Structure of 116247-92-8
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CAS No. : | 116247-92-8 |
Formula : | C9H11N3O |
M.W : | 177.20 |
SMILES Code : | C1=NC(=NC=C1)N2CCC(=O)CC2 |
MDL No. : | MFCD00231572 |
InChI Key : | ORFPLVFPQNNBST-UHFFFAOYSA-N |
Pubchem ID : | 1478856 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H317-H319-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | 6.10. Preparation of 2-r4-(Biphenyl-4-yloxy)-piperidin-l-yll-pyrimidine; To a solution of l-pyrimidin-2-yl-piperidin-4-one (50 mg, 0.282 mmol) in methanol (0.8 ml), was added sodium borohydride (12.0 mg, 0.282 mmol) at room temperature. After being stirred for 10 minutes, the mixture was treated with EtOAc (10 ml) and water (3 ml). The organic layer was washed with brine (2 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (20% EtOAc/hexanes) to give the corresponding alcohol (51 mg, 100%) as a white solid. To a mixture of the above alcohol (50 mg, 0.279 mmol), PPh3 (109.6 mg, 0.418 mmol) and biphenyl-4-ol (57.0 mg, 0.335 mmol) in THF (3 ml), was added DEAD (40% in toluene, 0.152 ml, 0.335 mmol) at O0C. After being stirred overnight, the mixture was treated with EtOAc (15 ml) and water (5 ml). The aqueous phase was extracted with EtOAc (2 x 5 ml). The combined organic layers were washed with brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (15% EtOAc/hexanes) to give the title compound (81 mg, 88%) as white crystals: 1U NMR (CDCl3, 400 MHz) delta 8.38 (d, J = 6.4 Hz, 2 H), 7.59-7.04 (m, 9 H), 6.61 (t, J= 6.4 Hz, 1 H), 4.62 (m, 1 H), 4.21 (m, 2 H), 3.68 (m, 2 H), 2.14 (m, 2 H), 1.83 (m, 2 H); MS calc'd for C2iH22N3O [M+H]+: 332; Found: 332. | |
100% | With sodium tetrahydroborate; In methanol; at 20℃; for 0.166667h; | 6.10. Preparation of 2-[4-(Biphenyl4-yloxy)-piperidin-1-yl]-pyrimidine To a solution of <strong>[116247-92-8]1-pyrimidin-2-yl-piperidin-4-one</strong> (50 mg, 0.282 mmol) in methanol (0.8 ml), was added sodium borohydride (12.0 mg, 0.282 mmol) at room temperature. After being stirred for 10 minutes, the mixture was treated with EtOAc (10 ml) and water (3 ml). The organic layer was washed with brine (2 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (20% EtOAc/hexanes) to give the corresponding alcohol (51 mg, 100%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With triethylamine; In ethanol;Heating / reflux;Product distribution / selectivity; | 5.1. Preparation of N-(3 '-chloro-3-methylbiphenyl-4-yl)-l-(pyrimidin-2- yl)piperidin-4-amineThe title compound was prepared stepwise, as described below. A. 1 -Pyrimidin-2-yl-piperidin-4-one : A mixture of 4-piperidone monohydrate hydrochloride (4.84 g, 31.5 mmol), 2-chloropyrimidine (3.44 g, 30 mmol) and TEA (10.04 ml, 72 mmol) in EtOH (150 ml) was heated at reflux for overnight. The mixture was concentrated to almost dry and diluted with EtOAc (400 ml). The EtOAc layer was washed with water (2 x 50 ml) and brine (2x50 ml). The aq layer was back extracted with EtOAc (4 x 100 ml). The combined EtOAc was dried (Na2SO4) and the solvent was removed. The residue was subjected to ISCO (12Og column, hexane 5 min., 0-80% EtOAc in hexane over 70 min., then EtOAc for 15 min) to give the titled compound (3.5 g, 66%). HPLC: column, Luna Phenyl-Hexyl 5 mum 4.6x50 mm, 10-90% solvent B (acetonitrile) in solvent A (10 mM ammonium acetate aq.) over 3 min., flow rate 3 ml/min, retention time, 0.97 and 1.08 min.; MS (MH+: 178).1H NMR (300 MHz, chloroform- d), delta ppm 2.52 (t, J=6.29 Hz, 4 H), 4.15 (t, J=6.20 Hz, 4 H), 6.60 (t, J=4.67 Hz, 1 H), 8.38 (d, J=4.77 Hz, 2 H). |
53% | A. 1 -Pyrimidin-2-yl-piperidin-4-one : To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with ethyl acetate (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40% ethyl acetate/hexanes) to give l-pyrimidin-2-yl-piperidin-4-one (320 mg, 53%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) delta 8.38 (d, J= 6.4 Hz, 2 H), 6.61 (t, J= 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H). | |
53% | A. 1 -Pyrimidin-2-yl-piperidin-4-one:; To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with ethyl acetate (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40% ethyl acetate/hexanes) to give l-pyrimidin-2-yl-piperidin-4-one (320 mg, 53%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) delta 8.38 (d, J= 6.4 Hz, 2 H), 6.61 (t, J= 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H). |
53% | In 1,4-dioxane; at 20 - 80℃; | 6.8. Preparation of Biphenyl-4-yl-fl-pyrimidin-2-yl-l,2,3i6-tetrahydro- pyridin-4-vl)-methanone; To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with EtOAc (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give l-pyrimidin-2-yl- piperidin-4-one (320 mg, 53%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) delta 8.38 (d, J = 6.4 Hz, 2 H), 6.61 (t, J = 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H). |
53% | In 1,4-dioxane; water; at 80℃; | To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 80 C. overnight and concentrated under reduced pressure. The residue was treated with EtOAc (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2×10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give 1-pyrimidin-2-yl-piperidin-4-one (320 mg, 53%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) delta 8.38 (d, J=6.4 Hz, 2 H), 6.61 (t, J=6.4 Hz, 9 H), 4.16 (t, J=5.6 Hz, 2 H), 2.53 (t, J=5.6 Hz, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With hydrogenchloride; In tetrahydrofuran; water; at 0 - 20℃; for 8h; | General procedure: To a solutionof N-heteroaryl-4-piperidone ethylene ketal (16ae or 16g)(1.20 mmol) in tetrahydrofuran (5 mL) was added 2 N hydrochloricacid solution (9 mL) dropwise at 0 C. After the addition wascomplete, the resulting mixture was stirred at room temperaturefor 8 h. Then aqueous saturated sodium hydrogen carbonate solutionwas added thereto, followed by extraction with ethyl acetate.The organic layer was washed with brine, dried over anhydroussodium sulfate, and concentrated in vacuum. The resulting residuewas purified by silica gel chromatography (dichloromethane/methanol, v/v, 99:1 to 95:5) to give the desired product. |
With sulfuric acid; In tetrahydrofuran; | B. 1-(2-Pyrimidinyl)-4-piperidinone A mixture of 8 g (0.036 mol) of the ketal of step A. above, 80 ml of 10% sulfuric acid solution, and 40 ml of tetrahydrofuran is stirred at ambient temperature for 3 days. The reaction mixture is diluted with water, basified with 2N sodium hydroxide solution and extracted with methylene chloride. The combined organic extracts are dried over Na2 SO4 and concentrated in vacuo to give a waxy solid. Trituration with ether affords 2.9 g (45%) of title compound: IR (KBr) 1710 and 1585 cm-1; NMR (CDCl3) delta 8.36 (d, 1H), 7.6 (t, 2H), 4.30-4.08 (m, 4H), and 2.62-2.46 (m, 4H). | |
With sulfuric acid; In tetrahydrofuran; | B. 1-(2-Pyrimidinyl)-4-piperidinone A mixture of 8 g (0.036 mol) of the ketal of step A, above, 80 ml of 10% sulfuric acid solution, and 40 ml of tetrahydrofuran is stirred at ambient temperature for 3 days. The reaction mixture is diluted with water, basified with 2N sodium hydroxide solution and extracted with methylene chloride. The combined organic extracts are dried over Na2 SO4 and concentrated in vacuo to give a waxy solid. Trituration with ether affords 2.9 g (45%) of title compound: IR (KBr) 1710 and 1585 cm-1; NMR (CDCl3) delta8.36 (d, 1H), 7.6 (t, 2H), 4.30-4.08 (m, 4H), and 2.62-2.46 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
B. (4-Bromo-2-methyl-phenyl)-( 1 -pyrimidin-2-yl-piperidin-4-yl)-amine : To the mixture of 4-bromo-2-methylaniline (285 mg, 1.5 mmol) and l-pyrimidin-2-yl-piperidin- 4-one (266 mg, 1.5 mmol) in MeOH/AcOH (10:1, 5 ml) was added BH3-Py in THF (8M, 188 mul). The mixture was stirred at rt for 2h. The reaction mixture was concentrated and to the residue was added HCl (10%, 10 ml). The resulting mixture was stirred at room temperature for 30 min., then with cooling, the mixture was adjusted to alkaline with solid Na2CO3 and water. The aqueous layer was extracted with EtOAc (5 x 30 ml). The EPO <DP n="19"/>EtOAc was dried (Na2SO4) and concentrated. The residue was subjected to ISCO to give the titled compound as a white solid (140 mg). HPLC: column, Luna Phenyl-Hexyl 5 mum 4.6x50 mm, 10-90% solvent B (acetonitrile) in solvent A (IO mM ammonium acetate aq) over 3 min., flow rate 3 ml/min, retention time, 2.71 min.; MS (MH+: 347 and 349). 1H NMR (400 MHz, chloroform- d), delta ppm 1.46 (ddd, J=24.30, 10.86, 4.04 Hz, 2H), 2.10 (s, 3 H), 2.17 (dd, J=13.14, 2.78 Hz, 2 H), 3.20 (ddd, J=14.00, 11.87, 2.78 Hz, 1 H), 3.40 (br. s., 1 H), 3.60 (br. s., 1 H), 4.68 (ddd, J=13.52, 3.41, 3.28 Hz, 2 H), 6.50 (t, J=4.67 Hz, 1 H), 6.57 (d, J=8.59 Hz, 1 H), 7.19 (s, 1 H), 7.23 (dd, J=8.59, 2.27 Hz, 1 H), 8.33 (d, J=4.80 Hz, 2 H).; B. (4-Bromo-2-methyl-phenyl)-( 1 -pyrimidin^-yl-piperidin^-yl)- amine : To the mixture of bromoaniline (285 mg, 1.5 mmol) and ketone (266 mg, 1.5 mmol) in MeOH/AcOH (10:1, 5 ml) was added BH3-Py in THF (8M, 188 mul). The mixture was stirred at rt for 2h. The reaction mixture was concentrated and to the residue was added HCl (10%, 10 ml). The resulting mixture was stirred at rt for 30 min., then with cooling, EPO <DP n="25"/>the mixture was adjusted to alkaline with solid Na2CO3 and water. The aq. layer was extracted with EtOAc (5x 30 ml). The EtOAc was dried (Na2SO4) and concentrated. The residue was subjected to ISCO to give the titled compound as a white solid (140 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The intermediates described below in Table 1 were prepared as follows: To 200 mg (1.130 mmol) of the appropriate ketone dissolved in 10 ml of 10% AcOH/MeOH was added 1.6 mmol (1.5 equiv) of the appropriate aniline, and then 0.14 ml (1.130 mmol) of 8 M BH3 py solution. The reaction mixture was stirred at rt for 2 hr and then the solvents were evaporated. To the residue was added 5 ml of 1 N HCl and stirred vigorously for about 5 min, and then 20 ml of DCM was added. Solid Na2CO3 was used to adjust the pH to 9. The organic layer was separated, and the aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine and dried over MgSO4. It was concentrated and purified by ISCO eluting with 5 -35% EtO Ac/hex. Yields on these reactions were all over 80%, except with the cyano anilines where the yields were about 22%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
