425638-74-0|2-(2-Chloroquinazolin-4-yl)acetamide| Ambeed

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Quality Control of [ 425638-74-0 ] Purity: 95% SDS Specification

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Product Details of [ 425638-74-0 ]

CAS No. :	425638-74-0
Formula :	C₁₀H₈ClN₃O
M.W :	221.64
SMILES Code :	O=C(N)CC1=C2C=CC=CC2=NC(Cl)=N1
MDL No. :	MFCD16627975
InChI Key :	HBENSHGDVIJNBK-UHFFFAOYSA-N
Pubchem ID :	18770867

Safety of [ 425638-74-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 425638-74-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	15
Num. arom. heavy atoms	10
Fraction Csp3	0.1
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	57.23
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	68.87 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.62
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	1.35
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.31
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.	0.78
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	2.01
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.42

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.43
Solubility	0.831 mg/ml ; 0.00375 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.	-2.4
Solubility	0.886 mg/ml ; 0.004 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	-3.95
Solubility	0.0251 mg/ml ; 0.000113 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	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	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.	-6.69 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<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)	1.82

Application In Synthesis of [ 425638-74-0 ]

* 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 [ 425638-74-0 ]

[ 425638-74-0 ] Synthesis Path-Downstream 1~26

1
[ 607-68-1 ]
[ 141-97-9 ]
[ 425638-74-0 ]

Yield	Reaction Conditions	Operation in experiment
54%		Lambda/, nu-dimethylaniline (33.4 g, 276 mmol, 1 .0 eq) was added dropwise to a solution of 2,4 (1 H, 3H)-quinazolinedione (50 g, 276 mmol, 1 .0 eq) in POCI3 (300 ml) and the mixture was heated to reflux for 3 hrs. The solution was cooled to room temperature, poured onto ice water and the resulting precipitate was filtered off and washed with water. The solid was dissolved in EtOAc and washed with water and brine. The organic fraction was dried over Na2S04, filtered, concentrated under reduced pressure, and washed with petroleum ether to give the corresponding dichloro-derivative (20 g, 34% yield).Ethyl-3-oxobutanoate (31.2 g, 240 mmol, 2.0 eq) was added dropwise to a suspension of NaH (6 g, 156 mmol, 1 .3 eq) in THF (520 ml) at 0 C. After stirring at 0 C for 1 h and removal of THF under reduced pressure, a solution of 2,4-dichloroquinazoline (24 g, 120 mmol, 1.0 eq) in toluene (350 ml) was added and the reaction mixture was heated to reflux for 30 min. After removal of toluene under reduced pressure, NH4OH (320 ml) was added. After stirring for 20 min, the mixture was concentrated to remove NH4OH. EtOAc (100 ml) and water (50 ml) were added to the mixture, that was filtered to give 2-(2- chloroquinazolin-4-yl)acetamide (14.4 g, 54 % yield).1 -Methylpiperazine (34 g, 339 mmol, 5.0 eq) was added to a solution of 2-(2- chloroquinazolin-4-yl)acetamide (14.4 g, 65 mmol, 1.0 eq) in NMP (250 ml) and stirred at 50 C for 30 min. After cooling to room temperature, EtOAc (100 ml) was added and the suspension was filtered to give 2-(2-(4-methylpiperazin-1 -yl)quinazolin-4-yl)acetamide (10.5 g, 55 % yield).fert-BuOK (215 ml_, 121 mmol, 3.0 eq) was added to a solution of 2-(2-(4-methylpiperazin- 1 -yl)quinazolin-4-yl)acetamide (10.5 g, 36.8 mmol, 1.0 eq) and Intermediate 2 (10.5 g, 40.5 mmol, 1.1 eq) in anhydrous THF (250 ml) at room temperature and the mixture was stirred for about 30 min, quenched with water, extracted with EtOAc, washed with brine, dried over Na2S04, concentrated and purified by column chromatography (silicagel) to give the methyl-ester of intermediate 8 (1 1 g, 60 % yield).
	With NaH; In tetrahydrofuran; aqueous NH4OH; ethyl acetate; toluene;	b) Ethyl acetoacetate (5.08 mL, 2.0 eq.) dissolved in THF (25 mL) is added dropwise to a suspension of NaH (60%, 1.04 g, 1.3 eq.) in THF (25 mL) at 0 C. The solution is stirred 30 min. at 0 C. and the solvent is evaporated. The residue is redissolved in toluene (125 mL) and 2,4-dicloro-quinazoline (4.0 g, 20.0 mmol) is added. The mixture is stirred 30 min. at reflux and the toluene is evaporated. The oily residue is redissolved in aqueous NH4OH 25% (80 mL) and stirred overnight at RT. All volatile materials are evaporated and the residue is taken up in AcOEt (80 mL). The suspension is heated at reflux for 15 min., cooled to 0 C. and filtered to afford 2-(2-chloro-quinazolin-4-yl)-acetamide as a white solid. EI-MS: 221 [M]+178; IR (KBr) numax 3302, 3138, 1681, 1542, 1388, 1287, 948, 771; 1 H NMR (DMS0, 400 MHz) 6 4.21 (s, 2H), 7.24 (br s, 1H), 7.75-7.84 (m, 2H), 7.97 (d, J=8.4 Hz, 1H), 8.08 (dd, J=8.4, 7.5 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H)

