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CAS No. : | 22536-65-8 | MDL No. : | MFCD08702770 |
Formula : | C5H5ClN2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RSUBGBZOMBTDTI-UHFFFAOYSA-N |
M.W : | 144.56 | Pubchem ID : | 589058 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.2 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 33.53 |
TPSA : | 35.01 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.37 cm/s |
Log Po/w (iLOGP) : | 1.81 |
Log Po/w (XLOGP3) : | 1.14 |
Log Po/w (WLOGP) : | 1.14 |
Log Po/w (MLOGP) : | -0.07 |
Log Po/w (SILICOS-IT) : | 1.56 |
Consensus Log Po/w : | 1.12 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.88 |
Solubility : | 1.9 mg/ml ; 0.0131 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.47 |
Solubility : | 4.91 mg/ml ; 0.0339 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.37 |
Solubility : | 0.612 mg/ml ; 0.00424 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.85 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
55% | With ammonia In water at 150℃; for 3 h; Irradiation | A MW reaction vessel was charged with 2-chloro-5- methoxypyrimidine (0.817 g, 5.65 mmol) and 25percent NH3(aq). The vessel was capped and heated to 150 0C for 3h. The mixture was evaporated to dryness. The resulting material was dissolved in CH2Cl2MeOH (1 : 1) and adsorbed onto silica. Purification by flash CC (eluent: 50-100 percent EtOAc in heptane) gave the title compound as colorless crystals (386 mg, 55percent). 1H NMR (400 MHz, dmso-d6) δ 8.02 (s, IH), 6.06 (br s, IH), 3.71 (s, 3H). |
45% | at 100℃; for 18 h; Sealed tube | A mixture of 2-chloro-5-methoxypyrimidine (7 g, 48.4 mmol) and ammonium hydroxide (113 mL, 2905 mmol) was heated at 100 °C in a sealed tube for 18 h. The mixture was cooled to rt and was concentrated. The residue was was purified on silica gel using 40-80 percent ethyl acetate in hexanes. The desired fractions were concentrated to give a pale yellow solid (2.75 g, 45 percent). 1H NMR (400 MHz, CDCl3) d ppm 8.02 (2 H, s), 4.80 (2 H, br. s.), 3.79 (3 H, s). LCMS (method B) tR, 0.81 min., MH+ = 293.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: With boron tribromide In dichloromethane at 20℃; Stage #2: With sodium hydrogencarbonate In dichloromethane; water |
2-Chloro-5-methoxypyrimidine (0.46 g, 3.18 mmol) in methylene chloride (10 mL) was treated with 1.0 N boron tribromide (16 mL, 16 mmol) at room temperature. The solution was stirred overnight. After this time the reaction was partitioned between saturated NaHCO3 and DCM. The aqueous layer was extraxted with additional DCM. The combined organic layers were dried (MgSO4), filtered, and concnetrated. The residue was purified by flash column chromatography on silica gel to give 0.26 g of compound 112A (62percent): 1H NMR (DMSO-D6): δ 10.03 (s, IH), 8.30 (s, 2H), ESI (-)/MS: 129 (M-H)-. |
61% | With boron tribromide In dichloromethane at 20℃; for 20 h; | Intermediate 4: 2-Chloro-5-hydroxypyrimidineTo a solution of 2-chloro-5-methoxypyrimidine (lOg, 0.069mol) in dichloromethane (84mL) was added dropwise boron tribromide (104mL, 1M solution in dichloromethane) at -78°C. The mixture was stirred at room temperature for 20h and then methanol (150mL) was added dropwise at -78°C. The reaction mixture was concentrated under reduced pressure and the pH adjusted to 5 with aq. sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure to give 2-chloro-5-hydroxypyrimidine (5.7g, 61percent).Mass: (ES-) 129NMR: 5H (d6-DMSO) 8.27 (2H, s) and 10.85 (1H, br s). |
55% | Stage #1: With boron tribromide In dichloromethane at -78 - 20℃; for 20 h; Stage #2: With methanol In dichloromethane at -78℃; Stage #3: With sodium hydroxide In methanol; water |
Intermediate 4: 2-Chloro-5-hydroxypyrimidine To a solution of 2-chloro-5-methoxypyrimidine (lOg, 0.069mol) in dichloromethane (84mL) was added dropwise boron tribromide (104mL, 1M solution in dichloromethane) at -78°C. The mixture was stirred at room temperature for 20h and then methanol (150mL) was added dropwise at -78°C. The reaction mixture was concentrated under reduced pressure and the pH adjusted to 5 with aq. sodium hydroxide solution. The mixture was extracted with ethyl acetate and washed with water and brine. The organic phase was dried (MgS04) and the solvent removed under reduced pressure to give 2-chloro-5-hydroxypyrimidine (5.0g, 55percent).Mass: (ES-) 129NMR: 5H (d6-DMSO) 8.27 (2H, s) and 10.85 (1H, br s). |
27% | With boron tribromide In dichloromethane at 0 - 20℃; for 16 h; | Boron tribromide (30mL) was slowly added to a solution of 2-chloro-5-methoxypyrimidine (2g, 13.83mmol) in DCM (lOmL) at 0 °C. Allowed the reaction mass to stir at room temperature for 16h. Then the reaction mixture was slowly quenched with ice cold water, warmed to room temperature and diluted with DCM (lOOmL). The aqueous layer was separated and extracted with DCM (3x25mL). The organic phase was washed with brine, dried over Na2S04, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography to afford desired title compound (0.5g, 27percent) as a solid. LCMS: m/z = 129.0 (M-H)+ (Negative mode). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With water; zinc In ethanol for 4 h; Reflux | Intermediate 3: 2-Chloro-5-methoxypyrimidine2,4-Dichloro-5-methoxypyrimidine (43g, 0.24mol), zinc dust (86g, 1.32mol), ethanol (200 mL) and water (200 mL) were heated under reflux for 4h. The hot mixture was filtered and the ethanol was removed under reduced pressure. After cooling, the product was collected in ether. Recrystallisation from light petroleum (b.p.: 40-60°C) gave 2-chloro-5-methoxypyrimidine (20g, 58percent). |
58% | With zinc In ethanol; water for 4 h; Reflux | Intermediate 3: -Chloro-5-methoxypyrimidine2,4-Dichloro-5-methoxypyrimidine (43g, 0.24mol), zinc dust (86g, 1.32mol), ethanol (200 mL) and water (200 mL) were heated under reflux for 4h. The hot mixture was filtered and the ethanol was removed under reduced pressure. After cooling, the product was extracted into diethyl ether. Recrystallisation from light petroleum (b.p.: 40-60°C) gave 2-chloro-5-methoxypyrimidine (20g, 58percent).Mass: (ES+) 145 (M+H)+ NMR: 5H ( 6-DMSO) 3.92 (3H, s) and 8.55 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In acetonitrile; at 200℃; for 0.866667h;Microwave irradiation; | A. (3f-Chlorobiphenyl-4-yl)(l-(4-methoxypyrimidin-2-yl)piperidin-4- yDmethanone: A suspension of (3' -chlorobiphenyl-4-yl)(piperidin-4-yl)methanone (0.44 g, 1.31 mmol), l-chloro-4-methoxypyrimidine (0.19 g, 1.31 mmol), triethylamine (0.36 ml, 1.32 mmol) and acetonitrile (3 ml) was microwaved at 2000C for 52 minutes. The mixture was cooled and concentrated in vacuo. To the residue was added methylene chloride (50 ml) and the organic phase was washed with brine, a saturated solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (SiO2: methylene chloride ) to yield 0.20 g of (3'- chlorobiphenyl-4-yl)(l-(4-methoxypyrimidin-2-yl)piperidin-4-yl)methanone as a clear oil. The spectral data was consistent with structure: 1H NMR (CDCl3): delta 8.05 (2H, s), EPO <DP n="20"/>7.95 (2H, m). 7.43 (6H, m), 4.65 (2H, d), 3.74 (3H, s), 3.48 (IH, m), 3.03( 2H, m), 1.77 (H, m). MS (M+ 1) = 408. | |
