2-[(6-Chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]benzonitrile

White Solid

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.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 98.2percentWas 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.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.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.(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.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.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.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.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).2-(6-Chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile (3). To a cold (0° C.) solution of benzylated 6-chlorouracil 2 (10 g, 38 mmol) in DMF-TH-F (1:1, 300 mL) under nitrogen, was added NaH (60percent, 1.6 g, 39.9 mmol) in portions, followed by adding LiBr (2 g). The mixture was stirred at RT for 20 min. After adding iodomethane (5.4 mL, 76 mmol), the flask was sealed and stirred at this temperature for 10 min, RT for 2 h, and 35° C. overnight, and then concentrated in vacuo. The residue was dissolved in CHClGeneral procedure: To a suspension of 5b (14.6 g, 73.5 mmol) and LiBr (5.6 g, 58.8 mmol) in DMF (150 mL) was added NaH (60percent, 3.82 g, 95.5 mmol) in portions under nitrogen at 0 °C. The mixture was stirred for 0.5 h. 2-Chloromethyl-4-methylquinazoline (15.6 g, 81 mmol) was added. The mixture was stirred overnight at 80 °C. The mixture was evaporated and azeotroped with water in vacuo to remove most of the DMF. The crude product was suspended in the mixture of hot EtOAc (100 mL) and isopropyl ether (200 mL). The suspension was stirred for 30 min and allowed to stand at -20 °C for 1 h. The formed precipitate was collected by filtration, washed with water, EtOH and isopropyl ether, and dried to give 6c as a yellow brown solid (21 g, 88percent).Step - II: Preparation of 2-((6-chloro-3-methyl-2, 4-dioxo-3, 4-dihydropyrimidin-l(2H)- yl)methyl)benzonitrileAcetone (286 ml) was added to 2-((6-chloro-2, 4-dioxo-3, 4-dihydropyrimidin- l(2H)-yl)methyl)benzonitrile (18.5 gm) and then added potassium carbonate (13 gm). To the reaction mixture was added methyl iodide (5.5 ml) slowly for 30 minutes and the temperature of the reaction mass was raised to 50 to 60°C. The reaction mass was maintained for 6 hours at 50 to 60°C and the acetone solvent was distilled off under vacuum at low temperature to obtain a residual mass. To the residual mass was added ethyl acetate (300 ml) and water (200 ml) and then the layers were separated. The separated organic layer was dried with sodium sulfate and the ethyl acetate solvent was distilled off under vacuum at low temperature to obtain a residual solid. To the residual solid was added hexane (200 ml) and stirred for 30 minutes. The separated solid was filtered and then dried to obtain 18 gm of 2-((6-chloro-3-methyl-2, 4-dioxo-3, 4- dihydropyrimidin-l(2H)-yl)methyl)benzonitrile.A solution of 5.66 g of 2-cyanobenzyl chloride (R1 is H and R2 is Cl), 6.00 g of 3-methyl-6-chlorouracil and 5.30 g of N, N-diisopropylethylamine in 78 ml of DMSO , The reaction mixture was stirred for 1 h at 60 ° C. The reaction was cooled to room temperature, 80 ml of ice water was slowly added dropwise, and the mixture was stirred for 1 hour under ice-cooling. The crude compound 9.08 was filtered off with a yield of 88.14percent. The crude compound III was beaten with 72.6 ml of ether at 15 ° C, filtered, washed and dried to give pure 8.82 g of compound III with a purity of 97.14percent. The total yield of compound III was 85.62percent and the purity was 99.10percent.To a cold (0 °C) solution ofbenzylated 6-chlorouracil 2 (10 g, 38 mmol) in DMF-THF (1:1, 300 mL) under nitrogen, was added NaH (60percent, 1.6 g, 39.9 mmol) in portions, followed by adding LiBr (2g). The mixture was stirred at r.t for 20 min. After adding iodomethane (5.4 mL, 76 mmol), the flask was sealed and stirred at this temperature for 10 min, rt for 2h, and 35 °C overnight, and then concentrated in vacuo. It will be understood that alkylation of the amine may be performed under standard conditions known in the art, including the use of a base such as NaH, LiH or the like in an organic solvent or mixture of solvents. The solvent may include DMSO, THF, DMF and the like, or mixtures thereof. In addition, additives may be used, including LiBr, LiI, NaI and the like. For example, the alkylation can be performed using methyliodide and KsCO3 in acetone. The reaction may be performed at about 15-45 °C, preferably at about 20-43 °C, and more preferably at about 35-41 °C until the reaction is complete. The residue was dissolved in CHCl3 and washed with water and brine, dried (Na2SO4), and filtered then concentrated in vacuo. The crude product was crystallized from THF-Hexanes to give 7.6 g (72percent) of the title compound 3. It will also be understood by those skilled in the art that the benzonitrile may be purified in a variety of organic solvents or solvent mixtures. For example, the benzonitrile can be purified by adding a mixture of dichloromethane and heptane. Optionally, the benzonitrile may be further purified in an organic solvent or mixture of solvents such as dichloromethane, chloroform, acetonitrile, THF, ethyl acetate, isopropyl acetate and the like. Preferably, the product is purified and washed with ethyl acetate. 1H NMR (400 MHz, DMSO): δ 7.87 (d, 1H, J = 7.6 Hz), 7.70 (t, 1H, J = 7.6 Hz), 7.51 (t, 1H, J = 7.6 Hz), 7.40 (d, 1H, J = 8 Hz), 6.21 (s, 1H), 5.38 (s, 2H), 3.28 (s, 3H). MS (ES) [m+H] calc'd for C13H11ClN3O2, 276.1; found 276.1.2-(6-Chloro-3-methyl-2, 4-dioxo-3, 4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile (C). l-(2-isocyanobenzyl)-3-methylpyrimidine-2, 4, 6(lH, 3H, 5H)-trione (30 g) was mixed with phosphorus oxychloride (300 ml) and cooled to 0°C. Water (9 ml) was added slowly, stirred for 10 min. and heated to reflux at 110°C for 5h. Progress of the reaction was monitored by TLC (50percent Ethyl acetate/Hexane). On completion of the reaction, phosphorus oxychloride was distilled off. The crude compound was dissolved in dichloromethane (500 ml) and poured into ice water (500 ml) by small portions. The layers were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined organic extracts were washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. The mixture of two isomers (4-chloro and 6-chloro derivatives = 1:1) was isolated and separated by column chromatography using neutral alumina and eluent - 25-50percent of ethylacetate and hexane). The off-white solid was obtained, yield - 37percent, purity - 99.8percent. 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.In an alternate embodiment, a solution of l-(2-isocyanobenzyl)-3-methylpyrimidine- 2, 4, 6(1 H, 3H, 5H)-trione (18 mmol), phosphorus oxychloride (85 ml), benzyltriethylammonium chloride (16.5 g, 72 mmol) and phosphorus pentachloride (3.8 g, 18 mol) in acetonitrile (80 ml) was refluxed for 4-5 h with stirring. After evaporation under reduced pressure, the resulting oily residue was mixed with methylene chloride (or chloroform) and the mixture was poured into water and ice (50 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined organic extracts were washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. Crude product was crystallized from THF-hexanes to give desired compound in 70.5percent yield.

Alogliptin (A575425) intermediate.

Molecular Weight:275.69
XLogP3:1.4
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:275.0461543
Monoisotopic Mass:275.0461543
Topological Polar Surface Area:64.4
Heavy Atom Count:19
Complexity:480
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes