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CAS No. : | 1217643-09-8 | MDL No. : | MFCD06762574 |
Formula : | C10H12ClN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | - |
M.W : | 181.66 | Pubchem ID : | - |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 55.44 |
TPSA : | 12.03 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.62 cm/s |
Log Po/w (iLOGP) : | 2.5 |
Log Po/w (XLOGP3) : | 2.52 |
Log Po/w (WLOGP) : | 2.06 |
Log Po/w (MLOGP) : | 2.66 |
Log Po/w (SILICOS-IT) : | 3.15 |
Consensus Log Po/w : | 2.58 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.86 |
Solubility : | 0.252 mg/ml ; 0.00139 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.42 |
Solubility : | 0.693 mg/ml ; 0.00381 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.94 |
Solubility : | 0.0208 mg/ml ; 0.000114 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.79 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P301+P312-P302+P352-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 |
---|---|---|
15.5 mg | With 4-methyl-morpholine; benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 12h; enantioselective reaction; | General procedure for preparation of CDK8 inhibitors General procedure: Compound 13 (0.1 mmol, 1 equiv) was added to a screw-top test tube that was equipped with a magnetic stirbar. The test tube was sealed with a screw-top septum and parafilm. The reaction vessel was evacuated (ca. 100 mtorr) and backfilled with argon 3 times. The reaction vessel was cooled to 0 °C. KOH (0.2 mmol, 2 equiv) inMeOH (0.3 mL) was then added via syringe. After 10 min, the reaction was warmed to rt, and was allowed to stir for an additional 12 h. The reaction mixture was diluted with water, and extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over Na2SO4, and solvent was removed under reduced pressure to provide the crude deprotected product. To the crude product, 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (14 mg, 0.08 mmol), N-(3-(dimethylamino)propyl)-N’-ethylcarbodiimide (29.4 μl, 0.16 mmol), and 1-hydroxybenzotriazole hydrate (10.8 mg, 0.08 mmol) were added, followed by N,N-dimethylformamide(0.4 mL). 4-Methylmorpholine (26.4 μl, 0.24 mmol) was added atrt, and the reaction mixture was allowed to stir for 12 h at rt. The mixture was diluted with ethyl acetate (2 mL), washed with water (3 x 3 mL) followed by brine (2 x 3 mL),and dried over Na2SO4. The solvent was removed under reduced pressure and dried invacuo to provide the crude product. The crude reaction product was purified by flash column chromatography (9:1:0.1 ethyl acetate: MeOH: triethylamine) to afford pure14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium hydroxide In methanol at 0 - 20℃; for 12.1667h; Sealed tube; Inert atmosphere; | General procedure for preparation of CDK8 inhibitors General procedure: Compound 13 (0.1 mmol, 1 equiv) was added to a screw-top test tube that was equipped with a magnetic stirbar. The test tube was sealed with a screw-top septum and parafilm. The reaction vessel was evacuated (ca. 100 mtorr) and backfilled with argon 3 times. The reaction vessel was cooled to 0 °C. KOH (0.2 mmol, 2 equiv) inMeOH (0.3 mL) was then added via syringe. After 10 min, the reaction was warmed to rt, and was allowed to stir for an additional 12 h. The reaction mixture was diluted with water, and extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over Na2SO4, and solvent was removed under reduced pressure to provide the crude deprotected product. To the crude product, 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (14 mg, 0.08 mmol), N-(3-(dimethylamino)propyl)-N’-ethylcarbodiimide (29.4 μl, 0.16 mmol), and 1-hydroxybenzotriazole hydrate (10.8 mg, 0.08 mmol) were added, followed by N,N-dimethylformamide(0.4 mL). 