58421-80-0|4-Chloro-8-methylquinazoline| Ambeed

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Quality Control of [ 58421-80-0 ] Purity: 97% SDS Specification

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Product Details of [ 58421-80-0 ]

CAS No. :	58421-80-0
Formula :	C₉H₇ClN₂
M.W :	178.62
SMILES Code :	CC1=CC=CC2=C(Cl)N=CN=C12
MDL No. :	MFCD08457971
InChI Key :	UTBDPFFXKANFFT-UHFFFAOYSA-N
Pubchem ID :	18185618

Safety of [ 58421-80-0 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H319
Precautionary Statements:	P305+P351+P338

Computational Chemistry of [ 58421-80-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	10
Fraction Csp3	0.11
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	49.51
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	25.78 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.17
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	2.87
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.59
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.	2.16
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	3.04
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.57

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.37
Solubility	0.0758 mg/ml ; 0.000424 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.	-3.07
Solubility	0.152 mg/ml ; 0.00085 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	0.00837 mg/ml ; 0.0000469 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	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.	-5.35 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	1.0
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)	1.32

Application In Synthesis of [ 58421-80-0 ]

* 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 [ 58421-80-0 ]

[ 58421-80-0 ] Synthesis Path-Downstream 1~35

1
[ 58421-80-0 ]
[ 19181-54-5 ]

References: [1]Chemische Berichte,1905,vol. 38,p. 3561.

2
[ 19181-54-5 ]
[ 58421-80-0 ]

Yield	Reaction Conditions	Operation in experiment
86%	With trichlorophosphate; at 120℃; for 12h;Inert atmosphere;	Phosphorous oxychloride (800 mL) was taken in a 2 L round bottom flask under nitrogen. To this was added 8-Methylquinazolin-4(3H)-one (125 g) in portions. The reactionminxture refluxed at 120 C for 12h. Reaction completion was monitored by TLC and LCMS. After completion, the reactionminxture was cooled to RT and evaporated to dryness under reduced pressure. The resulted residue was dissolved in DCM (500 mL) and quenched slowly into an ice cold solution of saturated K2C03 with constant stirring. Then the organic layer was separated and washed with brine solution, dried over sodium sulfate and concentrated under vacuum to afford 4-chloro-8-methylquinazoline (120 g, 86%) as yellow solid. This was taken for next step without further purification. MS: m/z = 179/18 1 [M+Hj.
35%	With trichlorophosphate; In acetonitrile;Reflux;	b. Preparation of Compound 12b To a solution of 8-methylquinazolin-4(3H)-one 12a (1.1 g, 6.92 mmol) in 155 ml ACN was added 10.1 mL POCl3. The reaction mixture is refluxed until completion, cooled to room temperature. The solvent was removed under vacuum, and the crude product was purified in ISCO using Ethyl acetate: hexane solvent system to afford the pure product (430 mg, 35% yield). 1H NMR (CDC13, 400 MHz) delta 9.06 (s, 1H), 8.12 (d, J= 8.4 Hz, 1H), 7.80 (d, J = 6.9 Hz, 1H), 7.61 (m, 1H), 2.78 (s, 3H).
35%	With trichlorophosphate; In acetonitrile;Reflux;	To a solution of 8-methylquinazolin-4(3H)-one 12a (1.1 g, 6.92 mmol) in 155 ml ACN was added 10.1 mE P0C13. The reaction mixture is refluxed until completion, cooled to room temperature. The solvent was removed under vacuum, and the crude product was purified in ISCO using Ethyl acetate:hexane solvent system to afford the pure product (430 mg, 35% yield). 1H NMR (CDCl3, 400 MHz) oe 9.06 (s, 1-H), 8.12 (d, J=8.4 Hz, 1H), 7.80 (d, J=6.9 Hz, 1-H), 7.61 (m, 1H), 2.78 (s, 3H).

	With trichlorophosphate; at 120℃; for 12h;Inert atmosphere;	POCI3 (300 mL) was taken in a 2 L round bottom flask under nitrogen. To this was added 8-Methylquinazolin-4(3H)-one (45 g) in portions. The reaction mixture refluxed at 120 C for 12h. Reaction completion was monitored by TLC and LCMS. After completion, the reaction mixture was cooled to RT and evaporated to dryness under reduced pressure. The resulted residue was dissolved in DCM (500 mL) and quenched slowly into an ice cold solution of saturated K2C03 with constant stirring. Then the organic layer was separated and washed with brine solution, dried over sodium sulphate and concentrated under vacuum to afford (45g, 90% yield) of the titled compound as yellow solid. This was taken for next step without further purification. H NMR (CDCI3, 400MHz) delta 9.03 (s, 1 H), 8.08-8.06 (dd, J = 8.9, 8.4 Hz, 1 H), 7.77-7.76 (d, J = 7.1 Hz, 1 H), 7.59-7.56 (d, J = 15.5 Hz, 1 H), 2.75 (s, 3H).
	With thionyl chloride; N,N-dimethyl-formamide; for 8h;Reflux;	General procedure: A mixture of 4-quinazolone analogues 2a-2j (8.0 mmol) in SOCI2 (27.4 mL) containing DMF (2 drops) was refluxed for 8 h. SOCI2 was removed under reduced pressure and the residue was dissolved in DCM. The solution was washed with saturated NaHCO3 solution and brine, respectively, dried over anhydrous Na2S04 and then concentrated under reduced pressure to yield the compounds 3a-3j (65.1-88.9percent yield) as white or off-white solid.
	With thionyl chloride; In N,N-dimethyl-formamide; for 5h;Reflux;	General procedure: A mixture of 4-hydroxyquinazoline (0.02 mol) in SOCl2 (20 mL)containing DMF (2 drops) was refluxed for 5 h. SOCl2 was removedunder reduced pressure, and the residue was dissolved in dichloromethane(DCM). The solution was washed with NaHCO3 solutionand brine, dried over anhydrous Na2SO4, and concentrated under reducedpressure to obtain the desired compound as a yellow solid.

