyl acetate; trifluoroacetic acid; trifluoroacetic anhydride
N,N-Dimethyl 3-((acetylthio(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)methyl)thio)propanamide
N,N-Dimethyl 3-((acetylthio(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)methyl)thio)propanamide To a solution of 3-(2-(7-chloro-2-quinolinyl)-ethenyl)benzaldehyde (10.74 g, 36.6 mmol) in 35 mL of TFA (trifluoroacetic acid) at r.t. was added thiolacetic acid (3.34 g, 3.14 mL, 43.9 mmol) followed by N,N-dimethyl-3-mercaptopropanamide (5.84 g, 43.9 mmol) in 5 mL of TFA. The mixture was stirred for 5 min, then poured into ice cold NH4 OAc buffer (500 mL). The aq layer was extracted with EtOAc (4*250 mL). The combined organic layers were washed with NH4 OAc buffer (250 mL), brine (250 mL) and dried over MgSO4. Plug filtration using EtOAc:hexane:MeOH 10:10:1 gave 10.6 g (60% yield) of the title product. Using the general procedure described above, the procedures of Examples 14, 33 and 228, Thiols 1, 3, 16 and 17, Iodides 1 and 2, and 2-(bromomethyl)benzonitrile, the compounds of Table 5 were synthesised. The tetrazoles (Examples 405 and 406) are obtained from the nitrile derivatives using the procedure of Example 40, Step 3.
With caesium carbonate;potassium iodide; In acetone; for 1h;Heating / reflux;
4-Phenylaminophenol (3.7 g; 20 mmol) is dissolved in 75 ml of acetone, and Cs2CO3 1.1 eq. (22 mmol; 7.17 g), 2-bromomethylbenzonitrile 1.2 eq. (24 mmol; 4.7 g) and one crystal of Kl are then added.The reaction medium is refluxed for one hour and then filtered and rinsed with acetone. The organic phases are combined and evaporated to dryness. The residue is taken up in ether and washed with water (3 times). The organic phase is dried over NaaSO^., evaporated to dryness and then chromatographed on silica gel (eluent: 1/5 EtOAc/hexane) to give 4.85 g of the expected product.Yield = 80.8%TLC: 1/3 EtOAc/hexane Rf = 0.341H NMR (CDCI3) = 6.6-7.6 (13H, m); 5.80 (1H, s exchangeable); 5.10 (2H, s).
With 1-methyl-pyrrolidin-2-one; N-ethyl-N,N-diisopropylamine; at 60 - 65℃; for 3h;Large scale;
(1) 29.0 kg of N-methylpyrrolidone, 16.0 kg of 6-chloro-3-methyluracil and 17.36 kg of N,N-diisopropylethylamine were placed in a 300 L glass-lined reaction vessel, and stirred until the solution was dissolved.(2) 16.32 kg of 2-cyanobenzyl bromide was added to the reaction vessel, and the mixture was stirred and dissolved.(3) The reaction kettle was heated, heated to 60-65 C, and stirred for 3 h; after 3 h, TLC monitoring was started until the end of the reaction, that is, the 6-chloro-3-methyluracil starting point disappeared; the sample was monitored every 0.5 hours.The reaction endpoint monitoring method is as follows.1 Preparation of the test solution: Take about 0.2 ml of the reaction solution, and dilute with 2 ml of N-methylpyrrolidone to obtain.2 Preparation of the control solution: about 2 mg of 6-chloro-3-methyluracil was added, and 2 ml of N-methylpyrrolidone was added to dissolve.3 Chromatographic conditions: stationary phase: silica gel G, developing solvent: petroleum ether (60 ~ 90 C) - ethyl acetate (2: 1).4 sample loading: 2~5ul.5 inspection method: iodine color development.(4) After the reaction was completed, the mixture was cooled to 25 C with iced water; 44.80 kg of purified water was slowly added to the reaction mixture under stirring, keeping the temperature below 40 C, and stirring was continued for 30 minutes after the addition.(5) Continue to cool down to 0~10 C, stir for 1 h with heat; then centrifuge, and filter cake washed twice with 40 kg of purified water.(6) The filter cake was transferred to a 300 L glass-lined reaction vessel, 41.6 kg of isopropanol was added, and the mixture was stirred at room temperature for 1 hour, centrifuged, and the filter cake was washed with 19.2 kg of isopropyl alcohol and dried.(7) Transfer the solid to a stainless steel pan, place it in a blast drying oven, control the temperature at 50~60 C, and dry for 6~10h to obtain a light red to brownish red powder.That is, the intermediate AGI powder was 26.4 kg, the content was 99.3%, and the yield was 96.42%.
95.8%
With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 40 - 45℃;
20.8 g of dichloromethane, 3.21 g of 6-chloro-3-methyluracil, 4.51 g of 2-cyanobenzyl bromide, and 5.16 g of DIPEA were successively added to the reaction flask with stirring, and the temperature was raised to reflux temperature. (40-45 C), HPLC sampling was run until 3-methyl-6-chlorouracil disappeared. After completion of the reaction, the reaction system was cooled to 20 ~ 25 C, dichloromethane was distilled off under reduced pressure, stirred with water after 1h was filtered, the filter cake was rinsed with water after adding ethanol, in the temperature 20 ~ 25 C, stirred for 1h After filtration, the filter cake is washed with ethanol andfinally dried under reduced pressure at a temperature of 60 to 70 C to obtain 5.28 g of a white crystalline solid 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)benzonitrile [hereinafter abbreviated as an intermediate], the yield was 95.8%.