D. To the mixture of bromoaniline (1.5 mmol) and ketone (266 mg, 1.5 mmol) in MeOH/ AcOH (10:1, 5 ml) was added BH3.Py in THF (8M, 188 mul). The mixture was stirred at rt for 2h. The reaction mixture was concentrated and to the residue was added HCl (10%, 10 ml). The resulting mixture was stirred at rt for 30 min., then with cooling, the mixture was adjusted to alkaline with solid Na2CO3 and water. The aq. layer was extracted with EtOAc (5x 30 ml). The EtOAc was dried (Na2SO4) and concentrated. The residue was subjected to ISCO to give the titled compound as a white solid (150 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A. (4-Bromo-2-fluoro-phenyl)-(l-pyrimidin-2-yl-piperidin-4-yl)-amine: To the mixture of bromoaniline (285 mg, 1.5 mmol) and ketone (266 mg, 1.5 mmol) in MeOH/AcOH (10:1, 5 ml) was added BH3-Py in THF (8M, 188 mul). The mixture was stirred at rt for 2h. The reaction mixture was concentrated and to the residue was added HCl (10%, 10 ml). The resulting mixture was stirred at rt for 30 min., then with cooling, the mixture was adjusted to alkaline with solid Na2CO3 and water. The aq. layer was extracted with EtOAc (5x 30 ml). The EtOAc was dried (Na2SO4) and concentrated. The residue was subjected to ISCO to give the titled compound as a white solid (230 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
C. (4-Bromo-3-fluoro-phenyl)-(l-pyrimidin-2-yl-piperidin-4-yl)- amine: To the mixture of bromoaniline (1.5 mmol) and ketone (266 mg, 1.5 mmol) in MeOH/ AcOH(10:1, 5 ml) was added BH3-Py in THF (8M, 188 mul). The mixture was stirred at rt for 2h. The reaction mixture was concentrated and to the residue was added HCl (10%, 10 ml). The resulting mixture was stirred at rt for 30 min., then with cooling, the mixture was adjusted to alkaline with solid Na2CO3 and water. The aq. layer was extracted with EtOAc (5x 30 ml). The EtOAc was dried (Na2SO4) and concentrated. The residue was subjected to ISCO to give the titled compound as a white solid (150 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In isopropyl alcohol; for 17h;Heating / reflux;Product distribution / selectivity; | A. 1 -Pyrimidin-2-yl-piperidin-4-one : 2-Propanol (125 ml) was added to a mixture of piperidine-4,4-diol hydrochloride (9.9g, 64.6 mmol), 2-chloropyrimidine (9.4 g, 81.8 mmol) and sodium bicarbonate (21.8g, 259.3 mmol). The rapidly stirred suspension was heated to reflux for 17 h, cooled, and filtered through celite, and evaporated to provide 13.2g of clear yellow oil which was used without further purification. MS: M+H = 178. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | To a stirred solution of N-(pyrimid-2-yl)-piperidin4-one (0.177 g, 1.0 mmol) in tetrahydrofuran (5 ml) at -70 C. under argon was added LDA (1.92M in THF) (0.57 ml, 1.1 mmol). The solution was stirred for 20 minutes, then a solution of N-phenyl-bis(trifluoromethane-sulfonimide) (0.382 g, 1.07 mmol) in THF (3 ml) was slowly added. The solution was stirred overnight with warming to ambient temperature. The solution was evaporated to dryness and purified by alumina MPLC [using a mixture of 5% ethyl acetate/hexane as eluant] to afford the title product. Yield=0.166 g (54%). NMR (250 MHz, CDCl3): delta: 2.55 (s, 2H), 4.10 (t2H), 4.39 (m, 2H), 5.88 (s, 1H), 6.55 (t, 1H), 8.35 (d, 2H). MS: ESP+(M+H)=310. | |
