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CAS No. : | 1234015-54-3 | MDL No. : | MFCD27918637 |
Formula : | C18H21Cl2N7O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | KMEIPKXRCJTZBZ-UHFFFAOYSA-N |
M.W : | 438.31 | Pubchem ID : | 46700755 |
Synonyms : |
LY2606368 dihydrochloride;LY2606368;Prexasertib HCl;Prexasertib dihydrochloride
|
Num. heavy atoms : | 29 |
Num. arom. heavy atoms : | 17 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 8 |
Num. H-bond acceptors : | 7.0 |
Num. H-bond donors : | 3.0 |
Molar Refractivity : | 113.11 |
TPSA : | 134.76 Ų |
GI absorption : | Low |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.87 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.96 |
Log Po/w (WLOGP) : | 3.82 |
Log Po/w (MLOGP) : | -0.25 |
Log Po/w (SILICOS-IT) : | 2.15 |
Consensus Log Po/w : | 1.74 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 1.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -4.33 |
Solubility : | 0.0206 mg/ml ; 0.000047 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.45 |
Solubility : | 0.00155 mg/ml ; 0.00000353 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -6.34 |
Solubility : | 0.000202 mg/ml ; 0.000000461 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 2.0 |
Synthetic accessibility : | 3.6 |
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 |
---|---|---|
100% | With hydrogenchloride In ethyl acetate at 10℃; for 5.25h; | 2 5-(5-(2-(3-Aminopropoxy)-6-methoxyphenyl)- 1H-pyrazol-3-ylamino)pyrazine-2-carhonitrile dihydrogen chloride salt A 5 1. flange-neck, round-bottom flask equipped with an air stirrer rod and paddle, thermometer, and air condenser with bubbler attached, is charged with tert-butyl 3-(2-(3- (5-cyanopyrazin.-2-yiamino)-1 Fi-pyrazol-5-yl)-3-niethoxyphenoxy)propylcarbamate (30.9g, 66.3 mmoi) and ethyl acetate (3 L). The mechanically stirred yellow suspension is cooled to just below 10 °C. Then hydrogen chloride from a lecture bottle is bubbled in vigorously through a gas inlet tube for 15 minutes with the ice-bath still in place. After 5 hours, the mixture is noticeably thickened in appearance. The solid is collected by filtration, washed with ethyl acetate, and then dried in vacuo at 60 °C overnight to givethe title compound (30.0 g, 100%). 1H NMR (400 MHz, d6-DMSO) ö 2.05 (m, 2H), 2.96(in, 2H). 3.81 (s, 3H). 4.12 (t, J 5,8 Hz, 2H), 6.08 (br s, 3H), 6,777 (d, J 8,2 Hz, IH),6.782 (d, 3 = 8.2 Hz, 1H), 6.8 (br s, IH), 7.34 (t, 3 = 8.2 Hz, 1H), 8.09 (br s, IH), 8.55(br s, 111), 8,71 (s, 111), 10.83 (s, 111), 12.43 (br s, 11-1). LC-ES/MS rnz 366.2 [M+lfF, |
With hydrogenchloride In ethyl acetate at 10℃; Cooling with ice; | 2 Example 2; 5 -(5 -(2-(3 -Aminopropoxy)-6-methoxyphenyl)- 1 H-pyrazol-3 -ylamino)pyrazine-2- carbonitrile dihydrogen chloride saltl; A 5 L flange-neck, round-bottom flask equipped with an air stirrer rod and paddle, thermometer, and air condenser with bubbler attached, is charged with tert-bvXyl 3-(2-(3- (5-cyanopyrazin-2-ylamino)-lH-pyrazol-5-yl)-3-methoxyphenoxy)propylcarbamate (30.9 g, 66.3 mmol) and ethyl acetate (3 L). The mechanically stirred yellow suspension is cooled to just below 10 0C. Then hydrogen chloride from a lecture bottle is bubbled in -29- vigorously through a gas inlet tube for 15 min with the ice-bath still in place. After 5 h the mixture is noticeably thickened in appearance. The solid is collected by filtration, washed with ethyl acetate, and then dried in vacuo at 60 0C overnight to give 30.0 g. 1H NMR (400 MHz, DMSO-d6) δ 2.05 (m, 2H), 2.96 (m, 2H), 3.81 (s, 3H), 4.12 (t, J = 5.8 Hz, 2H), 6.08 (br s, 3H), 6.777 (d, J = 8.2 Hz, IH), 6.782 (d, J = 8.2 Hz, IH), 6.88 (br s, IH), 7.34 (t, J = 8.2 Hz, IH), 8.09 (br s, IH), 8.55 (br s, IH), 8.71 (s, IH), 10.83 (s, IH), 12.43 (br s, IH). LC-ES/MS m/z 366.2 [M+lf. | |
