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Chemical Structure| 1301198-65-1 Chemical Structure| 1301198-65-1

Structure of 1301198-65-1

Chemical Structure| 1301198-65-1

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Product Details of [ 1301198-65-1 ]

CAS No. :1301198-65-1
Formula : C11H19BN2O3
M.W : 238.09
SMILES Code : CC1(C)C(C)(C)OB(C2=CN(COC)N=C2)O1
MDL No. :MFCD28128543
InChI Key :PEEYHAPMXMTNHS-UHFFFAOYSA-N
Pubchem ID :67193995

Safety of [ 1301198-65-1 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H320-H335
Precautionary Statements:P261-P280-P301+P312-P302+P352-P305+P351+P338

Computational Chemistry of [ 1301198-65-1 ] Show Less

Physicochemical Properties

Num. heavy atoms 17
Num. arom. heavy atoms 5
Fraction Csp3 0.73
Num. rotatable bonds 3
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 65.86
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

45.51 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.0
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

1.1
Log Po/w (WLOGP)?

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

0.63
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.

0.17
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

0.17
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

0.42

Water Solubility

Log S (ESOL):?

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

-2.03
Solubility 2.23 mg/ml ; 0.00936 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.

-1.65
Solubility 5.35 mg/ml ; 0.0225 mol/l
Class?

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

Very 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

-2.55
Solubility 0.673 mg/ml ; 0.00282 mol/l
Class?

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

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

Yes
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

No
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

No
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

No
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.

-6.97 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

1.0 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<1.0
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)

3.16

Application In Synthesis of [ 1301198-65-1 ]

* 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.

  • Downstream synthetic route of [ 1301198-65-1 ]

[ 1301198-65-1 ] Synthesis Path-Downstream   1~5

  • 1
  • [ 269410-08-4 ]
  • [ 13057-19-7 ]
  • [ 1301198-65-1 ]
YieldReaction ConditionsOperation in experiment
26% With potassium carbonate; In acetonitrile; at 35℃; for 3h;Inert atmosphere; Intermediate 941 -[(Methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (10.00 g, 51.5 mmol) was dissolved in acetonitrile (40 mL) and stirred at 35C for 5 min under nitrogen atmosphere then cooled to room temperature, lodomethyl methyl ether (21.83 mL, 258 mmol) and potassium carbonate (35.6 g, 258 mmol) were added and the resulting mixture was stirred at 35C for 3 h then cooled to room temeprature. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with water, dried over MgS04 and concentrated in vacuo. Purification of the residue by SP4 using a 100 G silca cartridge (gradient: 0 to 50% AcOEt in hexanes) gave 1 -[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)- 1 H-pyrazole (6.45 g, 50% pure by LCMS, 26%) as a yellow liquid which was used in the next step without further purification.LCMS (method G): Retention time 0.85 min, [M+H]+ = 238.8
With potassium carbonate; In acetonitrile; at 35℃; for 4.5h; 4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (400mg, 2.061 mmol) (Aldrich) was dissolved in acetonitrile (25ml) and stirred for 5min at 35C. lodomethyl methyl ether (0.873ml, 10.31 mmol) and potassium carbonate (1424mg, 10.31 mmol) were added and the mixture was allowed to stir at 35C for 3h.The LCMS showed incomplete reaction. The mixture was left to stir at 35C for one additional hour. The LCMS showed no progression so 2eq (349muIota) of the alkylating agent was added and the mixture was allowed to stir at 35C for 30min. Ammonium chloride was then added. The mixture was partitioned between ethyl acetate and water. The aqueous layer was re-extracted with ethyl acetate and the combined organic phases were washed with water, dried using a hydrophobic frit and concentrated to an oil. The oil was purified on 50g silica using an SP4 and eluted with a 0-100% ethyl acetate/cyclohexane gradient. The product was found in the waste, which was concentrated to give the title compound as an oil (260mg).LCMS (Method B): Rt = 0.84min, MH+ = 238.85
4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (10.00 g, 51.5 mmol) was dissolved in acetonitrile (40 mL) and stirred at 35 C. for 5 min under nitrogen atmosphere then cooled to room temperature. Iodomethyl methyl ether (21.83 mL, 258 mmol) and potassium carbonate (35.6 g, 258 mmol) were added and the resulting mixture was stirred at 35 C. for 3 h then cooled to room temperature. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. Purification of the residue by SP4 using a 100 G silica cartridge (gradient: 0 to 50% AcOEt in hexanes) gave 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.45 g, 50% pure by LCMS, 26%) as a yellow liquid which was used in the next step without further purification.LCMS (method G): Retention time 0.85 min, [M+H]+=238.8
260 mg With potassium carbonate; In acetonitrile; at 35℃; for 4.5h; Intermediate 12: 1-[(Methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole[0399]4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 2.061 mmol) (Aldrich) was dissolved in acetonitrile (25 ml) and stirred for 5 min at 35 C. Iodomethyl methyl ether (0.873 ml, 10.31 mmol) and potassium carbonate (1424 mg, 10.31 mmol) were added and the mixture was allowed to stir at 35 C. for 3 h.[0401]The LCMS showed incomplete reaction. The mixture was left to stir at 35 C. for one additional hour. The LCMS showed no progression so 2 eq (349 mul) of the alkylating agent was added and the mixture was allowed to stir at 35 C. for 30 min. Ammonium chloride was then added. The mixture was partitioned between ethyl acetate and water. The aqueous layer was re-extracted with ethyl acetate and the combined organic phases were washed with water, dried using a hydrophobic frit and concentrated to an oil. The oil was purified on 50 g silica using an SP4 and eluted with a 0-100% ethyl acetate/cyclohexane gradient. The product was found in the waste, which was concentrated to give the title compound as an oil (260 mg).[0402]LCMS (Method B): Rt=0.84 min, MH+=238.85