91.4%
With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 12h;
Methyl-6-chlorouracil And 117.6 g of alpha-bromo-o-methylbenzonitrile Dissolved in 400ml N, N-dimethylformamide, 103.5 g of potassium carbonate was added, Stirring and heating to 100 C, For 12 hours. Cooled to room temperature, filtered, 400 ml of water was added to the filtrate, Extracted three times with 400 ml of ethyl acetate, The organic layers were combined, The organic layer was washed with saturated brine, Dried over anhydrous sodium sulfate, The solvent was recovered to give the crude product, Recrystallization gave 125.9 g of an off-white solid, The yield was 91.4% HPLC content 98.2%
90%
With triethylamine; In 1-methyl-pyrrolidin-2-one; toluene; at 60 - 70℃;Large scale;
Was added to the reaction kettle 50L 6-chloro-3-methyluracil 1.62Kg, o-cyanobenzyl bromide 1.98Kg and triethylamine 1.98Kg, N-methylpyrrolidone and toluene (4: 1) mixed solution of 12Kg,the reaction was heated to 60 ~ 70 deg. C. After incubation for 2 to 3 hours, cooled to 20 ~ 25 deg. C, 26.10Kg of purified water was added slowly, followed by stirring at 20 ~ 25 deg. C for 1 hour and filtered to obtain 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile crude product. At 50 ~ 60 deg. C blast drying 20 to 24 hours to give the product 2.52Kg, yield 90%.
90.2%
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; toluene; at 70℃; for 1.5h;
10.0 g (62.3 mmol) SM1 at 25C40 mL of N-methylpyrrolidone, 12.1 g (93.6 mmol) of diisopropylethylamine were sequentially added to a 500 mL three-necked flask, and 40 mL of a toluene solution containing 13.4 g (68.4 mmol) of SM2 dissolved therein was added dropwise to the reaction flask while stirring. After completion of the dropwise addition, the temperature was raised to 70C and the reaction was carried out for 1.5 hours. The reaction system was cooled to room temperature, 40 mL of water was added thereto, and the mixture was stirred at 25 C. for 30 minutes, cooled to 0 C., stirred for 1 hour, and suction-filtered. The filter cake was rinsed with 10 mL of isopropanol and dried to give 15.5 g of an off-white solid with a yield of 90.2%.5.5 g (20 mmol, 1 eq) of TM1 was added to 100 mL of tert-butanol, and 50 g of an aqueous solution of 5.0 g (60 mmol, 3 eq) of sodium hydrogencarbonate was added dropwise at room temperature at 25C, and the mixture was stirred at 70C for 12 hours at room temperature.Concentrated hydrochloric acid was added dropwise to the system at 10 C in a cold water bath, and the pH was adjusted to 5-6. The tert-butyl alcohol was removed by rotary evaporation in a water bath at 40C. 100 mL of water and 100 mL of dichloromethane were added to separate the mixture. The aqueous phase was extracted with 100 mL of dichloromethane. Three times, the combined organic phases were dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation in a 40 C. water bath to obtain a brown-red oil. 20 mL of methylene chloride was added to dissolve the oil, 80 mL of isopropyl ether was added, and frozen at -10 C. to precipitate a solid, which was filtered and blown at 40 C. to dry to obtain 2.7 g of a yellow solid with a content of 99.2% and a yield of 44%.
90.1%
With N-ethyl-N,N-diisopropylamine; In ethyl acetate; at 70 - 75℃; for 4h;Large scale;
In a 200L reactor with mechanical stirring and condenser, add 6-chloro-3-methyluracil (8kg,49.83 mol), 2-cyanobenzyl bromide (10.58 kg, 53.97 mol), ethyl acetate (6.4 kg),Diisopropylethylamine (10.2kg, 78.92mol) is controlled at a temperature of about 70-75C for 4 hours and cooled to -5C to 0C.Stir for 3 hours, suction filtration, rinsing with a small amount of cold ethyl acetate to obtain a wet product, adding 800 g of purified water,The temperature was stirred at about 25C for 20 minutes, suction filtered, and the wet product was dried at 50C to obtain 12.38 kg of an off-white solid.Yield: 90.1%, HPLC purity: 99.91%.
86%
With tributyl-amine; In toluene; at 80℃; for 5h;
(1) At room temperature,6-Chloro-3-methyluracil (160 g, 1 mol),2-cyanobromobenzyl (243 g, 1.24 mol)And tri-n-butylamine (275 g, 1.5 mol)And toluene (800 mL) were successively added to the reaction kettle,Stirred for 10 minutes,Stirring was continued and the temperature was raised to 80 C.The reaction was carried out at 80 C for 5 h (the progress of the reaction was monitored by HPLC)After completion of the reaction, the reaction was cooled down to 5 C or lower, 320 g of purified water was added, and the mixture was stirred at 0 to 5 C for 40 minutes. A large amount of solid precipitated and was filtered off.The cake was dried at 80 ± 5 C to give a pale yellow solid2- (6-Chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin- 1 (2H) -ylmethyl) -benzonitrile 236.5 g, HPLC purity: 98.5%, yield: 86%.
