1056636-11-3|(4-((Cyanomethyl)carbamoyl)phenyl)boronic acid| Ambeed

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Quality Control of [ 1056636-11-3 ] Purity: 98% SDS Specification

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Product Details of [ 1056636-11-3 ]

CAS No. :	1056636-11-3
Formula :	C₉H₉BN₂O₃
M.W :	203.99
SMILES Code :	O=C(C1=CC=C(B(O)O)C=C1)NCC#N
MDL No. :	MFCD24566607
InChI Key :	XHRYRSBKDZTAEB-UHFFFAOYSA-N
Pubchem ID :	86643816

Safety of [ 1056636-11-3 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 1056636-11-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	6
Fraction Csp3	0.11
Num. rotatable bonds	4
Num. H-bond acceptors	4.0
Num. H-bond donors	3.0
Molar Refractivity	53.82
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	93.35 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	-0.11
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	-1.38
Log P_o/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.	-0.8
Log P_o/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	-1.29
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	-0.72

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.07
Solubility	17.5 mg/ml ; 0.0856 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.4
Solubility	8.17 mg/ml ; 0.04 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	-1.78
Solubility	3.35 mg/ml ; 0.0164 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	No
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	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.	-7.62 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	2.0 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)	1.53

Application In Synthesis of [ 1056636-11-3 ]

* 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 [ 1056636-11-3 ]

[ 1056636-11-3 ] Synthesis Path-Downstream 1~17

1
[ 3934-20-1 ]
[ 1056636-11-3 ]
[ 1056636-12-4 ]

Yield	Reaction Conditions	Operation in experiment
33%	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In propan-1-ol; water; toluene; at 90℃; for 24h;	To a solution of 2,4-dichloropyrimidine (3.2 g, 0.22 mmol) and A- (cyanomethylcarbamoyi)phenylboronic acid (3.0 g, 15 mmol) in toluene (146 mL) were added n-propanol (44 mL), aqueous sodium bicarbonate (2M, 22 mL) and tetrakis(triphenylphosphine)palladium[0] (850 mg, 0.7 mmol). The reaction was heated at 9O0C for 24 h, then partitioned between ethyl acetate and water. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions washed with brine, dried (Na2SO4) filtered and concentrated. Silica gel chromatography using 30-70% ethyl acetate in petroleum spirit as eluent provided 4-(2-chloropyrimidin-4-yl)-7V- (cyanomethyl)benzamide as a pale yellow waxy solid (1.35 g, 33%). 1H NMR (J6-DMSO, 300 MHz) delta 9.40 (IH, t, J= 5.4 Hz), 8.88 (IH, d, J= 5.2 Hz), 8.32 (2H, d, J= 8.7 Hz), 8.23 (IH3 d, J= 5.1 Hz), 8.05 (2H, d, J= 8.7 Hz), 4.36 (2H, d, J= 5.4 Hz). LC-MS: rt 5.3 min.; m/z 273.2/275.2 [M+H]+.
33%	With sodium hydrogencarbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; at 90℃; for 24h;	To a solution of 2,4-dichloropyrimidine (3.2 g, 0.22 mmol) and 4- (cyanomethylcarbamoyl)phenylboronic acid (3.0 g, 15 mmol) in toluene (146 mL) were added n-propanol (44 mL), aqueous sodium bicarbonate (2M, 22 mL) and tetrakis(triphenylphosphine)palladium[0] (850 mg, 0.7 mmol). The reaction was heated at 9O0C for 24 h, then partitioned between ethyl acetate and water. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions washed with brine, dried (Na2SO4) filtered and concentrated. Silica gel chromatography using 30-70% ethyl acetate/petroleum spirit as eluent provided 4-(2-chloropyrimidin-4-yl)-N-(cyanomethyl)benzamide as a pale yellow waxy solid (1.35 g, 33%). 1H NMR (300 MHz, ^6-DMSO) delta 9.40 (t, J= 5.4 Hz, IH), 8.88 (d, J= 5.2 Hz, IH), 8.32 (d, J= 8.7 Hz, 2H), 8.23 (d, J= 5.1 Hz, IH), 8.05 (d, J= 8.7 Hz, 2H), 4.36 (d, J= 5.4 Hz, 2H); LC-ESI-MS (method B): rt 5.3 min.; m/z 273.2/275.2 [M+H]+.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium carbonate; In water; acetonitrile; at 75℃;Inert atmosphere;	A suspension of <strong>[1056636-11-3]{4-[(cyanomethyl)carbamoyl]phenyl}boronic acid</strong> (4.2 g, 20.6 mmol), 2,4-dichloropyrimidine (4.3 g, 28.8 mmol), potassium carbonate (2.8 kg, 20.6 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (84 mg, 0.10 mmol) in acetonitrile (21 mL) and water (11 mL) was sparged with N2 for 30 minutes. The mixture was heated to 75 C. until the reaction was complete. The mixture was cooled to 60 C. and the layers were separated. An aqueous N-acetyl cysteine solution (6 mL) was added followed by the addition of water (15 mL). The mixture was cooled to 20 C. The solids were filtered, washed with H2O/CH3CN (3:1), and dried at 50 C. to provide 4-(2-chloropyrimidin-4-yl)-N-(cyanomethyl)benzamide having the below structure: 1H NMR (300 MHz, DMSO-d6): delta 4.36 (d, J=5.5 Hz, 2H), 8.05 (m, J=8.5 Hz, 2H), 8.24 (d, J=5.3 Hz, 1H), 8.32 (m, J=8.5 Hz, 2H), 8.89 (d, J=5.2 Hz, 1H), 9.39 (t, J=5.5 Hz, 1H). HRMS (ESI+): calcd. for C13H10ClN4O [M+1]: 273.15 found 273.25.

