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CAS No. : | 152459-94-4 | MDL No. : | MFCD00945675 |
Formula : | C23H19N5O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UOEJSOXEHKCNAE-UHFFFAOYSA-N |
M.W : | 381.43 | Pubchem ID : | 9864718 |
Synonyms : |
|
Num. heavy atoms : | 29 |
Num. arom. heavy atoms : | 24 |
Fraction Csp3 : | 0.04 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 113.99 |
TPSA : | 79.8 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -5.88 cm/s |
Log Po/w (iLOGP) : | 2.81 |
Log Po/w (XLOGP3) : | 3.87 |
Log Po/w (WLOGP) : | 4.65 |
Log Po/w (MLOGP) : | 2.52 |
Log Po/w (SILICOS-IT) : | 3.79 |
Consensus Log Po/w : | 3.53 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.86 |
Solubility : | 0.00527 mg/ml ; 0.0000138 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.24 |
Solubility : | 0.00218 mg/ml ; 0.00000572 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -9.21 |
Solubility : | 0.000000236 mg/ml ; 0.0000000006 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.02 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-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 |
---|---|---|
97% | With triethylamine; In tetrahydrofuran; at 0 - 25℃; for 3h; | will1c (7.5g, 0.027mol, Suzhou Xinkai Bio-pharmaceutical Technology Co., Ltd.) Into a 250mL three-necked flask, add tetrahydrofuran (135mL) and triethylamine (7.53mL), stirring to reduce the internal temperature 0 ~ 3 C, 1b ( 5.75g, 0.041mol) in tetrahydrofuran (57mL) solution, the internal temperature is controlled below 5 C, after the drop is complete, the temperature is raised to 20 ~ 25 C, the reaction is incubated for 3 hours, stirringPurified water (415 mL) was added thereto, lowered to room temperature, filtered, and washed with purified water (30 mL×2) and vacuum dried at 75 to 80 C. for 2 hours to obtain N-[4-methyl-3-[[4] as a yellow solid. -(3-pyridyl)-2-pyrimidinyl]amino]phenyl]benzamide (1d) 10 g, yield 97%. |
With triethylamine; In dichloromethane; at 0℃; for 4h; | General procedure: The imatinib analogs 3,4-R1,R2-N-(4-methyl-3(4-(pyridine-3-yl)pyrimidin-2-ylamino)phenyl)benzamide (R1 = R2 = H (1); R1 = H, R2 = SCH3 (2); R1 = NO2, R2 = H (3); R1 = NH2, R2 = H (4); R1 = R2 = NO (5)) and N-(4-methyl-3-(4-(pyridin-3-yl) pyrimidin-2-ylamino)phenyl)picolinamide (6) was synthesized following a modified procedure described in the literature16 as shown in Scheme 1. Briefly, an excess amount of benzoyl chloride compound 1b, 2b, 3b, 4b, 5b or 6b was added to a suspension of 6-methyl-N-(4-(pyridin-3-yl)pyrimidin-2-yl) benzene-1,3-diamine (0.5 g, 2 mmol) in dichloromethane (10 mL) containing TEA (0.58 mL, 4 mmol), and the mixture was reacted at 0 C for 4 h, and TLC of reaction mass indicated the absence of starting compound. The solution was then filtered and washed with dichloromethane, the excess dichloromethane was removed in vacuo, and the residue was purified by recrystallization from ethanol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
or 3wherein the compound is selected from the group comprising: ... 2-Methoxy-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide; 2-Methoxy-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide; 4-Methyl-N-[3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide; 4-Methyl-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide; N-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide; 1(3,5-Diacetyl-phenyl)-3-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-pheny]-urea; 1-{3,5-Bis-(amidinohydrazone)-phenyl}-3-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-urea; N-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-nicotinamide; ... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | N-[3-(4-Oxopyrimidin-2-ylamino)-4-methylphenyl]-benzamide (0.36 g, 1.12 mmol), PyBrOP (0.55 g, 1.18 mmol) and 0.47 ml of triethylamine in anhydrous dioxane (15 ml) was stirred at 45 C under argon for 0.5 h. To the solution 3-pyridinylboronic acid (145 mg, 1.18 mmol) and catalyst PdCl2(PPh3)2 (39.4 mg, 5 -mol%) was sequentially added under argon. After stirring for 0.5 h at room temperature deaerated aqueous solution of 1 M Na2CO3 (3.4 ml, 3.4 mmol) was added by syringe and stirring was continued for 24 h at 100 C under argon. Reaction mixture diluted with ethyl acetate (30 ml) and brine (5 % solution). Organic phase was separated, washed with brine (15 ml) and filtered through celite and dried. After evaporation of solvent the residue was crystallized from ethanol to obtain 0.21 g (49%) of amorphous substance with mp.178-182 C. [BioMed.Chem.Lett, 201 1 , 21 , 6964 m.p. 190-191 C] 1 H NMR (DMSO-Ok): 2.22 (s,3H), 7.43 (d J= 5.2 Hz, 1 H), 7.52 (m, 5H), 7.95 (m, 2H), 8.09 (d J= 1.9 Hz, 1 H), 8.48 (dt J= 8.1 ; 1.8 Hz, 1 H), 8.51 (d J= 5.2 Hz, 1 H), 8.68 (dd J= 4.8; 1.8 Hz, 1 H), 8.97 (s, 1 H), 9.29 (d J= 1.9 Hz, 1 H), 10.20 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at -20 - 20℃; for 72h; | Synthesis of (1e) 1d (10 g, 0.027 mol) was put into a 500 mL three-necked flask, methylene chloride (350 mL) was added, and m-chloroperbenzoic acid (11.2 g, 0.065 mol, Sigma-Aldrich Sigmamae) was added at -20C. (Drich Shanghai Trading Co., Ltd.), raised to room temperature, reacted for 72 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure, and purified by silica gel column chromatography with eluent: methanol: dichloromethane=1:20 (volume ratio, v /v) gives N-[4-methyl-3-[[4-(1-oxo-3-pyridyl)-3-oxo-2-pyrimidinyl]amino]phenyl]benzene as a yellow solid Amide (1e) 5.47 g, yield 49%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; In N,N-dimethyl-formamide; at 20℃; for 1h; | General procedure: The final target compounds were synthesized from 6-methyl-N-(4-(pyridin-3-yl) pyrimidin-2-yl) benzene-1,3-diamine 8(2 mmol), DMF (10 mL), and DIPEA (4 mmol) followed by substituted aromatic acid (2 mmol) was added and stirred at room temperature for 1 h. After completion of the reaction mixture was poured into ice-cold water. The obtained yellow precipitate washed with water and dried to get target titled product pyrimidine scaffold benzamide derivatives (9 a-k). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: N-(4-methyl-3(4-(pyridine-3-yl)pyrimidin-2-ylamino)phenyl)benzamide With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at 25℃; | Take 0.1 mol of the aniline pyrimidine compound shown in Table 1 and dissolve it in tetrahydrofuran to obtain a saturated solution. After cooling to -78°C, add a saturated tetrahydrofuran solution containing 0.1 mol of Lithium hexamethyldisilazane to it dropwise while stirring at -78°C. The reaction was stirred until TLC tracked that the reaction was complete. After the temperature was raised to 25°C, a saturated tetrahydrofuran solution containing 0.15 mol di-tert-butyl dicarbonate was added dropwise to the reaction solution, and the mixture was stirred at 25°C until TLC tracking showed that the reaction was complete.The resulting reaction solution was slowly heated to 60°C and then slowly added dropwise containing 0.1 mol of triethylamine and 0.1 mol (S)-1-((2S,3S)-3-hexyl-4-oxooxetine -2-yl) tridecane-2-yl L-leucine ester in saturated tetrahydrofuran,And stir at 60°C in the dark until the TLC track shows that the reaction is complete. The reaction solvent was removed by rotary evaporation, and the obtained product was purified by HPLC to obtain various conjugates shown in Table 1. | |
Stage #1: N-(4-methyl-3(4-(pyridine-3-yl)pyrimidin-2-ylamino)phenyl)benzamide With lithium hexamethyldisilazane In tetrahydrofuran Stage #2: di-<i>tert</i>-butyl dicarbonate at 25℃; | Take 0.1 mol of the aniline pyrimidine compound shown in Table 1 and dissolve it in tetrahydrofuran to obtain a saturated solution,After cooling to -78°C, a saturated tetrahydrofuran solution containing 0.1 mol Lithium hexamethyldisilazane was added dropwise with stirring,-And stir the reaction at -78°C until TLC traces that the reaction is complete.After heating to 25°C, a saturated tetrahydrofuran solution containing 0.15 mol di-tert-butyl dicarbonate was added dropwise to the reaction solution,It was stirred at 25°C until TLC tracked that the reaction was complete.The resulting reaction solution was slowly heated to 60°C, and then slowly dropped into it containing 0.1 mol of triethylamine and 0.1 mol(S)-1-((2S,3S)-3-hexyl-4-oxooxetan-2-yl)tridecane-2-yl L-leucine ester in saturated tetrahydrofuran,And stir at 60°C in the dark until TLC traces indicate that the reaction is complete.The reaction solvent was removed by rotary evaporation, and the obtained product was purified by HPLC to obtain various conjugates shown in Table 1. | |