With hydrogenchloride In ethyl acetate at 10℃; for 5.25h; Cooling with ice; | C.2 5-(5-(2-(3-Aminopropoxy)-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile dihydrogen chloride salt A 5 L flange-neck, round-bottom flask equipped with an air stirrer rod and paddle, thermometer, and air condenser with bubbler attached, is charged with tert-butyl 3-(2-(3-(5-cyanopyrazin-2-ylamino)-1H-pyrazol-5-yl)-3-methoxyphenoxy)propylcarbamate (30.9 g, 66.3 mmol) and ethyl acetate (3 L). The mechanically stirred yellow suspension is cooled to just below 10° C. Then hydrogen chloride from a lecture bottle is bubbled in vigorously through a gas inlet tube for 15 min with the ice-bath still in place. After 5 h the mixture is noticeably thickened in appearance. The solid is collected by filtration, washed with ethyl acetate, and then dried in vacuo at 60° C. overnight to give 30.0 g. 1H NMR (400 MHz, DMSO-d6) δ 2.05 (m, 2H), 2.96 (m, 2H), 3.81 (s, 3H), 4.12 (t, J=5.8 Hz, 2H), 6.08 (br s, 3H), 6.777 (d, J=8.2 Hz, 1H), 6.782 (d, J=8.2 Hz, 1H), 6.88 (br s, 1H), 7.34 (t, J=8.2 Hz, 1H), 8.09 (br s, 1H), 8.55 (br s, 1H), 8.71 (s, 1H), 10.83 (s, 1H), 12.43 (br s, 1H). LC-ES/MS m/z 366.2 [M+1]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium hydroxide; In dichloromethane; water; at 20℃;Inert atmosphere; | Example 3; 5 -(5 -(2-(3 -Aminopropoxy)-6-methoxyphenyl)- 1 H-pyrazol-3 -ylamino)pyrazine-2- carbonitrile; 5-(5-(2-(3-Aminopropoxy)-6-methoxyphenyl)-lH-pyrazol-3-ylamino)pyrazine-2- carbonitrile dihydrogen chloride salt (3.0 g, 6.84 mmol) is suspended in 200 mL of CH2Cl2. 1 N NaOH is added (200 mL, 200 mmol). The mixture is magnetically stirred under nitrogen at room temperature for 5 h. The solid is collected by filtration and washed thoroughly with water. The filter cake is dried in vacuo at 50 0C overnight to give 2.26 g (90%) of the free base as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.81 (m, 2H), 2.73 (t, J = 6.2 Hz, 2H), 3.82 (s, 3H), 4.09 (t, J = 6.2 Hz, 2H), 6.76 (t, J = 8.2 Hz, 2H), 6.93 (br s, IH), 7.31 (t, J = 8.2 Hz, IH), 8.52 (br s, IH), 8.67 (s, IH). LC- MS /ES m/z 366.2 [M+ 1]+. |
90% | With sodium hydroxide; In dichloromethane; water; at 20℃; for 5.0h;Inert atmosphere; | 5-(5-(2-(3-Aminopropoxy)-6-methoxyphenyl)-1H-pyrazol-3-ylamino)pyrazine-2-carbonitrile dihydrogen chloride salt (3.0 g, 6.84 mmol) is suspended in 200 mL of CH2Cl2.1N NaOH is added (200 mL, 200 mmol). The mixture is magnetically stirred under nitrogen at room temperature for 5 h. The solid is collected by filtration and washed thoroughly with water. The filter cake is dried in vacuo at 50 C. overnight to give 2.26 g (90%) of the free base as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 1.81 (m, 2H), 2.73 (t, J=6.2 Hz, 2H), 3.82 (s, 3H), 4.09 (t, J=6.2 Hz, 2H), 6.76 (t, J=8.2 Hz, 2H), 6.93 (br s, 1H), 7.31 (t, J=8.2 Hz, 1H), 8.52 (br s, 1H), 8.67 (s, 1H). LC-MS/ES m/z 366.2 [M+1]+. |
90% | With sodium hydroxide; In dichloromethane; at 20℃; for 5.0h;Inert atmosphere; | 5-(5-(2-(3-Aniinopropoxy)-6-methoxyphenyi)- IH-pyrazol-3-ylarnino)pyrazine-2-carbonitrile dihydrogen chloride salt (3.0 g, 6,84 mniol) is suspended in CH2CI2 (200 ml ‘ 1 N 1aOH is added (200 ml , 200 rnmol) Ihe mixture is magnLflcally stirred under nitrogen at room temperature for 5 hours. The solid is collected by filtration and washed thoroughly with water. The filter cake is dried in vacuo at 50 C overnight to give (2.26 g, 90%) of the free base as a yellow solid. ‘H NMR (400 MHz, d-DMSO) 1.81 (m, 2H), 2.73 (t, J 6.2 Hz, 2H), 3.82 (s. 3H), 4.09 (t, J 6.2 Hz, 211), 6.76 (t, J8.2 2H), 6.93 (br s, 1H), 7.31 (t, J 8.2 Hz, IH), 8.52 (br s, IH), 8.67 (s, 1H). LCMS/ES mz 366.2 [M+1]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1.1: n-butyllithium / hexane; tetrahydrofuran / 1.25 h / -78 - 20 °C 1.2: 10.25 h / 0 °C / Reflux 1.3: 8 h / Reflux 2.1: hydrogenchloride / methanol / 2.33 h 3.1: di-isopropyl azodicarboxylate / tetrahydrofuran / 0.75 h / 20 °C 4.