86.7%
With tributyl-amine; In acetonitrile; for 6h;Reflux;
1000ml three-necked flask by adding acetonitrile 600ml,O-bromomethylbenzonitrile 100.0 g,3-methyl-6-chlorouracil, 81.9 g,Tri-n-butylamine 113.5 g, stirred,The temperature was raised to reflux for 6 hours(TLC monitoring reaction end point,O-bromomethylbenzonitrile spots disappear),Cooling,After removing the solvent by steaming at 40 C,Add 500ml of anhydrous ethanol,Reflux stirring dissolved,Cooling to 10 below the crystallization,filter,The filter cake was washed with 100 ml of cyclohexane,And blasted at 60 C,Get 121.9g products,Yield 86.7%HPLC purity 98.97%.
86.77%
With triethylamine; In dimethyl sulfoxide; at 50℃; for 1h;
7.71 g of 2-cyanobenzyl bromide (R1 is H and R2 is Br), 6.00 g of 3-methyl-6-chlorouracil and 4.20 g of triethylamine were dissolved in a mixed solution of 78 ml of DMSO and THF, and the temperature was raised The reaction was stirred at 50 C for 1 h, and the reaction was cooled to room temperature. 80 ml of ice water was slowly added dropwise, and the mixture was stirred for 1 h under ice-cooling. The crude product of compound III was 9.15 g. The yield was 88.81%. The crude compound III was rinsed with ethyl acetate at 25 C, filtered, washed and dried to give pure Compound III 8.94. The purification yield was 97.90%. The total yield of compound was 86.77% and the purity was 89.70%.
85%
With tributyl-amine; In toluene; at 80℃; for 3h;Green chemistry;
6-Chloro-3-methyl uracil 565.5g (3.5mol), 2- bromomethyl-benzonitrile 754.6g (3.85mol), tri-n-butylamine 1240ml (5.25mol) and toluene 3.65L, with inputs to mechanical stirring, 10L glass three-necked flask with a thermometer and a reflux tube.Oil bath was heated to 80 , heat the reaction was stirred 3h.Heating was stopped, the oil bath was removed, the water bath was cooled to room temperature, 1.2 L of water was added, stirring was cooled to ice bath change 0-5 , heat stirred 30min, filtered off with suction, washed with a small amount of solid was scraped into blast oven 50 and dried overnight to give a tan powdery solid 819.7g, a yield of 85.0%, a purity of 98.04%.
76%
With potassium carbonate; triethylamine; In tetrahydrofuran; at 80℃; for 4h;
1 6-chloro-3-methyluracil (16 g, 0.1 mol)Add to a 1000ml single-mouth bottle,Add 300 ml of tetrahydrofuran and add magnetons.Turn on the stirrer to stir.At this point, triethylamine (10.1 g, 0.1 mol) was added.And potassium carbonate (13.8 g, 0.1 mol)Add cyanobenzyl bromide (29.4 g, 0.15 mol) in one portion.The heating was turned on, the temperature was set to 80 C, and after 4 hours of reaction, the plate was placed and the reaction of the raw materials was completed. Evaporation of the solvent gave a yellow oil.Then adding a mixed solvent of ethanol and water,Stirring to precipitate a brownish yellow solid 21The molar yield was 76%.Send feedbackHistorySavedCommunity
70%
6-methyl-3-chlorouracil (200 g) was added to a 10 L three-necked flask at 0 C under N2 protection and dissolved in DMF / DMS0 (4.5 L, 5/1) LiBr (87 g, 1 mol) was added and stirring continued for 20 min. To which was then added dropwise a solution of o-nitrobenzyl bromide (244 g, 1. 25 mmol). After 1 hour reaction, the reaction was continued to room temperature. TLC was followed until complete reaction of the starting material. The solvent was distilled off under reduced pressure. The residue was subjected to extraction with CH2C12 (1LX 3 times). The organic phase was combined with The solvent was evaporated under reduced pressure to give 380 g of a reddish-brown residue which was refluxed for 1 hour with 3 times the absolute ethanol, cooled to room temperature, filtered and the cake was dried at 50 C for 3 hours. (3L), a large amount of solid precipitation, stirring at room temperature for 2h, filtration, 50 degrees for 3 hours drying to get 260. 7 light yellow solid. (2L) Yield: 70%, m.p. 165-167 C).
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 0 - 70℃;Inert atmosphere;
2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (2a). To a solution of 6-chloro-3-methyluracil (1 equiv., 1 wt.), N-methylpyrrolidone (NMP; 4 vol.) and diisopropylethylamine (Huenig's base, 1.5 equiv., 1.21 wt.), was added a solution of alpha-bromotoluoylnitrile (1.1 equiv., 1.35 wt.) and toluene (4 vol.). The mixture was heated at 60-70 C. and agitated for 2-3 hrs, or until completion. The solution was then cooled to 20-30 C., quenched with deionized water (5 vol.) at less than 35 C., agitated for 30 min, cooled to 0-5 C., and then agitated for at least one hour. The resultant slurry was filtered, reslurried in isopropanol, displacement washed with isopropanol, and dried under vacuum at 55-60 C.