4-Methylmorpholine (26.4 μl, 0.24 mmol) was added atrt, and the reaction mixture was allowed to stir for 12 h at rt. The mixture was diluted with ethyl acetate (2 mL), washed with water (3 x 3 mL) followed by brine (2 x 3 mL),and dried over Na2SO4. The solvent was removed under reduced pressure and dried invacuo to provide the crude product. The crude reaction product was purified by flash column chromatography (9:1:0.1 ethyl acetate: MeOH: triethylamine) to afford pure14. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With hydrogenchloride; 2,3,4,5,6-pentahydroxy-hexanal; nicotinamide adenine dinucleotide phosphate In aq. phosphate buffer; water; dimethyl sulfoxide at 30℃; for 24h; Enzymatic reaction; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70 % ee | With diethoxymethylane; diethylzinc; ((2S,2'S)-((2-hydroxy-5-methyl-1,3-phenylene)bis(methylene))bis(pyrrolidine-1,2-diyl))bis(diphenylmethanol) In tetrahydrofuran; toluene at 4℃; for 48h; Inert atmosphere; Overall yield = 94 percent; Overall yield = 85 mg; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.5% | With sodium tris(acetoxy)borohydride In dichloromethane at 25℃; | 33 Synthesis of 4-{2-[(2S)-2-(3-chlorophenyl)pyrrolidin-1-yl]-7-azaspiro[3.5]nonan-7-yl}-N-{3-nitro- 4-[(oxan-4-ylmethyl)amino]benzenesulfonyl}-2-[(11 R,15S)-4-[2-(trimethylsilyl)ethoxy]methyl}-13,16- d ioxa-2,4, 10-triazatetracyclo[7.7.0.0A{3,7}.0A{11 ,15}]hexadeca-1 (9),2, 5, 7-tetraen-1 O-yl]benzamide: Into a 20 mL vial were added N-{3-nitro-4-[(oxan-4-ylmethyl)amino]benzenesulfonyl}-4-{2-oxo-7-azaspiro[3.5]nonan- 7-yl}-2-[( 11 R, 15S)-4-[2-(trimethy Isi ly l)ethoxy]methy I}- 13, 16-dioxa-2,4, 10- triazatetracyclo[7.7.0.0A{3,7}.0A{11,15}]hexadeca-1(9),2,5,7-tetraen-10-yl]benzamide (60 mg, 0.1 mmol, 1.0 eq), (2S)-2-(3-chlorophenyl)pyrrolidine (12 mg, 0.1 mmol, 1.0 eq), CH2CI2 (3 mL), NaBH(0Ac)3 (28 mg, 0.1 mmol, 2.0 eq). The resulting mixture was stirred for overnight at 25°C. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane/methanol=12: 1) to afford 4-{2-[(2S)-2- (3-chlorophenyl)pyrrolidin-1-yl]-7-azaspiro[3.5]nonan-7-yl}-N-{3-nitro-4-[(oxan-4- ylmethyl)amino]benzenesulfonyl}-2-[(11 R, 15S)-4-[2-(trimethy Isi ly l)ethoxy]methy I}- 13, 16-dioxa-2,4, 10- triazatetracyclo[7.7.0.0A{3,7}.0A{11,15}]hexadeca-1(9),2,5,7-tetraen-10-yl]benzamide (60 mg, 84.5%) as a yellow solid. LC-MS (ESI, m/z) M+1 :1067. |
84.5% | With sodium tris(acetoxy)borohydride In dichloromethane at 25℃; | 33 Synthesis of 4-{2-[(2S)-2-(3-chlorophenyl)pyrrolidin-1-yl]-7-azaspiro[3.5]nonan-7-yl}-N-{3-nitro- 4-[(oxan-4-ylmethyl)amino]benzenesulfonyl}-2-[(11 R,15S)-4-[2-(trimethylsilyl)ethoxy]methyl}-13,16- d ioxa-2,4, 10-triazatetracyclo[7.7.0.0A{3,7}.0A{11 ,15}]hexadeca-1 (9),2, 5, 7-tetraen-1 O-yl]benzamide: Into a 20 mL vial were added N-{3-nitro-4-[(oxan-4-ylmethyl)amino]benzenesulfonyl}-4-{2-oxo-7-azaspiro[3.5]nonan- 7-yl}-2-[( 11 R, 15S)-4-[2-(trimethy Isi ly l)ethoxy]methy I}- 13, 16-dioxa-2,4, 10- triazatetracyclo[7.7.0.0A{3,7}.0A{11,15}]hexadeca-1(9),2,5,7-tetraen-10-yl]benzamide (60 mg, 0.1 mmol, 1.0 eq), (2S)-2-(3-chlorophenyl)pyrrolidine (12 mg, 0.1 mmol, 1.0 eq), CH2CI2 (3 mL), NaBH(0Ac)3 (28 mg, 0.1 mmol, 2.0 eq). The resulting mixture was stirred for overnight at 25°C. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-TLC (dichloromethane/methanol=12: 1) to afford 4-{2-[(2S)-2- (3-chlorophenyl)pyrrolidin-1-yl]-7-azaspiro[3.5]nonan-7-yl}-N-{3-nitro-4-[(oxan-4- ylmethyl)amino]benzenesulfonyl}-2-[(11 R, 15S)-4-[2-(trimethy Isi ly l)ethoxy]methy I}- 13, 16-dioxa-2,4, 10- triazatetracyclo[7.7.0.0A{3,7}.0A{11,15}]hexadeca-1(9),2,5,7-tetraen-10-yl]benzamide (60 mg, 84.5%) as a yellow solid. LC-MS (ESI, m/z) M+1 :1067. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: sodium tris(acetoxy)borohydride / dichloromethane / 25 °C 2: N,N,N-tributylbutan-1-aminium fluoride; Ethane-1,2-diamine / tetrahydrofuran / 3 h / 70 °C |
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