With triethylamine; In acetonitrile; at 200℃; for 0.866667h;microwave irradiation; | A. (3f-Chlorobiphenyl-4-yl)(l-(4-methoxypyrimidin-2-yl)piperidin-4- vDmethanone:; A suspension of (3' -chlorobiphenyl-4-yl)(piperidin-4-yl)methanone (0.44 g, 1.31 mmol), l-chloro-4-methoxypyrimidine (0.19 g, 1.31 mmol), triethylamine (0.36 ml, 1.32 mmol) and acetonitrile (3 ml) was microwaved at 2000C for 52 minutes. The mixture was cooled and concentrated in vacuo. To the residue was added methylene chloride (50 ml) and the organic phase was washed with brine, a saturated solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (SiO2: methylene chloride ) to yield 0.20 g of (3'- chlorobiphenyl-4-yl)(l-(4-methoxypyrimidin-2-yl)piperidin-4-yl)methanone as a clear oil. The spectral data was consistent with structure: 1H NMR (CDCl3): delta 8.05 (2H, s), <n="20"/>7.95 (2H, m). 7.43 (6H, m), 4.65 (2H, d), 3.74 (3H, s), 3.48 (IH, m), 3.03( 2H, m), 1.77 (H, m). MS (M+ 1) = 408. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.6% | With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 100℃; for 0.833333h; | Preparation 18 2-(4-Chlorophenyl)-5-methoxypyrimidine 4-Chlorobenzeneboronic acid (7.25 g, 46.35 mmol) was added to a stirred solution of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (6.70 g, 46.35 mmol) in 1,4-dioxane (66 mL) and water (33 mL). Potassium carbonate (6.41 g, 46.35 mmol) and tetrakis(triphenylphosphine) palladium(0) (2.68 g, 46.35 mmol) were added and the resulting mixture was stirred at 100° C. for 50 minutes. The mixture was partitioned between diethyl ether (350 mL) and aqueous sodium hydroxide solution (1M, 200 mL). The aqueous layer was re-extracted with diethyl ether (2*100 mL). The combined organic extracts were dried over sodium sulphate, filtered through a plug of silica and concentrated under reduced pressure to afford the title compound, after trituration with diethyl ether (100 mL), as a white solid in 39.6percent yield, 4.05 g. LRMS ES m/z 221 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With water; zinc; In ethanol; for 4h;Reflux; | Intermediate 3: 2-Chloro-5-methoxypyrimidine2,4-Dichloro-5-methoxypyrimidine (43g, 0.24mol), zinc dust (86g, 1.32mol), ethanol (200 mL) and water (200 mL) were heated under reflux for 4h. The hot mixture was filtered and the ethanol was removed under reduced pressure. After cooling, the product was collected in ether. Recrystallisation from light petroleum (b.p.: 40-60°C) gave 2-chloro-5-methoxypyrimidine (20g, 58percent). |
58% | With zinc; In ethanol; water; for 4h;Reflux; | Intermediate 3: -Chloro-5-methoxypyrimidine2,4-Dichloro-5-methoxypyrimidine (43g, 0.24mol), zinc dust (86g, 1.32mol), ethanol (200 mL) and water (200 mL) were heated under reflux for 4h. The hot mixture was filtered and the ethanol was removed under reduced pressure. After cooling, the product was extracted into diethyl ether. Recrystallisation from light petroleum (b.p.: 40-60°C) gave 2-chloro-5-methoxypyrimidine (20g, 58percent).Mass: (ES+) 145 (M+H)+ NMR: 5H ( 6-DMSO) 3.92 (3H, s) and 8.55 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With caesium carbonate; In 1-methyl-pyrrolidin-2-one; at 80℃; for 74h; | Example 72 N-[1-(5-methoxypyrimidin-2-yl)piperidin-4-yl]-6-[5-(methylsulfonyl)-2,3-dihydro-1H-indol-1-yl]-N-(trifluoromethyl)pyrimidin-4-amine; [Show Image] 6-[5-(Methylsulfonyl)-2,3-dihydro-1H-indol-1-yl]-N-(piperidin-4-yl)-N-(trifluoromethyl)pyrimidin-4-amine (100 mg, 0.227 mmol) obtained in Reference Example 34 and <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (131 mg, 0.906 mmol) were dissolved in NMP (5.0 mL). Cesium carbonate (295 mg, 0.906 mmol) was added thereto, and the mixture was stirred at 80°C for 74 hr. After cooling to room temperature, the mixture was diluted with ethyl acetate, and water was added thereto. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=6:4 (volume ratio)-->hexane:ethyl acetate=2:8 (volume ratio)], and the obtained solid was suspended in diisopropyl ether. The precipitate was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to give the title compound (17.8 mg, yield 14percent) as a white solid. 1H-NMR (300 MHz, CDC13) delta:1.90 - 2.03 (m, 2 H), 2.04 - 2.24 (m, 2 H), 2.93 (t, J=12.7 Hz, 2 H), 3.04 (s, 3 H), 3.32 (t, J=8.7 Hz, 2 H), 3.81 (s, 3 H), 4.12 (t, J=8.9 Hz, 2 H), 4.69 - 4.88 (m, 3 H), 6.24 - 6.31 (m, 1 H), 7.73 (d, J=1.1 Hz, 1 H), 7.80 (dd, J=8.7, 1.9 Hz, 1H), 8.10 (s, 2 H), 8.56 (d, J=8.7 Hz, 1 H), 8.62 (d, J=1.1 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26.7% | With potassium carbonate; In isopropyl alcohol; at 100℃; for 4h;Microwave irradiation; | Example 1.40: Preparation of 4-((lr,4r)-4-(l-(5-Methoxypyrimidin-2-yl)piperidin-4- yloxy)cyclohexyloxy)nicotinonitrile (Compound 39).A mixture of 4-((lr,4r)-4-(piperidin-4-yloxy)cyclohexyloxy)nicotinonitriledihydrochloride (25 mg, 66.79 muiotaetaomicron), <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (30 mg, 0.208 mmol), and potassium carbonate (50 mg, 0.362 mmol) in PrOH (1 mL) was heated under microwave irradiation at 100 °C for 4 h. Mixture was purified by HPLC (CH3CN/H20 gradient + 0.5percentTFA). Fractions containing product were partly concentrated and residue was portioned between 1 M NaOH and CH2C12. The organic phases were dried over MgS04, filtered, and concentrated to give 4-((lr,4r)-4-(l-(5-methoxypyrimidin-2-yl)piperidin-4- yloxy)cyclohexyloxy)nicotinonitrile (7.3 mg, 17.83 muiotaetaomicron, 26.7 percent) as a white solid. Exact mass calculated for C22H27N503: 409.2, found: LCMS mlz = 410.4 [M+H]+; lU NMR (400 MHz, CDC13) 8 ppm 1.51 -1.62 (m, 4H), 1.68-1.78 (m, 2H), 1.85-1.93 (m, 2H), 1.97-2.03 (m, 2H), 2.08-2.17 (m, 2H), 3.27-3.36 (m, 2H), 3.60-3.68 (m, 2H), 3.80 (s, 3H), 4.20-4.27 (m, 2H), 4.56- 4.63 (m, 1H), 6.88 (d, J = 6.06 Hz, 1H), 8.09 (s, 2H), 8.59 (d, J = 6.06 Hz, 1H), 8.67 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; at 100℃; for 1.25h;Inert atmosphere; | 2-Chloro-5-methoxypyrimidine (0.96 g, 6.62 mmol), PdCl2(dppf DCM adduct (0.54 g, 0.66 mmol), Na2C03 (6.62 mL, 13.24 mmoL) and 3-chlorophenylboronic acid (1.55 g, 9.93 mmol) were taken up in 1 ,4-dioxane (9.6 mL). The flask was evacuated and back-filled with N2 (X3) before stirring at 100 °C for 75 minutes. Room temperature was attained, saturated NH4CI was added and the products extracted into EtOAc (X2). The combined organic extracts were washed with brine, dried over MgS04, filtered through Celite and concentrated in vacuo. Purification- of the residue by flash chromatography (MPLC, 1 -20percent EtOAc-hexanes) gave 2-(3- chlorophenyl)-5-methoxypyrimidine as a white solid.LRMS (ESI) calc'd for CI 1H10C1N2O [M+H]+: 221, Found: 221. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35.8% | With tetrakis(triphenylphosphine) palladium(0); In toluene;Inert atmosphere; Reflux; | Weigh <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> 3g (20.8mmol, 1.0eq) and Pd(PPh3)41.2 mg (1.08 mmol, 0.05 eq) in a 100 mL two-necked flask,Under the protection of argon atmosphere, add 20 mL of anhydrous toluene and stir.Then add hexabutyldistannane15mL (31.1mmol, 1.5eq),Heated to reflux,The reaction was overnight.Allow to cool to room temperature,The reaction solution was added with 150 mL of ethyl acetate and 250 mL of water.Mix well and separate the organic phase,The aqueous phase was extracted with ethyl acetate (100 mL×2) and washed with a saturated NaCI solution (200 mL×2);Dry over anhydrous MgSO4, filtered and evaporated.Purification by flash column chromatography (10percent EA/PE),A colorless transparent liquid of 2.9 g was obtained; the yield was 35.8percent. |