  • 2
  • [ 1300031-98-4 ]
  • [ 1301198-65-1 ]
  • [ 1301197-82-9 ]
YieldReaction ConditionsOperation in experiment
20% With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80℃; for 18h;Inert atmosphere; Example 1061 -Methylethyl ((2S,4 ?)-1 -acetyl-2-methyl-6-{1 -[(methyloxy)methyl]-1 H-pyrazol-4-yl}- 1 ,2,3,4-tetrahydro-4-quinolinyl)carbamateA flask was charged with 1 -methylethyl [(2S,4R)-1 -acetyl-6-bromo-2-methyl-1 ,2,3,4- tetrahydro-4-quinolinyl]carbamate (0.185 g, 0.500 mmol) (for a preparation see Example 4), 1 -[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrazole (for a preparation see Intermediate 94) (143 mg, 0.600 mmol), K2C03 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80C for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2S04 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave 1 -methylethyl ((2S,4R)-1 -acetyl-2-methyl-6-{1 - [(methyloxy)methyl]-1 /-/-pyrazol-4-yl}-1 ,2,3,4-tetrahydro-4-quinolinyl)carbamate (42.2 mg, 0.105 mmol, 20%) as an off-white foam.LCMS (method A): Retention time 0.84 min, [M+H]+ = 401 .08
20% With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; at 80℃; for 18h; A flask was charged with 1-methylethyl [(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (0.185 g, 0.500 mmol) (for a preparation see Example 4), <strong>[1301198-65-1]1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (for a preparation see Intermediate 94) (143 mg, 0.600 mmol), K2CO3 (90 mg, 0.650 mmol) and tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) then filled with EtOH (1 mL) and toluene (1 mL) and the resulting mixture was stirred at 80 C. for 18 h then cooled to room temperature and concentrated in vacuo. The residue was partitioned between AcOEt (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with AcOEt and the combined organic phases were washed with brine (25 mL), dried over Na2SO4 and concentrated in vacuo. Purification of the residue using MDAP (modifier: formic acid) gave 1-methylethyl ((2S,4R)-1-acetyl-2-methyl-6-{1-[(methyloxy)methyl]-1H-pyrazol-4-yl}-1,2,3,4-tetrahydro-4-quinolinyl)carbamate (42.2 mg, 0.105 mmol, 20%) as an off-white foam.LCMS (method A): Retention time 0.84 min, [M+H]+=401.08
  • 3
  • [ 1301198-65-1 ]
  • [ 1345458-71-0 ]
  • 4
  • [ 1301198-65-1 ]
  • N-[(3S)-3-fluoro-3-piperidinyl]methyl}-7-{1-[(methyloxy)methyl]-1H-pyrazol-4-yl}-1,6-naphthyridin-5-amine hydrochloride [ No CAS ]
  • 5
  • [ 1301198-65-1 ]
  • [ 1345456-59-8 ]
  • [ 1345457-29-5 ]
YieldReaction ConditionsOperation in experiment
With potassium hydroxide;PEPPSI; In 1,2-dimethoxyethane; ethanol; water; at 130℃;Inert atmosphere; To 1 ,1 -dimethylethyl (3R)-3-[(7-chloro-1 ,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1 - piperidinecarboxylate (650mg, 1.646mmol) in DME (5ml), water (2.5ml), ethanol (5.00ml) was added 1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 H-pyrazole (1.03g 4.33mmol), potassium hydroxide (3.95ml, 3.95 mmol, 1 M aqueous solution) and PEPPSI (1 12mg, 0.165mmol). The reaction was refluxed at 130C under nitrogen for 4 nights. LCMS showed main peak as product. The reaction mixture was filtered through celite and the solvent removed. The residue was dissolved in DCM and loaded onto a 25g silica column and purified on the SP4 eluting with a 50-100% ethyl acetate in cyclohexane gradient. Appropriate fractions were combined and the solvent removed to give a yellow oil which was dried under high vacuum overnight to give the title compound as a yellow solid/film (813mg). LCMS (Method B): Rt = 0.86min, MH+ 471
813 mg With potassium hydroxide; In 1,2-dimethoxyethane; ethanol; water; at 130℃; for 96h;Inert atmosphere; Intermediate 15: 1,1-Dimethylethyl (3R)-3-fluoro-3-[(7-{1-[(methyloxy)methyl]-1H-pyrazol-4-yl}-1,6-naphthyridin-5-yl)amino]methyl}-1-piperidinecarboxylate[0410]1,1-dimethylethyl (3R)-3-[(7-chloro-1,6-naphthyridin-5-yl)amino]methyl}-3-fluoro-1-piperidinecarboxylate (650 mg, 1.646 mmol) in DME (5 ml), water (2.5 ml), ethanol (5.00 ml) was added <strong>[1301198-65-1]1-[(methyloxy)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole</strong> (1.03 g 4.33 mmol), potassium hydroxide (3.95 ml, 3.95 mmol, 1M aqueous solution) and PEPPSI (112 mg, 0.165 mmol). The reaction was refluxed at 130 C. under nitrogen for 4 nights. LCMS showed main peak as product. The reaction mixture was filtered through celite and the solvent removed. The residue was dissolved in DCM and loaded onto a 25 g silica column and purified on the SP4 eluting with a 50-100% ethyl acetate in cyclohexane gradient. Appropriate fractions were combined and the solvent removed to give a yellow oil which was dried under high vacuum overnight to give the title compound as a yellow solid/film (813 mg).[0412]LCMS (Method B): Rt=0.86 min, MH+ 471
 

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