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 5.1: hydrogenchloride / ethyl acetate / 5.25 h / 10 °C / Cooling with ice | ||
Multi-step reaction with 5 steps 1.1: sodium hydride / tetrahydrofuran / 2.08 h / 22 °C / Inert atmosphere 1.2: 20.75 h / 20 - 65 °C / Reflux 2.1: hydrazine hydrate; acetic acid / ethanol / 65 - 70 °C 3.1: hydrogenchloride / 1,4-dioxane / 20 - 65 °C 4.1: triethylamine / tetrahydrofuran / -5 - 5 °C / Acetone/ice bath 4.2: -5 - 20 °C / Acetone/ice bath 5.1: hydrogenchloride / ethyl acetate / 5.25 h / 10 °C / Cooling with ice | ||
Multi-step reaction with 5 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 1.25 h / -78 - 20 °C 1.2: 10.25 h / 0 °C / Reflux 1.3: 8 h / Reflux 2.1: hydrogenchloride / methanol / 2.33 h 3.1: di-isopropyl azodicarboxylate / tetrahydrofuran / 0.75 h 4.1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 5.1: hydrogenchloride / ethyl acetate / 5.25 h / 10 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 2: hydrogenchloride / ethyl acetate / 5.25 h / 10 °C / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1.1: hydrazine hydrate; acetic acid / ethanol / 65 - 70 °C 2.1: hydrogenchloride / 1,4-dioxane / 20 - 65 °C 3.1: triethylamine / tetrahydrofuran / -5 - 5 °C / Acetone/ice bath 3.2: -5 - 20 °C / Acetone/ice bath 4.1: hydrogenchloride / ethyl acetate / 5.25 h / 10 °C / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1.1: hydrogenchloride / 1,4-dioxane / 20 - 65 °C 2.1: triethylamine / tetrahydrofuran / -5 - 5 °C / Acetone/ice bath 2.2: -5 - 20 °C / Acetone/ice bath 3.1: hydrogenchloride / ethyl acetate / 5.25 h / 10 °C / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1.1: triethylamine / tetrahydrofuran / -5 - 5 °C / Acetone/ice bath 1.2: -5 - 20 °C / Acetone/ice bath 2.1: hydrogenchloride / ethyl acetate / 5.25 h / 10 °C / Cooling with ice |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium hydroxide / dichloromethane / 5 h / 20 °C / Inert atmosphere 2: methanol / 0.25 h / Sonication |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: hydrogenchloride / methanol / 2.33 h 2: di-isopropyl azodicarboxylate / tetrahydrofuran / 0.75 h / 20 °C 3: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 4: hydrogenchloride / ethyl acetate / 5.25 h / 10 °C / Cooling with ice | ||
Multi-step reaction with 4 steps 1: hydrogenchloride / methanol / 2.33 h 2: di-isopropyl azodicarboxylate / tetrahydrofuran / 0.75 h 3: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 4: hydrogenchloride / ethyl acetate / 5.25 h / 10 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: di-isopropyl azodicarboxylate / tetrahydrofuran / 0.75 h / 20 °C 2: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 3: hydrogenchloride / ethyl acetate / 5.25 h / 10 °C / Cooling with ice | ||
Multi-step reaction with 3 steps 1: di-isopropyl azodicarboxylate / tetrahydrofuran / 0.75 h 2: tetrakis(triphenylphosphine) palladium(0) / N,N-dimethyl-formamide / 80 °C / Inert atmosphere 3: hydrogenchloride / ethyl acetate / 5.25 h / 10 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium hydroxide / dichloromethane; water / 5 h / 20 °C / Inert atmosphere 2: methanol / -15 °C / Sonication |