References: [1]Patent: WO2017/106607,2017,A1 .Location in patent: Paragraph 00224.
[2]Synthetic Communications,2011,vol. 41,p. 3644 - 3653.
[3]Patent: WO2013/106756,2013,A2 .Location in patent: Page/Page column 40.
[4]Patent: US9822108,2017,B2 .Location in patent: Page/Page column 42.
[5]Bioorganic and Medicinal Chemistry,1996,vol. 4,p. 1203 - 1207.
[6]Organic Letters,2010,vol. 12,p. 552 - 555.
[7]Patent: WO2013/96194,2013,A1 .Location in patent: Page/Page column 29.
[8]European Journal of Medicinal Chemistry,2013,vol. 63,p. 662 - 669.
[9]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 4968 - 4974.
[10]Medicinal Chemistry Research,2014,vol. 23,p. 2584 - 2595.
[11]Bioorganic and Medicinal Chemistry Letters,2017,vol. 27,p. 4885 - 4888.
[12]Bioorganic Chemistry,2018,vol. 80,p. 433 - 443.

3
[ 58421-80-0 ]
[ 108-42-9 ]
(3-Chloro-phenyl)-(8-methyl-quinazolin-4-yl)-amine; hydrochloride [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,1996,vol. 4,p. 1203 - 1207.

Yield	Reaction Conditions	Operation in experiment
89%	With thionyl chloride; N,N-dimethyl-formamide;Reflux;	General procedure: 6,7-Dimethoxyquinazolin-4(3H)-one (20 g, 9.7 mmol) and 0.1 mL of /V,//-dimethylformamide were added to 50 mL of thionyl chloride. The resulting mixture was stirred at reflux for overnight. After cooled to room temperature, the solvent was removed in vacuo and saturated sodium carbonate solution was added to adjust the pH value to 8 at 0 C. The resulting mixture was extracted with dichloromethane and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to give 1.96 g (88%) of the tilte compound as a yellow solid. MS (ESIpos): m/z = 225 (M+H)+; LC-MS [Method 1] : Rt = 0.91 min.

5
8-methyl-quinazolone-⁽⁴⁾ [ No CAS ]
[ 58421-80-0 ]

References: [1]Chemische Berichte,1905,vol. 38,p. 3561.

6
[ 4389-45-1 ]
[ 58421-80-0 ]

References: [1]Bioorganic and Medicinal Chemistry,1996,vol. 4,p. 1203 - 1207.
[2]Patent: WO2013/96194,2013,A1 .
[3]European Journal of Medicinal Chemistry,2013,vol. 63,p. 662 - 669.
[4]Medicinal Chemistry Research,2014,vol. 23,p. 2584 - 2595.
[5]Patent: WO2017/106607,2017,A1 .

7
[ 58421-80-0 ]
[ 1820-80-0 ]
[ 1206694-12-3 ]
[ 1206694-11-2 ]

References: [1]Organic Letters,2010,vol. 12,p. 552 - 555.

8
[ 58421-80-0 ]
[ 1820-80-0 ]
[ 1206694-30-5 ]

References: [1]Organic Letters,2010,vol. 12,p. 552 - 555.

9
[ 58421-80-0 ]
[ 31230-17-8 ]
8-methyl-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine [ No CAS ]

References: [1]Organic Letters,2010,vol. 12,p. 552 - 555.

10
[ 58421-80-0 ]
[ 31230-17-8 ]
[ 1206693-98-2 ]

References: [1]Organic Letters,2010,vol. 12,p. 552 - 555.

11
[ 58421-80-0 ]
C₂₄H₂₁FN₆O₅S [ No CAS ]

References: [1]Patent: WO2013/96194,2013,A1 .

12
[ 58421-80-0 ]
[ 1445781-41-8 ]

References: [1]Patent: WO2013/96194,2013,A1 .
[2]Patent: WO2017/106607,2017,A1 .

