| 80% |
With sodium hydrogencarbonate; In isopropyl alcohol; at 100℃; for 2h;Molecular sieve; |
General procedure: A mixture of 6c (8 g, 22.5 mmol), (R)-3-aminopiperidine dihydrochloride (4.67 g, 27 mmol), NaHCO3 (9.45 g, 112.5 mmol) and activated 4 A MS (2.6 g) in isopropanol (150 mL) was stirred at 100 C for 2 h. The reaction mixture was filtered through Celite and concentrated in vacuo. The residue was diluted with DCM, washed with water and saturated brine, dried over anhydrous Na2SO4, and concentrated. The crude product was purified by flash chromatography (DCM/MeOH/TEA, 100:0.5:0.5) to give pure 2h as a light yellow solid (8 g, 85%). |
| 72.79% |
With triethylamine; In water; isopropyl alcohol; at 60℃; for 13h; |
5.0 g of 2 - [(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H) -pyrimidinyl) methyl]Benzonitrile (Compound III, R1 is H), 3.30 g of (R) -3-aminopiperidine dihydrochloride and 8.00 g of triethylamine were dissolved in a mixed solution of 60 ml of isopropanol and 1 ml of water, and the temperature was raised to 60 C The reaction was stirred for 13h. The reaction was cooled to room temperature and 60 ml of a mixed solution of acetonitrile and heptane was slowly added dropwise. After stirring for 1 hour, the mixture was stirred under ice-cooling for 1 hour and filtered with suction to obtain 5.23 g of crude compound V with a yield of 84.97% and a purity of 95.80%. The crude compound was recrystallized from isopropanol, filtered, washed and dried to give 4.48 g of pure compound V. The purification yield was 85.66%. The total yield of compound V was 72.79% and the purity was 99.50%. |
| 70 - 76% |
With sodium hydrogencarbonate; In methanol; at 100℃; for 2h;Molecular sieve; |
2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2-H-pyrimidin-1-ylmethyl)-benzonitrile (330 mg, 1.08 mmol), (R)-3-amino-piperidine dihydrochloride (246 mg, 1.4 mmol) and sodium bicarbonate (500mg, 5.4 mmol) were stirred with 200 mg activated molecular sieves (4A) in dry MeOH (5 mL) at 100 C for 2 h. The reaction was filtered through Celite, concentrated in vacuo, and then diluted with CHCl3, and washed with water. The water phase was extracted with CHCl3 and the combined organic phases were washed with water, dried (Na2SO4), and filtered. TFA (1mL) was added into the solution which was then concentrated in vacuo. The residue was dissolved in a small amount of MeOH, and Et2O was added to force precipitation. The mixture was allowed to stand at RT overnight. It will be understood by those skilled in the art that condensation with the amine or amine hydrochloride may be performed in a solvent or mixture of solvents with a base, such as potassium carbonate, sodium bicarbonate and the like, or mixtures thereof. The solvent may comprise both protic and aprotic solvents, or mixtures thereof. For example, the solvent may comprise a mixture of isopropyl alcohol and water. Further, the reaction may be heated to about 30-100 C, preferably about 35-55 C, and more preferably about 45-50 C until the reaction is complete. Solvents were decanted, and the solid was washed with Et2O two times to give 270 mg product as off-white powder. It will also be understood that the product may be further purified by washing with an organic solvent or mixture of solvents. Non-limiting examples of solvent or solvent mixtures include isopropyl acetate, ethyl acetate, dichloromethane, heptane, and the like. Further, the product may optionally be purified by column chromatography. The benzonitrile product may be isolated as the free base if desired, but preferably, the product may be further converted to the corresponding acid addition salt, such as the benzoic acid salt. Preferably, the benzonitrile product is treated with benzoic acid to form 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile benzoate (4). Preparation and isolation of the benzoate salt may be performed by conventional methods for the formation of acid addition salts. 1H-NMR (400 MHz, CDCl3-CD3OD 10:1): delta 7.82 (d, 1H, J = 7.6 Hz), 7.65 (t, 1H, J = 7.6 Hz), 7.46 (t, 1H, J = 7.6 Hz), 7.23 (d, 1H, J = 8.0 Hz), 5.42 (s, 1H), 5.50-5.00 (ABq, 2H, J = 41.6, 15.2 Hz), 3.30 (m, 2H), 3.16 (s, 3H), 2.91 (m, 1H), 2.76 (m, 2H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 2H). MS (ES) [m+H] calc'd for C18H22N5O2, 340.2; found, 340.2. |
| 65.69% |
With potassium carbonate; In isopropyl alcohol; at 55 - 65℃;Large scale; |