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 6193 - 6196.
[2]Journal of Medicinal Chemistry,2011,vol. 54,p. 6028 - 6039.
[3]Patent: WO2013/4709,2013,A1 .Location in patent: Page/Page column 54-55.
[4]Patent: US2003/69424,2003,A1 .

2
[ 109-01-3 ]
[ 425638-74-0 ]
[ 425638-73-9 ]

Yield	Reaction Conditions	Operation in experiment
70%	In 1-methyl-pyrrolidin-2-one; at 60℃; for 0.5h;Inert atmosphere;	2-(2-(4-Methylpiperazin-1-yl)quinazolin-4-yl)acetamide To solution of 2-(2-chloroquinazolin-4-yl) acetamide (8.20 g, 37.0 mmol, Preparation #D.1) in NMP (74 mL) was added 1-methylpiperazine (20.5 mL, 185 mmol). The reaction mixture was heated to about 60 C. and stirred for about 30 min. The reaction was cooled to ambient temperature, EtOAc (90 mL) was added and the mixture was stirred at ambient temperature for about 2 h. The reaction was cooled to about 0 C. and the solids were collected by filtration washing with EtOAc to give 2-(2-(4-methylpiperazin-1-yl)quinazolin-4-yl)acetamide (7.37 g, 70% yield): LC/MS (Table 1, Method c) Rt=1.41 min; MS m/z: 286 (M+H)+.
55%	In 1-methyl-pyrrolidin-2-one; at 50℃; for 0.5h;	Lambda/, nu-dimethylaniline (33.4 g, 276 mmol, 1 .0 eq) was added dropwise to a solution of 2,4 (1 H, 3H)-quinazolinedione (50 g, 276 mmol, 1 .0 eq) in POCI3 (300 ml) and the mixture was heated to reflux for 3 hrs. The solution was cooled to room temperature, poured onto ice water and the resulting precipitate was filtered off and washed with water. The solid was dissolved in EtOAc and washed with water and brine. The organic fraction was dried over Na2S04, filtered, concentrated under reduced pressure, and washed with petroleum ether to give the corresponding dichloro-derivative (20 g, 34% yield).Ethyl-3-oxobutanoate (31.2 g, 240 mmol, 2.0 eq) was added dropwise to a suspension of NaH (6 g, 156 mmol, 1 .3 eq) in THF (520 ml) at 0 C. After stirring at 0 C for 1 h and removal of THF under reduced pressure, a solution of 2,4-dichloroquinazoline (24 g, 120 mmol, 1.0 eq) in toluene (350 ml) was added and the reaction mixture was heated to reflux for 30 min. After removal of toluene under reduced pressure, NH4OH (320 ml) was added. After stirring for 20 min, the mixture was concentrated to remove NH4OH. EtOAc (100 ml) and water (50 ml) were added to the mixture, that was filtered to give 2-(2- chloroquinazolin-4-yl)acetamide (14.4 g, 54 % yield).1 -Methylpiperazine (34 g, 339 mmol, 5.0 eq) was added to a solution of 2-(2- chloroquinazolin-4-yl)acetamide (14.4 g, 65 mmol, 1.0 eq) in NMP (250 ml) and stirred at 50 C for 30 min. After cooling to room temperature, EtOAc (100 ml) was added and the suspension was filtered to give 2-(2-(4-methylpiperazin-1 -yl)quinazolin-4-yl)acetamide (10.5 g, 55 % yield).fert-BuOK (215 ml_, 121 mmol, 3.0 eq) was added to a solution of 2-(2-(4-methylpiperazin- 1 -yl)quinazolin-4-yl)acetamide (10.5 g, 36.8 mmol, 1.0 eq) and Intermediate 2 (10.5 g, 40.5 mmol, 1.1 eq) in anhydrous THF (250 ml) at room temperature and the mixture was stirred for about 30 min, quenched with water, extracted with EtOAc, washed with brine, dried over Na2S04, concentrated and purified by column chromatography (silicagel) to give the methyl-ester of intermediate 8 (1 1 g, 60 % yield).
	In 1-methyl-pyrrolidin-2-one; ethyl acetate;	c) <strong>[425638-74-0]2-(2-chloro-quinazolin-4-yl)-acetamide</strong> (221 mg, 1.0 mmol) is dissolved in 1-methyl-2-pyrrolidinone (2.0 mL) and N-methylpiperazine (555 muL, 5.0 eq.) is added. The mixture is heated 45 min. at 50 C. AcOEt is added and the suspension is filtered to afford 2-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-acetamide as a white solid. ESI-MS: 284 [M-H]+, 241; 1H NMR (DMSO, 400 MHz) delta 2.24 (s, 3H), 2.40 (m, 4H), 3.86 (m, 4H), 3.98 (s, 2H), 7.12 (brs, 1H), 7.24 (dd, J=8.2, 7.5 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.63-7.72 (m, 2H), 7.95 (d, J=8.2 Hz, 1H);