References: [1]Patent: WO2009/29998,2009,A1 .Location in patent: Page/Page column 53.
[2]Patent: WO2008/109943,2008,A1 .Location in patent: Page/Page column 60.
[3]Patent: US2015/361050,2015,A1 .Location in patent: Paragraph 0205-0206.
[4]Journal of Medicinal Chemistry,2018,vol. 61,p. 6056 - 6074.

2
[ 14047-29-1 ]
[ 6011-14-9 ]
[ 1056636-11-3 ]

Yield	Reaction Conditions	Operation in experiment
87%		To a suspension of 4-carboxyphenylboronic acid (5.0 g, 30 mmol) in DMF (5 mL) and dichloromethane (200 mL) at 0C was added oxalylchloride (5.9 mL, 66 mmol) dropwise. <n="54"/>When gas evolution slowed, the ice bath was removed and the reaction allowed to warm to room temperature over 30 min. The reaction was then heated at 4O0C for 3 h by which time all solids had dissolved. The dichloromethane was removed by distillation and the DMF solution cooled to 00C. A solution of aminoacetonitrile hydrochloride (3.05 g, 33 mmol) in DMF (80 rnL) and DIPEA (13 mL, 75 mmol) was then added dropwise. After the addition was complete the ice bath was removed and the solution allowed to stir at room temperature for 16 h. Most of the DMF was then removed in vacuo and the reaction was partitioned between ethyl acetate and 2 M aqueous hydrochloric acid. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions dried (Na2SO4) filtered and concentrated under reduced pressure to afford 4-(cyanomethylcarbamoyl)phenylboronic acid as a waxy pale yellow solid (5.34 g, 87%). 1HNMR (J6-DMSO, 300 MHz) delta 9.18 (IH, br. t, J= 5.1Hz), 7.8-7.9 (4H, m), 4.31 (2H, d, J= 5.4 Hz). LC-MS: rt 0.9 min.; m/z 203.3 [M-H]".
87%		Example 3 - Synthesis of Compound 90; To a suspension of 4-carboxyphenylboronic acid (5.0 g, 30 mmol) in DMF (5 mL) and dichloromethane (200 mL) at 0C was added oxalylchloride (5.9 mL, 66 mmol) dropwise. When gas evolution slowed, the ice bath was removed and the reaction allowed to warm to room temperature over 30 min. The reaction was then heated at 400C for three hours by which time all solids had dissolved. The dichloromethane was removed by distillation and the DMF solution cooled to 0C. A solution of aminoacetonitrile hydrochloride (3.05 g, 33 mmol) in DMF (80 mL) and DIPEA (13 mL, 75 mmol) was then added dropwise. After the addition was complete the ice bath was removed and the solution allowed to stir at room temperature for 16 h. Most of the DMF was then removed in vacuo and the reaction was partitioned between ethyl acetate and 2 M aqueous hydrochloric acid. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions dried (Na2SO4) filtered and concentrated under reduced pressure to afford 4-(cyanomethylcarbamoyl)phenylboronic acid as a waxy pale yellow solid (5.34 g, 87%). 1H NMR (300 MHz, J6-DMSO): 9.18 (br. t, J- 5.1Hz, IH), 7.8-7.9 (m, 4H), 4.31 (d, J= 5.4 Hz, 2H); LC-ESI-MS (method B): rt 0.9 min.; m/z 203.3 [M-H]-.

References: [1]Patent: WO2009/29998,2009,A1 .Location in patent: Page/Page column 52-53.
[2]Patent: WO2008/109943,2008,A1 .Location in patent: Page/Page column 60.

3
[ 112889-66-4 ]
[ 1056636-11-3 ]
[ 1056636-16-8 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In toluene; at 80℃;	To a mixture of <strong>[1056636-11-3]4-(cyanomethylcarbamoyl)phenylboronic acid</strong> (see example 3) (185 mg, 0.9 mmol) and 5-bromo-2,4-diiodopyrimidine (410 mg,1.0 mmol) in 1,4- dioxane (10 mL), was added 2M aqueous potassium carbonate (100 muL). The resulting mixture was stirred under nitrogen for 5 minutes then tetrakis(triphenylphophine)palladium(0) (52 mg, 0.045 mmol) was added under a nitrogen atmosphere. The mixture was heated at 8O0C overnight. The cooled reaction mixture was diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with water then brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product as a brown solid. The crude material was purified by flash chromatography, eluting with 50% ethyl acetate / petroleum spirit to give 4-(5-bromo-2-iodopyrimidin-4-yl)-N-(cyanomethyl)benzamide (200 mg, 35% over 2 steps). LC-ESI-MS (method B): rt 6.2 min.; m/z 443.0/445.0 [M+H]+.

References: [1]Patent: WO2008/109943,2008,A1 .Location in patent: Page/Page column 63.

4
[ 1056636-11-3 ]
N-(cyanomethyl)-4-(2-((4-((2-hydroxyethyl)amino)phenyl)amino)pyrimidin-4-yl)benzamide [ No CAS ]

References: [1]Patent: US2015/361050,2015,A1 .

5
[ 1056636-11-3 ]
4-(2-((4-aminophenyl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide [ No CAS ]

References: [1]Patent: US2015/361050,2015,A1 .

6
[ 1056636-11-3 ]
4-(2-((4-acetamidophenyl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide [ No CAS ]

References: [1]Patent: US2015/361050,2015,A1 .

7
[ 1056636-11-3 ]
1-(4-((4-(4-((cyanomethyl)carbamoyl)phenyl)pyrimidin-2-yl)amino)phenyl)-N-hydroxypiperidine-4-carboxamide [ No CAS ]