49% | B. Triflate: To a solution of LDA (prepared from diopropylamine (167.4 mg, 1.658 mmol) and n-BuLi (2.5 M in hexanes, 0.663 ml, 1.658 mmol) at -780C, was added a solution of the above l-pyrimidin-2-yl-piperidin-4-one (320 mg, 1.382 mmol). The mixture was stirred at the same temperature for 1 hour, followed by the addition of PhNTf2 (543.1 mg, 1.52 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 hours before it was quenched with the addition of saturated ammonium chloride (15 ml) and ethyl acetate (40 ml). After separation of the layers, the aqueous phase was extracted with ethyl acetate (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (20% ethyl acetate/hexanes) to give the corresponding triflate (210.7 mg, 49%) as a white solid as long with recovered starting material (142.9 mg): 1H NMR (CDCl3, 400 MHz) delta 8.37 (d, J= 6.4 Hz, 2 H), 6.59 (t, J= 6.4 Hz, 1 H), 5.91 (m, 1 H), 4.41 (m, 2 H), 4.11 (t, J= 5.6 Hz, 2 H), 2.55 (m, 2 H); MS calc'd for C10HnF3N3O3S [M+H]+: 310; Found: 310. | |
49% | B. Triflate:; To a solution of LDA (prepared from diopropylamine (167.4 mg, 1.658 mmol) and n-BuLi (2.5 M in hexanes, 0.663 ml, 1.658 mmol) at -780C, was added a solution of the above l-pyrimidin-2-yl-piperidin-4-one (320 mg, 1.382 mmol). The mixture was stirred at the same temperature for 1 hour, followed by the addition of PhNTf2 (543.1 mg, 1.52 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 hours before it was quenched with the addition of saturated ammonium chloride (15 ml) and ethyl acetate (40 ml). After separation of the layers, the aqueous phase was extracted with ethyl acetate (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (20% ethyl acetate/hexanes) to give the corresponding triflate (210.7 mg, 49%) as a white solid as long with recovered starting material (142.9 mg): 1H NMR (CDCl3, 400 MHz) delta 8.37 (d, J= 6.4 Hz, 2 H), 6.59 (t, J= 6.4 Hz, 1 H), 5.91 (m, 1 H), 4.41 (m, 2 H), 4.11 (t, J= 5.6 Hz, 2 H), 2.55 (m, 2 H); MS calc'd for C10HnF3N3O3S [M+H]+: 310; Found: 310. |
49% | 6.8. Preparation of Biphenyl-4-yl-fl-pyrimidin-2-yl-l,2,3i6-tetrahydro- pyridin-4-vl)-methanone; To a solution of 2-chloropyrimidine (300 mg, 2.619 mmol) in dioxane (5 ml), was added piperidin-4-one hydrochloride monohydrate (402.3 mg, 2.619 mmol) at room temperature. The mixture was heated at 8O0C overnight and concentrated under reduced pressure. The residue was treated with EtOAc (30 ml) and saturated NaHCO3 (10 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish a crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give l-pyrimidin-2-yl- piperidin-4-one (320 mg, 53%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) delta 8.38 (d, J = 6.4 Hz, 2 H), 6.61 (t, J = 6.4 Hz, 9 H), 4.16 (t, J= 5.6 Hz, 2 H), 2.53 (t, J= 5.6 Hz, 2 H); To a solution of LDA (prepared from diopropylamine (167.4 mg, 1.658 mmol) and n-BuLi (2.5 M in hexanes, 0.663 ml, 1.658 mmol) at -780C, was added a solution of the above l-pyrimidin-2-yl-piperidin-4-one (320 mg, 1.382 mmol). The mixture was stirred at the same temperature for 1 hour, followed by the addition OfPhNTf2 (543.1 mg, 1.52 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 hours before it was quenched with the addition of saturated ammonium chloride (15 ml) and EtOAc (40 ml). After separation of the layers, the aqueous phase was extracted with <n="55"/>EtOAc (2 x 10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (20% EtOAc/hexanes) to give the corresponding triflate (210.7 mg, 49%) as a white solid as long with recovered starting material (142.9 mg): 1U NMR (CDCl3, 400 MHz) delta 8.37 (d, J= 6.4 Hz, 2 H), 6.59 (t, J = 6.4 Hz, 1 H), 5.91 (m, 1 H), 4.41 (m, 2 H), 4.11 (t, J= 5.6 Hz, 2 H), 2.55 (m, 2 H); MS calc'd for CiOHnF3N3O3S [M+H]+: 310; Found: 310. | |