References: [1]Patent: US2011/152243,2011,A1 .Location in patent: Page/Page column 47-48.
[2]Journal of Medicinal Chemistry,2009,vol. 52,p. 6193 - 6196.
[3]Journal of Medicinal Chemistry,2011,vol. 54,p. 6028 - 6039.
[4]Patent: WO2013/4709,2013,A1 .Location in patent: Page/Page column 54-55.
[5]Patent: US2003/69424,2003,A1 .

3
[ 110-91-8 ]
[ 425638-74-0 ]
[ 425639-12-9 ]

References: [1]Journal of Medicinal Chemistry,2009,vol. 52,p. 6193 - 6196.

4
[ 425638-74-0 ]
[ 1312783-50-8 ]

References: [1]Patent: US2011/152243,2011,A1 .

5
[ 425638-74-0 ]
[ 1312783-51-9 ]

References: [1]Patent: US2011/152243,2011,A1 .

6
[ 425638-74-0 ]
[ 1312784-30-7 ]
[ 1312784-36-3 ]

Yield	Reaction Conditions	Operation in experiment
63%		3-(2-Chloroquinazolin-4-yl)-4-(6H-thieno[2,3-b]pyrrol-4-yl)-1H-pyrrole-2,5-dione A round-bottomed flask was charged with tert-butyl 4-(2-ethoxy-2-oxoacetyl)-6H-thieno[2,3-b]pyrrole-6-carboxylate (1.00 g, 3.09 mmol, Preparation #C.1), <strong>[425638-74-0]2-(2-chloroquinazolin-4-yl)acetamide</strong> (0.823 g, 3.71 mmol, Preparation #D.1), and THF (20 mL) under a nitrogen atmosphere. The suspension was cooled to about -20 C. and KOt-Bu (1 M solution in THF, 23.2 mL, 23.2 mmol) was added dropwise via syringe over about 30 min. The reaction was stirred at about -20 C. for about 1 h and then at about 0 C. for about 1 h. Brine (50 mL) and EtOAc (150 mL) were added. The pH was adjusted to about 9 with 2 N aqueous HCl (7 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 5% MeOH/DCM (20 mL), silica gel (4.3 g) was added, and the volatiles were removed under reduced pressure. The resulting solid was purified by flash column chromatography on silica gel eluting with a gradient of 0% (10% MeOH in DCM)/DCM for 3 min, 0-35% (10% MeOH in DCM)/DCM over 17 min, 35-40% (10% MeOH in DCM)/DCM over 10 min, 40-50% (10% MeOH in DCM)/DCM over 10 min. The product containing fractions were combined and concentrated under reduced pressure to give 3-(2-chloroquinazolin-4-yl)-4-(6H-thieno[2,3-b]pyrrol-4-yl)-1H-pyrrole-2,5-dione (0.740 g, 63% yield): LC/MS (Table 1, Method c) Rt=1.95 min; MS m/z: 381 (M+H)+.