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; toluene; at 45 - 55℃;
[Production step of 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (2a) in the above-mentioned formula 1] Toluene (1.7-fold amount), alpha-bromotoluoylnitrile (1.1 equivalents, 1.34 wt.), 6-chloro-3-methyluracil (1a) (1 equivalent, 1 wt.), and N-methylpyrrolidone (NMP; 3-fold amount) were heated to an inside temperature of 45 - 55C. Diisopropylethylamine (Hunig base, 1.5 equivalents, 1.21 wt.) was added while keeping the inside temperature of 45 - 55C. The mixture was stirred at 45 - 55C for 3 - 7 hr or until completion of the reaction. Then, the solution was cooled to 25 - 35C, and isopropanol (5.8-fold amount, 4.6 wt.) was added while keeping 25 - 35C. Water (4-fold amount) was added while keeping the inside temperature of 25 - 35C, and the mixture was stirred for about 30 min. The mixture was cooled to 0 - 5C, and thereafter stirred for at least 1 hr. The obtained slurry was filtered, washed with isopropanol (4.4-fold amount, 3.5 wt.) cooled to 0 - 5C, and vacuum dried at not more than 60C to give the above-mentioned compound (2a).
With potassium carbonate; In N,N-dimethyl acetamide; at 50 - 100℃;
Example 2: Protected Alogliptin To the 500cc dimethylacetamide charged 1.24mole potassium carbonate after stirring it for 10-30 min at ambient temperature added 0.62mole of formula-IV with 0.68mole of formula-Ill (Where X= Br) and stirred reaction mass for 45-150 min at elevated temperature of 50-100C. The insitu reaction was carry forward by adding 0.625mole of formula- VI and 1.13moleof potassium carbonate at elevated temperature and further stirred for 75-175min. After completion of reaction, 2000cc water was slowly added at 20-60C and further stirred for 10-30 min. The wet solid was dried at 40-90C to obtain 94% of protected Alogliptin. HPLC Purity: 96-98%
146.62 g
With triethylamine; In toluene; at 80℃;
In toluene was added with stirring 506.77 g of methyl-6-chloro-uracil 96.36 g, 2-cyanobenzylbromide 129.36 g, triethylamine 45.54 g, the reaction was stirred for about 80 C, cooled to room temperature, purified water was added with stirring analysis crystal suction filtration and dried to afford the product 146.62 g, mp: 164.6-166.5 C
2-(2-chloro-5-fluoro-6-oxo-6H-pyrimidin-1-ylmethyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
45%
The title compound of Example 1b was also prepared from <strong>[155-12-4]5-fluoro-2-chloro-3H-pyrimidin-4-one</strong> as follows. To a solution of <strong>[155-12-4]5-fluoro-2-chloro-3H-pyrimidin-4-one</strong> (100.00 g, 0.67 mol) in 1:1 DMF/DME (440 mL) under a nitrogen atmosphere was added sodium iodide (10 g, 67 mmol) and the resulting slurry cooled to 0 C. While maintaining the internal temperature to 12 C., 1,1,3,3-tetramethylguanidine (94 mL, 0.74 mol) was added dropwise over 45 minutes to form a homogeneous solution. The ice bath was removed and a solution of 2-(bromomethyl)benzonitrile (145 g, 0.74 mol) in 1:1 DMF/DME (600 mL) was added all at once and the reaction mixture heated to 70 C. for 18 h. In-process assay (by HPLC analysis) showed complete consumption of the starting material. The reaction mixture was cooled to 30 C. and then MTBE (1.14 L) and DI water (2.29 L) were added to form a slurry which was stirred at ambient temperature for 1 h. The crude product was collected by filtration and washed with MTBE (1.14 L). The phases of the filtrate were separated and the organic layer was combined with the filter-cake and concentrated to a thick slurry which was subsequently reslurried with DME (1.00 L). Insoluble impurities were removed by vacuum filtration and washed with DME (500 mL). The filtrate was concentrated to a wet residue which was reslurried with 2-propanol (365 mL) and the solid product collected by vacuum filtration. After removal of residual IPA, the product was reslurried in ethyl acetate (6 vol) at 70 C. and heptane (6 vol) was added slowly while maintaining the internal temperature at 68-70 C. At the end of the addition of heptane, insoluble materials were still visible. The mixture was stirred for an additional 10 min after which insoluble impurities were removed by hot vacuum filtration. The filtrate was slowly cooled to room temperature and then cooled further to about 0 C. by means of a salt-ice bath. The crystallized product was collected by vacuum filtration and then reslurried in ethanol (6 vol) at 50 C., cooled to 40 C., and the product collected by vacuum filtration to give 80.62 g (45%, 95.6% AUC by HPLC) of 2-(2-chloro-5-fluoro-6-oxo-6H-pyrimidin-1-ylmethyl)-benzonitrile as an off-white solid.