With tetrakis(triphenylphosphine) palladium(0); In toluene; for 15h;Inert atmosphere; Reflux; | Example 138 A mixture of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (1.5 g, 6.38 mmol, 1.0 eq), bis(tri-butyltin) (4.07 g, 7.01 mmol, 1.1 eq), Pd(PPh3)4 (368 mg, 0.319 mmol, 0.05 eq) in toluene (20 mL) was stirred under argon at reflux for 15 h. The mixture was allowed to cool to RT and then filtered. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (0-5% MeOH-DCM) to afford the tri-butylstannane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | Example 3 (-)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-methoxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol To 100 mg (0.15 mmol) of (-)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 64 mg (0.44 mmol) of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> and 1 ml of 1,4-dioxane were added, and the reaction solution was stirred at 80° C. for 26.6 hours. After completion of the reaction, 0.5 ml of 6 N hydrochloric acid was added to the reaction solution and the mixture was stirred at 50° C. for 8 hours. After completion of the reaction, saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=4/1 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. n-Hexane was added to the obtained residue and the precipitate was obtained by filtration to provide 44 mg of the title compound as a white powder (yield: 45percent). Specific optical rotation: [alpha]D27=-85° (C=0.13, methanol). 1H-NMR spectrum (300 MHz, CDCl3) delta ppm: 8.04 (2H, s), 7.63 (2H, d, J=8 Hz), 7.36 (2H, d, J=8 Hz), 7.20 (1H, d, J=48 Hz), 5.12 (1H, dt, J=6, 6 Hz), 4.72-4.61 (1H, m), 4.44-4.32 (1H, m), 3.77 (3H, s), 3.71-3.54 (1H, m), 2.91-2.57 (4H, m), 2.39-1.61 (15H, m), 1.15 (3H, s), 1.00 (3H, s), 0.70-0.56 (1H, m). Mass spectrum (EI, m/z): 662 [M+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.1% | With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 48h;Sealed tube; | To a stirred solution of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (1 g, 6.92 mmol) in DMF (20 mL) was added tert-butyl piperazine-1-carboxylate (1.2 g, 6.44 mmol) and TEA (3 mL, 21.52 mmol) in a sealed tube mixture was stirred at 60 °C for 48 h. The completion of the reaction was monitored by LCMS. The solvent was removed under reduced pressure to get cmde residue, which was dissolved in ethyl acetate (100 mL) and washed with water (2* 100 mL), the organic layer was dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to get crude (1.5 g) as brown liquid. The crude compound was purified by combi (24g silica gel column, eluted with 15percent ethyl acetate / Pet ether) to get tert-butyl 4-(5- methoxypyrimidin-2-yl)piperazine- 1 -carboxylate (550 mg, 1.738 mmol, 25.1 percentyield) as off white solid.LCMS: Column-Ascentis Express C18 (50X2.lmm-2.7iim), Mphase A: 10mM NH4COOH IN WATER:ACN(98:02), Mphase B: 10mM NH4COOH IN WATER:ACN(02:98), Flow = 1ML/MIN, Time: percentB:: 0.0 : 0.0:: 1.7: 100.0:: 3.0:100.0:: 3.2: 0.0, LCMS RT = 2.2 mm M(+1) -295. |
957 mg | With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 144h; | 6.01.02.01 4-(5-methoxy-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester 1.5 g piperazine-1-carboxylic acid tert-butyl ester was added to 1.2 g <strong>[22536-65-8]2-chlor-5-methoxy-pyrimidine</strong> and 2.2 mL triethylamine in 30 mL DMF. The reaction was stirred 6 days at 60° C. The solvent was removed and the residue was dissolved in dichlormethane and extracted with water. The organic layer was washed with a saturated sodiumchloride-solution and evaporated. The residue was purified by HPLC to give 957 mg desired product. Rt: 0.82 min (method E), (M+H)+: 295 |
957 mg | With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 144h; | 6.01.02.01 4- 5-methoxy-pyrimidin-2-yl)-piperazine- 1 -carboxylic acid tert-butyl ester 1.5 g piperazine-1 -carboxylic acid tert-butyl ester was added to 1.2 g 2-chlor-5-methoxy- pyrimidine and 2.2 mL triethylamine in 30 mL DMF. The reaction was stirred 6 days at 60°C. The solvent was removed and the residue was dissolved in dichlormethane and extracted with water. The organic layer was washed with a saturated sodiumchloride-solution and evaporated. The residue was purified by HPLC to give 957 mg desired product. Rt: 0.82 min (method E), (M+H)+: 295 |
957 mg | With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 144h; | 6.02.08.01 4- 5-methoxy-pyrimidin-2-yl)-piperazine-l-carboxylic acid tert-butyl ester 1.5 g piperazine-l-carboxylic acid tert-butyl ester was added to 1.2 g 2-chlor-5-methoxy- pyrimidine and 2.2 mL triethylamine in 30 mL DMF. The reaction was stirred 6 days at 60°C. The solvent was removed and the residue was dissolved in dichlormethane and extracted with water. The organic layer was washed with a saturated sodium chloride solution and evaporated to give 957 mg desired product. Rt: 0.82 min (method E), (M+H)+: 295 |
957 mg | With triethylamine; In N,N-dimethyl-formamide; at 60℃; for 144h; | 6.02.08.01 4-(5-methoxy-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester 1.5 g piperazine-1-carboxylic acid tert-butyl ester was added to 1.2 g <strong>[22536-65-8]2-chlor-5-methoxy-pyrimidine</strong> and 2.2 mL triethylamine in 30 mL DMF. The reaction was stirred 6 days at 60° C. The solvent was removed and the residue was dissolved in dichlormethane and extracted with water. The organic layer was washed with a saturated sodium chloride solution and evaporated to give 957 mg desired product. Rt: 0.82 min (method E), (M+H)+: 295 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate; In N,N-dimethyl-formamide; at 100℃;Inert atmosphere; | 2-((l-S,2i?)-2-(Piperidin-4-yl)cyclopropyl)ethanol (2.5 g, 14.77 mmol) was dissolved in DMF (30 ml) at RT under N2 and cesium carbonate (7.22 g, 22.15 mmol) was added. The mixture was stirred at RT for 5 min and <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (2.56 g, 17.72 mmol) was added. The mixture was stirred at 100 °C overnight. The mixture was diluted with EtOAc (100 ml), washed with sat. NH4C1 (100 ml), dried over MgS04, and the concentrated in vacuo. The crude material was purified by silica gel column (100 g SNAP, 20-60percent EtOAc in hexane) to afford the title compound as a white solid. LC/MS (m/z): 278 (M+H)+ Rf was 0.4 50percent EtOAc in hexanes (blue spot on CAM stain). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With copper; potassium carbonate; In N,N-dimethyl-formamide; at 120℃; for 16h; | 2-Chloro-5-methoxypyrimidine (8-1, 5.13 g, 35.6 mmol) and 1-(4-hydroxy-2,6- dimethylphenyl)ethanone (4-2, 6.10 g, 37.2mmol) were suspended in DMF (80.0 ml) and added with copper powder (0.78 g, 7.8 mmol) and potassium carbonate (15.31 g, 0.11 mol). The reaction was heated at 120 °C for 16 h. The reaction was cooled to room temperature and diluted with EtOAc (90 mL). The organic phase was washed with 15percent NaOH and water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (40percent EtOAc in hexanes as eluant) to give 1-{4-((5-methoxypyrimidin-2-yl)oxy)-2,6-dimethylphenyl}ethanone (8-2, 2.33 g) as light yellow solids in 24percent yield: 1H NMR (500 MHz, DMSO-d6) delta 8.41 (s, 2 H), 6.86 (s, 2 H), 3.86 (s, 3 H), 2.47 (s, 3H), 2.18 (s, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 45℃; for 96h; | General procedure: 0.69 g (3.59 mmol) 5-bromo-2-chloro-pyrimidine and 0.70 g (2.99 mmol) of the amine Xlll.1 are added to 10 mL DMSO and 0.78 mL (4.49 mmol) DIPEA. The mixture is stirred at 35° C over night and afterwards purified by HPLC (MeOH/H20/NH3).C17H19BrN4O2 (M= 391 .3 g/mol)ESI-MS: 391/393 [M+H]+Rt (HPLC): 1 .80 min (method A) The following compounds are prepared analogously to example 3.1 : For the example 3.2 the reaction mixture is stirred for 4 d at 45° C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 96.1 : 5-(3-Chloro-2-fluoro-phenyl)-2-(2-chloro-5-methoxy-pyrimidin-4-yl)-6-(4-chloro-phenyl)-1- isopropyl-5,6-dihvdro-1 H-pyrrolor3,4-dlimidazol-4-one To a solution of intermediate G (300 mg, 0.6 mmol) in dioxane ( 6.4 ml.) was added Pd(PPh3)4 (144 mg, 0.1 mmol), then the product from step 96.2 (487 mg, 1.9 mmol) and the reaction mixture was stirred at 70°C for 1 h and at 80°C for 1 h more. The mixture was diluted with EtOAc and extracted with H20. The organic layers were dried (Na2S04), filtered and concentrated. The residue was purified by preparative HPLC (Waters Sun Fire C18, 30 x 100mm, 5 muetaeta; 0.1 percent TFA- water/acetonitrile; gradient acetonitrile 50-70percent in 16 min) to give the title compound. tR: 1.22 min (LC-MS 2); ESI-MS: 546.1 [M+H]+ (LC-MS 2). Step 96.2: (2-Chloro-5-methoxypyrimidin-4-yl)zinc A solution of dry ZnCI (400 mg, 2.9 mmol) and 2,2,6,6-tetramethylpiperidinylmagnesiumchloride lithium chloride complex, 1 M in THF (5.5 ml_, 5.53 mmol) was stirred at RT for 16 h. Then 2-chloro- 5-methoxypyrimidine (800 mg, 5.53 mmol) was added dropwise and the mixture was stirred at rt for 1 h. The product was used as a stock solution for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine; In N,N-dimethyl-formamide; at 120℃; under 22502.3 Torr; | To a solution of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (5.0 g, 34.6 mmol, 1.0 equiv) in MeOH (100 mL) and DMF (20 mL) were added triethylamine (10.5 g, 103.8 mmol, 3.0 equiv) and Pd(dppf)Cl2 (3.8 g, 5.2 mmol, 0.15 equiv). The suspension was degassed and purged with CO several times. The mixture was stirred under CO (3 Mpa) at l20C for 72 hours. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography (eluted with PE/EtOAc = 20/1 ~ 10/1) to afford the title compound methyl 5-methoxypyrimidine-2-carboxylate as a light yellow solid (3.3 g, 57% yield). LCMS: m/z: 169.0 (M+H) + |
52% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; triethylamine; In acetonitrile; at 20 - 100℃;Inert atmosphere; | [0595] Synthesis of methyl 5-methoxypyrimidine-2-carboxylate: [0596] To a stirred solution of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (1 g, 6.92 mmol) in MeOH: CH3CN (4: 1, 20 mL) under argon atmosphere were added Pd(dppf)Cl2 (1 g, 1.38 mmol) and triethyl amine (1.9 mL, 13.84 mmol) at RT; heated to 100 C and stirred for 16 h in steel bomb under CO pressure. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 60% EtOAc/ Hexanes to afford methyl 5-methoxypyrimidine-2-carboxylate (600 mg, 52%) as brown solid. [0597] 1H-NMR (CDC13, 400 MHz): delta 8.54 (s, 2H), 4.06 (s, 3H), 4.00 (s, 3H); LC-MS: 98.52%; 169 (M++l); (column: X Bridge C-18, 50 3.0 mm, 3.5 mupiiota); RT 2.26 min. 0.05% Aq TFA: ACN; 0.8 mL/min); TLC: 70% EtOAc/ Hexanes (R 0.2). |
52% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; triethylamine; In acetonitrile; at 100℃; for 18h;Autoclave; | (A)A mixture of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (10 g, 69.44 mmol, 1 eq) MeOH-CH3CN 4:1 (160 ml -40ml), TEA (20 ml) and Pd(dppf)Cl2 DCM (6 g, 7.34 mmol, 0.1 eq) in an autoclave, was stirred at 100C for18 h under CO gas atmosphere. The RM was cooled to RT, filtered through celite, washed with MeOH(100 ml), and the filtrate was concentrated. The residue upon purification by CC (silica gel; EtOAc - PE;3:7) afforded methyl 5-methoxypyrim idine-2-carboxylate (6 g, 52%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; sodium t-butanolate; In toluene; at 70℃; for 72h;Inert atmosphere; | Example 88rac-((2 S,3R)-2-(((5 -methoxypyrimidin-2-yl)amino)methyl)-3 -methylpiperidin- 1 -yl) (5 -(4- fluorophenyl-2-methylthiazol-4-ylmethanone A mixture of ((2S,3 R)-2-(aminomethyl)-3 -methylpiperidin- 1 -yl)(5-(4-fluorophenyl)- 2-methylthiazol-4-yl)methanone, <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong>, Pd2dba3, BII?AP, andNaOtBu in toluene was purged with argon, and then stirred at 70 °C for 72h. The reaction was cooled, filtered through a pad of silica gel and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS(ESI) 456.2 (M+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With caesium carbonate; In acetonitrile; at 160℃; for 1.5h;Microwave irradiation; | General procedure: In a reaction vial designed for microwave heating, the considered alkoxypyrazole (2 mmol), the considered halogenated heteroaryl (2.2 mmol) and cesium carbonate (2.8 mmol) were stirred in dimethylformamide or acetonitrile (3 mL) as specified in the examples. This was heated using a microwave at a temperature between 120 °C and 180 °C for the individually specified duration. The resulting suspension was diluted in water, extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate and concentrated to dryness. The residue was further purified as described below. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.5 g | With 1,4-diaza-bicyclo[2.2.2]octane; In water; dimethyl sulfoxide; at 70℃; for 5h; | A) 5-methoxypyrimidine-2-carbonitrile To a solution of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (4.4 g) and 1,4-diazabicyclo[2.2.2]octane (6.7 g) in a mixed solvent of dimethyl sulfoxide (114 mL) and water (18 mL) was added potassium cyanide (4.00 g). The reaction mixture was stirred at 70°C for 5 hr, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.5 g). 1H NMR (400 MHz, CDCl3) delta 4.02 (3H, s), 8.47 (2H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 2h; | Step 1 : ( )-(l-(5-Methoxypyrimidin-2-yl)pyrrolidin-2-yl)methanol To a stirring solution of (5)-pyrrolidin-2-ylmethanol (0.202 g, 2 mmol) in THF (2 mL) was added iBuOK (1M in THF) (2 mL, 2 mmol) followed by 2-chloro-5- methoxypyrimidine (0.145 g, 1 mmol). The reaction mixture was stirred at rt for 2 h to give the title compound after purification on silica gel column; MS (ESI) 210 (M + H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.1 g | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,2-dimethoxyethane; water; for 5h;Reflux; | Production Example 163 (0925) A mixture of 0.30 g of CA25 mentioned in Reference Production Example 25, 0.16 g of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong>, 0.45 g of tripotassium phosphate, 1.00 ml of water, 0.06 g of [1,1?