References: [1]Patent: US2011/152243,2011,A1 .Location in patent: Page/Page column 70.

7
[ 425638-74-0 ]
[ 1312784-31-8 ]
[ 1312783-39-3 ]

References: [1]Patent: US2011/152243,2011,A1 .

8
[ 425638-74-0 ]
[ 1312784-31-8 ]
[ 1312784-37-4 ]

Yield	Reaction Conditions	Operation in experiment
79%		3-(2-Chloroquinazolin-4-yl)-4-(4H-thieno[3,2-b]pyrrol-6-yl)-1H-pyrrole-2,5-dione A round bottomed flask was charged with <strong>[425638-74-0]2-(2-chloroquinazolin-4-yl)acetamide</strong> (1.00 g, 4.51 mmol, Preparation #D.1), tert-butyl 6-(2-ethoxy-2-oxoacetyl)-4H-thieno[3,2-b]pyrrole-4-carboxylate (1.46 g, 4.51 mmol, Preparation #C.2) and THF (19.4 mL) under a nitrogen atmosphere. The suspension was cooled to about -20 C. and KOt-Bu (1 M solution in THF, 8.46 mL, 8.46 mmol) was added dropwise and stirred for about 1 h. Water (50 mL) was added and the mixture was warmed to ambient temperature. The solvent was removed under reduced pressure and the aqueous phase was neutralized by adding 2 N aqueous HCl. EtOAc (75 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (2*75 mL). The combined organics were dried over MgSO4, filtered and concentrated under reduce pressure to give 3-(2-chloroquinazolin-4-yl)-4-(4H-thieno[3,2-b]pyrrol-6-yl)-1H-pyrrole-2,5-dione (1.35 g, 79% yield): LC/MS (Table 1, Method a) Rt=1.98 min; MS m/z: 381 (M+H)+.

References: [1]Patent: US2011/152243,2011,A1 .Location in patent: Page/Page column 70.

9
[ 607-68-1 ]
[ 425638-74-0 ]

References: [1]Patent: US2011/152243,2011,A1 .

10
[ 425638-74-0 ]
[ 1312784-30-7 ]
[ 1312782-80-1 ]

References: [1]Patent: US2011/152243,2011,A1 .

11
C₁₂H₁₁ClN₂O₂ [ No CAS ]
[ 425638-74-0 ]

Yield	Reaction Conditions	Operation in experiment
	With ammonium hydroxide; In ethanol; at 20 - 50℃; for 23.5h;	NH4OH (434 mL, 3120 mmol) was added and the mixture was stirred at ambient temperature for about 1.5 h. EtOH (180 mL) was added and the reaction mixture was heated to about 50 C. for about 22 h. The reaction was cooled to ambient temperature and the volume was reduced by about half under reduced pressure forming a heterogeneous mixture. After about 2 h at ambient temperature, the mixture was cooled to about 0 C. The precipitate was collected by filtration and the solids were washed with water (2*60 mL) to give 2-(2-chloroquinazolin-4-yl)acetamide (14.3 g, 56% yield): LC/MS (Table 1, Method b) Rt=1.04 min; MS m/z: 222 (M+H)+.

References: [1]Patent: US2011/152243,2011,A1 .Location in patent: Page/Page column 47.

12
[ 110-85-0 ]
[ 425638-74-0 ]
[ 425639-09-4 ]