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CAS No. : | 936250-22-5 | MDL No. : | MFCD07375147 |
Formula : | C4H6BN3O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | CGHYQZASLKERLV-UHFFFAOYSA-N |
M.W : | 138.92 | Pubchem ID : | 17750211 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 36.26 |
TPSA : | 92.26 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -8.03 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | -1.24 |
Log Po/w (WLOGP) : | -2.25 |
Log Po/w (MLOGP) : | -2.4 |
Log Po/w (SILICOS-IT) : | -2.19 |
Consensus Log Po/w : | -1.62 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.3 |
Solubility : | 69.9 mg/ml ; 0.503 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.2 |
Solubility : | 87.3 mg/ml ; 0.628 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.16 |
Solubility : | 97.0 mg/ml ; 0.698 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.91 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-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 |
---|---|---|
90% | With hydrogenchloride In water | Example 17 2-Aminopyrimidin-5-ylboronic acid III To a mixture of [2-[(tert-butoxycarbonyl)amino]pyrimidin-5-yl]boronic acid 12 (40.0 kg, 49 wt percent by HPLC, 82.0 mol) in water (245 kg) was added concentrated hydrochloric acid (39.6 L) while maintaining the temperature below 30° C. The reaction mixture was stirred for 12 h and was then cooled to 10° C. The pH of the mixture was adjusted to 6.5 by addition of 50percent aqueous sodium hydroxide solution while maintaining the temperature below 15° C. and the mixture was then stirred for 1 h. Water (69.0 kg) was added and the mixture was aged for 30 min. The resulting slurry was filtered and the cake was dried under vacuum at 50° C. to afford 2-aminopyrimidin-5-ylboronic acid III (10.2 kg, 90percent yield). 1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 2H), 7.97 (s, 2H), 6.74 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With hydrogenchloride; n-butyllithium; lithium hexamethyldisilazane In tetrahydrofuran; methanol; tert-butyl methyl ether; water | By the alternative synthetic route in Scheme 8, to a 3-L flask under nitrogen was charged tetrahydrofuran (1055 mL), followed by 5-bromopyrimidine-2-amine 9 (70.0 g, 0.40 mol). The mixture was cooled to a temperature between -60° C. and -70° C. and lithium bis(trimethylsilyl)amide (LiHMDS) (1M in tetrahydrofuran, 483 mL, 0.483 mol) was charged over 30 min while maintaining the temperature between -60° C. and -70° C. The mixture was stirred at -60° C. to -70° C. for 1 h. n-Butyllithium (2.5 M in hexanes, 515 mL, 1.29 mol) was charged over 1 h while maintaining the temperature between -60° C. and -70° C., and the reaction mixture was then aged for 2 h. Additional n-butyllithium (2.5 M in hexanes, 48 mL, 0.12 mol) was charged over 15 min while maintaining the temperature between -60° C. and -70° C., and the reaction mixture was stirred for 1 h. To the mixture was added triisopropyl borate (91.0 g, 0.48 mol) over 1 h while maintaining the temperature between -60° C. and -70° C., and the reaction mixture was stirred for 1 h. The mixture was then allowed to warm to 0-5° C. and water (700 mL) was added over 1 h. After being aged at 0-5° C. for 30 min, the resulting layers were separated. To the aqueous layer was added water (420 mL) over 30 min, followed by addition of tert-butyl methyl ether (822 mL). The mixture was allowed to warm to 20-25° C. and was stirred for 30 min. The layers were separated and the aqueous layer was washed with tert-butyl methyl ether (5*700 mL). The aqueous layer was cooled to 0-5° C., and 35percent aqueous hydrochloric acid solution (137 mL) was added over 1 h while maintaining the temperature between 0-5° C. The mixture was stirred at 0-5° C. for 1.5 h, filtered, washed with water (14 mL) and the cake was dried under vacuum at 45-50° C. to afford the crude product (26.7 g). The crude product was charged to a 5-L flask, followed by addition of methanol (908 mL), and the mixture was stirred at room temperature (rt) for 20 min. The mixture was warmed to 65° C. and stirred for 1.5 h. To the mixture was added water (2136 mL) over 2 h and the suspension was stirred for 1.5 h. The mixture was cooled to 20° C. and stirred for 14 h. The solid was collected by filtration and the filter cake was washed with water (13 mL), dried under vacuum at 45-50° C. for 12 h to afford 2-aminopyrimidin-5-ylboronic acid III (23.6 g, 42percent yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 175℃; for 0.166667 - 0.333333h; | To a microwave processing tube dimethoxyethane (10 mL), 2M aqueous Na2CO3 solution or saturated aqueous NaHCO3 (2 eq), (Ph3P)4Pd (233 mg, 0.2 mmol, 0.05 eq), appropriate boronic acid (1.2 eq) and 9-(1-Benzyl-piperidin-4-yl)-2-chloro-6-morpholin-4-yl-9H-purine (1 eq) are added and the vessel sealed. The mixture is heated to 175 C. for 10 to 20 minutes. The solvents are distilled on a rotary evaporator and the crude compound is purified by preparative HPLC (high pressure liquid chromatography) using ACN/water/NH3-gradients as eluent or column chromatography with CH2Cl2/MeOH/NH3 to give the product (in 25-65% yield); 5-[9-(1-benzylpiperidin-4-yl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine is prepared from 9-(1-Benzyl-piperidin-4-yl)-2-chloro-6-morpholin-4-yl-9H-purine (100 mg, 0.24 mmol, 1 eq), saturated aqueous NaHCO3 solution (1 ml), (Ph3P)4Pd (25 mg, 0.01 mmol, 0.05 eq), and 2-aminopyrimidine boronic acid (51 mg, 0.363 mmol, 1.5 eq) according to procedure A giving title product (57 mg, 48% yield; mp 238-240 C.; MS (ESI) m/z 472.4). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | To a solution of PT-387 (855 mg, 2.00 mmol) and (20) (500 mg, 3.00 mmol) in DMF (15 mL) was added K2CO3 (830 mg, 6.00 mmol) and H2O (3 mL). The reaction mixture was stirred for 5 min under an atmosphere of dry N2. PdCl2(PPh3)2 (70 mg, 0.10 mmol) was added, and the resulting mixture was heated at 86 C. for 5 h. The mixture was cooled, diluted with EtOAc (20 mL), filtered through a layer of celite, washed with EtOAc (80 mL) and H2O (80 mL) and transferred to a separation funnel. The organic phase was washed with 0.1 N LiOH (100 mL, 10.00 mmol), and the combined aqeuous phase was washed with diethyl ether (50 mL), then EtOAc (2×50 mL). The pH value was adjusted to 2-3, and the milkish precipitate was filtered, washed with H2O (500 mL), and dried to give a gel-like solid. LCMS showed only 70% as the desired product. To the crude product was added boiling EtOAc (30 mL) and the mixture was sonicated, filtered, washed with EtOAc (30 mL), and dried to afford a white solid PT-254 (286 mg, 31%). MS m/z 468.2 (M+H). >94% HPLC purity. 1H NMR (400 MHz; dmso-D6) 11.3 (s, 1H); 7.98 (d, J=8.6 Hz, 2H); 7.30-7.60 (m, 5H); 7.10-7.28 (m, 4H); 6.84 (d, J=6.3 Hz, 2H); 6.73 (s, 1H); 4.96 (q, J=13.0 Hz, 2H); 2.53 (d, J=2.0 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In water; acetonitrile; at 130℃; for 0.25h;Microwave irradiation; | Example 55; 2-(5-(2-aminopyrimidin-5-yl)-7-mophiholinothiazolo[5,4- d]pyrimidin-2-yl)propan-2-ol 130[00358] 2-(5-Chloro-7-morpholinothiazolo[5,4-d]pyrimidin-2-yl)propan-2-ol, 5- pyrimidine-2-amine boronic acid 68 (1.2eq), and trans- dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts IM sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 130 0C for15 minutes. The solution was evaporated to dryness and purified by reverse phase silica gel chromatography to give the product 130. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In water; acetonitrile; at 130℃; for 0.133333h;Microwave irradiation; | Example 47; 5-(2-((4-(methylsulfonyl)piperazin-l-yl)methyl)-7- morpholinothiazolo[5,4-d]pyrimidin-5-yl)pyrimidin-2-amine 122[00340] 5-Chloro-2-((4-methylsulfonylpiperazin-l-yl)methyl)-7-morpholinothiazolo[5,4- djpyrimidine ,5-pyrimidine-2-amine boronic acid (1.2eq), and trans- dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts IM sodium carbonate (3 eq) and acetonitrile. The solution was microwaved at 130 C for 8 minutes. The solvents were removed and the resulting residue was purified by reverse phase silica gel chromatography to give 122. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In water; acetonitrile; at 130℃; for 0.25h;Microwave irradiation; | 2-(5-Chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)propan-2-ol, 5- pyrimidine-2-amine boronic acid (1.2eq), and trans- dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts IM sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was micro waved at 130 0C for15 minutes. The solution was evaporated to dryness and purified by reverse phase silica gel chromatography to give the product 137. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In water; acetonitrile; at 130℃; for 0.25h;Microwave irradiation; | 5-Chloro-7-morpholino-2-(thiazol-4-yl)thiazolo[4,5-d]pyrimidine , 5-pyrimidine-2-amine boronic acid (1.2eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) <n="95"/>were slurried with equal parts IM sodium carbonate (3 eq) and acetonitrile. The solution was microwaved at 130 C for 15 minutes. Acetonitrile was added and the solution was filtered. The resulting organic layer was purified by reverse phase silica gel chromatography to give the product 138. MS data: (ESI+): MH+ 399. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In water; acetonitrile; at 150℃; for 0.333333h;Microwave irradiation; | 5-Chloro-2,7-dimophiholinothiazolo[4,5-d]pyrimidine 79, 5-pyrimidine-2- amine boronic acid (1.2eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts IM sodium carbonate (3 eq) and acetonitrile. The solution was micro waved at 150 C for 10 minutes. An additionally 0.1 equivalents of trans- dichlorobis(triphenylphosphine)palladium(II) was added and the solution was microwaved an additional 10 minutes at 150 C. Water was added and the solution was filtered. The resulting precipitate was purified by reverse phase silica gel chromatography to give 139. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In water; acetonitrile; at 150℃; for 0.166667h;Microwave irradiation; | The aqueous layer was dried and combined with 5-pyrimidine-2-amine boronic acid (1.2eq) and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) and slurried with equal parts IM sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 150 C for 10 minutes. Water was added and the solution was filtered. The resulting precipitate was purified by reverse phase silica gel chromatography to yield 140. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;trans-bis(triphenylphosphine)palladium dichloride; In water; acetonitrile; at 150℃; for 0.166667h;Microwave irradiation; | The aqueous layer was dried and combined with 5-pyrimidine-2-amine boronic acid (1.2eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts IM sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 150 C for 10 minutes. Water was added and the solution was filtered. The resulting precipitate was purified by reverse phase silica gel chromatography to yield 142. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In water; acetonitrile; at 130℃; for 0.416667h;Microwave irradiation; | A) Suzuki CouplingA typical Suzuki coupling is shown below in the preparation of Compound 10A mixture of 4-(4-chloro-6-phenoxy-pyrimidin-2-yl)-morpholine (105mg), 2- aminopyrimidine-5-boronic acid (75mg, 1.5 equivalents), sodium carbonate solution <n="63"/>(115mg of sodium carbonate in ImL of water), PdO2(PPh3)2 (13mg, 5%) and acetonitrile (3mL) was heated to 130C for 25 minutes in the microwave (CEM Discover). The reaction mixture was allowed to cool, poured onto HCl (2N) and washed with ethyl acetate. The acidic phase was then basified (sodium carbonate) resulting in a white precipitate which was collected by filtration and air-dried. Further purification, using flash chromatography yielded 2-morpholin-4-yl-6-phenoxy-[4,5']bipyrimidinyl- 2'-ylamine (42mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 110℃; for 0.25h;Microwave irradiation; | Example 44: N-(4-(2-aminopyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide; [0168] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-3-oxo-2,3-dihydro- [l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (36 mg, 0.083 mmol), 2-aminopyrimidin-5- ylboronic acid (12 mg, 0.083 mmol) and PdCl2(dppf)2 (5 mg) in 2 mL of 1 ,4-dioxane/2M K2CO3 was heated in microwave reactor at 1100C for 15 min. The solid was filtered off and the crude product was purified by Mass-triggered HPLC (Gradient: 20-50% ACN containing 0.035% TFA in water containing 0.05% TFA) 11.2 mg (isolated yield: 30%) to give the title compound. 1H NMR (400 MHz, DMSO-d6) delta: 12.66 (s, IH), 9.20 (t, J = 8.0, 4.0 Hz, NH, IH), 8.63 (s, 2H), 8.54 (s, IH), 7.49-7.70 (m, 4H), 7.28 (d, J = 12.0 Hz, IH), 4.53 (d, J = 4.0 Hz, 2H). [M+H] calc'd for Ci9Hi4F3N7O3, 446; Found, 446. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 110℃; for 0.25h;Microwave irradiation; | Example 52: N-(4-(2-aminopyrimidin-5-yl)-2-(trifluoromethoxy)benzyl)-2-(2- cyanoethyl)-3-oxo-2,3-dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide; [0184] A mixture of N-(4-bromo-2-(trifluoromethoxy)benzyl)-2-(2-cyanoethyl)-3-oxo-2,3- dihydro-[l,2,4]triazolo[4,3-a]pyridine-6-carboxamide (25 mg, 0.052 mmol), 2- aminopyrimidin-5-ylboronic acid (9 mg, 0.062 mmol) and PdCl2(dppf)2 (5 mg) in 2 mL of 1 ,4-dioxane/2M K2CO3 was heated in microwave reactor at 11O0C for 15 min. The solid was filtered off and the crude product was purified by Mass-triggered HPLC (Gradient: 20-40% ACN containing 0.035% TFA in water containing 0.05% TFA) 10 mg (isolated yield: 39%) to give the title compound. 1H NMR (400 MHz, DMSO-d6) delta: 8.60 (s, 2H), 8.44 (s, IH), 7.47- 7.60 (m, 4H), 7.19 (d, J = 8.0 Hz, IH), 4.55 (s, 2H), 4.17 (t, J = 8.0, 8.0 Hz, 2H), 2.94 (t, J = 8.0, 8.0 Hz, 2H). [M+H] calc'd for C22HnF3N8O3, 499; Found, 499. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 110℃; for 0.25h;microwave vial; | Lambda/-(4-Bromo-2-(trifluoromethoxy)benzyl)-2,6-dioxo- 1 -(pyridin-2-ylmethyl)- 1 ,2,3,6- tetrahydropyrimidine-4-carboxamide (100 mg, 0.200 mmol), 2-aminopyrimidin-5- ylboronic acid (33.4 mg, 0.240 mmol), dioxane (1 mL) and sodium bicarbonate (sat., 1 mL) were added to a microwave vial. PdCl2(dppf) (7.33 mg, 10.02 mumol) was added and the tube was capped. The mixture was sonicated and microwaved as a high absorber at 1100C for 15 minutes. The solvent was evaporated under vacuum to give a residue, which was triturated with methanol (2 mL). The mixture was filtered and the filtrate was purified by mass-triggered HPLC (15% ACN in water containing 0.05% TFA) to give the title compound. MS [M+H] found 514. 1H NMR (400 MHz, DMSO-J6) delta ppm 4.53 (d, J=5.56 Hz, 2 H), 5.10 (s, 2 H), 6.30 (d, J=I.52 Hz, 1 H), 7.08 (d, J=9.60 Hz, 1 H), 7.29 - 7.36 (m, 2 H), 7.59 (d, J=8.08 Hz, 1 H), 7.68 - 7.74 (m, 2 H), 7.82 (td, J=7.71, 1.77 Hz, 1 H), 8.20 - 8.34 (m, 2 H), 8.37 (d, J=IJl Hz, 1 H), 8.48 (d, J=4.29 Hz, 1 H), 9.54 (t, J=5.81 Hz, 1 H), 11.28 (s, 1 H); mp = 207.7-220.10C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); In 1,2-dimethoxyethane; at 120℃; for 2h; | To a mixture of I-04 (30 mg, 0.108 mmol) in 1 ,2-dimethoxyethane (1 mL), 2- aminopyrimidine-5-boronic acid (29 mg, 0.129 mmol), PdCI2(dppf) (9 mg, 0.011 mmol) and a satured K2C03 solution (0.3 mL) were added. The reaction mixture was heated at 120 C for 2h. Then, water was added and it was extracted with dichloromethane, dried over Na2S04 and evaporated to dryness. The resulting residue was purified by was purified by CCTLC in the Chromatotron (CH2CI2:MeOH, 15:1), and then by HPLC to obtain 5mg of expected compound 5- 02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); In 1,2-dimethoxyethane; for 10h;Reflux; | A mixture of I-05 (40 mg, 0.10 mmol, 1 eq), <strong>[936250-22-5]2-aminopyrimidine-5-boronic acid</strong>, pinacol ester (27 mg, 0.12 mmol, 1.2 eq), and PdCI2(dppf) (9 mg, 0.01 mmol, 0.1 eq) in DME (5 mL) was added saturated aqueous solution of potassium carbonate (0.5 mL). The mixture was refluxed for 10 h. The solvent was removed in vacuo and the residue was triturated from Acetonitrile/water to give a brown solid that was filtered off, and washed with water. This residue was purified by column chromatography (EtOAc/MeOH mixtures as eluent) to afford final product 5-03, (7 mg, % yield) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; water; N,N-dimethyl-formamide; at 80℃; for 12.5h;Inert atmosphere; | Example 93 2-(1-(4-amino-3-(2-aminopyrimidin-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-3-(3-fluorophenyl)-4H-chromen-4-one To a solution of Example 57c (0.350 g, 0.663 mmoles) in DMF (4 ml), ethanol (2 ml) and water (2 ml), <strong>[936250-22-5]2-aminopyrimidine-5-boronic acid</strong> (0.184 g, 1.327 mmoles) and sodium carbonate (0.351 g, 3.318 mmoles) were added and the system is degassed for 30 min. Tetrakistriphenylphosphine Palladium (0.151 g, 0.130 mmoles) was added under nitrogen atmosphere and heated to 80 C. After 12 h, the reaction mixture was celite filtered, concentrated and extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as brown solid (0.045 g, 14% yield). MP: 264-268 C. 1H-NMR (delta ppm, DMSO-d6, 400 MHz): delta 8.38 (s, 2H), 8.05 (s, 1H), 8.03 (d, J=7.9, Hz, 1H), 7.85 (m, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.52 (t, J=7.3 Hz, 1H), 7.29 (br s, 1H), 7.07-6.93 (m, 5H), 5.99 (q, J=7.0 Hz, 1H), 1.88 (d, J=7.0 Hz, 3H). Mass: 494.86 (M+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; at 130℃; for 