13
[ 58421-80-0 ]
[ 1445781-42-9 ]

References: [1]Patent: WO2013/96194,2013,A1 .
[2]Patent: WO2017/106607,2017,A1 .

14
[ 58421-80-0 ]
[ 1445781-43-0 ]

References: [1]Patent: WO2013/96194,2013,A1 .
[2]Patent: WO2017/106607,2017,A1 .

15
[ 58421-80-0 ]
[ 1445781-44-1 ]

References: [1]Patent: WO2013/96194,2013,A1 .
[2]Patent: WO2017/106607,2017,A1 .

16
[ 58421-80-0 ]
[ 1445781-40-7 ]

References: [1]Patent: WO2013/96194,2013,A1 .
[2]Patent: WO2017/106607,2017,A1 .
[3]Patent: WO2017/106607,2017,A1 .

17
[ 58421-80-0 ]
trans-tert-butyl 3-((8-cyano-quinazolin-5-yl)amino)-4-(4-(trifluoromethoxy)phenyl)pyrrolidine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2013/96194,2013,A1 .

18
[ 58421-80-0 ]
trans-tert-butyl 3-((8-carbamoylquinazolin-5-yl)amino)-4-(4-(trifluoromethoxy)phenyl)pyrrolidine-1-carboxylate [ No CAS ]

References: [1]Patent: WO2013/96194,2013,A1 .

19
[ 58421-80-0 ]
trans-5-((4-(4-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)amino)quinazoline-8-carboxamide monohydrochloride [ No CAS ]

References: [1]Patent: WO2013/96194,2013,A1 .

20
[ 58421-80-0 ]
[ 7557-03-1 ]

Yield	Reaction Conditions	Operation in experiment
61%	With toluene-4-sulfonic acid hydrazide; In dichloromethane; at 45℃; for 12h;Inert atmosphere;	To a stirred solution of 4-Chloro-8-methylquinazoline (120 g,0.674 mol) in DCM (700 mL) under nitrogen was added p-toluenesulfonylhydrazide (175.7 g,0.943 mol) in portions. The reactionminxture was heated at 45 C for 12h. The reaction completionwas monitored by LCMS and TLC. After completion, the reactionminxture was cooled to RT, thesolvent evaporated to dryness, the resulted residue dissolved in EtOH (500 mL), added SN NaOH solution (500 mL) and refluxed for 6h. The reaction completion was monitored by LCMS. After completion, the reactionminxture was cooled to RT and extracted with MTBE (3 x 600 mL). The combined organic layers were washed with a brine solution, dried over sodium sulfate and concentrated under vacuum. The resulted residue was purified by chromatography using neutralised silica gel (60-l20mesh) and eluted with pet ether ethyl acetate to yield 8- methylquinazoline (60 g, 61%) as a low melting yellow solid. 1H NMR (400 MHz, DMSO-d6, ppm) 9.54 (s, 1H), 9.31 (s, 1H), 7.96 (dd, J= 8.8, 8.1 Hz, 1H), 7.87-7.84 (m, 1H), 7.64 (d, J= 15.2 Hz, 1H), 2.67 (s, 3H).
15 g	With toluene-4-sulfonic acid hydrazide; In dichloromethane; at 45℃; for 12h;Inert atmosphere;	To a stirred solution of 4-Chloro-8-methylquinazoline (45 g, 0.252 mol) in DCM (700 mL) under N2 was added p-toluenesulfonylhydrazide (65.9 g, 0.353 mol) in portions. The reaction mixture was heated at 45C for 12h. The reaction completion was monitored by LCMS and TLC. After completion, the reaction mixture was cooled to RT, the solvent evaporated to dryness and the resulted residue redissolved in EtOH (500 mL) and added 2N NaOH solution (300 mL) and refluxed for 6h. After confirming by LCMS, the reaction mixture was cooled to RT and extracted with MTBE (3 x 600 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under vacuum. The resulted residue was filtered through column chromatography using neutralized silica gel (60-120mesh) and pet ether/ ethyl acetate as an elutent to yield (15 g, 27% yield) of the titled compound as a low melting yellow solid. H NMR (DMSO-d6, 400MHz) delta 9.54 (s, 1 H), 9.31 (s, 1 H), 7.97-7.94 (dd, J = 8.8, 8.1 Hz, 1 H), 7.87-7.84 (m, 1 H), 7.65-7.62 (d, J = 15.2 Hz, 1 H), 2.67 (s, 3H).

References: [1]Patent: WO2017/106607,2017,A1 .Location in patent: Paragraph 00225.
[2]Patent: WO2013/96194,2013,A1 .Location in patent: Page/Page column 29-30.

21
[ 58421-80-0 ]
[ 1445781-75-8 ]

References: [1]Patent: WO2013/96194,2013,A1 .

22
[ 58421-80-0 ]
[ 1445781-73-6 ]

References: [1]Patent: WO2013/96194,2013,A1 .

23
[ 58421-80-0 ]
[ 6051-53-2 ]
[ 1442476-82-5 ]