44%
Example 1b 2-(2-Chloro-5-fluoro-6-oxo-6H-pyrimidin-1-ylmethyl)-benzonitrile The title compound was prepared in 44% yield from <strong>[155-12-4]2-chloro-5-fluoro-3H-pyrimidin-4-one</strong> as described in U.S. patent application Ser. No. 10/918,317. Specifically, 5-Fluoro-2-chloro-3H-pyrimidin-4-one was stirred in DME/DMF under nitrogen at 0 C. Sodium hydride (95%) was added in portions. After 10 min, lithium bromide was added and the reaction stirred at r.t. alpha-Bromo-o-tolunitrile was added, and the reaction stirred at 65 C. for 8 h. The solution was diluted with EtOAc, washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography (1:1:1 EtOAc/hexanes/CHCl3) gave the title compound. Also obtained from the reaction were impure fractions of the less polar O-alkylated isomer, and the more polar N3-alkylated isomer. 1H NMR (400 MHz, CDCl3): delta 7.81 (s, 1H), 7.74 (dd, 1H, J=7.6, 1.2 Hz), 7.59 (td, 1H, J=7.6, 1.2 Hz), 7.45 (t, 1H, J=7.6 Hz), 7.15 (d, 1H, J=7.6 Hz), 5.67 (s, 2H). MS (ES) [m+H] calc'd for C12H7N3OFCl, 264, 266; found 264, 266.
<strong>[155-12-4]2-chloro-5-fluoro-3H-pyrimidin-4-one</strong> was stirred in DME/DMF under nitrogen at 0 C. Sodium hydride was added in portions. After 10 min, lithium bromide was added and the reaction stirred for 15 min at r.t. alpha-Bromo-o-tolunitrile was added, and the reaction stirred at 65 C. for 8 h. The solution was diluted with EtOAc, washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by silica gel chromatography gave the title compound. 1H NMR (400 MHz, CDCl3): delta 7.81 (s, 1H), 7.74 (dd, 1H, J=7.6, 1.2 Hz), 7.59 (td, 1H, J=7.6, 1.2 Hz), 7.45 (t, 1H, J=7.6 Hz), 7.15 (d, 1H, J=7.6 Hz), 5.67 (s, 2H). MS (ES) [m+H] calc'd for C12H7N3OFCl, 264, 266; found 264, 266.
Stage #1: 2-chloro-3H,4H-thieno[3,2-d]pyrimidin-4-one With sodium hydride In 1,2-dimethoxyethane; N,N-dimethyl-formamide at 0℃; for 0.333333h;
Stage #2: With lithium bromide In 1,2-dimethoxyethane; N,N-dimethyl-formamide at 0 - 20℃; for 0.25h;
Stage #3: 2-(bromomethyl)benzonitrile In 1,2-dimethoxyethane; N,N-dimethyl-formamide at 65℃;
5.6.1. 2-((2-Chloro-4-oxothieno-[2,3-d]pyrimidin-3-(4H)-yl)-methyl)benzonitrile (9a)
General procedure: NaH (2.1 g, 51.6 mmol) was added to a stirred solution of 8a (8.4 g, 44.9 mmol) in DME (120 mL) and DMF (30 mL) at 0 °C. Twenty minutes later, LiBr (7.9 g, 89.7 mmol) was added, and the mixture was allowed to warm to room temperature. After 15 min, α-bromo-o-tolunitrile (10.15 g, 51.6 mmol) was then added, and the mixture was heated at 65 °C overnight. After cooling, the mixture was poured into water (1000 mL) with stirring to yield a precipitate. This solid was filtered and dried to give the title compound 9a (11 g, yield 81%). 1H NMR (400 MHz, CDCl3): δ 7.78-7.70 (m, 1H), 7.58-7.49 (m, 2H), 7.45-7.40 (m, 1H), 7.33 (d, J = 6.4 Hz, 1H), 6.87 (d, J = 6.4 Hz, 1H), 5.75 (s, 2H).
Stage #1: (3,4,5-trifluorophenyl)methanol With sodium hydride In tetrahydrofuran at 20℃; for 0.5h; Inert atmosphere;
Stage #2: 2-(bromomethyl)benzonitrile In tetrahydrofuran at 20℃; for 12h; Inert atmosphere;
5-(2-cyanophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2(4H)-one[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
22.6 g
With potassium carbonate; In acetonitrile; at -10 - 45℃; for 4h;
To a reaction flask equipped with a stirrer, a condenser and a thermometer was added 19.2 g of 5,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2(4H)-one, which was then dissolved in 70 mL acetonitrile and cooled to -10 C. under stirring. 41.5 g of anhydrous potassium carbonate were added to the mixture. After addition of 19.6 g of 2-cyanobenzyl bromide to the reaction system in batches, the reaction mixture was heated to 45 C. and continued to react for 4 h (completion of the reaction was monitored by TLC). Then the reaction mixture was filtered and the solvent acetonitrile in the filtrate was evaporated to dryness. 50 mL of dichloromethane was added to the residue, and the mixture was washed with water (3×50 mL). The dichloromethane layer was separated, fully dried over anhydrous sodium sulfate, and filtered. The dichloromethane was evaporated off under reduced pressure to obtain 22.6 g yellow oil product (HPLC: 97.2%). Rf=0.47 [single point, developing solvent: v (petroleum ether): v (ethyl acetate)=1:2]. MS, m/Z: 270.0 (M).
22.6 g
With potassium carbonate; In acetonitrile; at -10 - 45℃; for 4h;
The stirring, condenser, thermometer into the reaction bottle 5, 6, 7, 7a-tetrahydro-thieno [3,2-c] pyridine -2 (4H)-ketone 19.2g, with 70 ml acetonitrile dissolves it, cooling to -10 C under stirring, by adding anhydrous potassium carbonate 41.5 g. The 2-cyano bromo 19.6g in the batch are added to a reaction system, the temperature rising to is omitted 45 C to continue reaction 4h (ply display the reaction is complete). Filtering, evaporating the filtrate solvent acetonitrile, by adding 50 ml of methylene chloride, with 3×50 ml water to wash the reaction liquid, tapping methylene chloride level, sufficient drying with anhydrous sodium sulfate, filtered, pressure-reducing steams dichloromethane, to obtain a yellow oily product (HPLC: 97.2%) 22.6g.