0.5h;Microwave irradiation; | Preparation of final product 2-14; To a reaction mixture of intermediate 1-10 (100 mg), 2-aminopyrimidine boronate (72mg), and PdCI2(dppf), (22 mg) in DME (2 ml), was added a saturated solution of potassium carbonate (1ml). The mixture was heated at 130C under microwave irradiation for 30 min. The mixture was filtered through celite, the filtrate was extracted with water. The organic phase was dried (Na2S04), filtered and evaporated. The residue was precipitated with MeOH and washed with Et20 to obtain impure final compound, which was purified by sep pack chromatography in DC /MeOH 100 to 98:2 to obtain 5 mg of a white solid after liophilization as final product 2-14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl acetamide; water; at 135℃; for 1h;Microwave irradiation; Inert atmosphere; | Step 21c: N-(4-acrylamidophenethyl)-2-(2-aminopyrimidin-5-yl)-6-morpholinoisonicotinamide (XII-2) Under Ar, a mixture of Intermediate 21b (11 mg, 26 umol), 2-aminopyrimidine 5-boronic acid (5 mg; 36 umol), PdCl2(dppf)2 (1 mg, 5% mol), in 600 uL of DMA and 100 uL of 1 M aqueous Na2CO3 was heated at 135 C. for 60 min in CEM microwave. The resulting black mixture was filtrated, and purified by prep-HPLC, giving 8 mg of desired product as white solid. LC-MS: m/z 474.0 (ES+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With potassium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere; | 5-{5-[1-Benzenesulfonyl-2-(2,6-difluoro-phenyl)-1H-indol-5-yl]-1-methy 1-1H-pyrazol-3-yl}-pyrimidin-2-ylamine: To a solution of 1-Benzenesulfonyl-5-(5-bromo-2-methyl-2H-pyrazol-3-yl)-2-(2,6-difluoro-phenyl)-1H-indole (50 mg, 0.09 mmol) and Pyrimidin-2-ylamine-4-boronic acid (21 mg, 0.09 mmol) in 1,4-dioxane (2 mL) was degassed with nitrogen (10 min), then aqueous K2CO3 (2 M, 0.09 mL) was added and the mixture purged again (5 min). Pd(dppf)Cl2 (8 mg, 0.009 mmol) was then added to the above reaction mixture and stirred at 100 C. for 4 h. Upon cooling the mixture was filtered through Celite, and the filtrate extracted with EtOAc (3*20 mL). The organic phase (EtOAc layer) was washed with brine, dried over Na2SO4, concentrated, and purified by column chromatography to give 5-{5-[1-Benzenesulfonyl-2-(2,6-difluoro-phenyl)-1H-indol-5-yl]-1-methyl-1H-pyrazol-3-yl}-pyrimidin-2-ylamine (18 mg, 35%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(II) acetate monohydrate; In methanol; at 65℃; for 1h; | General procedure: 6-Methoxypyridin-3-ylboronic acid (115 mg, 0.75 mmol), di-tert-butylazodicarboxylate ?DBAD? (115 mg, 0.5 mmol) and Cu(II)OAc-H2O (5.1 mg, 0.025 mmol) were combined in 3 mL MeOH in a 20 mL scintillation vial and heated for 1 h at 65 C. The mixture was cooled to room temperature and 2-phenylacetaldehyde (90 mg, 0.75 mmol) was added followed by addition of 2 mL 4 N HCl in dioxane and the mixture was placed in an 80 C heating block for 18 h. The reaction was cooled to room temperature and volatiles were removed in vacuo to give a crude oil which was partitioned between 25 mL of satd aq NaHCO3 and 100 mL CH2Cl2. Organics were extracted, dried (MgSO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography though silica gel using ethyl acetate in heptanes to elute providing 78 mg (70%) of 5-methoxy-3-phenyl-1H-pyrrolo[3,2-b]pyridine (Table 1, entry 1a) as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; tricyclohexylphosphine;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; water; at 90℃; for 19h;Inert atmosphere; | N-(5-bromo-2-morpholinopyridin-4-yl)-5,7-difluoro-3-methyl-2-(pyridin-2- yl)quinolin-4-amine (72.7 mg, 0.14 mmol), <strong>[936250-22-5]2-aminopyrimidin-5-ylboronic acid</strong> (41.3 mg, 0.3 mmol), tricyclohexylphosphine (6.7 mg, 0.024 mmol), and tris(dibenzylideneacetone)dipalladium (0) (11.6 mg, 0.013 mmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (3.0 mL) and aq. 1.3M potassium phosphate tribasic (0.22 mL, 0.29 mmol) were added by syringe. The resulting reaction was heated to 90 C and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-75% of a premixed solution of 89:9: 1 DCM: MeOH: ammonium hydroxide in DCM) to afford a film that was triturated with MeOH to afford a light yellow solid as N-(5-(2- aminopyrimidin-5 -yl)-2-morpholinopyridin-4-yl)-5 ,7-difluoro-3 -methyl-2-(pyridin-2-yl)quinolin-4-amine. .H NMR (400 MHz, DMSO-d6) delta ppm 8.71 (1 H, ddd, J=4.8, 1.8, 0.9 Hz), 8.23 (2 H, s), 8.07 (1 H, s), 8.02 (1 H, td, J=7.7, 1.9 Hz), 7.89 (1 H, d, J=7.8 Hz), 7.76 (1 H, s), 7.70 (1 H, m), 7.55 (2 H, m), 6.68 (2 H, s), 5.56 (1 H, s), 3.64 (4 H, m), 3.27 (4 H, m), 2.24 (3 H, s). Mass Spectrum (pos.) m/e: 527.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; water; toluene; at 90℃; for 2h; | To a suspension of 1-33 (156 mg, 0.35 mmol), <strong>[936250-22-5]2-aminopyrimidine-5-boronic acid</strong> (58 mg, 0.42 mmol) and 2M aqueous Na2C03 (0.53 mL) in ethanol: toluene (4: 1, 2 ml) in a pressure tube is added [l,l'-bis(diphenylphosphino)-ferrocene]dichloro palladium (II) (25 mg, 0.030mmol) and l,l'-bis(diphenylphosphino)ferrocene (15 mg, 0.02 mmol). The reaction mixture is stirred at 90 C for 2 h. The reaction mixture is filtered through a pad of Celite, washed with EtOAc and CH2C12. The collected filtrate is concentrated in vacuo. Purification by preparative HPLC gives the title compound (72 mg). | |
72 mg | With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; water; toluene; at 90℃; for 2h;Sealed tube; | To a suspension of I-33 (156 mg, 0.35 mmol), <strong>[936250-22-5]2-aminopyrimidine-5-boronic acid</strong> (58 mg, 0.42 mmol) and 2M aqueous Na2CO3 (0.53 mL) in ethanol:toluene (4:1, 2 ml) in a pressure tube is added [1,1?-bis(diphenylphosphino)-ferrocene]dichloro palladium (II) (25 mg, 0.030 mmol) and 1,1?-bis(diphenylphosphino)ferrocene (15 mg, 0.02 mmol). The reaction mixture is stirred at 90 C. for 2 h. The reaction mixture is filtered through a pad of Celite, washed with EtOAc and CH2Cl2. The collected filtrate is concentrated in vacuo. Purification by preparative HPLC gives the title compound (72 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; at 100℃; for 2h; | To a mixture of 1-87 (59 mg, 0.14 mmol), R-24 (23 mg, 0.17 mmol), PdCl2dppf (5 mg, 0.07 mmol), dppf (4 mg, 0.07 mmol) in EtOH (0.4 mL) and toluene (0.1 mL) at room temperature is added 2M Na2C03 solution (0.2 mL). The mixture is refluxed for 16 hours, allowed to cool to room temperature, and partitioned between CH2CI2 and ¾0. The combined organics are washed with saturated NaHC03 solution, dried with Na2S04, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (Si02, 0-10% MeOH in CH2C12) to give title compound 132 (15 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | Example 1 5-(5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)pyrimidin-2-amine A mixture of 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 308 mg, 1.359 mmol), <strong>[936250-22-5]2-aminopyrimidin-5-ylboronic acid</strong> (378 mg, 2.72 mmol) and PdCl2(dppf) (49.7 mg, 0.068 mmol) was partially dissolved in dioxane (8 mL) and aqueous saturated NaHCO3 (1.6 mL). The resulting brown suspension was heated in a microwave on high absorbance at 120 C. for 2 hours. The reaction mixture was subsequently diluted with ethyl acetate and washed with brine (3*15 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by LC/MS using a gradient of 1-20% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to afford a TFA salt of the title compound as an off-white solid (85.3 mg, 22%). 1H NMR (400 MHz, ACETONITRILE-d3) delta 3.01 (dd, J=11.87, 8.34 Hz, 1H), 3.15-3.24 (m, 1H), 3.25-3.33 (m, 1H), 3.41 (dd, J=11.87, 4.29 Hz, 1H), 3.57 (d, J=2.78 Hz, 1H), 3.77-3.86 (m, 1H), 3.93-3.99 (m, 1H), 4.00-4.07 (m, 1H), 4.82-4.90 (m, 1H), 6.23-6.36 (br s, 1H), 7.56 (s, 1H), 8.99 (s, 2H). ESI-MS m/z [M+H]+ calc'd for C13H15N7O, 286.13. found 286.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | 0750] Step 3 : Synthesis of 6-(2-aminopyrimidin-5-yl)-N-((4,6-dimethyl-2-oxo-l,2- dihydropyridin-3-yl)methyl)-l-isopropyl-lH-pyrazolo[3,4-b]pyridine-4-carboxamide[0751] A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-l,2-dihydropyridin-3-yl)methyl)- l-isopropyl-lH-pyrazolo[3,4-b]pyridine-4-carboxamide (1 equiv.), (2-aminopyrimidin-5- yl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1 ,4-dioxane was purged with argon for 10 min. Then, 2 M Na2C03 (3.6 equiv.) in water was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100 C for 1 h. After completion of the reaction, water was added to it and extraction was carried out using EtOAc. The combined organic layers were washed with water, dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (45% yield). LCMS:433.20(M + 1)+; HPLC: 98.75% (@ 254 nm) (R,;5.252); NMR (DMSO- ¼, 400 MHz) 5 11.55 (s, 1 H), 9.09 (s, 2H), 8.84 (t, 1H), 8.33 (s, 1 H), 8.07 (s, 1H), 7.15 (s, 2H), 5.89 (s, 1H), 5.32-5.28 (m, 1H), 4.40 (d, 2H, J=4.0 Hz), 2.22 (s, 3H), 2.12 (s, 3H), 1.51 (d, 6H,J=6.8 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 95℃; for 2h; | Intermediate 17 5-(5-bromo-4-methylpyridin-2-yl)pyrimidin-2-amine 5-(5-bromo-4-methylpyridin-2-yl)pyrimidin-2-amine: To a mixture of 2,5-dibromo-4-methylpyridine (550 mg, 2.19 mmol, Eq: 1.00), <strong>[936250-22-5]2-aminopyrimidin-5-ylboronic acid</strong> (365 mg, 2.63 mmol, Eq: 1.2), tetrakis(triphenylphosphine)palladium (0) (253 mg, 219 mumol, Eq: 0.1) and potassium carbonate (909 mg, 6.58 mmol, Eq: 3) was added dioxane (39.0 ml) and water (9.74 ml). The reaction mixture was then heated to 95 C. for 2 hrs. Upon completion, the mixture was concentrated under reduced pressure, and the crude material purified by chromatography using a (MeOH/DCM gradient) to give 5-(5-bromo-4-methylpyridin-2-yl)pyrimidin-2-amine (478 mg, 1.8 mmol, 82% yield) as an off-white solid. |
82% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 95℃; for 2h; | 5-(5-bromo-4-methylpyridin-2-yl)pyrimidin-2-amine: To a mixture of 2,5-dibromo-4-methylpyridine (550 mg, 2.19 mmol, Eq: 1.00), <strong>[936250-22-5]2-aminopyrimidin-5-ylboronic acid</strong> (365 mg, 2.63 mmol, Eq: 1.2), tetrakis(triphenylphosphine)palladium (0) (253 mg, 219 mumol, Eq: 0.1) and potassium carbonate (909 mg, 6.58 mmol, Eq; 3) was added dioxane (39.0 ml) and water (9.74 ml). The reaction mixture was then heated to 95 C. for 2 hrs. Upon completion, the mixture was concentrated under reduced pressure, and the crude material purified by chromatography using a (MeOH/DCM gradient) to give 5-(5-bromo-4-methylpyridin-2-yl)pyrimidin-2-amine (478 mg, 1.8 mmol, 82% yield) as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20.8% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; at 100℃; for 0.333333h;Microwave irradiation; | General procedure: 5-Bromo-1-octyl-1H-indole (20) and (5-bromo-1-octyl-1H-indol-3-ylmethyl)ethylamine (21) were prepared as previously described [10]. To a suspension of 21 (0.8 mmol), the substituted phenyl, pyridine or pyrimidine boronic acid (1.25 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.05 mmol) in dry 1,4-dioxane (3 mL) in a microwave reaction tube (20 mL) was added K2CO3 solution (2 mL, 1.5 mM) and subjected to microwave heating (20 min, 100 C) with stirring. The resulting dark colored solution was extracted with ethyl acetate (25 mL x 2), the combined organic layers were washed consecutively with water and brine, and dried (anhydrous Na2SO4). The organic solvent was removed in vacuo and the residue purified by column chromatography with CHCl3-methanol as eluting solvents. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97 mg | With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In ethanol; toluene; at 95℃; for 18h;Inert atmosphere; Sealed tube; | Method 26 Synthesis of [4-(2-aminopyrimidin-5-yl)phenyl]-(1-methylindazol-3-yl)methanone (Intermediate 37) A suspension of the I-36 (250 mg, 0.69 mmol), <strong>[936250-22-5]2-aminopyrimidine-5-boronic acid</strong> (115 mg, 0.83 mmol), 1,1-(bisdiphenylphosphino)ferrocene (11 mg, 20 mumol) and 2 M aqueous Na2CO3 (1.04 mL, 2.08 mmol) in a 4:1 mixture of EtOH:toluene (2.5 mL) is degassed for 5 min then [1,1-(bisdiphenylphosphino)ferrocene]dichloropalladium(II) (8 mg, 11 mumol) is added. The reaction vessel is sealed under N2 and heated to 95 C. for 18 h. On cooling to room temperature the mixture is diluted with DCM and washed with saturated aqueous NaHCO3. The organic phase is dried over anhydrous Na2SO4 and the solvent removed in vacuo to give I-37 (97 mg). The following intermediates are also prepared according to the method described in Method 26: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82 mg | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 80℃; for 3h; | General procedure: To a suspension of I-19.6 (150 mg, 0.35 mmol), <strong>[936250-22-5]2-aminopyrimidine-5-boronic acid</strong> pinacol ester (93 mg, 0.42 mmol) and 2 M aqueous Na2CO3 (0.35 mL, 0.70 mmol) in DMF (1.5 mL) is added bis(triphenylphosphino)palladium (II) chloride (25 mg, 0.03 mmol). The reaction vessel is sealed under N2 and heated to 80 C. for 30 min. On cooling to room temperature the reaction mixture is filtered through Celite and the solvent removed in vacuo. The residue is taken up in DCM and washed with saturated NaHCO3 and brine then dried over Na2SO4. The solvent is removed in vacuo to leave a residue which is purified by flash chromatography (SiO2, 3% MeOH in DCM) to give Example 6 (82 mg). LCMS (ESMS): Rt 3.89 min (Method F) m/z 398.42 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In ethanol; toluene; at 95℃; for 2h; | General procedure: To a suspension of I-19.6 (150 mg, 0.35 mmol), <strong>[936250-22-5]2-aminopyrimidine-5-boronic acid</strong> pinacol ester (93 mg, 0.42 mmol) and 2 M aqueous Na2CO3 (0.35 mL, 0.70 mmol) in DMF (1.5 mL) is added bis(triphenylphosphino)palladium (II) chloride (25 mg, 0.03 mmol). The reaction vessel is sealed under N2 and heated to 80 C. for 30 min. On cooling to room temperature the reaction mixture is filtered through Celite and the solvent removed in vacuo. The residue is taken up in DCM and washed with saturated NaHCO3 and brine then dried over Na2SO4. The solvent is removed in vacuo to leave a residue which is purified by flash chromatography (SiO2, 3% MeOH in DCM) to give Example 6 (82 mg). LCMS (ESMS): Rt 3.89 min (Method F) m/z 398.42 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82 mg | With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In methanol; N,N-dimethyl-formamide; at 90℃; | General procedure: To a suspension of I-19.6 (150 mg, 0.35 mmol), <strong>[936250-22-5]2-aminopyrimidine-5-boronic acid</strong> pinacol ester (93 mg, 0.42 mmol) and 2 M aqueous Na2CO3 (0.35 mL, 0.70 mmol) in DMF (1.5 mL) is added bis(triphenylphosphino)palladium (II) chloride (25 mg, 0.03 mmol). The reaction vessel is sealed under N2 and heated to 80 C. for 30 min. On cooling to room temperature the reaction mixture is filtered through Celite and the solvent removed in vacuo. The residue is taken up in DCM and washed with saturated NaHCO3 and brine then dried over Na2SO4. The solvent is removed in vacuo to leave a residue which is purified by flash chromatography (SiO2, 3% MeOH in DCM) to give Example 6 (82 mg). LCMS (ESMS): Rt 3.89 min (Method F) m/z 398.42 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-triphenylphosphine-palladium(II) chloride; sodium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 1h;Sealed tube; | General procedure: To a suspension of I-19.6 (150 mg, 0.35 mmol), <strong>[936250-22-5]2-aminopyrimidine-5-boronic acid</strong> pinacol ester (93 mg, 0.42 mmol) and 2 M aqueous Na2CO3 (0.35 mL, 0.70 mmol) in DMF (1.5 mL) is added bis(triphenylphosphino)palladium (II) chloride (25 mg, 0.03 mmol). The reaction vessel is sealed under N2 and heated to 80 C. for 30 min. On cooling to room temperature the reaction mixture is filtered through Celite and the solvent removed in vacuo. The residue is taken up in DCM and washed with saturated NaHCO3 and brine then dried over Na2SO4. The solvent is removed in vacuo to leave a residue which is purified by flash chromatography (SiO2, 3% MeOH in DCM) to give Example 6 (82 mg). LCMS (ESMS): Rt 3.89 min (Method F) m/z 398.42 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 3: Intermediate 6005B (300 mg, 0.600 mmol) is charged in a round-bottom flask with 2- aminopyrimidine-5-boronic acid, pinacol ester (Frontier) (199 mg, 0.900 mmol, 1 .50 eq) and potassium carbonate (249 mg, 1 .80 mmol, 3.00 eq) then water (400 mu) and DMF (4 mL) are added. The solution is degassed by bubbling argon through the solution for 5 min, then tetrakis(triphenylphosphine) palladium(O) (48.5 mg, 0.0420 mmol, 0.0700 eq) is added. The reaction mixture is heated in a microwave oven at 100 C for 7 h. The cooled solution is diluted with EtOAc and washed with water (2x). The organic layer is dried over MgS04, and the solution is filtered and concentrated under reduced pressure. The crude mixture is dissolved in MeOH (2 mL) and THF (4 mL), then a 1 .0 M aqueous solution of NaOH (2.00 mL, 2.00 mmol, 3.33 eq) is added. The solution is stirred at RT for 16 h. The reaction mixture is concentrated under reduced pressure, diluted with water and washed with Et20. The aqueous layer is neutralized to approximately pH=7 with a 1 .0 M aqueous solution of HCI. The resulting precipitate is filtered and dried under vacuum to afford intermediate 6005C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; sodium carbonate; In 1,2-dimethoxyethane; at 140℃; for 0.5h;Inert atmosphere; Microwave irradiation; | [00330] A