(1) 176.8 kg of isopropanol and 18.20 kg of purified water were added to a 300 L glass-lined reactor, and stirring was started, followed by the addition of alogliptin intermediate I26.0 kg, R-3-aminopiperidine dihydrochloride 11.44 kg and Potassium carbonate 24.70 kg, stir well.(2) Heating and heating, so that the temperature in the glass-lined reactor is raised to 55~65 C, stirring, temperature control reaction for 16~20h, and TLC monitoring is started after 16h until the end of the reaction.(3) After the reaction is completed, the temperature is lowered to 40-45 C, filtered into a 300 L glass-lined concentrator. After the filtration is completed, the filtration is stopped. Then, 33.6 kg of isopropyl alcohol is added to the suction filter, the filter cake is thoroughly stirred, and then the filtration is continued. The filtrate was transferred to a 300 L stainless steel reaction vessel. After the 300 L glass-lined concentrate vessel was cleaned, the combined filtrate was transferred to a 300 L concentrator.(4) heating the concentrating kettle, heating the kettle to 60-70 C, opening the vacuum pump, decompressing the vacuum to a temperature between -0.080 and -0.096 MPa, and concentrating to dryness, as the liquid is discharged as a drying standard, and brown is obtained. Yellow semi-solid.(5) Add 33.6 kg of tetrahydrofuran to the concentrator again, continue to reduce the pressure, and make the vacuum between -0.080 and -0.096 MPa, keep the temperature in the concentrated kettle at 60-70 C, and continue to concentrate under reduced pressure until dry. The liquid flow is a dry standard and the distillation is stopped.(6) 185.1 kg of tetrahydrofuran was added, stirred to dissolve, and 45.0 kg of anhydrous sodium sulfate was added, and the mixture was stirred and dried for 10 hours.(7) Filtration into a 300L stainless steel reaction vessel, the filter cake was washed twice with 65.0 kg of tetrahydrofuran, and all the filtrates were combined and transferred to a 300 L glass-lined reactor, the temperature in the kettle was maintained at 60-70 C, and the filtrate was concentrated to dryness under reduced pressure. In view of the absence of liquid outflow as a drying standard.(8) Add 44.20kg of anhydrous ethanol, heat to dissolve it, slowly cool down to 5~10 C, and heat crystallization for 2h.(9) Centrifugation, wash the filter cake with 15.0kg of absolute ethanol at 5~10 C, dry it, transfer the solid to the tray, and dry it with blast at 6~10h at 50~60C to obtain white to yellow. 21.1 kg of solid, ie, alogliptin intermediate II, ie AGII, was sampled for intermediate detection content of 99.62%, yield 65.69%. |
|
With sodium hydrogencarbonate; In methanol; at 100℃; for 2h;Molecular sieve; |
2-{6-[3(R)-Amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile (D). 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2-H-pyrimidin-1-ylmethyl)-benzonitrile (330 mg, 1.08 mmol), (R)-3-amino-piperidine dihydrochloride (246 mg, 1.4 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred with 200 mg activated molecular sieves (4A) in dry MeOH (5 mL) at 100 C. for 2 h. The reaction was filtered through Celite, concentrated in vacuo, and then diluted with CHCl3, and washed with water. The water phase was extracted with CHCl3 and the combined organic phases were washed with water, dried (Na2SO4), and filtered. TFA (1 mL) was added into the solution which was then concentrated in vacuo. The residue was dissolved in a small amount of MeOH, and Et2O was added to force precipitation. The mixture was allowed to stand at RT overnight. Solvents were decanted, and the solid was washed with Et2O two times to give 270 mg product as off-white powder. 1H-NMR(400 MHz, CDCl3-CD3OD 10:1): delta 7.82 (d, 1H, J=7.6 Hz), 7.65 (t, 1H, J=7.6 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.23 (d, 1H, J=8.0 Hz), 5.42 (s, 1H), 5.50-5.00 (ABq, 2H, J =41.6, 15.2 Hz), 3.30 (m, 2H), 3.16 (s, 3H), 2.91 (m, 1H), 2.76 (m, 2H), 1.93 (m, 1H), 1.79 (m, 1H), 1.51 (m, 2H). MS (ES) [m+H] calc'd for C18H22N5O2, 340.2; found, 340.2. |
|
With sodium hydrogencarbonate; In water; isopropyl alcohol; at 70℃; for 40h;Product distribution / selectivity; |