2-(((trifluoromethyl)thio)methyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
In acetonitrile; at 20.0℃; for 8.0h;
General procedure: Benzyl bromide 1 (0.17mmol), [(bpy)Cu(SCF3)] (80mg, 0.25mmol, 1.5equiv), and CH3CN (1.0mL) were added to a reaction tube equipped with a stir bar. The mixture was stirred at room temperature for 8-24h until the reaction was judged complete by TLC analysis. The reaction mixture was filtered through a pad of Celite. The filtrate was added water (3×10mL) at 0C. The resulting mixture was extracted with Et2O (3×15mL), and the combined organic layers was washed with water, and then dried over MgSO4. The solvent was removed to give the desired product 3 without further purification.
1,1′-methylenebis{3-(2-cyanobenzyl)imidazolium} dibromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In 1,4-dioxane; at 100℃; for 24h;Reflux;
2-(Bromomethylene)-benzonitrile (2.65 g, 13.6 mM) was added to a stirring solution of 1,1?-methylenebis(imidazole) (1.0 g, 6.8 mM) in 1,4-dioxane (100 mL). The mixture was refluxed at100 C for 24 h and the solution was evaporated under vacuum to yield a brownish thickfluid (L1). To purify, the bromide salt was directly converted to its hexafluorophosphate(PF6-) salt by metathesis using potassium hexafluorophosphate (KPF6) (1.25 g, 6.8 mM) in50 mL of methanol; the mixture was stirred for 3 h. The salt was obtained as a white crystallinesolid. Single crystals suitable for X-ray diffraction were obtained by exposing a saturatedsolution of L1.2PF6 in acetonitrile to the vapors of diethyl ether at room temperature.For characterization, the PF6 salt of L1 was used whereas for further synthesis halide saltwas used. Colorless cubes. Yield 1.8 g (49%).
The mixture of ethyl 5-bromonicotinate (1 g, 4.34 mmol, 1.0 eq), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (l . lg, 4.34 mmol, 1.0 eq), Pd(dppf)Cl2 (157 mg, 5%) and KOAc (1.27 g, 13 mmol, 3.0 eq) in dioxane (36 mL) was degassed with N2 and stirred at 85 C overnight. After cooling to rt, 2- (bromomethyl)benzonitrile (0.85 g, 4.34 mmol, 1.0 eq), Pd(dppf)Ci2 (157 mg, 5%>) and an aqueous solution of Na2CC>3 ( 1.38 g, 13 mmol, 3.0 eq) in 10 mL of water were added. The mixture was degassed with N2 and stirred at 95 C for 2 h. Then the mixture was concentrated. The residue was diluted with EtOAc (100 mL), washed with water, brine and dried over anhydrous sodium sulfate, filtered and purified via silica flash chromatography (PE/EtOAc = 5/1) to afford ethyl 5-(2-cyanobenzyl)nicotinate as a yellow oil (750 mg, 65%).
A 250 mL round bottom flask equipped with a magnetic stir bar was chargedwith 100 mL of methanol, <strong>[6832-87-7]2-bromo-N-methylaniline</strong> (2f; 2.00 g; 10.75 mmol),1.1 equiv of 2-(bromomethyl)benzonitrile (1; 2.31 g; 12.07 mmol), and1.1 equiv of triethylamine (1.82 mL; 1.33 g; 13.10 mmol). The mixture wasallowed to stir overnight and was then concentrated in vacuo and 100 mL ofdiethyl ether was added to the residue. The resulting precipitate was removedusing vacuum filtration and the filtrate was again concentrated in vacuo toprovide crude 2f (2.55 g; 78.8%) as an oil which was purified using flashchromatography on silica gel eluting with hexanes/EtOAc to provide the pureproduct as a water-white oil, yield = 0.785 g (24.3%): 1H NMR (CDCl3,300 MHz) d 2.56 (s, NCH3; 3H), 4.25 (s, ArCH2, 2H), 7.73-6.77 (m, ArH, 8H);13C NMR (CDCl3, 75 MHz) d 41.2, 58.0, 111.8, 118.8, 120.4, 122.4, 125.0, 127.6,128.3, 129.4, 132.6, 132.9, 134.0, 142.1, 151.1. IR: 2228 cm1; Anal. Calcd forC15H13BrN2: C, 59.82; H, 4.35; Br, 26.53; N, 9.30. Found: C, 59.49; H, 4.00; Br,26.51; N, 9.16.
In a dry flask charged toluene (150 ml), N-methylbarbituric acid (50 gm), phosphorous oxychloride (64.5 gm) and N,N-dimethylaniline (20 ml). Heated the reaction mass to 90C - 95C and maintained the reaction at this temperature for 2 hours. The reaction progress was monitored by TLC. After completion of the reaction, cooled the reaction mass to 10C - 15C and charged methanol (150 ml) in the reaction mass and stirred at this temperature for 1 hour. The reaction mass was allowed to settle and the solvent was removed from the reaction mass. Charged again methanol (50 ml), stirred and separated the solvent from the reaction mixture to get the residual solid mass of the intermediate compound.To the solution of the intermediate compound charged solvent tetrahydrofuran (300 ml), 2-(bromomethyl)benzonitrile (67.3 gm) and dii sopropylethylamine (60.5 gm). Raised the temperature of the reaction mass to 60C - 65C and maintained at this temperature for 4 - 5 hours. The reaction progress was monitored by TLC. After the completion of the reaction the solvent was concentrated and to the residual mass charged water (300 ml) and stirred the reaction mass at 25C - 30C for 1 hour. Filtered the reaction mass and washed the solid mass with water (50 ml). The filtered wet solid mass was taken in solventisopropyl alcohol (150 ml) and stirred at 25C - 30C for 1 hour. Filtered the solid and washed with isopropyl alcohol (50 ml) and dried the compound to get 2-[(6- chloro-3 -methyl-2,4-dioxo-3 ,4-dihydropyrimidin- 1 -(2H)-yl)methyl]benzonitrile.Dry weight = 52 gm.
12-N-(2-cyanobenzyl)aloperine hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
General procedure: Take <strong>[56293-29-9]aloperine</strong> (1) 0.5 g (0,002 mol),Was added to 20 ml of acetonitrile, and 1.8 g (0.006 mol) of anhydrous potassium carbonate and substituted bromobenzyl or benzyl chloride (0.003 mol) were successively added to the reaction solution, followed by stirring at room temperature.TLC was detected until the reaction was complete. The organic phase was concentrated and evaporated to dryness. The solvent was dissolved in dichloromethane and washed successively with water and saturated brine. The methylene chloride layer was dried and the solvent was evaporated to dryness with a rotary evaporator to give the crude 12-N-benzyl <strong>[56293-29-9]aloperine</strong> derivative. The solution was dissolved in 20 ml of methylene chloride solventAnd then separated by column chromatography to give pure product of 12-N-benzyl-<strong>[56293-29-9]aloperine</strong> derivative (2). The resulting compound was dissolved in 5 ml of ether,And then with 1N HCl / Et2O adjusted PH = 6-7, filtered, 12-N-benzyl ether alkalis derivatives pure hydrochloric acid.
2-((5-chloro-7-oxopyrazolo[1,5-a]pyrimidin-4(7H)-yl)methyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
60%
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 80.0℃;
A mixture of 400 mg (2.36 mM) of 5-chloropyrazolo [1,5-a] pyridine-7 (4H) -one 3, 462 mg (2.36 mM) of 2-cyanobenzyl bromide and 0.8 mL (4.72 mM) Diisopropylethylamine was dissolved in 5 mL of DMF and heated to 80 C overnight, The reaction was monitored by thin layer chromatography. After completion of the reaction, the reaction solution was cooled and 100 mL of ethyl acetate was added, The organic phase was washed three times with 20 mL and dried with saturated brine. The organic phase was distilled under reduced pressure to give the crude product. The crude product was purified by column chromatography and eluted with petroleum ether: ethyl acetate 2: 1. To give the title product 400 mg (yield = 60%).
59.56%
In N,N-dimethyl-formamide; at 90.0℃;Inert atmosphere;
General procedure: To a solution of <strong>[99898-84-7]5-chloropyrazolo[1,5-a]pyrimidin-7(4H)-one</strong> (1eq) in DMF was added 2 eq. of Cs2CO3 or K2CO3 or DIPEA and thecorresponding (bromomethyl)benzene analog. The reaction washeated to 90 C overnight. After the completion of the reaction,EA and water were added, the organic layer was washed withwater 3 times. Collect the organic layer, remove the solvent toobtain the crude product. The crude product was purified by F.C.C. to obtain the corresponding product.
A solution of 6-chloro-3-methyl uracil (20.0 g, 125 mmol), acetonitrile (200 mL), 2- cyanobenzyl bromide (27.0 g, 138 mmol), N, N- diisopropylethyl Amine (96.8 g, 750 mmol) and warmed to reflux (80 C) for 6 hours.(R) -3-Aminopiperidine dihydrochloride (23.6 g, 138 mmol) was added and reflux was continued for 8 hours.After the reaction was completed, the temperature was lowered to 30 C, added to 1000 mL of water, and then cooled to 5 C and stirred for 4 hours.Filter, filter cake washed twice with water, each 400 mL, pumpingdry. Get alogliptin 31.0 g. Yield 73%, purity 99.8%.
5-(2-cyanophenyl)-4,5,6,7-tetrahydrothiophene[3,2-c]pyridine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96.1%
With sodium carbonate; In tetrahydrofuran; at 25 - 30℃; for 4h;
17.6 g (0.1 mol) of <strong>[54903-50-3]4,5,6,7-tetrahydrothieno[3,2-c]pyridine</strong> was added to a thermometer equipped withCondenser tube in a 250ml three-necked bottle,Add 130 ml of tetrahydrofuran (THF),Stir to completely dissolve,Then 21.2 g (0.2 mol) of sodium carbonate and 23.5 g (0.12 mol) are addedo-Cyanobenzyl bromide,Gradually warm up to 2530C,Reaction 4h,The reaction was completed by TLC (petroleum ether:ethyl acetate=1:2).Stop the reaction,The reaction solution was washed with saturated saline (50 ml x 3).The organic phase was dried over anhydrous magnesium sulfate.Suction filtrationThe filtrate was spin-dried to give 24.4 g of 5-(2-cyanophenyl)-4,5,6,7-tetrahydrothiophene[3,2-c]pyridine as a white solid.The yield was 96.1%.