mixture of (R)-5-chloro-6-(3-hydroxypyrrolidin-l-yl)-N-(4- (trifluoromethoxy)phenyl)nicotinamide (Stage 38.1, 50 mg, 0.124 mmol), (2-aminopyrimidin-5- yl)boronic acid (26 mg, 0.187 mmol), 2 M Na2C03 (0.124 mL, 0.249 mmol) and DME (2.5 mL) was flushed with argon and Rho02(rhorhoiota)(Omicron202) (10 mg, 0.012 mmol) was added .The mixture was subjected to MW irradiation 140C for 30 min, passed throug a PL-Thiol MP SPE cartridge (StratoSpheres), the cartridge was washed with MeOH and the solvent was evaporated off under reduced pressure to give a residue which was purified by preparative LC-MS to afford the title compound. LC-MS (Condition 5) tR = 1.53 min, m/z = 461.1 [M+H]+, m/z = 459.1 [M-H] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In water; N,N-dimethyl-formamide; at 95℃; for 2h;Inert atmosphere; | To a 25 mL round bottom flask, 1-(4-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (0.1 g, 0.0002 mol), <strong>[936250-22-5]2-aminopyrimidine-5-boronic acid</strong> (0.085 g, 0.0003 mol), cesium carbonate 0.149 g, 0.0004 mol), DMF (10 mL) and water (3 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.008 g, 0.00001 mol) was added and degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95 C. for 2 hours. The reaction mass was diluted with water and extracted with ethyl acetate (3×25 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by column chromatography (60-120 silica gel, 8% methanol in chloroform), followed by preparative HPLC (0.1% TFA in water and acetonitrile) to provide the title compound (0.007 g, 6%). 1H NMR (400 MHz, DMSO-d6): delta 9.18 (s, 2H), 8.82 (s, 1H), 8.25 (s, 1H), 4.72 (br s, 4H), 4.21 (s, 2H), 3.93-3.82 (m, 10H), 3.00 (br s, 4H), 1.33 (d, J=6.4 Hz, 3H): LC-MS (ESI): Calculated mass. 479.24, Observed mass [M+H]+: 480.2 (RT=0.22 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In water; N,N-dimethyl-formamide; at 95℃; for 2h;Inert atmosphere; | To a 50 mL round bottom flask, 4-(2-chloro-6-fluoro-7-(3-(methylsulfonyl)phenyl)quinazolin-4-yl)morpholine (0.06 g, 0.00015 mol), <strong>[936250-22-5](2-aminopyrimidin-5-yl)boronic acid</strong> (0.03 g, 0.00023 mol), cesium carbonate (0.097 g, 0.0003 mol), DMF (5 mL) and water (2 mL) were added. The reaction vessel was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd(PPh3)2Cl2 (0.005 g, 0.0000075 mol) was added and again degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95 C. for 2 hours. The reaction mixture was cooled and water was added. The crude product was extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under the reduced pressure to afford the crude product. The crude product was purified by column chromatography (60-120 silica gel, 0-5% methanol in chloroform) to provide the desired product (0.05 g, 7%). 1H NMR (400 MHz, DMSO-d6): delta 9.22 (s, 2H), 8.36 (s, 1H), 8.25 (s, 1H), 8.22 (d, J=2.0 Hz, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.87-7.80 (m, 2H), 7.21 (s, 2H), 3.85 (s, 8H); 1H NMR (400 MHz, DMSO-d6+D2O): delta 9.12 (s, 2H), 8.20 (s, 1H), 8.14-8.06 (m, 3H), 7.95 (d, J=7.6 Hz, 1H), 7.79 (t, J=7.2 Hz, 2H), 3.83-3.77 (m, 8H), 3.21 (s, 3H). LC-MS (ESI): Calculated mass: 462.1; Observed mass [M+H]+: 463.1 (RT=0.23 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82.4% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | Step 30-1 5-(4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d] pyrimidin-5 -y l)pyrimidin-2 -amine (30b) To a solution of 30a (409 mg, 1 mmol) in 1 ,4-dioxane/water (10 mL / 1 mL) was added <strong>[936250-22-5]2-aminopyrimidin-5-ylboronic acid</strong> (139 mg, 1 mmol), Pd(dppf)Cl2 (81.6mg, 0.1 mmol) and K2CO3 (414 mg, 3 mmol). Under N2, the reaction mixture was heated at 100 C for 2 h. Then the solvent was removed in reduced pressure and the residue was purified by flash column chromatography eluting with MeOH/DCM to give 30b as a yellow solid (310 mg, yield: 82.4%). MS (m/z): 377.1 (M+H)+ |
82.4% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | To a solution of 30a (409 mg, 1 mmol) in 1,4-dioxane/water (10 mL / 1 mL) was added <strong>[936250-22-5]2-aminopyrimidin-5-ylboronic acid</strong> (139 mg, 1 mmol), Pd(dppf)Cl2 (81.6mg, 0.1 mmol) and K2CO3 (414 mg, 3 mmol). Under N2, the reaction mixture was heated at 100 C for 2 h. Then the solvent was removed in reduced pressure and the residue was purified by flash column chromatography eluting with MeOH/DCM to give 30b as a yellow solid (310 mg, yield: 82.4%). MS (m/z): 377.1 (M+H)+ |
82.4% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; water; at 100℃; for 2h;Inert atmosphere; | To a solution of 30a (409 mg, 1 mmol) in 1,4-dioxane/water (10 mL / 1 mL) was added <strong>[936250-22-5]2-aminopyrimidin-5-ylboronic acid</strong> (139 mg, 1 mmol), Pd(dppf)Cl2 (81.6mg, 0.1 mmol) and K2CO3 (414 mg, 3 mmol). Under N2, the reaction mixture was heated at 100 C for 2 h. Then the solvent was removed in reduced pressure and the residue was purified by flash column chromatography eluting with MeOH/DCM to give 30b as a yellow solid (310 mg, yield: 82.4%). MS (m/z): 377.1 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In tetrahydrofuran; at 120℃; for 0.25h;Microwave irradiation; | Preparation Example 6. Synthesis of 4-(2-aminopyrimidin-5-yl)-2,6-dimethylphenol(Compound 6-4): 2-Aminopyrimidin-5-ylboronic acid (0.76 g, 5.4 mmol) was dissolved in dimethoxyethane/water (2:1). 4-Bromo-2,6-dimethylphenol (0.91 g, 4.52 mmol) and Pd(dppf)Cl2 (0.19 g, 0.14 mmol), sodium carbonate (1.4 g, 14 mmol) were added thereto, followed by reacting in microwave reactor at 120 C for 15 minutes. After the completion of the reaction, the reaction mixture was added with water, and extracted with dichloromethane.The obtained organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 4-(2-aminopyrimidin-5-yl)-2,6- dimethyiphenol (0.27 g, 27 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | Example 13 (S)-1-(4-((2-(2-Aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one, GDC-0980, Formula I Method A: (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II (22.0 g, 50.0 mmol) was charged to a suitably sized reactor, followed by n-propanol (198 mL), <strong>[936250-22-5]2-aminopyrimidin-5-ylboronic acid</strong> III (8.30 g, 59.7 mmol) and potassium phosphate (21.3 g, 100 mmol). The resulting mixture was degassed by vacuum/argon purge three times. Bis(triphenylphosphine)palladium (II) chloride (0.053 g, 0.076 mmol) was added and the slurry was again degassed by vacuum/argon purge three times. The mixture was heated within 2 h to 85 C. and stirred for 30 min. The reaction mixture was cooled to rt, water (200 mL) was added and the pH was adjusted to 6.0-8.0 with 37 wt % aqueous hydrochloric acid solution (6.92 mL). The biphasic mixture was heated to 80 C. and stirred for 1 h. The organic phase was separated and slowly filtered over a preheated pressure filter loaded with a ZETACARBON R55SP pad (Cuno Inc., a 3M Company, Meriden Conn.). The filter unit was washed with a warm (80 C.) mixture of n-propanol (45 mL) and water (24 mL). The filtrate was concentrated under reduced pressure while keeping the volume constant by addition of water (150 mL). The resulting slurry was cooled to 26-36 C., filtered and rinsed with a mixture of n-propanol (15 mL) and water (108 mL). The cake was dried under reduced pressure at 45 C. to afford the crude product as a yellowish white solid (20.7 g). The crude product was charged to a suitably sized reactor, followed by n-propanol (116 mL) and water (62 mL). The suspension was heated to 85 C. and stirred to afford a clear solution. The solution was filtered over a preheated polishing filter unit and rinsed with a mixture of n-propanol (23 mL) and water (12 mL). The filtrate was cooled to -10 C., aged for 1 h and filtered. The filter cake was washed with n-propanol (77 mL) and dried under reduced pressure at 60-70 C. to afford (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one, GDC-0980, Formula I as a yellowish white to white solid (18.9 g, 76%). 