Structure of Palbociclib Impurity 53
CAS No.: 733039-20-8
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 733039-20-8 |
Formula : | C9H11BrClN3 |
M.W : | 276.56 |
SMILES Code : | ClC1=NC(NC2CCCC2)=C(Br)C=N1 |
MDL No. : | MFCD13181206 |
InChI Key : | DIVUXBABVYOIOT-UHFFFAOYSA-N |
Pubchem ID : | 44248247 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P280-P305+P351+P338-P310 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.56 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 61.16 |
TPSA ? Topological Polar Surface Area: Calculated from |
37.81 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.79 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
3.44 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
3.06 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.93 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.84 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.81 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.91 |
Solubility | 0.0343 mg/ml ; 0.000124 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-3.91 |
Solubility | 0.0336 mg/ml ; 0.000122 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-4.33 |
Solubility | 0.013 mg/ml ; 0.000047 mol/l |
Class? Solubility class: Log S scale |
Moderately soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
Yes |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
Yes |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.54 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<0.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.07 |
* 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 |
---|---|---|
81% | Stage #1: With palladium diacetate; triethylamine In 1-methyl-pyrrolidin-2-one at 65℃; Inert atmosphere Stage #2: With acetic anhydride In 1-methyl-pyrrolidin-2-one at 65℃; Inert atmosphere |
To a vessel was added 5-bromo-2-chloro-6-cyclopentylamino-pyridimidine (10.0 g, 1.0 equiv.) along with N-methylpyrrolidone (NMP) (50 mL, 5.0 vol.) at ambient temperature. To the reaction mixture was added crotonic acid (4.7 g, 1.5 equiv.) and triethylamine (20.2 mL, 4.0 equiv.). The vessel was degassed and purged three times with nitrogen. To the degassed reaction mixture was added Pd(OAc)2(0.25 g, 0.03 equiv.). The vessel was degassed and purged three times with nitrogen using the same method as step 3. The mixture was heated to 65°C and allowed to stir until starting material was consumed (at least 6 hours).Acetic anhydride (6.8 mL, 2.0 equiv) was added to the reaction mixture. The reaction was allowed to react at 65 °C until starting material was consumed (usually 1-2 hours). The reaction mixture was cooled to 20°C and H20 (100 mL, 10 vol) was added to dissolve triethylamine-HBr salts and precipitate out 2-chloro-8-cyclopentyl-5-methyl-8/-/- pyrido[2,3-c]pyrimidin-7-one. The material was granulated at 20 °C for 1 hour. The solids were filtered and washed with H20 (20 mL, 2.0 vol), and a 4: 1 mixture of isopropanol/H20 (50 mL, 5.0 vol). The crude product was dried under vacuum at 55-70°C to give 2-chloro-8-cyclopentyl-5- methyl-8/-/-pyrido[2,3-c]pyrimidin-7-one, (7.8 g; 81 percent) as a tan to gray solid. |
68% | Stage #1: With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 70℃; for 16 h; Stage #2: With acetic anhydride In tetrahydrofuran for 1.5 h; |