(S)-2-[(5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-4-oxochroman-7-yl)oxy]methyl}benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
65%
With potassium carbonate; In N,N-dimethyl-formamide; at 20℃;Alkaline conditions;
General procedure: K2CO3 (172.76 mg, 1.25 mmol) and the appropriate substitutedbromine (4-10 mmol) were added, under stirring, to a solution of <strong>[520-33-2]hesperetin</strong>(604 mg, 2 mmol) in anhydrous DMF (15 mL). Another 1 mmolof K2CO3 was intermittently added to the solution to keep the pH as aweak alkaline. The mixture was reacted at room temperature for 4-6 hunder atmospheric conditions. The progress of the reaction was monitoredby TLC. The reaction mixture poured into ice cold water thenacidified by dilute hydrochloric acid and extracted with ethyl acetate,then washed three times with saturated aqueous NaCl solution. After drying with anhydrous sodium sulfate, the solution was filtered throughabsorbent cotton. The precipitate obtained by removing the solventunder reduced pressure was purified by column chromatography (SiO2)using trichloromethane/petroleum ether (1:1-5) as eluent. The purifiedprecipitate was recrystallized from dichloromethane/petroleum ether.
With cobalt(II) pyridine-2-carboxylate; palladium diacetate; sodium hydroxide; In methanol; at 150℃; under 11251.1 Torr; for 6h;Autoclave;
312 ml of methanol, 0.55 g of cobalt pyridine-2-carboxylate,1.37 g of palladium acetate was added to the autoclave reactor.The catalyst was dissolved by stirring for 5 minutes, and the air in the kettle was replaced with CO three times, and the temperature was raised to 150 ° C.Rush into the CO until the pressure rises to 1.5 MPa. Within 1 hour,At the same time, 78.4 g (0.4 mol) of o-cyanobenzyl bromide and 30percent of NaOH 160 g (1.2 mol) were added dropwise to the reaction vessel.After reacting for 5 hours, the temperature was lowered to room temperature, methanol was removed by distillation under reduced pressure, and the catalyst was filtered off.Add 30percent hydrochloric acid to adjust the pH to 1, filter,Dry to obtain o-cyanophenylacetic acid, the purity is:98.56percent, the yield was 61percent.
2-(((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)thio)methyl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
73%
Stage #1: 2-(bromomethyl)benzonitrile With [2,2]bipyridinyl; copper(ll) sulfate pentahydrate; Sodium thiosulfate pentahydrate In d(4)-methanol; water at 80℃; for 2h;
Stage #2: Lenalidomide With tert.-butylnitrite In methanol; water at 0 - 80℃;
1-[(2-cyanophenyl)methyl]-6-methoxyindole-3-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
280 mg
Stage #1: 6-methoxy-1H-indole-3-carboxylic acid; 2-(bromomethyl)benzonitrile With potassium carbonate In 1-methyl-pyrrolidin-2-one for 14h;
Stage #2: With sodium hydroxide In 1-methyl-pyrrolidin-2-one at 50℃; for 12h;
25 1-[(2-Cyanophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide
To a stirred mixture of 6-methoxy-1H-indole-3-carboxylic acid (220 mg, 1.15 mmol) and K2CO3 (477 mg, 3.45 mmol) in NMP (16 mL) was added 2-(bromomethyl)benzonitrile (563 mg, 2.88 mmol). The mixture was stirred for 14 h.2 N NaOH (2.8 mL) was added and the stirred mixture was heated to 50 oC for 12 h. The cooled solution was poured into H2O and acidified to pH 2.0 using 1.0 M HCl. The resulting precipitate was collected by filtration, washed with H2O and air dried to give 280 mg of 1-[(2-cyanophenyl)methyl]-6- methoxy-indole-3-carboxylic acid.
1-(2-cyanobenzyl)-4,4'-bipyridinium bromide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
52.5%
In acetonitrile at -0.16 - 79.84℃; for 24.1667h;
2.1.1. Synthesis of 1
General procedure: A mixture of 4,40-bipyridine (3.101 g,20 mmol), 2-cyanobenzyl chloride (3.129 g, 20 mmol) andacetonitrile (30 ml) was added to a 100 ml distillation flask,stirred at room temperature for 10 min, and then heated andrefluxed at 353 K for 24 h. Filtration after cooling to roomtemperature gave colourless block-shaped crystals of salt 1 in61.9% yield based on 4,40-bipyridine.
3-(2-cyanobenzyl)thiazolidin-2-ylidenecyanamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85.7%
With sodium hydroxide; In water; acetonitrile; at 20℃; for 8h;
General procedure: Thiazolidin-2-ylidene-cyanamide (0.317 g, 2.50 mmol) inacetonitrile (20 mL) was dropwise added to a stirred solutionof substituted benzyl bromide (2.5 mmol) and 14 mL NaOHaqueous solution (1 M). The mixture is stirred at room temperaturefor 8-10 h. The soild was collected by filtration,washed with n-hexane and dried in vacuo.
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