-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, and 10 mL of dimethoxyethane was stirred with heating under reflux for 5 hours. After cooling, water was poured into the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 0.10 g of 1-{2-[3-(5-methoxypyrimidin-2-yl)phenoxymethyl]-3-methylphenyl}-4-methyl-1,4-dihydrotetrazol-5-one (hereinafter referred to as the present compound 163). (0926) 1H-NMR (CDCl3) delta (ppm): 8.47 (2H, s), 7.96 (1H, dt, J=7.7, 1.2 Hz), 7.91-7.90 (1H, m), 7.45-7.40 (2H, m), 7.36 (1H, t, J=7.9 Hz), 7.29 (1H, dd, J=6.7, 2.4 Hz), 6.96-6.93 (1H, m), 5.13 (2H, s), 3.97 (3H, s), 3.62 (3H, s), 2.52 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 90℃; | To a stirred solution of Intermediate 11 (0.2 g, 0.8 mmol) in dry DMF (2 mL), triethylamine (0.57 mL, 4.0 mmol, spectrochem) and 2-chloro-5-methoxy pyrimidine (0.14 g, 0.9 mmol , Combi-Blocks) were added and the resulting mixture was heated at 90 °C overnight. The reaction mixture was cooled down to rt and concentrated. Dichloromethane (25 mL) was added and the resulting mixture was washed with water (20 mL), brine (20 mL) and dried over Na2SO4. After evaporation of the solvents, the crude product was purified by flash chromatography to afford the title compound (gray solid). 1H NMR (400 MHz, DMSO-d6): delta 8.93-8.91 (m, 2H), 8.17 (s, 2H), 8.07 (d, J = 8.8 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J = 8.8 Hz, 1H), 3.75-3.74 (m, 1H), 3.74 (s, 3H), 3.62-3.60 (m, 4H), 2.52-2.49 (m, 4H), 1.42 (d, J = 6.8 Hz, 3H). LCMS: (Method A) 351.0 (M+H), Rt. 2.38 min, 99.86percent (Max). HPLC: (Method A) Rt. 2.17 min, 98.71 percent (Max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 12h; | To a stirred solution of Intermediate 16 (0.55 g, 2.07 mmol) in dry DMF (5 mL), triethylamine (0.9 mL, 6.21 mmol, spectrochem) and 2-chloro-5-methoxy pyrimidine (0.3 g, 2.07mmol, Combi-Blocks) were added and the resulting mixture was heated to 90 °C for 12 h. The reaction mixture was cooled down to rt and concentrated. Dichloromethane (25 mL) was added and the resulting solution was washed with water (20 mL), brind (20 mL) and dired over Na2SO4. After evaporation of the solvents, the crude product was purified by flash column chromatography to afford the title compound (brown solid). 1H NMR (400 MHz, DMSO-de): delta 8.18 (s, 2H), 6.87 (m, 2H), 6.76 (d, J = 8.0 Hz, 1H), 5.99-5.98 (m, 2H), 3.76 (s, 3H), 3.58 (t, J = 4.8 Hz, 4H), 3.38-3.36 (m, 1H), 2.45-2.42 (m, 2H), 2.36-2.33 (m, 2H), 1.28 (d, J = 6.8 Hz, 3H). LCMS: (Method A) 343.2 (M+H), Rt. 2.73 min, 99.83percent (Max). HPLC: (Method A) Rt. 2.71 min, 99.41 percent (Max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 110℃;Inert atmosphere; Sealed tube; | Step 2, Method 8: 5-(5-Methoxypyrimidin-2-yl)-2-(pyridin-3-yl)-1,3-benzoxazole 191551 2-Chloro-5 -methoxypyrimidiae (69 mg, 0.48 mmol) and 2-(pyridin-3-yl)-5- (tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzoxazole (140 mg, 0.43 mmol) were dissolved in 1,4-dioxane (3 mL) under nitrogen in a sealed tube. 2 M sodium carbonate (0.43 mL, 0.87mmol) was added followed by tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol). The reaction mixture was stirred at 110 °C overnight. The reaction mixture was cooled to room temperature, diluted with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. Purification by FCC (silica, 0-2percent methanol in dichloromethane) gave the title compound 24 mg (18percent yield) as a white solid.Example 1, Method 8: (125-1) 5-(5-Methoxypyrimidin-2-yl)-2-(pyridin-3-yl)-1,3- heuzoxazolejOlS6j 8r NMR (500 MHz, DM50) 9.38 (d, .1 = 2.0 Hz, 1H), 8.83 (dd, J = 4.8, 1.6 Hz, IH), 8.69 (s, 2H), 8.66 (d, J = 1.5 Hz, 1H), 8.57 (dl, J = 8.0, 1.9 Hz, 1H), 8.46 (dd, J = 8.6, 1.7 Hz, 1H), 7.93 (d, J = 8.6 Hz, IH), 7.67 (dd, J = 7.9, 4.8 Hz, IH), 3.98 (s, 3H). Tr(MET-uHPLCAB-lOl) = 2.87 mm, (Est) (M+H)t 305. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | In isopropyl alcohol; at 140℃; for 1h;Microwave irradiation; | General procedure: j0248J Two microwave tubes were charged with <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (2 x 250 mg, 3.46 mmol) and piperazine (2 x 1.49 g, 34.6 mmol). Isopropanol (2 x 2.5 mL) was added to each and the reaction mixtures were stirred at 140 °C in a microwave for 1 hour. The reaction mixtures were combined, diluted with diethyl ether (50 mL), filtered, the filtrate concentrated and partitioned between water (50 mL) and diethyl ether (50 mL). The aqueous layer was extracted with diethyl ether (2 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound 277 mg (32percent yield) as a white solid. oH NMR (500 MHz, chloroform) 8.10 (s, 2H), 3.80 (s, 3H), 3.78 -3.73 (m, 4H), 3.03 - 293 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4.6% | With dicyclohexyl-(2?,4?,6?-triisopropyl-3,6-dimethoxy-[1,1?-biphenyl]-2-yl)phosphine; palladium diacetate; sodium t-butanolate; In 1,4-dioxane; at 85℃; for 14h;Inert atmosphere; Sealed tube; | Intermediate 58C (45 mg, 0.124 mmol) was dissolved in Dioxane (621 mu) and 2- chloro-5-methoxypyrimidine (26.9 mg, 0.186 mmol), dicyclohexyl(2',4',6'-triisopropyl- 3,6-dimethoxy-[l, l'-biphenyl]-2-yl)phosphine (6.66 mg, 0.012 mmol), sodium tert- butoxide (17.89 mg, 0.186 mmol), and palladium(II) acetate (2.79 mg, 0.012 mmol) were added. Reaction was degassed with nitrogen bubbling/sonication for 5 minutes, then it was sealed at heated to 85 C for 14 hours. The reaction was diluted with water, acidified with 1 N HC1, and extracted with EtOAc. The combined organics were dried with sodium sulfate, filtered and concentrated. The crude residue was dissolved in DMF, filtered, and purified via preparative HPLC to give Racemic Example 63 (2.5 mg, 0.006 mmol, 4.6%). LC-MS Anal. Calc'd for C24H34N4O4 442.26, found [M+H] 443.3. Tr = 1.869 min (Method B). 1H MR (500 MHz, DMSO-d6) delta: 8.62 (s, IH), 8.34 (s, 2H), 8.12 (d, J=2.7 Hz, IH), 7.14 (d, J=8.7 Hz, IH), 6.35 (dd, J=8.5, 2.7 Hz, IH), 4.72 (q, J=6.5 Hz, IH), 3.83 (s, 3H), 1.76-1.91 (m, 2H), 1.67 (d, J=10.9 Hz, 2H), 1.51-1.54 (m, IH), 1.49 (d, J=6.6 Hz, 3H), 1.15 (t, J=7.2 Hz, 9H), 0.81 (br. s., 6H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: j00728j A mixture of aryl halide (1-2 eq.), compound A-2 (racemic or a single enantiomer, 1 eq.), palladium complex (0.05-0.10 eq.), ligand (0.05-0.10 eq), and base (1-2 eq.) in dioxane (5-10 mL/mmol) under nitrogen was heated with stirring at the indicated temperature for the indicated time. On completion, the mixture was filtered and concentrated under vacuum. The residue was purified byprep HPLC or silica gel chromatography, and mixtures of enantiomers were separated by chiral SFC. Most compounds were treated with 0.2 M hydrochloric acid and lyophilized to give hydrochloride salts. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With potassium carbonate; In dimethyl sulfoxide; at 160℃; for 12h; | 2-Chloro-5-methoxypyrimidine (144 mg, 1 mmol),N-methyltetrahydropyrrole (170 mg, 2 mmol),Phthalimide (294 mg, 2 mmol), potassium carbonate (276 mg, 2 mmol),Dimethyl sulfoxide (2 ml) was added to the dry reaction tube and suspended in an oil bath at 160 ° C for 12 h.After cooling the reaction system, 15 ml of water was added and the aqueous phase was extracted three times with 30 ml of ethyl acetate,The organic phases were combined and the solvent was evaporated under reduced pressure. Column chromatography gave a colorless solid2- (4- (5-methoxypyridine) 2- (methyl) amino) butyl) isoindole-1,3-dione286 mg, the yield was 85percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 100℃; for 120h;Inert atmosphere; | A solution of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (400 mg, 2.77 mmol), 2-amino-1-(piperidin-1-yl)ethanone hydrochloride (643 mg, 3.60 mmol) and DIPEA (1.450 mL, 8.30 mmol) in acetonitrile (3 mL) was heated to 100 °C for 2 days. An extra portion of 2-amino-1-(piperidin-1-yl)ethanone hydrochloride (643 mg, 3.60 mmol) and DIPEA (1.450 mL, 8.30 mmol) was added and the reaction was heated to 100 °C for 3 days. The reaction mixture was concentrated in vacuo and dissolved in ethyl acetate (15 mL) and water (20 mL). The organic layer was separated. The aqueous layer was then washed with ethyl acetate (8 x 15 mL). The combined organic phases were dried through a hydrophobic frit and concentrated in vacuo. The material was purified on a silica gel column using a gradient 0-100 percent (3:1 ethyl acetate:ethanol + 1 percenttriethylamine)/cyclohexane. The relevant fractions were combined and concentrated in vacuo to yield 2-((5-methoxypyrimidin-2-yl)amino)-1-(piperidin-1-yl)ethanone (82 mg, 0.328 mmol, 12percent yield) as a white powder. LCMS (High pH, ES+): tR = 0.74 min, [M+H]+ 251.18. 1H NMR (400 MHz, CDCl3) delta 1.53 - 1.63 (m, 4 H), 1.63 - 1.71 (m, 2 H), 3.38 - 3.44 (m, 2 H), 3.58 - 3.63 (m, 2 H), 3.80 (s, 3 H), 4.14 (d, J = 4.3 Hz, 2 H), 5.96 (br. s., 1 H), 8.05 - 8.09 (m, 2 H). 13C NMR (101 MHz, CDCl3) delta 24.4, 25.5, 26.3, 43.2, 43.7, 45.4, 57.0, 145.3, 147.0, 157.6, 166.9. HRMS: (C12H18N4O2) [M+H]+ requires 251.1503, found [M+H]+ 251.1496. numax (neat): 3341, 2936, 1646, 1509, 1479, 1439, 1420, 1265, 1228, 1011, 786 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 140℃; for 0.25h;Microwave irradiation; | III.1665-methoxy-2-(4-piperidyl)pyrimidine A mixture of 2.1 g (14.5 mmol) <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong>, 4.9 g (16.0 mmol) tert- butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1- carboxylate, 339 mg (0.29 mmol) tetrakis(triphenylphosphine)palladium(0), 14.5 ml (29 mmol) 2M Na2CO3 solution and dioxane is heated to 140°C for 15 min using a microwave reactor. The reaction mixture is cooled to RT and DCM and water are added, the organic phase is separated and evaporated and purified by HPLC. Giving rise to tert-butyl 4-(5-methoxypyrimidin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate. Yield: 3.5 g (83percent), ESI-MS: m/z = 292 (M+H)+ |
83% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; at 140℃; for 0.25h;Microwave irradiation; | A mixture of 2.1 g (14.5 mmol) <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong>, 4.9 g (16.0 mmol) tert- butyl 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1 - carboxylate, 339 mg (0.29 mmol) tetrakis(triphenylphosphine)palladium(0), 14.5 ml (29 mmol) 2M Na2CO3 solution and dioxane is heated to 140°C for 15 min using a microwave reactor. The reaction mixture is cooled to RT and DCM and water are added, the organic phase is separated and evaporated and purified by HPLC. Giving rise to tert-butyl 4-(5-methoxypyrimidin-2-yl)-3,6-dihydro-2H-pyridine-1 -carboxylate.Yield: 3.5 g (83percent), ESI-MS: m/z = 292 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In N,N-dimethyl-formamide; at 90℃; for 12h; | To a stirred solution of Intermediate 16 (0.55 g, 2.07 mmol) in dry DMF (5 mL), triethylamine (0.9 mL, 6.21 mmol, spectrochem) and 2-chloro-5-methoxy pyrimidine (0.3 g, 2.O7mmol, Combi-Blocks) were added and the resulting mixture was heated to 90 °C for 12 h. The reaction mixture was cooled down to rt and concentrated.Dichloromethane (25 mL) was added and the resulting solution was washed with water(20 mL), brind (20 mL) and dired over Na2SO4. After evaporation of the solvents, thecrude product was purified by flash column chromatography to afford the titlecompound (brown solid). 1H NMR (400 MHz, DMSO-d6): 6 8.18 (s, 2H), 6.87 (m, 2H),6.76 (d, J = 8.0 Hz, I H), 5.99-5.98 (m, 2H), 3.76 (s, 3H), 3.58 (t, J = 4.8 Hz, 4H), 3.38-3.36 (m, IH), 2.45-2.42 (m, 2H), 2.36-2.33 (m, 2H), 1.28 (d, J = 6.8 Hz, 3H). LCMS:(Method A) 343.2 (M+H), Rt. 2.73 mm, 99.83percent (Max). HPLC: (Method A) Rt. 2.71 mm, 99.41percent (Max). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To (1 -(3-(difluoromethyl)phenyl)-5-methyl-1 H-i 2,3- triazol-4-yl)methanol (45 mg, 0.19 mmol) stirring in THF (1 mL) was added NaH (60percent dispersion in mineral oil, 22.6 mg, 0.56 mmol) and the reaction wasstirred for 5 mi 2-Chloro-5-methoxypyrimidine was then added and the reaction was stirred at rt for 1 h. The reaction was quenched with H20, then diluted with EtOAc and H20. The layers were separated and the aqueous layer was extracted with EtOAc (3X). The combined organic layers were washed with H20 (ix), brine (ix), then dried (Na2504) and concentratedunder reduced pressure. Purification (FCC, 5i02, EtOAc/hexanes 0 - 60percent)afforded the title compound (41 mg, 62percent). MS (ESI): mass calcd. forC15H15F2N502, 347.1; m/zfound, 348.0 [M+H]. 1H NMR (400 MHz, CDCI3) O8.24 (5, 2H), 7.71 ? 7.56 (m, 4H), 6.73 (t, J = 56.1 Hz, 1 H), 5.56 (5, 2H), 3.88(5, 3H), 2.45 (5, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | To a suspension of (S)-(5 -phenyl-4,5 -dihydro- 1H-pyrazol- 1 -yl)(piperidin-4-yl)methanone,1R-(-)-camphor-10-sulphonic acid salt (600 mg, 1.2 mmol) in MeCN (10 mL) were added 2- chloro-5-methoxypyrimindine (177 mg, 1.2 mmol) and DIPEA (0.54 mL, 3.1 mmol). The reaction vessel was sealed, stirred at 150 °C for 2 h and then concentrated in vacuo. This residue was dissolved in DCM (100 mL) and boron tribrominde 1 M solution in DCM (3.1mL, 3.1 mmol) was added dropwise. The minxture was stirred at 0 °C for 2 h. Water (300 mL) and DCM (100 mL) were added. After separation, the aqueous layer was washed with DCM (100 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by normal phase column chromatography [CyHI(EtOHIEtOAc 4:1) 100/0 to 70/301. A trituration into lPr2O afforded, after filtration,(S)-( 1-(5-hydroxypyrimindin-2-yl)piperidin-4-yl)(5-phenyl-4,5-dihydro- 1H-pyrazol- 1- yl)methanone (30 mg, 0.09 mmol, purity: 100 percent, recovery: 7 percent) as a cream-colored powder. LCMS (m/z) 352 (M+H), retention time: 2.04 min LC/MS Method 1. ?H NMR (400 min-Tz,DMSO-d6) delta ppm 9.17 (s, 1H), 8.01 (s, 2H), 7.32 (dd, J=7.6, 7.2 Hz, 2H), 7.23 (m, 2H), 7.10(d, J7.4 Hz, 2H), 5.30 (dd, J12.0, 4.6 Hz, 1H), 4.49 (d, J=12.7 Hz, 2H), 3.49 (dd, J=18.3,12.4 Hz, 1H), 3.32 (m, 1H), 2.87 (m, 2H), 2.67 (dd, J=18.9, 4.6 Hz, 1H), 1.83 (d, J=11.8 Hz,1H), 1.70 (d, J=12.1 Hz, 1H), 1.46 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