1H NMR (400 MHz, DMSO-d6) delta 9.15 (s, 2H), 7.05 (s, 2H), 4.84 (d, J=6.98 Hz, 1H), 4.35-4.48 (m, 1H), 3.89-4.00 (m, 4H), 3.84 (s, 2H), 3.67-3.78 (m, 4H), 3.36-3.64 (m, 4H), 2.38-2.60 (m, 4H), 2.34 (s, 3H), 1.18 (d, J=6.53 Hz, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In water; | Method B: (S)-1-(4-((2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one II (33.0 g, 75 mmol) was charged to a suitably sized reactor, followed by n-propanol (337 g), water (450 g), <strong>[936250-22-5]2-aminopyrimidin-5-ylboronic acid</strong> III (12.5 g, 90 mmol) and dipotassium hydrogen phosphate (39.2 g, 225 mmol). The resulting mixture was degassed by vacuum/argon purge three times. Bis(triphenylphosphine)palladium (II) chloride (0.079 g, 0.112 mmol) was added and the slurry was again degassed by vacuum/argon purge three times. The mixture was heated within 2 h to 65 C. and stirred for 10 hours. The organic phase was separated and slowly filtered over a preheated pressure filter loaded with a ZETACARBON R55SP pad (Cuno Inc., a 3M Company, Meriden Conn.). The filter unit was washed with a warm (80 C.) n-propanol (45 mL). Water (750 mL) were added to the filtrate and the resulting suspension was cooled to 10 C., aged for 1 h and filtered. The filter cake was washed with water (150 g) and dried under reduced pressure at 45 C. to afford (S)-1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one, GDC-0980, Formula I as a white solid (30.1 g, 79%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42% | With hydrogenchloride; n-butyllithium; lithium hexamethyldisilazane; In tetrahydrofuran; methanol; tert-butyl methyl ether; water; | By the alternative synthetic route in Scheme 8, to a 3-L flask under nitrogen was charged tetrahydrofuran (1055 mL), followed by 5-bromopyrimidine-2-amine 9 (70.0 g, 0.40 mol). The mixture was cooled to a temperature between -60 C. and -70 C. and lithium bis(trimethylsilyl)amide (LiHMDS) (1M in tetrahydrofuran, 483 mL, 0.483 mol) was charged over 30 min while maintaining the temperature between -60 C. and -70 C. The mixture was stirred at -60 C. to -70 C. for 1 h. n-Butyllithium (2.5 M in hexanes, 515 mL, 1.29 mol) was charged over 1 h while maintaining the temperature between -60 C. and -70 C., and the reaction mixture was then aged for 2 h. Additional n-butyllithium (2.5 M in hexanes, 48 mL, 0.12 mol) was charged over 15 min while maintaining the temperature between -60 C. and -70 C., and the reaction mixture was stirred for 1 h. To the mixture was added triisopropyl borate (91.0 g, 0.48 mol) over 1 h while maintaining the temperature between -60 C. and -70 C., and the reaction mixture was stirred for 1 h. The mixture was then allowed to warm to 0-5 C. and water (700 mL) was added over 1 h. After being aged at 0-5 C. for 30 min, the resulting layers were separated. To the aqueous layer was added water (420 mL) over 30 min, followed by addition of tert-butyl methyl ether (822 mL). The mixture was allowed to warm to 20-25 C. and was stirred for 30 min. The layers were separated and the aqueous layer was washed with tert-butyl methyl ether (5*700 mL). The aqueous layer was cooled to 0-5 C., and 35% aqueous hydrochloric acid solution (137 mL) was added over 1 h while maintaining the temperature between 0-5 C. The mixture was stirred at 0-5 C. for 1.5 h, filtered, washed with water (14 mL) and the cake was dried under vacuum at 45-50 C. to afford the crude product (26.7 g). The crude product was charged to a 5-L flask, followed by addition of methanol (908 mL), and the mixture was stirred at room temperature (rt) for 20 min. The mixture was warmed to 65 C. and stirred for 1.5 h. To the mixture was added water (2136 mL) over 2 h and the suspension was stirred for 1.5 h. The mixture was cooled to 20 C. and stirred for 14 h. The solid was collected by filtration and the filter cake was washed with water (13 mL), dried under vacuum at 45-50 C. for 12 h to afford 2-aminopyrimidin-5-ylboronic acid III (23.6 g, 42% yield) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With hydrogenchloride; In water; | Example 17 2-Aminopyrimidin-5-ylboronic acid III To a mixture of [2-[(tert-butoxycarbonyl)amino]pyrimidin-5-yl]boronic acid 12 (40.0 kg, 49 wt % by HPLC, 82.0 mol) in water (245 kg) was added concentrated hydrochloric acid (39.6 L) while maintaining the temperature below 30 C. The reaction mixture was stirred for 12 h and was then cooled to 10 C. The pH of the mixture was adjusted to 6.5 by addition of 50% aqueous sodium hydroxide solution while maintaining the temperature below 15 C. and the mixture was then stirred for 1 h. Water (69.0 kg) was added and the mixture was aged for 30 min. The resulting slurry was filtered and the cake was dried under vacuum at 50 C. to afford 2-aminopyrimidin-5-ylboronic acid III (10.2 kg, 90% yield). 1H NMR (300 MHz, DMSO-d6) delta 8.50 (s, 2H), 7.97 (s, 2H), 6.74 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
246.9 g | With hydrogenchloride; In tert-butyl methyl ether; water; for 4h;pH 1.3; | To a dry, clean jacket reactor (which was rendered inert, nitrogen atmosphere) with mechanical stirring, electronic thermometer, and two reservoirs (dropping funnels) are charged 804 g dry THF and cooled to -95C. In one of the reservoirs (R1) a solution of 172 g benzhydrylidene-(5-bromo-pyrimidin-2-yl)-amine, 115 g triisopropylborate (1.2 eq.) and additional 1609 g THF is prepared. To the second dropping funnel (R2) are charged 155 g n-butyllithium (2.5M, 1.1 eq.). Now from Ri, 568 g solution (0.3 eq.) areadded dropwise, mantaining a temperature below -90C. Subsequently, 21.1 g of nbutyllithium solution from R2 (0.15 eq.) are added, again maintaining the temperature below -90C. Then, another 284 g solution from R1 (0.15 eq.) are added followed by 21.1 g n-BuLi from R2 (0.15 eq.). The procedure is repeated again by the addition of 284 g solution from R1 (0.15 eq.) and subsequently 21.2 g n-BuLi from R2 (0.15 eq.). The conversion is monitored by HPLC. One continues with addition of 284.0 g solution from Ri (0.15 eq.) followed by 21.1 g n-BuLi from R2 (0.15 eq.). At this point in total 0.75 eq. of the precursor and 0.6 eq. n-BuLi have been added. Additional 284.0 g solution from Ri (0.15 eq.) followed by 21.1 g n-BuLi (0.15 eq.) are added. The conversion is checked by HPLC again. Additional 190 g solution from Ri (0.1 eq.) and 35.3 g n-BuLi (0.25 eq.) are added. The batch is analyzed per HPLC again. In most cases, another 14.1 g n-BuLi (0.1 eq.) have to be added additionally. The batch is warmed to -60C and quenched onto 1540 g water. The reaction mixture is allowed to warm to room temperature and stirred for at least 30 mi ii25 g Toluene are added and the batch is stirred for further is mm. The layers are separated and the aqueous is extracted again with 510 g toluene. To the aqueous product layer, 563 g MTBE are added and the pH is adjusted to about 1.3 by addition of about 200 g 20% hydrochloric acid. Now the batch is allowed to stir for at least 4 hours and subsequently, the layers are separated. The aqueous layer is extracted with 563 g MTBE and after the layers are separated7 the pH is adjusted using 65.0 g 33% caustic soda lye to roughly 7.5. The obtained slurry is stirred for one hour at room temperature and filtered. 126 g of a white crude product containing residual moisture is obtained. It is reslurried in 395 g water and 95.0 g Isopropanol. The mixture is warmed to 50C and stirred for at least one hour at this temperature. The batch is cooled to room temperature and the fine product is filtered. A wet fine product is obtained, which is dried in a tray drier at 40C to 45C and 100 to 200 mbar leaving 57.6 g of the white, fine crystalline boronic acid (81%). 1H-NMR (400 MHz, dmso-d6+D2O) delta =6.82 (s, 2H), NH2, B(OH)2 not observed due to H-D exchange. MP : 186-188C |
To a dry, clean jacket reactor (which was rendered inert, nitrogen atmosphere) with mechanical stirring, electronic thermometer, and two reservoirs (dropping funnels) are charged 804 g dry THF and cooled to -95 C. In one of the reservoirs (R1) a solution of 172 g benzhydrylidene-(5-bromo-pyrimidin-2-yl)-amine, 115 g triisopropylborate (1.2 eq.) and additional 1609 g THF is prepared. To the second dropping funnel (R2) are charged 155 g n-butyllithium (2.5M, 1.1 eq.). Now from R1, 568 g solution (0.3 eq.) are added dropwise, maintaining a temperature below -90 C. Subsequently, 21.1 g of n-butyllithium solution from R2 (0.15 eq.) are added, again maintaining the temperature below -90 C. Then, another 284 g solution from R1 (0.15 eq.) are added followed by 21.1 g n-BuLi from R2 (0.15 eq.). The procedure is repeated again by the addition of 284 g solution from R1 (0.15 eq.) and subsequently 21.2 g n-BuLi from R2 (0.15 eq.). The conversion is monitored by HPLC. One continues with addition of 284.0 g solution from R1 (0.15 eq.) followed by 21.1 g n-BuLi from R2 (0.15 eq.). At this point in total 0.75 eq. of the precursor and 0.6 eq. n-BuLi have been added. Additional 284.0 g solution from R1 (0.15 eq.) followed by 21.1 g n-BuLi (0.15 eq.) are added. The conversion is checked by HPLC again. Additional 190 g solution from R1 (0.1 eq.) and 35.3 g n-BuLi (0.25 eq.) are added. The batch is analyzed per HPLC again. Another 14.1 g n-BuLi (0.1 eq.) may need to be added. The batch is warmed to -60 C. and quenched onto 1540 g water. The reaction mixture is allowed to warm to room temperature and stirred for at least 30 min. 1125 g Toluene are added and the batch is stirred for further 15 min. The layers are separated and the aqueous is extracted again with 510 g toluene. To the aqueous product layer, 563 g MTBE are added and the pH is adjusted to about 1.3 by addition of about 200 g 20% hydrochloric acid. Now the batch is allowed to stir for at least 4 hours and subsequently, the layers are separated. The aqueous layer is extracted with 563 g MTBE and after the layers are separated7 the pH is adjusted using 65.0 g 33% caustic soda lye to roughly 7.5. The obtained slurry is stirred for one hour at room temperature and filtered. 