127724-75-8|3-Chloro-7,8-dihydroquinolin-5(6H)-one| Ambeed

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Quality Control of [ 127724-75-8 ] Purity: 95% SDS Specification

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Product Details of [ 127724-75-8 ]

CAS No. :	127724-75-8
Formula :	C₉H₈ClNO
M.W :	181.62
SMILES Code :	O=C1C2=C(N=CC(Cl)=C2)CCC1
MDL No. :	MFCD10696330
InChI Key :	RKZNIWFFGNBOLH-UHFFFAOYSA-N
Pubchem ID :	10997654

Safety of [ 127724-75-8 ]

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

Computational Chemistry of [ 127724-75-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.33
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	47.1
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	29.96 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.82
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	1.62
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.25
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.	1.35
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	3.12
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.03

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.36
Solubility	0.799 mg/ml ; 0.0044 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.	-1.86
Solubility	2.5 mg/ml ; 0.0138 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	-3.64
Solubility	0.0418 mg/ml ; 0.00023 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.	-6.26 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)	1.98

Application In Synthesis of [ 127724-75-8 ]

* 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.

Downstream synthetic route of [ 127724-75-8 ]

[ 127724-75-8 ] Synthesis Path-Downstream 1~17

1
[ 137628-23-0 ]
[ 127724-75-8 ]

References: [1]Journal of Organic Chemistry,1992,vol. 57,p. 761 - 764.

2
2-((Z)-2-Chloro-3-dimethylamino-allylidene)-cyclohexane-1,3-dione [ No CAS ]
[ 127724-75-8 ]

References: [1]Journal of Organic Chemistry,2001,vol. 66,p. 4194 - 4199.

3
[ 504-02-9 ]
[ 127724-75-8 ]

References: [1]Journal of Organic Chemistry,2001,vol. 66,p. 4194 - 4199.

4
[ 137628-19-4 ]
[ 127724-75-8 ]

References: [1]Journal of Organic Chemistry,1992,vol. 57,p. 761 - 764.

5
[ 137628-22-9 ]
[ 127724-75-8 ]

References: [1]Journal of Organic Chemistry,1992,vol. 57,p. 761 - 764.

6
[ 137628-18-3 ]
[ 127724-75-8 ]

References: [1]Journal of Organic Chemistry,1992,vol. 57,p. 761 - 764.

Yield	Reaction Conditions	Operation in experiment
15.5 mg, (50%)		EXAMPLE 6 3-Chloro-7,8-dihydro-5(6H)-quinolone (11) The compound of Example 5 (50 mg, 0.164 mmol) in 2.0 ml of diisopropylether was cooled to -70 C. 150 microliters (0.255 mmol) of t-butyllithium was added. The reaction was stirred for 45 minutes and then quenched with 2N HCl. 10 ml of water and 10 ml of diisopropylether were added and the phases separated. The aqueous phase was again extracted twice with diisopropylether (210 ml each). The combined organic extracts were treated with sodium sulfate, and the solvent removed under vacuum affording 24 mg of an amber oil. The oil was chromatographed on silica with 30% ethyl acetate in hexane yielding 15.5 mg, (50%) of the title compound as white needles. mp=84-86 C. IR (nujol): 2960, 2930, 2860, 1690, 1572, 1540, 1469, 1385, 1290, 1050, 990 cm-1. 1 H NMR (CDCl3) delta: 8.58 (d, J=2.5 Hz, 1H); 8.18 (d, J= 2.5 Hz, 1H); 3.10 (t, J=10 Hz, 2H); 2.65 (t, J=10Hz, 2H); 2.16 (m, 2H). 13 C NMR (CDCl3) delta: 196.6, 161.4, 152.2, 134.1, 130.8, 128.7, 38.2, 32.0, 21.7. High resolution mass spectrum: m/e=183.022 (calculated for C9 H8 ClNO m/e=183.265).