390 mg | A solution of (5R,8R)-3-(2,6-difluorophenyl)-9,9-dimethyl-6,7-dihydro-5,8-methanocinnoline- 8(5H)-carboxylic acid (1 g, 3.02 mmol, 1.00 equiv), <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (880 mg, 6.08 mmol, 2.01 equiv), AgNO3 (120 mg, 0.71 mmol, 0.23 equiv) in CH3CN (10 mL) and water(10 mL) was stirred for 10 min at 25 oC. Then (NH4)2S2O8 (1.4 g, 6.13 mmol, 2.02 equiv) was added to the system, and the mixture was stirred for 10 h at 25 oC. After completion, the solution was diluted with 100mL of water and extracted with 3x100mL of EtOAc and washed with 3x50 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 390 mg of the title compound as a yellow solid. LCMS ES+ 429 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.96% | With potassium phosphate; (2-dicyclohexylphosphino-2?,6?-dimethoxybiphenyl)[2-(2?-amino-1,1?-biphenyl)]palladium(II) methanesulfonate; In 1,4-dioxane; water; at 60℃; for 3h;Inert atmosphere; | To a 14 mL test tube equipped with a stir bar was added (S)-(5-(1-(tert-butoxy)-2- isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin- 1 -yl)-6-methylpyridin-3 -yl)boronic acid (113 mg, 0.269 mmol) and SPhos-Pd-G3 (10.47 mg, 0.013 mmol), tribasic potassium phosphate (514 mg, 2.419 mmol) and <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (38.9 mg, 0.269 mmol) . The flask was sealed with a rubber septum, then was placed under N2 atm(vac/fill x 3). To the flask was added degassed (N2bubbling for 5 mm) dioxane (1008 .il) and water (336 .il). The test tube was placed in a 60 °C heating block with stirring (t=0). The reaction was stirred for 3 hrs. The reaction was cooled to RT and diluted with EtOAc and water. The organic layer was washed with brine, collected, dried over MgSO4, filtered and the volatiles evaporated to afford the cmde product. The crude product waspurified on silica gel (24 g column, 20-100percent EtOAc:Hex) to afford the product (S)isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin- 1 -yl)-5-(5-methoxypyrimidin-2-yl)- 2-methylpyridin-3-yl)acetate (26 mg, 0.054 mmol, 19.96 percent yield) as a brown oil. ESIMS(+) m/z = 485.3 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; In 1,4-dioxane; water; at 120℃; for 1h;Microwave irradiation; | General procedure: To a solution of 1.0 eq. of VII and 1.20 eq. of a 2-halopyrimidine in H20 and dioxane was added 2.0 eq. of potassium fluoride. The mixture was subjected to microwave irradiation maintaining a reaction temperature of 120 C for 1 h. The solvent was removed in vacuo, andthe residue was purified by chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2 g | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,2-dimethoxyethane; at 80℃; for 3h;Inert atmosphere; | To a mixture of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (1.5 g), 2-(2-fluoro-4-(trifluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (2.5 g), a 2 M sodium carbonate aqueous solution (11 mL), and DME (10 mL) was added tetrakistriphenylphosphinepalladium(0) (500 mg) under nitrogen atmosphere. The resulting mixture was heated with stirring at 80° C. for 3 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The resulting organic layers were washed with saturated brine, and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residues were subjected to silica gel chromatography to give the Intermediate compound 1 represented by the following formula (2.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With N-ethyl-N,N-diisopropylamine; In acetonitrile;Reflux; | A suspension of 4-((4-((benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidine (155 mg, 0.45 mmol)), <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (78 mg, 0.54 mmol) and diisopropylethylamine (87 mg, 0.68 mmol) in acetonitrile (10 mL) was stirred at reflux overnight. Upon cooling, the reaction mixture was allowed to cool to ambient temperature and the solvent was removed in vacuo and the crude product was purified by column chromatography eluting with hexanes: ethyl acetate (4: 1) to obtain the title product (63 mg, 31%) as a white powder. |
31% | With N-ethyl-N,N-diisopropylamine; In acetonitrile;Reflux; | [0663] A suspension of 4-((4-((benzo[d][1,3]oxathiol-6-yl)-2-fluorophenoxy)methyl)piperidine (155 mg, 0.45 mmol)), <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (78 mg, 0.54 mmol) and diisopropylethylamine (87 mg, 0.68 mmol) in acetonitrile (10 mL) was stirred at reflux overnight. Upon cooling, the reaction mixture was allowed to cool to ambient temperature and the solvent was removed in vacuo and the crude product was purified by column chromatography eluting with hexanes: ethyl acetate (4:1) to obtain the title product (63 mg, 31%) as a white powder. 1H NMR (400 MHz, DMSO-d6) delta 8.19 (s, 2H), 7.52 (d, J = 13.1Hz, 1H), 7.41 (d, J = 8.2 Hz, 1H), 7.33 (d, J = 8.2 Hz, 1H), 7.24-7.16 (m, 3H), 5.80 (s, 2H), 4.58 (d, J = 12.8 Hz, 2H), 3.96 (d, J = 6.5 Hz, 2H), 3.76 (s, 3H), 2.87 (t, J = 12.5 Hz, 2H), 2.15-2.03 (bs, 1H), 1.83 (d, J = 12.5 Hz, 2H), 1.29-1.17 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With triethylamine; In acetonitrile; for 6h;Reflux; | A solution of (R)-4-((2-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[ d] [1.3]oxathiole 3- oxide (150 mg, 0.41 mmol)), <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (72 mg, 0.49 mmol) and triethylamine (63 mg, 0.60 mmol) in acetonitrile (20 mL) was stirred at reflux for 6 hours. Upon cooling, a precipitate was formed, filtered off and washed sequentially with water and with hexanes. The crude product after washing was subjected to column chromatography eluting with dichloromethane to obtain the title compound (58 mg, 30 percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 140℃; for 17h;Microwave irradiation; | To a solution of 4-((4-bromo-2-fluorophenoxy)methyl)piperidine hydrochloride (5.6 g, 17.3 mmol) in dimethylformamide (20 mL) was added <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (2.7 g, 19.0mmol) and diisopropylethylamine (5.6 g, 43.3 mmol). The reaction mixture was stirred and heated in "CEM" microwave system (140C, 17 hours). Upon completion, the reaction mixture was poured into water (100 mL). A precipitate was filtered, air-dried and purified by column chromatography eluting with hexanes: ethyl acetate mixture (9: 1) to afford the title compound as a yellow solid (2.9 g, 42 %). |
42% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 140℃; for 17h;Microwave irradiation; | [0681] To a solution of 4-((4-bromo-2-fluorophenoxy)methyl)piperidine hydrochloride (5.6 g, 17.3 mmol) in dimethylformamide (20 mL) was added <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (2.7 g, 19.0mmol) and diisopropylethylamine (5.6 g, 43.3 mmol). The reaction mixture was stirred and heated in "CEM" microwave system (140C, 17 hours). Upon completion, the reaction mixture was poured into water (100 mL). A precipitate was filtered, air-dried and purified by column chromatography eluting with hexanes: ethyl acetate mixture (9:1) to afford the title compound as a yellow solid (2.9 g, 42 %). 