126 g of a white crude product containing residual moisture is obtained. It is reslurried in 395 g water and 95.0 g Isopropanol. The mixture is warmed to 50 C. and stirred for at least one hour at this temperature. The batch is cooled to room temperature and the fine product is filtered. A wet fine product is obtained, which is dried in a tray drier at 40 C. to 45 C. and 100 to 200 mbar leaving 57.6 g of the white, fine crystalline boronic acid (81%). [0297] 1H-NNR (400 MHz, dmso-d6+D2O) [0298] delta=6.82 (s, 2H), NH2, B(OH)2 not observed due to H-D exchange. [0299] MP: 186-188 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In water; N,N-dimethyl-formamide; at 110℃; for 2h;Microwave irradiation; Inert atmosphere; | General procedure: Method B: In a20 mL microwave Biotage tube, a 1M Na2CO3 aqueous solution(5 mL) purged with argon were introduced into a mixture purged with argon of <strong>[71759-89-2]4-iodo-1H-imidazole</strong> (1a) (0.194 g, 1.0 mmol), a boronicacid 2 (1.6 mmol) and Pd(PPh3)4 (0.80 g, 0.05 mmol) in DMF (15 mL). The mixture washeated under microwaveirradiation. When the reaction was complete, the mixture was cooled toroom temperature and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel to provide compounds 3j and 3p-3u in yields ranging from 30 to 95%. Time and temperaturereactions were collected in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.9% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 120℃;Inert atmosphere; | 3 -(1 -(4-amino-3 -iodo- 1 H-pyrazo lo [3 ,4-d]pyrimidin- 1 -yl)ethyl)-4-phenyl- 1 H-isochromen-1-one (Intermediate D2a, 60mg, 0.118 mmol), K2C03 (32.6 mg, 0.236 mmol), <strong>[936250-22-5]2-aminopyrimidin-5-ylboronic acid</strong> (32.7 mg, 0.236 mmol) and Pd(dppf)C12 (4.31 mg, 5.89 jimol) were reacted in 2 ml of dioxane, purged with argon and heated overnight at 120C. The reaction was quenched by the addition of 1M HClaqueous (2m1) and the resulting mixture was straightforward purified via reverse phase chromatography using aBiotage C18 30g SNAP with a gradient of water and acetonitrile (prior to drying 2 ml of1M HClaqueous were added) to give the title compound (16.2 mg, 28.9 %) as a yellow solid.1H NMR (400 MHz, DMSO-d6) oe ppm 8.47 (s, 2 H), 8.22 (s, 2 H), 7.86 - 8.05 (m,1 H), 7.77 (m, 1 H), 7.63 (m, 1 H), 7.53 (m, 1 H), 7.42 (m, 3 H), 7.20 - 7.33 (m, 1 H),7.06 - 7.18 (m, 1 H), 6.89 (d, J7.94 Hz, 1 H), 5.74 (d, J7.06 Hz, 1 H), 1.85 (d, J=7.06Hz, 3 H). UPLC-MS: 4.56 mm, 477.1 [M+H]+, method 7. |
28.9% | With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium carbonate; In 1,4-dioxane; at 120℃;Inert atmosphere; | 3-(1-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)-4-phenyl-1H-isochromen-1-one (Intermediate D2a, 60 mg, 0.118 mmol), K2CO3 (32.6 mg, 0.236 mmol), <strong>[936250-22-5]2-aminopyrimidin-5-ylboronic acid</strong> (32.7 mg, 0.236 mmol) and Pd(dppf)Cl2 (4.31 mg, 5.89 mumol) were reacted in 2 ml of dioxane, purged with argon and heated overnight at 120 C. The reaction was quenched by the addition of 1M HClaqueous (2 ml) and the resulting mixture was straightforward purified via reverse phase chromatography using a Biotage C18 30 g SNAP with a gradient of water and acetonitrile (prior to drying 2 ml of 1M HClaqueous were added) to give the title compound (16.2 mg, 28.9%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) delta ppm 8.47 (s, 2H), 8.22 (s, 2H), 7.86-8.05 (m, 1H), 7.77 (m, 1H), 7.63 (m, 1H), 7.53 (m, 1H), 7.42 (m, 3H), 7.20-7.33 (m, 1H), 7.06-7.18 (m, 1H), 6.89 (d, J=7.94 Hz, 1H), 5.74 (d, J=7.06 Hz, 1H), 1.85 (d, J=7.06 Hz, 3H). UPLC-MS: 4.56 min, 477.1 [M+H]+, method 7. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane;Inert atmosphere; | General procedure: General procedure (a): a mixture of bromoacetamide 2a or 10a, arylboronic acid (1.5 equiv), CsF (2.2 equiv) and Pd(PPh3)4 or PEPPSI-iPr (0.1-0.15 equiv) in dry 1,2-dimethoxyethane (DME, 3 mL) was stirred under Ar at 85 C for 16 h. The reaction mixture was diluted with AcOEt, washed with brine and dried over MgSO4. The solvent was evaporated and the residue purified by flash chromatography (cyclohexane/AcOEt). General procedure (b): same procedure with K2CO3 (1.5 equiv) as base and in DME and H2O as reaction solvent 5/1. General procedure (c): same procedure with K2CO3 (3 equiv) as base and in DME and H2O as reaction solvent 4/1. The reaction mixture was then heated at 125 C under microwave irradiation for 30 min. General procedure (d): same procedure with K2CO3 (4 equiv) as base, and in DME and H2O as reaction solvent 4/1. The reaction mixture was then heated at 125 C under microwave irradiation for 30 min. 6.4.1.5 7-tert-Butoxycarbonylamino-1-(2-amino-5-pyrimidyl)-5,7,8,9-tetrahydrobenzocyclohepten-6-one (9a) Pale yellow solid. Mp 121-122 C. IR (KBr): 3427, 2980, 2930, 1701, 1630, 1487, 1366, 1165, 805 cm-1. 1H NMR (CDCl3, 300 MHz): 8.26 (s, 2H, H-4' and H-6'); 7.24 (m, 2H, H-2 and H-3); 7.15 (dd, 1H, J = 5.5 and 1.5 Hz, H-4); 5.45 (d, 1H, NH); 5.29 (br s, 2H, NH2); 4.57 (ddd, 1H, H-7); 3.94 (d, 1H, Ha-5); 3.73 (d, 1H, Hb-5); 2.89 (m, 2H, CH2-9); 2.53 (ddd, 1H, Ha-8); 1.49 (ddd, 1H, Hb-8); 1.42 (s, 9H, tBu). J(5a,5b) = 16.1, J(NH,7) = 6.8, J(7,8a) = 7.1, J(7,8b) = 11.3 Hz. 13C NMR (CDCl3, 100 MHz): 205.2 (C(6)); 162.1 (NCO2); 158.0 (C(4') and C(6')); 138.0 (C(2')); 135.4 (C(9a)); 133.7 (C(4a)); 130.0 (C(2)); 129.8 (C(3)); 127.2 (C(4)); 124.9 (C(1)); 111.7 (C(5')); 79.8 (CMe3); 59.6 (C(7)); 48.3 (C(5)); 34.2 (C(8)); 28.3 (CMe3); 26.2 (C(9)). HR-MS (ESI-QTof) calcd for C20H25N4O3 [M+H]+: 369.1921; found: 369.1906. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,2-dimethoxyethane;Inert atmosphere; | General procedure: General procedure (a): a mixture of bromoacetamide 2a or 10a, arylboronic acid (1.5 equiv), CsF (2.2 equiv) and Pd(PPh3)4 or PEPPSI-iPr (0.1-0.15 equiv) in dry 1,2-dimethoxyethane (DME, 3 mL) was stirred under Ar at 85 C for 16 h. The reaction mixture was diluted with AcOEt, washed with brine and dried over MgSO4. The solvent was evaporated and the residue purified by flash chromatography (cyclohexane/AcOEt). General procedure (b): same procedure with K2CO3 (1.5 equiv) as base and in DME and H2O as reaction solvent 5/1. General procedure (c): same procedure with K2CO3 (3 equiv) as base and in DME and H2O as reaction solvent 4/1. The reaction mixture was then heated at 125 C under microwave irradiation for 30 min. General procedure (d): same procedure with K2CO3 (4 equiv) as base, and in DME and H2O as reaction solvent 4/1. The reaction mixture was then heated at 125 C under microwave irradiation for 30 min. 6.4.1.34 7-tert-Butoxycarbonylamino-4-(2-amino-5-pyrimidyl)-5,7,8,9-tetrahydrobenzocyclohepten-6-one (40a) Yellow solid. Mp 105-106 C. IR (KBr): 3294, 2977, 2929, 1724, 1704, 1677, 1544, 1460, 1184, 722, 541 cm-1. 1H NMR (CDCl3, 400 MHz): 8.42 (s, 2H, H-4' and H-6'); 7.22 (m, 2H, H-2 and H-3); 7.15 (dd, 1H, J = 7.5 and 1.6 Hz, H-1); 5.45 (d, 1H, NH); 5.15 (br s, 2H, NH2); 4.59 (ddd, 1H, H-7); 3.85 (d, 1H, Ha-5); 3.66 (d, 1H, Hb-5); 3.11 (ddd, 1H, Ha-9); 2.99 (ddd, 1H, Hb-9); 2.70 (m, 1H, Ha-8); 1.49 (m, 1H, Hb-8); 1.44 (s, 9H, tBu). J(5a,5b) = 14.2, J(NH,7) = 6.5, J(7,8a) = 6.3, J(7,8b) = 11.3, J(8a,9a) = 2.9, J(8a,9b) = 8.5, J(8b,9a) = 9.4, J(8b,9b) = 3.1, J(9a,9b) = 14.9 Hz. 13C NMR (CDCl3, 100 MHz): 204.8 (C(6)); 162.4 (NCO2); 159.2 (C(4') and C(6')); 142.0 (C(2')); 136.3 (C(9a)); 133.5 (C(4)); 131.0 (C(4a)); 129.9 (C(1)); 129.7 (C(3)); 128.1 (C(2)); 125.0 (C(5')); 80.3 (CMe3); 61.8 (C(7)); 43.7 (C(5)); 35.2 (C(8)); 32.0 (C(9)); 28.8 (CMe3). HR-MS (ESI-QTof) calcd for C20H25N4O3 [M+H]+: 369.1921; found: 369.1926. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With bis-triphenylphosphine-palladium(II) chloride; potassium phosphate monohydrate; In tert-butyl alcohol; at 50℃; for 6h;Schlenk technique; Inert atmosphere; Sealed tube; | General procedure: Procedure A: To a Schlenk tube equipped with a magnetic stiring bar and a teflon septum was charged K3PO4.H2O (1.5 mmol, 3 equiv), aryl pentafluorobenzene sulfonate (0.5 mmol, 1.0 equiv), aryl boronic acid (0.75 mmol, 1.5 equiv) and Pd(PPh3)2Cl2 (0.015 mmol, 3 mol%). The tube was then capped with a rubber septum, evacuated and backfilled with nitrogen and this cycle was repeated twice. Under an inertatmosphere, tert - butanol (3 mL) was added via syringe. Under a positive pressure of nitrogen, the rubber septum was replaced with a Teflon screw cap and this was sealed. The Schlenk tube was stirred at room temperature for the time indicated. When the reaction was completed according to TLC or GCMS (FID), thereaction mixture was diluted with EtOAc (5 mL) and filtered through celite bed. The organic layer was concentrated under reduced pressure. The residue was purified through silica gel (230 - 400 mesh) column chromatography using 1-10% ethyl acetate in petroleum ether to afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83 mg | To a microwave vial was added 150 mg of this material, (2- aminopyrimidin-5-yl)boronic acid (74.0 mg, 0.54 mmol), cesium carbonate (194 mg, 0.60 mmol) and a DMF / water mixture (2:1, 4.5 mL). The resulting suspension was purged with argon, treated with dichloro[bis(triphenylphosphoranyl)]palladium (Pd(PPh3 Cl2, 10.4 mg, 0.02 mmol) and sealed. The resulting mixture was heated with a microwave apparatus at 100 C for 0.5 h, was then cooled to room temperature. The reaction mixture was diluted with water and ethyl acetate. The phases were separated and the precipitate in the aqueous phase was collected by filtration, washed with ethyl acetate and dried to give 83.0 mg of the title compound. 1H-NM (400 MHz, DMSO-d6): delta [ppm] = 2.55 - 2.61 (m, 4H), 3.23 (s, 2H), 3.61 - 3.69 (m, 4H), 7.10 (s, 2H), 7.61 (dd, 1H), 7.96 (dd, 1H), 8.20 (d, 1H), 8.38 (d, 1H), 8.86 (d, 1H), 8.96 (s, 2H), 9.91 (s, 1H), 11.66 (s, 1H). (0873) LC-MS (Method 4): Rt = 0.75 min; MS (ESIpos): m/z = 519 [M+H]+. (0874) Example 14 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72 mg | 900 mg (2.39 mmol) of the compound of intermediate 1 were provided in 20 mL of toluene, 0.29 mL (3.58 mmol) of chloroacetyl chloride were added, and the mixture was stirred for 2 h at 100 C. After concentration 1.05 g of a mixture of N-(6-bromopyridazin-3-yl)-3-[(chloroacetyl)amino]-4- (trifluoromethoxy)benzamide and 3-[(chloroacetyl)amino]-N-(6-chloropyridazin-3-yl)-4- (0817) (trifluoromethoxy)benzamide were obtained, which were used without further purification. To a suspension of this raw material in 17 mL of DMF were added 0.65 mL of triethylamine (4.63 mmol), 0.51 mL of methylpiperazine (4.63 mmol), and 77 mg of potassium iodide (0.46 mmol). The reaction mixture was stirred at room temperature over night. After concentration, the remaining material was triturated with 500 mL of water and 300 mL of ethanol and stirred for 30 minutes. The precipitate was removed by filtration, washed with ethanol and dried under reduced pressure to yield 540 mg of a mixture of N-(6-bromopyridazin-3-yl)-3-[(4-methylpiperazin-l-yl)acetyl]amino}-4- (trifluoromethoxy)benzamide and N-(6-chloropyridazin-3-yl)-3-[(4-methylpiperazin-l- yl)acetyl]amino}-4-(trifluoromethoxy)benzamide, which were used without further purification. To a microwave vial was added 100 mg of this raw material, <strong>[936250-22-5](2-aminopyrimidin-5-yl)boronic acid</strong> (40.0 mg, 0.29 mmol), cesium carbonate (126 mg, 0.39 mmol) and a DMF / water mixture (2:1, 3 mL). The resulting suspension was purged with argon, treated with dichloro[bis(triphenylphosphoranyl)]palladium (Pd(PPh3 Cl2, 6.8 mg, 0.01 mmol) and sealed. The resulting mixture was heated with a microwave apparatus at 100 C for 0.5 h, was then cooled to room temperature. The reaction mixture was diluted with water and ethyl acetate. The precipitate was removed by filtration and dried under reduced pressure to give 72.0 mg (70% of theory) of the title compound. 1H-NM (400 MHz, DMSO-d6): delta [ppm] = 2.18 (s, 3H), 2.34 - 2.46 (m, 4H), 2.55 - 2.64 (m, 4H), 3.21 (s, 2H), 7.09 (s, 2H), 7.61 (d, 1H), 7.94 (dd, 1H), 8.20 (d, 1H), 8.38 (d, 1H), 8.93 (d, 1H), 8.97 (s, 2H), 9.92 (s, 1H), 11.64 (s, 1H). (0818) LC-MS (Method 3): Rt = 0.96 min; MS (ESIpos): m/z = 532 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In 1,2-dimethoxyethane; water; N,N-dimethyl-formamide; at 95℃; for 1h; | 80.0 mg (0.16 mmol) of N-(5-bromopyrazin-2-yl)-3-[(4-methylpiperazin-l-yl)acetyl]amino}-4- (trifluoromethoxy)benzamide (intermediate 28), 32.2 mg (0.23 mmol) of (2-aminopyrimidin-5- yl)boronic acid, 47.7 mg (0.31 mmol) of potassium carbonate, 133 mu of DMF, 533 mu of water, 733 mu of DME and 6.3 mg (7.71 muiotatauiotaomicronIota) of l,l'-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride dichloromethane complex were stirred for 1 h at 95 C. The reaction mixture was allowed to reach rt, and was concentrated and purified by HPLC (method 5) to obtain 20 mg (24% of theory) of the title compound. (1000) XH-NMR (400 MHz, DMSO-d6) delta [ppm]: 2.179 (14.67), 2.318 (0.52), 2.322 (0.80), 2.327 (1.01), 2.331 (0.90), 2.337 (0.68), 2.343 (0.60), 2.394 (0.96), 2.523 (4.28), 2.582 (2.07), 2.586 (2.11), 2.665 (0.64), 2.669 (0.82), 2.673 (0.62), 3.211 (9.41), 7.071 (6.01), 7.600 (1.19), 7.604 (1.33), 7.608 (0.56), 7.617 (0.66), 7.621 (1.49), 7.626 (1.37), 7.899 (1.85), 7.905 (1.89), 7.921 (1.53), 7.927 (1.65), 8.912 (3.14), 8.918 (3.14), 8.961 (16.00), 8.996 (4.12), 9.000 (4.28), 9.386 (4.48), 9.390 (4.46), 9.933 (2.93), 11.323 (1.75). LC-MS (Method 3): t = 1.01 min; MS (ESIpos): m/z = 532 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation; | To a microwave vial was added the compound of intermediate 19 (150 mg, 0.29 mmol), (2- aminopyrimidin-5-yl)boronic acid (73.0 mg, 0.52 mmol, 1.8 equiv), cesium carbonate (189 mg, 0.58 mmol, 2 equiv) and a DMF / water mixture (2:1, 4.5 mL). The resulting suspension was purged with argon, treated with dichloro[bis(triphenylphosphoranyl)]palladium (Pd(PPh3)2C12, 10.2 mg, 0.02 mmol, 5 mol%) and sealed. The resulting mixture was heated with a microwave apparatus at 100 C for 0.5 h, was then cooled to room temperature. The reaction mixture was diluted with water and ethyl acetate. The precipitate was collected by filtration and dried. 105 mg (65% of theory) of the title compound were obtained.?H-NMR (300 MHz, DMSO-d6): 6 [ppm] = 2.18 (s, 3H), 2.29 - 2.45 (m, 4H), 2.55 - 2.63 (m, 4H), 3.21 (s,2H), 6.86 (s, 2H), 7.59 (d, 1H), 7.89 (dd, 1H), 8.09 - 8.16 (m, 1H), 8.23 (d, 1H), 8.65 (s, 2H), 8.68 (d,1H), 8.89 (d, 1H), 9.92 (s, 1H), 11.05 (s, 1H).LC-MS (Method 4): R = 0.70 mm; MS (ESIpos): m/z = 531 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With bis-triphenylphosphine-palladium(II) chloride; caesium carbonate; In water; N,N-dimethyl-formamide; at 100℃; for 0.5h;Inert atmosphere; Sealed tube; Microwave irradiation; | To a microwave vial was added the compound of intermediate 20 (150 mg, 0.30 mmol), <strong>[936250-22-5](2-aminopyrimidin-5-yl)boronic acid</strong> (75.0 mg, 0.54 mmol, 1.8 equiv), cesium carbonate (194 mg, 0.60mmol, 2 equiv) and a DMF / water mixture (2:1, 4.5 mL). The resulting suspension was purged with argon, treated with dichloro[bis(triphenylphosphoranyl)]palladium (Pd(PPh3)2C12, 10.5 mg, 0.02 mmol, 5 mol%) and sealed. The resulting mixture was heated with a microwave apparatus at 100 C for 0.5 h, was then cooled to room temperature. The reaction mixture was diluted with water andethyl acetate. The precipitate was collected by filtration and dried. 116 mg (75% of theory) of the title compound were obtained.?H-NMR (400 MHz, DMSO-d6): 6 [ppm] = 2.55 - 2.61 (m, 4H), 3.23 (s, 2H), 3.62 - 3.69 (m, 4H), 6.84 (s, 2H), 7.57 (dd, 1H), 7.91 (dd, 1H), 8.10 (dd, 1H), 8.21 (d, 1H), 8.64 (s, 2H), 8.66 - 8.69 (m, 1H), 8.82 (d, 1H), 9.90 (s, 1H), 11.04 (s, 1H).LC-MS (Method 4): R = 0.80 mm; MS (ESIpos): m/z = 518 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With tetrakis(triphenylphosphine) palladium(0); caesium carbonate; In water; N,N-dimethyl-formamide; at 90℃; for 2h;Inert atmosphere; | To a suspension of (4) (200mg, 0.50mmol), <strong>[936250-22-5](2-aminopyrimidin-5-yl)boronic acid</strong> (84mg, 0.6mmol) and Cs2C03 (326mg, LOmmol) in DMF (4ml_) and H20 (1 mL) was added Pd(PPh3)4 (58mg, 0.05mmol). The reaction mixture was flushed with N2(g) then heated up to 90C for 2h. Once cooled down, H20 (20mL) was added and the formed precipitate was left to settle at rt for 72h. Filtration, washings with H20 (2ml_) and drying in vacuo yielded (5) (187 mg, 90%) as a green solid. H NMR (500 MHz, Methanol-cf4), deltaEta ppm: 8.59 (s, 2H), 8.58 (s, 1 H), 8.35 (d, J^5.3 Hz, 1 H), 8.25-8.29 (m, 1 H), 8.04 (d, J=2.5 Hz, 1 H), 7.93 (d, J^8.3 Hz, 2H), 7.52 (s, 1 H), 7.50 (d, J=8.1 Hz, 2H), 7.33 (d, J^5.3 Hz, 1 H), 5.57 (s, 2H), 3.86 (s, 3H). LCMS (ES): Found 414.5 [M+H]+. |
Tags: 936250-22-5 synthesis path| 936250-22-5 SDS| 936250-22-5 COA| 936250-22-5 purity| 936250-22-5 application| 936250-22-5 NMR| 936250-22-5 COA| 936250-22-5 structure
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