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Chemical Structure| 733039-20-8 Chemical Structure| 733039-20-8

Structure of Palbociclib Impurity 53
CAS No.: 733039-20-8

Chemical Structure| 733039-20-8

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Product Details of [ 733039-20-8 ]

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

Safety of [ 733039-20-8 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H332-H335
Precautionary Statements:P280-P305+P351+P338-P310

Computational Chemistry of [ 733039-20-8 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

37.81 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.79
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

3.44
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

3.06
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

1.93
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

2.84
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.81

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-3.91
Solubility 0.0343 mg/ml ; 0.000124 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-3.91
Solubility 0.0336 mg/ml ; 0.000122 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-4.33
Solubility 0.013 mg/ml ; 0.000047 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

No
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

Yes
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

Yes
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

Yes
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-5.54 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

0.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<0.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

2.07

Application In Synthesis of [ 733039-20-8 ]

* 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.

  • Upstream synthesis route of [ 733039-20-8 ]
  • Downstream synthetic route of [ 733039-20-8 ]

[ 733039-20-8 ] Synthesis Path-Upstream   1~4

  • 1
  • [ 733039-20-8 ]
  • [ 107-93-7 ]
  • [ 1013916-37-4 ]
YieldReaction ConditionsOperation 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).
References: [1] Patent: WO2014/128588, 2014, A1, . Location in patent: Page/Page column 34; 35.
[2] Patent: WO2008/32157, 2008, A2, . Location in patent: Page/Page column 26.
  • 2
  • [ 3724-65-0 ]
  • [ 733039-20-8 ]
  • [ 1013916-37-4 ]
YieldReaction ConditionsOperation 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).
References: [1] Patent: CN108117550, 2018, A, . Location in patent: Paragraph 0029; 0030, 0031; 0034; 0036; 0037.
[2] Patent: WO2016/30439, 2016, A1, . Location in patent: Page/Page column 31; 32.
  • 3
  • [ 733039-20-8 ]
  • [ 18269-64-2 ]
  • [ 1013916-37-4 ]
References: [1] Patent: WO2016/16769, 2016, A1, . Location in patent: Page/Page column 9; 10.
  • 4
  • [ 733039-20-8 ]
  • [ 1013916-37-4 ]
References: [1] Organic Process Research and Development, 2016, vol. 20, # 7, p. 1191 - 1202.
[2] Patent: CN104447739, 2016, B, .
[3] Patent: CN108299422, 2018, A, .
 

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