Stage #1: N-(4-methyl-3(4-(pyridine-3-yl)pyrimidin-2-ylamino)phenyl)benzamide With lithium hexamethyldisilazane In tetrahydrofuran at -78℃; Stage #2: di-<i>tert</i>-butyl dicarbonate In tetrahydrofuran at 25℃; | General procedure: Take 0.1 mol of the aniline pyrimidine compound shown in Table 1 and dissolve it in tetrahydrofuran to obtain a saturated solution. After cooling to -78°C, a saturated tetrahydrofuran solution containing 0.1 mol lithium hexamethyldisilazane was added dropwise to it with stirring, and the reaction was stirred at -78°C until TLC tracking showed that the reaction was complete. After the temperature was raised to 25°C, a saturated tetrahydrofuran solution containing 0.15 mol di-tert-butyl dicarbonate was added dropwise to the reaction solution, and the mixture was stirred at 25°C until TLC tracking showed that the reaction was complete. The resulting reaction solution was slowly heated to 60°C and then slowly dropped into it containing 0.1 mol of triethylamine and 0.1mol (S)-1-((2S,3S)-3-hexyl-4-oxooxetan-2-yl)tridecan-2-yl L-leucine ester in saturated tetrahydrofuran, and stir at 60°C in the dark until TLC traces indicate that the reaction is complete. The reaction solvent was removed by rotary evaporation, and the obtained product was purified by HPLC to obtain various conjugates shown in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In tetrahydrofuran at 60℃; | Take 0.1 mol of the aniline pyrimidine compound shown in Table 1 and dissolve it in tetrahydrofuran to obtain a saturated solution. After cooling to -78°C, add a saturated tetrahydrofuran solution containing 0.1 mol of lithium hexamethyldisilazane to it dropwise while stirring at -78°C. The reaction was stirred until TLC tracked that the reaction was complete. After the temperature was raised to 25°C, a saturated tetrahydrofuran solution containing 0.15 mol di-tert-butyl dicarbonate was added dropwise to the reaction solution, and the mixture was stirred at 25°C until TLC tracking showed that the reaction was complete.The resulting reaction solution was slowly heated to 60°C and then slowly added dropwise containing 0.1 mol of triethylamine and 0.1 mol (S)-1-((2S,3S)-3-hexyl-4-oxooxetine-2-yl)tridecane-2-yl L-leucine ester in saturated tetrahydrofuran,And stir at 60°C in the dark until the TLC track shows that the reaction is complete. The reaction solvent was removed by rotary evaporation, and the obtained product was purified by HPLC to obtain various conjugates shown in Table 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In tetrahydrofuran at 60℃; Darkness; | Take 0.1 mol of the aniline pyrimidine compound shown in Table 1 and dissolve it in tetrahydrofuran to obtain a saturated solution,After cooling to -78°C, a saturated tetrahydrofuran solution containing 0.1 mol Lithium hexamethyldisilazane was added dropwise with stirring,-And stir the reaction at -78°C until TLC traces that the reaction is complete.After heating to 25°C, a saturated tetrahydrofuran solution containing 0.15 mol di-tert-butyl dicarbonate was added dropwise to the reaction solution,It was stirred at 25°C until TLC tracked that the reaction was complete.The resulting reaction solution was slowly heated to 60°C, and then slowly dropped into it containing 0.1 mol of triethylamine and 0.1 mol(S)-1-((2S,3S)-3-hexyl-4-oxooxetan-2-yl)tridecane-2-yl L-leucine ester in saturated tetrahydrofuran,And stir at 60°C in the dark until TLC traces indicate that the reaction is complete.The reaction solvent was removed by rotary evaporation, and the obtained product was purified by HPLC to obtain various conjugates shown in Table 1. |