Example 3:2-[6-[3(R)-Aminopiperidin-1 -yl]-3-methyl-2, 4-dioxo-1 , 2, 3, 4-tetrahydropyrimidin- c1 -ylmethyl]-benzonitrileA mixture of (R)-3-aminopiperidin.2HCI (0.70 g, 4.0 mmol) and NaHCO3 (1.70 g, 20.2 mmol) and H2O (1 ml) was stirred for 5 minutes. 2-Propanol (4 ml) und 6-chloro-2-(2- cyanobenzyl)-3-methyluracil (0.93 g, 3.4 mmol) were then added to the aqueous mix- ture. The mixture was then stirred at a bath temperature of about 700C for 40 hours. Most of 2-propanol was then removed from the reaction mixture by distillation in vacuo. To the residue was added CH2CI2 (25 ml) and H2O (15 ml). The layers were separated and the aqueous layer was extracted with CH2CI2 (15 ml). The combined organic layers were extracted twice with 1 M hydrochloric acid (25 and 10 ml). The acidic aqueous phase was washed with CH2CI2 (5 ml), pH was adjusted to approximately 7.5 by addition of solid NaHCO3 with stirring. The aqueous solution was then extracted twice with CH2CI2 (25 und 15 ml). The organic layer was dried with anhydrous MgSO4, filtered and concentrated to a volume of about 2 ml . To the residue was added n-hexane (5 ml) at room temperature within approximately 20 min with stirring. Crystals precipitated from the solution and the suspension was stirred at ambient temperature ( about 22C) for 4 hours. The crystals were then isolated by filtration, washed with n-hexane (5 ml) and dried in vacuo overnight.Yield: 0.87 g Water content (KF ): 0.25% |
| 42 g |
With sodium hydrogencarbonate; In methanol; at 65 - 70℃; for 6h;Molecular sieve; |
Step - III: Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-l(2H)-yl)methyl)benzonitrile (Alogliptin)Methanol (518 ml), 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin- l(2H)-yl)methyl)benzonitrile (41.5 gm), sodium bicarbonate (63 gm), (R)-piperidin-3- amine dihydrochloride salt (34 gm) and molecular sieves (25 gm) were added at room temperature under stirring. The temperature of the reaction mass was raised to 65 to 70C and maintained for 6 hours. The reaction mass was filtered through hi-flow bed and the solvent was distilled off under vacuum at low temperature to obtain a residual solid. To the residual solid was added water (275 ml) and pH was adjusted to 7.0. The reaction mass was extracted with methylene chloride and then the layers were separated. The organic layer was dried with sodium sulfate and then concentrated to obtain a solid. The solid obtained was then dried to obtain 42 gm of alogliptin |
|
With sodium hydrogencarbonate; In ethanol; at 75℃; for 6h;Green chemistry; |
2- (6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro -2H- pyrimidin-1-ylmethyl) - benzonitrile 79.62g (0.29mol), (R ) -3-amino-piperidine dihydrochloride 55.02g (0.32mol), sodium hydrogen carbonate 121.38g (1.45mol), ethanol 580mL, into 2L three-necked flask.Was stirred in an oil bath inner temperature was raised to 75 , heat the reaction was stirred 6h, heating was stopped, cooling was started, the temperature dropped to 60 ~ 70 , filtered off with suction, the filter cake was washed with small amount of absolute ethanol, the filtrate was collected.The filtrate was concentrated to dryness to give a yellow oil, after a clear solution with 350mL methylene chloride, with 1mol / L hydrochloric acid solution was adjusted pH = 2 ~ 3 (about 290 mL), allowed to stand and partitioned, the aqueous phase was separated.The organic phase was washed with water 240mL × 2 extraction, the aqueous phase were combined, washed once with 400 mL of ethyl acetate, was allowed to separate.Aqueous phase was added 350mL of methylene chloride, with 1mol / L aqueous sodium hydroxide solution adjusted pH = 10 ~ 11 (about 300 mL), stirred for 5min, allowed to stand, the organic phase was separated, the aqueous phase was extracted with dichloromethane 230mL × 2, The organic phases were combined, dried over anhydrous sodium sulfate, suction filtered, the filter cake was washed with a little dichloromethane, the filtrate was collected. The filtrate was concentrated to dryness to give a yellow oil, a clear solution was added 580mL ethanol, benzoic acid was added 35.29g (0.29 mol).Stirring was warmed to 70 , heat the reaction was stirred for 30min, and then stopped heating, cooled with stirring to 0 ~ 5 , crystallization was stirred 3h, filtered off with suction, the filter cake was washed with a little ethanol, scraped into the blast oven 45 dried overnight to give 100.12g alogliptin benzoate, yield 75.1%, purity 99.92%.Two steps 63.8% overall yield. |
| 138.63 g |
With sodium hydrogencarbonate; In ethanol; at 80℃; for 6h; |
Adding (compound) 119.45 g and stirring in absolute ethanol and 82.53 g of (R)-3-aminopiperidine dihydrochloride, 181.56 g of sodium hydrogencarbonate, refluxing at 80 C for 6 hours, cooling, suction filtration, extraction with dichloromethane and purified water, stirring to pH 3 with concentrated hydrochloric acid, extracted three times in a row, the aqueous layer was collected, followed by addition of dichloromethane, washed with sodium hydroxide solution to pH 10-11 with stirring down, water was added and extracted three times with dichloromethane layers were combined, dried, and rotary evaporated to give a pale yellow powder 138.63 g, mp: 126.0-128.0 C) |
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