49% | To a solution of LDA (prepared from diisopropylamine (167.4 mg, 1.658 mmol) and n-BuLi (2.5 M in hexanes, 0.663 ml, 1.658 mmol) at -78 C., was added a solution of the above <strong>[116247-92-8]1-pyrimidin-2-yl-piperidin-4-one</strong> (320 mg, 1.382 mmol). The mixture was stirred at the same temperature for 1 hour, followed by the addition of PhNTf2 (543.1 mg, 1.52 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 hours before it was quenched with the addition of saturated ammonium chloride (15 ml) and EtOAc (40 ml). After separation of the layers, the aqueous phase was extracted with EtOAc (2*10 ml). The combined organic layers were washed with brine (10 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (20% EtOAc/hexanes) to give the corresponding triflate (210.7 mg, 49%) as a white solid as long with recovered starting material (142.9 mg): 1H NMR (CDCl3, 400 MHz) delta 8.37 (d, J=6.4 Hz, 2 H), 6.59 (t, J=6.4 Hz, 1 H), 5.91 (m, 1 H), 4.41 (m, 2 H), 4.11 (t, J=5.6 Hz, 2 H), 2.55 (m, 2 H); MS calc'd for C10H11F3N3O3S [M+H]+: 310; Found: 310. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | 6.12. Preparation of 4-(4'-Chloro-biphenyl-4-yl)-1-pyrimidin-2-yl-piperidin-4-ol To a solution of 1,4-dibromobenzene (213.3 mg, 0.904 mmol) in THF (4 ml), was added n-BuLi (2.5 M in hexanes, 0.362 ml, 0.904 mmol) at -78 C. After being stirred for 30 minutes at the same temperature, a solution of <strong>[116247-92-8]1-pyrimidin-2-yl-piperidin-4-one</strong> (80 mg, 0.452 mmol) in THF (3 ml) was added. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with addition of water (10 ml) and EtOAc (50 ml). The organic layer was washed with brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give 4-(4-Bromo-phenyl)-1-pyrimidin-2-yl-piperidin-4-ol as a colorless oil (140 mg, 93%): 1H NMR (CDCl3, 400 MHz) delta 8.33 (d, J=6.4 Hz, 2 H), 7.47 (d, J=12.0 Hz, 2 H), 7.41 (d, J=12.0 Hz, 2 H), 6.49 (t, J=6.4 Hz, 1 H), 4.72 (m, 2 H), 3.40 (m, 2 H), 2.05 (m, 2 H), 1.78 (m, 2 H); MS calc'd for C15H17BrN3O [M+H]+: 335; Found: 335. | |
6.12. Preparation of 4-(4'-Chloro-biphenyl-4-yl)-l-pyrimidin-2-yl-piperidin- 4-ol; To a solution of 1 ,4-dibromobenzene (213.3 mg, 0.904 mmol) in THF (4 ml), was added /?-BuLi (2.5 M in hexanes, 0.362 ml, 0.904 mmol) at -780C. After being stirred for 30 minutes at the same temperature, a solution of l-pyrimidin-2-yl-piperidin-4-one (80 mg, 0.452 mmol) in THF (3 ml) was added. The mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was quenched with addition of water (10 ml) and EtOAc (50 ml). The organic layer was washed with brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (40% EtOAc/hexanes) to give 4-(4- Bromo-phenyl)-l-pyrimidin-2-yl-piperidin-4-ol as a colorless oil (140 mg, 93%): 1H NMR (CDCl3, 400 MHz) delta 8.33 (d, J= 6.4 Hz, 2 H), 7.47 (d, J= 12.0 Hz, 2 H), 7.41 (d, J = 12.0 Hz, 2 H), 6.49 (t, J= 6.4 Hz, 1 H), 4.72 (m, 2 H), 3.40 (m, 2 H), 2.05 (m, 2 H), 1.78 (m, 2 H); MS calc'd for Ci5Hi7BrN3O [M+H]+: 335; Found: 335. |
Yield | Reaction Conditions | Operation in experiment |