8
[ 5220-49-5 ]
[ 6695-22-3 ]
[ 127724-75-8 ]

Yield	Reaction Conditions	Operation in experiment
	With lithium chloride; In N-methyl-acetamide;	PREPARATION D To a mechanically-stirred slurry consisting of 60 g. of lithium chloride in 350 ml. of anhydrous dimethylformamide at 40 C., there were added 88.9 g. (0.80 mole) of 3-amino-2-cyclohexene-1-one (the product of Preparation C). When all this material had dissolved, the temperature was increased to 60 C. and all of the 1,2-dichloro-1-propen-3-al obtained in Preparation B (i.e., the product of Preparation B) was added in one portion. This resulted in a mild exotherm accompanied by vigorous bubbling. After allowing the reaction mixture to stand at 90 C. for a period of one hour, the reaction flask and its contents were cooled to 25 C. and the contents were poured over 400 ml. of water. The resulting slurry was then extracted with twelve-500 ml. portions of hexanes, which were subsequently combined and then dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there were eventually obtained 51.62 g. (28%) of pure 3-chloro-5,6,7,8-tetrahydro-5-quinolone in the form of a yellow solid melting at 88-94 C.; 1 H-NMR (300 MHz, DMSO-d6)delta2.10 (m, 2H), 2.65 (t, 2H), 3.05 (t, 2H), 8.08 (s, 1H), 8.70 (s, 1H).

References: [1]Patent: US4952694,1990,A .

9
[ 504-02-9 ]
[ 944905-54-8 ]
[ 127724-75-8 ]

References: [1]Patent: WO2012/52451,2012,A1 .

10
[ 1162663-26-4 ]
[ 5220-49-5 ]
[ 944905-54-8 ]
[ 127724-75-8 ]

Yield	Reaction Conditions	Operation in experiment
		Example 983-((6-Aminopyridin-2-yl)ethynyl)-7,8-dihydroquinolin-5(6H)-one[00286] A mixture of cyclohexane-1 ,3-dione (30.0 g, 0.27 mol), ammonium acetate (44.49 g, 0.54 mol), and acetic acid (1 mL) in benzene (300 mL) is stirred at reflux for 7 h using a Dean-Stark trap, cooled down to r.t., concentrated at reduced pressure, and diluted with EtOH. The mixture is neutralized by means of NaHC03. The formed solid is collected by filtration, and the filtrate is concentrated in vacuo. The obtained residue is dissolved in dioxane, and the residual solids are filtered. A precipitate is formed, which is collected by filtration and dried at 50 C to give 3-aminocyclohex-2-enone (intermediate I) (6.77 g, 23%) as yellow solid.[00287]A mixture of 2-bromomalonaldehyde (7.51 g, 49.75 mmol) and thionyl chloride (3.65 mL, 49.75 mmol) in anhydrous DCM (35 mL) is stirred at reflux for 9 h, cooled down to r.t. and concentrated at reduced pressure to give 2-bromo-3- chloroacrylaldehyde (intermediate II) (6.55 g, 88%) as red oil, which is used in the next step without additional purification.[00288] Intermediate I (3.90 g, 35.10 mmol) is added to a solution of LiCI (2.60 g, 61 .45 mmol) in DMF (60 mL) at 40 C, and the resulting solution is stirred at 50 C for 5 min. Intermediate II (6.550 g, 43.91 mmol) is added, and the reaction mixture is stirred at 90 C for 1.5 h, cooled down to r.t., poured into water and extracted with EtOAc. The organic phase is concentrated at reduced pressure. The obtained residue is purified by column chromatography (silica gel, EtOAc/hexane) to give a mixture of 3-bromo-7,8- dihydroquinolin-5(6/-/)-one and 3-chloro-7,8-dihydroquinolin-5(6/-/)-one (4.940 g) as yellowish oil (ratio approx. 1 : 1 according to LCMS). [00289]According to General Procedure 1 , the 1 : 1 mixture of halogenated 7,8- dihydroquinolin-5(6/-/)-ones (500 mg, approx. 2.45 mmol) is reacted with 6- ethynylpyridin-2-amine (292 mg, 2.45 mmol) in the presence of PdCI2[PPh3]2 (52 mg, 0.07 mmol), P(f-Bu)3 (0.061 mL, 0.25 mmol), and TEA (4 mL) in acetonitrile (4 mL) at 100 C for 2 h. The crude product is purified by column chromatography (silica gel, EtOAc/hexane) to provide the title compound (90 mg, 14%).1H NMR (De-DMSO), deltaEta, 2.05-2.15 (m, 2H), 2.67 (t, 2H), 3.09 (t, 2H), 6.1 1 (br s, 2H), 6.48 (d, 1 H), 6.80 (d, 1 H), 7.40 (dd, 1 H), 8.18 (s, 1 H), 8.83 (s, 1 H).LC/MS (M+H)+ = 264