1H NMR (400 MHz, DMSO-d6) delta 8.18 (s, 2H), 7.51 (d, J = 11.0 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 7.14 (t, J = 9.0 Hz, 1H), 4.56 (d, J = 13.2 Hz, 2H), 3.98- 3.88 (m, 2H), 3.75 (s, 3H), 2.85 (t, J = 12.7 Hz, 2H), 2.15- 1.92 (m, 1H), 1.80 (d, J = 13.2 Hz, 2H), 1.22 (dd, J = 22.1, 9.6 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With triethylamine; In acetonitrile; for 6h;Reflux; | To a suspensiOn of 6-(3-fluoro-4-(piperidin-4-yl)phenyl)-2H-benzo[d][l,3]oxathiole 3,3- dioxide (290 mg, 0.7 mmol) and <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (115 mg, 0.85 mmol) in acetonitrile (20 mL) was added triethylamine (63 mg, 0.6 mmol) and the reaction mixture was heated to reflux for 6 hours. Upon completion, the reaction mixture was cooled to ambient temperature. A white precipitate was formed which was filtered which was filtered off, washed with cold water and hexanes and then the crude product was purified by column chromatography on silica gel, eluting with dichloromethane to give the title compound (76 mg, 22 percent) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With caesium carbonate; In N,N-dimethyl acetamide; at 130℃; for 3h;Microwave irradiation; | A suspension of 6-(3-fluoro-4-(piperidin-4-ylmethoxy)phenyl-2H-benzo[ d] [ 1,3]oxathiole-3- oxide hydrochloride (0.20 g, 0.65 mmol), <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (0.13 g, 0.90 mmol) and cesium carbonate (0.25 g, 0.75 mmol) in dimethylacetamide (10 mL) was heated in CEM microwave system at 130C for 3 hours. The reaction mixture was cooled to ambient temperature and extracted with a mixture of ethyl acetate (100 mL) and water (100 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The oily residue was washed with methanol (20 mL) to form a solid material was filtered off and air-dried. This material was subjected to column chromatography on silica gel eluting with ethyl acetate-hexanes mixture ( 1:1) to afford the title compound as a white solid (76 mg, 27 %). |
27% | With caesium carbonate; In N,N-dimethyl acetamide; at 130℃; for 3h;Microwave irradiation; | [0634] A suspension of 6-(3-fluoro-4-(piperidin-4-ylmethoxy)phenyl-2H-benzo[d][1,3]oxathiole-3- oxide hydrochloride (0.20 g, 0.65 mmol), <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (0.13 g, 0.90 mmol) and cesium carbonate (0.25 g, 0.75 mmol) in dimethylacetamide (10 mL) was heated in CEM microwave system at 130C for 3 hours. The reaction mixture was cooled to ambient temperature and extracted with a mixture of ethyl acetate (100 mL) and water (100 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The oily residue was washed with methanol (20 mL) to form a solid material was filtered off and air-dried. This material was subjected to column chromatography on silica gel eluting with ethyl acetate-hexanes mixture (1:1) to afford the title compound as a white solid (76 mg, 27 %). 1H NMR (400 MHz, DMSO- d6) delta 8.19 (s, 2H), 8.07 (d, J = 7.8 Hz, 1H), 7.69 (m, 1H), 7.63 (s, 1H), 7.49-7.59 (m, 2H), 7.28 (t, J = 8.6 Hz, 1H), 5.63 (d, J = 11.4 Hz, 1H), 5.24 (d, J =11.4 Hz, 1H), 4.56 (d, J = 13.2 Hz, 2H), 4.01 (d, J = 6.4 Hz, 2H), 3.76 (s, 3H), 2.88 (t, J =11.6 Hz, 2H), 2.08 (m, 1H), 1.82 (d, J =13.3 Hz, 2H), 1.18-1.32 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With triethylamine; In acetonitrile; for 6h;Reflux; | [0686] A solution of (R)-4-((2-fluoro-4-piperidin-4-ylmethoxy)phenyl)-2H-benzo[d][1.3]oxathiole 3- oxide (150 mg, 0.41 mmol)), <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (72 mg, 0.49 mmol) and triethylamine (63 mg, 0.60 mmol) in acetonitrile (20 mL) was stirred at reflux for 6 hours. Upon cooling, a precipitate was formed, filtered off and washed sequentially with water and with hexanes. The crude product after washing was subjected to column chromatography eluting with dichloromethane to obtain the title compound (58 mg, 30 %) as a white solid. 1H NMR (400 MHz, DMSO-d6) delta 8.19(s, 2H), 8.07(d, J = 7.8 Hz, 1H), 7.69 (m, 1H), 7.63 (s, 1H), 7.49-7.59(m, 2H), 7.28(t, J = 8.6 Hz, 1H), 5.63(d, J = 11.4 Hz, 1H), 5.24(d, J = 11.4 Hz, 1H), 4.56(d, J = 13.2 Hz, 2H), 4.01(d, J = 6.4 Hz, 2H), 3.76 (s, 3 H), 2.88(t, J = 11.6 Hz, 2H), 2.08 (m, 1H), 1.82(d, J = 13.3 Hz, 2H), 1.18-1.32(m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.2% | With dipotassium peroxodisulfate; silver nitrate; In dichloromethane; water; at 20℃; for 12h; | To a mixture of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (885 mg, 6.12 mmol), pivalic acid (500 mg, 4.90 mmol) in DCM (20 mL) and H20 (20 mL) was added AgNCb (166 mg, 0.979 mmol), and K2S2O8 (1323 mg, 4.90 mmol) at RT. The mixture was stirred at RT for 12 h, then was extracted with DCM (20 mL) and washed with H2O (20 mL). The organic extract was dried (Na2S04) and concentrated in vacuo. The crude product was chromatographed (40 g S1O2; continuous gradient from 0% to 30% EtOAc:hexane over 15 min, then hold at 30% for 10 min)to provide the title compound (110 mg, 0.548 mmol, 11.2 % yield) as a colorless oil. 1H NMR (500 MHz, CDCb) d 8.13 (s, 1H), 3.96 (s, 3H), 1.40 (s, 9H). [M+H]+ = 201.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | With boron tribromide; In dichloromethane; at -78 - 20℃; | To a stirred solution of <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (10 g, 69.1 mmol) in anhydrous dichloromethane (60 mL) was added a solution of boron tribromide (34.7 g, 138.5 mmol) in dichloromethane (100 mL) at -78°C. The mixture was allowed to warm up to room temperature and stirred at room temperature overnight. The reaction was quenched by addition of methanol (80 mL) dropwise at -78°C. Solvent was removed under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluted with 2-5 percent methanol in anhydrous dichloromethane) to afford 2- bromopyrimidin-5-ol (6.5 g, yield 54percent) as a yellow solid.1HNMR (400MHz, DMSO-d6): delta 8.26(s, 2H), 8.49 (s, 1H); chemical formula: C4H3BrN2O; molecular meight: 174.98 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In 1,4-dioxane; at 90℃; for 40h;Inert atmosphere; | Under Ar(g), to a mixture of pyrazin-2-amine (1) (289mg, 3.0mmol), 2- chloro-5-methoxypyrimidine (2) (289mg, 2.0mmol), Cs2C03 (1.30g, 4.0mmol) was added degassed dry 1 ,4-dioxane (13ml_). The reaction mixture was then flushed with Ar(g) for 1 min before Pd2(dba)3 (92mg, 0.1 mmol) and Xantphos (127mg, 0.22mmol) were added. The reaction mixture was heated up to 90C for 40h. It was then cooled down to rt. EtOAc (15ml_), H20 (10ml_) and brine (5mL) were added to the reaction mixture. The organic phase was separated and the aqueous phase was extracted with EtOAc (15ml_). The organic layers were combined and Pd-scavenger (MP-TMT, ~400mg, 1.3mmol/g) was added. This was shaken for several hours followed by filtration. The filtrate was concentrated in vacuo, dissolved in DMSO (4ml_) and purified by basic prep LCMS to yield (3) as a solid (70mg, 17% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51.4% | With potassium carbonate; In acetonitrile; at 80℃; for 23h; | To 50mL In the round bottom flask <strong>[22536-65-8]2-chloro-5-methoxypyrimidine</strong> (0.150 g, 1.038 mmol), ciprofloxacin (0.344g, 1.038mmol)And potassium carbonate(0 · 171g, 1·246mmol),Add 10mL of acetonitrile,Reflow at 80 ° C23 hours.After the reaction,The reaction mixture was concentrated under reduced pressure, get crude productsAnd use it as an eluent(methanol / dichloromethane,1/10, V/V)Purified by silica gel column chromatography,get 0.226g.Compound 1-9, yellow solid. Yield: 51.4percent. |
Tags: 22536-65-8 synthesis path| 22536-65-8 SDS| 22536-65-8 COA| 22536-65-8 purity| 22536-65-8 application| 22536-65-8 NMR| 22536-65-8 COA| 22536-65-8 structure
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P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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