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74% | With (R)-10-camphorsulfonic acid; magnesium sulfate; In ISOPROPYLAMIDE; at 100℃; for 1h; | A mixture of 3-amino-5- (5-methyl-lH-pyrazol-4- yl) thiophene-2-carboxamide (111 mg, 0.50 mmol) , l-(2- pyrimidinyl) -piperidin-4-one (266 mg, 1.50 mmol), CSA (11.6 mg, 0.05 mmol), MgSO4 (120 mg, 1.00 mmol) and DMA (4 mL) was stirred at 1000C for 1 h. The mixture was poured into saturated aqueous NaHCO3 and extracted with 3:1 EtOAc/THF, and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, EtOAc to 80:20 EtOAc/MeOH) . The obtained yellow solid was triturated with MeOH/EtOAc and collected by filtration to afford the title compound (141 mg, 74%) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) 6 1.74-1.98 (4H, m) , 2.34-2.40 (3H, m) , 3.55-3.64 (2H, m) , 4.12-4.20 (2H, m) , 6.60-6.63 (2H, m) , 7.24 (IH, br s) , 7.52 (IH, br s) , 7.71 (0.67H, br s) , 8.08 (0.33H, br s) , 8.35-8.37 (2H, m) , 12.79 (0.33H, br s) , 12.87 (0.67H, br s) . |
Yield | Reaction Conditions | Operation in experiment |
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32.9 mg | To a mixture of (trans)-2-((E)-l-phenylprop-l-en-2-yl)cyclopropan-l-amine (110.00 mg, 634.92 umol, 1.00 eq) and l-(pyrimidin-2-yl)piperidin-4-one (112.51 mg, 634.92 umol, 1.00 eq) in DCE (2.00 mL) was added acetic acid (38.13 mg, 634.92 umol, 1.00 eq) and the mixture was stirred at 20 C for 2 h. NaBH3CN (79.80 mg, 1.27 mmol, 2.00 eq) was added to the mixture and the reaction was stirred at 20 C for 2 h. The mixture was concentrated and the crude residue was purified by prep-HPLC (HQ) to afford N-((trans)-2- ((E)- 1-phenylprop- l-en-2-yl)cyclopropyl)- l-(pyrimidin-2-yl)piperidin-4-amine hydrochloride (32.90 mg) as a yellow solid. LCMS (M + H+) m/z: 335. 1H NMR (400MHz, METHANOL-d4) delta = 8.51 (d, J=5.0 Hz, 2H), 7.37 - 7.29 (m, 2H), 7.26 - 7.18 (m, 3H), 6.86 (t, J=5.0 Hz, 1H), 6.45 (s, 1H), 4.83 (d, J=14.6 Hz, 2H), 3.76 - 3.67 (m, 1H), 3.21 (t, J=13.1 Hz, 2H), 3.00 (td, J=4.0, 7.7 Hz, 1H), 2.35 (d, J=12.0 Hz, 2H), 2.18 - 2.12 (m, 1H), 1.85 (s, 3H), 1.80 - 1.68 (m, 2H), 1.40 - 1.28 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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21.54% | With triethylamine; In 1,4-dioxane; at 90℃; for 12h; | To a mixture of 2-chloropyrimidine (300.00 mg, 2.62 mmol, 1.00 eq) and piperidin-4-one (311.59 mg, 3.14 mmol, 1.20 eq) in dioxane (5.00 mL) was added triethylamine (795.35 mg, 7.86 mmol, 3.00 eq) and the mixture was stirred at 90 C for 12 h. The mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (Si02, PE/EA=10/1 to 1/1) to afford l-pyrimidin-2-ylpiperidin-4- one (100.00 mg, 564.33 umol, 21.54% yield) as a yellow solid. 1H NMR (400MHz, CHLOROFORM-d) delta = 8.37 (d, J=4.9 Hz, 2H), 6.59 (t, J=4.6 Hz, 1H), 4.21 - 4.11 (m, 4H), 2.51 (t, J=6.2 Hz, 4H). |
Yield | Reaction Conditions | Operation in experiment |
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77% | General procedure: Pyrrolidine (10.5 mmol, 1.05 equiv)was added to a solution of 4-piperidone (19am or 19or) (10 mmol, 1.0 equiv) in isopropanol(20 mL). The reaction mixture was stirred at 55 C for 2 h. The reactionmixture was cooled to room temperature. Then elementalsulfur (10 mmol, 1.0 equiv) was added in one portion, followed bydropwise addition of the solution of cyanamide (10.5 mmol, 1.05equiv) in isopropanol (10 mL) at 0 C. The reaction mixture wasstirred for 6 h at room temperature. The reaction mixture wasfiltered and solid was washed with ethyl acetate, then dried undervacuum to obtain the desired product. |