Example 3: Preparation of 2-Chloro-8-Cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one 41.5 g (0.15 mol) of δ-bromo^-chlorcMl-cyclopentylaminopyrimidine 3a and 32.3g (0.375 mol) of crotonic acid were mixed in 100L of THF and 105ml (1.6 mol) diisopropyl ethylamine under nitrogen. The slurry was stirred, evacuated and refilled with nitrogen three times, after which 860mg (0.0022 mol) palladium dichloride dibenzonitrile complex and 685mg(0.0022mol) tri-ortho-tolylphosphine were added and the resulting slurry degassed an additional three times. The mixture was then heated and stirred at 700C for 16hrs, after which 35 ml acetic anhydride was added and the mixture stirred for an additional 1.5hrs. The mixture was cooled and diluted with 100ml MTBE and then extracted with 1NHCI, then aqueous sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered, concentrated in vacuo, and recrystallized from IPA to yield 31.2 g {68percent) of crude product {3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.8% | With triethylamine; palladium dichloride In 1-methyl-pyrrolidin-2-one at 20 - 75℃; for 6 h; Inert atmosphere | Compound 2 (10.0 g, 36.2 mmol, 1.0 eq) was added at room temperature.N-methylpyrrolidone (NMP, 50 mL),Crotonic acid (4.7 g, 54.6 mmol, 1.5 eq) and triethylamine (14.7 g, 144.9 mol, 4.0 eq).The container is passed through three times of nitrogen,PdCl 2 (0.195 g, 1.10 mmol, 0.03 eq) was added to the exhausted reaction mixture.Three more nitrogen passes.After the raw materials are stirred and dissolved at room temperature,Rapidly warm up to 75 ° C,The stirring reaction was closed for 6 h,Sampling (diluted with ethyl acetate),TLC detection (DCM: MeOH = 12:1),The starting compound 1 is completely reacted,Add acetic anhydride to react 0.5h sampling point plate,The intermediate reaction is complete,The reaction mixture will be brought to 20 ° C,Add triethylamine hydrobromide solution (100 mL),Stir for 1h,Filtering,Water washing,Get a gray solid. Add ethyl acetate to dissolve,Add anhydrous magnesium sulfate to dry the mixture,Insoluble matter (salt and insoluble catalyst) is filtered out,Wash with ethyl acetate.Concentrate the filtrate to a low volume,Add n-hexane,Beating at 65 ° C for 30 min,Cool to 20 ° C and stir for 1 h.Filtering the solid,Vacuum drying,Obtained a brownish yellow solid,That is, Compound 1 (9.04 g, yield 94.8percent, purity 99.1percent). |
80% | Stage #1: With bis(benzonitrile)palladium(II) dichloride; N-ethyl-N,N-diisopropylamine; tris-(o-tolyl)phosphine In tetrahydrofuran at 75℃; for 20 h; Inert atmosphere Stage #2: at 75℃; for 2 h; |
Step ii): synthesis of 2-Chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin- 7-one formula 15)Step ii): A 1 L 3-necked RBF was charged with 50.0 g of (5-Bromo-2-chloro-pyrimidin- 4-yl)-cyclopentyl-amine (0.181 mol, 1 .00 eq.), 39.0 g crotonic acid (0.452 mol, 2.5 eq.), 125 ml diisopropylethylamine (0.741 mol, 4.1 eq.) and 125 ml THF. The mixture was degassed by applying 3 vacuum/argon cycles then 1 .10 g of tri-o-tolyl-phosphine (3.62 mmol, 0.02 eq.) and 1 .39 g dichlorobis(benzonitrile)palladium(ll) (3.62 mmol, 0.02 eq.) were added. The mixture was degassed again by applying 3 vacuum/argon cycles then heated to 75°C and stirred under argon for 20 h. Then, 43.0 ml of acetic anhydride (0.452 mol, 2.5 eq.) were added and the mixture further stirred at 75^ for 2 h. The reaction was quenched with 250 ml water and the mixture allowed to cool down to RT. After 1 h stirring, 125 ml water was added while cooling to Ι δ'. The precipitated solid was collected by filtration, washed with water (125 ml), cold isopropanol (3 x 125 ml), dried in air for 10 min then at 50<€/25 mbar for 20 h to give 38.13 g of 2-Chloro-8- cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one (formula 15) (80.0percent yield) as yellowish solid. HPLC (Method 1 ): 8.67 min (99.6percent) (254 nm).1H NMR (400 MHz, CDCI3, δ ppm): 1 .68 (br. s, 2 H), 1 .84 - 1 .98 (m, 2 H), 2.12 (br. s, 2 H), 2.22 (br. s, 2 H), 2.44 (s, 3 H), 5.84 (m, 1 H), 6.53 (br. s, 1 H), 8.74 (s, 1 H). |
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