References: [1]Patent: WO2012/52451,2012,A1 .Location in patent: Page/Page column 102-103.

11
[ 504-02-9 ]
N-(2-chloro-3-(dimethylamino)allylidene)-N-methylmethanaminium hexafluorophosphate(V) [ No CAS ]
[ 127724-75-8 ]

Yield	Reaction Conditions	Operation in experiment
29%		To a cyclohexane-1,3-dione (0.824 g, 7.35 muMol) solution in THF (20 mL), a 1 mol/L potassium tert-butoxide/tetrahydrofuran solution (8.00 mL, 8.00 muMol) was added dropwise at 0C. After the mixture was stirred at roomtemperature for 30 minutes, 2-chloro-N,N-dimethylaminotrimethynium hexafluorophosphate (1.50 g, 4.89 muMol) wasadded to the mixture. The mixture was stirred at 50C for one hour. Next, ammonium acetate (1.70 g, 22.05 muMol) wasadded to the mixture, and the mixture was stirred at 100C for 1.5 hours. After the reaction liquid was concentratedunder reduced pressure, ethyl acetate was added to the residue. The mixture was washed with water and saturatedsaline and dried over anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography (heptane/ethyl acetate = 100/0 -> 70/30) to obtain compound 102-1 (257.4 mg, 29%).1H NMR (400 MHz, CDCl3, delta): 8.64 (d, J = 2.7 Hz, 1H), 8.24 (d, J = 2.7 Hz, 1H), 3.14 (t, J = 6.3 Hz, 2H), 2.70 (dd, J =7.2, 5.9 Hz, 2H), 2.21 (m, 2H).

References: [1]Patent: EP3401309,2018,A1 .Location in patent: Paragraph 0806.

12
[ 127724-75-8 ]
3-chloro-5,6,7,8-tetrahydroquinolin-5-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
91%	With methanol; sodium tetrahydroborate; at 0 - 20℃; for 0.25h;	To a methanol solution (10 mL) of compound 102-1 (322.6 mg, 1.776 muMol), sodium borohydride (160.0 mg,4.230 muMol) was added in small portions at 0C. After the mixture was stirred at room temperature for 15 minutes, waterwas added to the mixture. The mixture was extracted with chloroform. After the extracted liquid was dried over anhydrousmagnesium sulfate, the residue was purified by silica gel column chromatography (heptane/ethyl acetate = 100/0 ->50/50) to obtain compound 102-2 (296.7 mg, 91%).1H NMR (400 MHz, CDCl3, delta): 8.25 (d, J = 2.7 Hz, 1H), 7.80 (d, J = 2.7 Hz, 1H), 4.74 (m, 1H), 4.62 (br d, J = 6.3 Hz,1H), 2.83 (m, 2H), 2.05 (m, 2H), 1.80 (m, 2H);ESIMS m/z: [M + H]+ 184, 186.

References: [1]Patent: EP3401309,2018,A1 .Location in patent: Paragraph 0807.

13
[ 127724-75-8 ]
5-azido-3-chloro-5,6,7,8-tetrahydroquinoline [ No CAS ]