31736-73-9|1-(4-Bromophenyl)-3-chloropropan-1-one| Ambeed

CAS No. :	31736-73-9
Formula :	C₉H₈BrClO
M.W :	247.52
SMILES Code :	ClCCC(=O)C1=CC=C(Br)C=C1
MDL No. :	MFCD00018979
InChI Key :	SYWQQEVHZPPLNQ-UHFFFAOYSA-N
Pubchem ID :	95790

Safety of [ 31736-73-9 ]

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

Computational Chemistry of [ 31736-73-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.22
Num. rotatable bonds	3
Num. H-bond acceptors	1.0
Num. H-bond donors	0.0
Molar Refractivity	53.94
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	17.07 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.38
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	2.82
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.26
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.	3.1
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	3.68
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.05

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.32
Solubility	0.118 mg/ml ; 0.000475 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.	-2.84
Solubility	0.361 mg/ml ; 0.00146 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	-4.63
Solubility	0.00582 mg/ml ; 0.0000235 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	Yes
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.	-5.81 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	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)	1.36

Application In Synthesis of [ 31736-73-9 ]

* 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.

Upstream synthesis route of [ 31736-73-9 ]
Downstream synthetic route of [ 31736-73-9 ]

[ 31736-73-9 ] Synthesis Path-Upstream 1~4

1
[ 108-86-1 ]
[ 161386-38-5 ]
[ 625-36-5 ]
[ 31736-73-9 ]

Yield	Reaction Conditions	Operation in experiment
85%	With hydrogenchloride In dichloromethane	The 5-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio]indan-1-one used as a starting material was obtained as follows: A solution of 3-chloropropionyl chloride (15 ml) in methylene chloride (10 ml) was added to a stirred suspension of aluminium chloride (20.1 g) in methylene chloride (35 ml) and the mixture was stirred at ambient temperature for 15 minutes. A mixture of bromobenzene (15 ml) in methylene chloride (10 ml) was added portionwise during a period of 1 hour. The mixture was stirred at ambient temperature for 16 hours. The mixture was poured onto a mixture of ice and 1N aqueous hydrochloric acid. The organic phase was washed with water and with a saturated aqueous sodium bicarbonate solution, dried (MgSO₄) and evaporated. The residue was purified by column chromatography using a 15:1 mixture of petroleum ether and ethyl acetate as eluent. There was thus obtained 4-bromophenyl 2-chloroethyl ketone (27.9 g, 85percent).

References: [1] Patent: US5332757, 1994, A, .

2
[ 108-86-1 ]
[ 625-36-5 ]
[ 31736-73-9 ]

References: [1] Organic Preparations and Procedures International, 1997, vol. 29, # 2, p. 214 - 218.
[2] Canadian Journal of Research, 1933, vol. 8, p. 440,444.
[3] Journal of the American Chemical Society, 1964, vol. 86, p. 4645 - 4650.
[4] Tetrahedron Asymmetry, 2008, vol. 19, # 9, p. 1078 - 1083.
[5] Journal of the American Chemical Society, 2012, vol. 134, # 2, p. 828 - 831.
[6] Journal of Materials Chemistry, 2012, vol. 22, # 10, p. 4483 - 4490.
[7] Patent: US2012/277423, 2012, A1, . Location in patent: Page/Page column 25.
[8] Chemical Communications, 2016, vol. 52, # 56, p. 8757 - 8760.

3
[ 106-37-6 ]
[ 625-36-5 ]
[ 31736-73-9 ]

References: [1] Journal of Fluorine Chemistry, 2015, vol. 173, p. 63 - 68.

4
[ 109240-30-4 ]
[ 31736-73-9 ]

References: [1] Organic Letters, 2016, vol. 18, # 4, p. 684 - 687.

[ 31736-73-9 ] Synthesis Path-Downstream 1~55

1
[ 578-66-5 ]
[ 31736-73-9 ]
[ 97802-07-8 ]

References: [1]Journal of the Chemical Society. Perkin transactions II,1985,p. 705 - 710.
[2]Patent: US2018/212158,2018,A1 .Location in patent: Paragraph 0550.

2
[ 540-73-8 ]
[ 31736-73-9 ]
3-(4'-bromophenyl)-1,1-dimethyl-2-pyrazolinium chloride [ No CAS ]

References: [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1992,vol. 31,p. 172 - 176.

3
[ 31736-73-9 ]
[ 97802-11-4 ]
[ 97802-08-9 ]

Yield	Reaction Conditions	Operation in experiment
	With phosphoric acid; orthoarsenic acid; at 100 - 150℃;Inert atmosphere;	General procedure: 4-(4-Fluoro-phenyl)-quinolin-8-ylamine (7.067 g, 29.661 mmol), arsenic acid (8.960 g, 23.333 mmol) and o-phosphoric acid (27 mL) were heated to 100 C under nitrogen. To this a melt of 8.333 g of p-fluoro-3-chloropropriophenone (44.655 mmol) was added drop wise. The solution was then heated to 140-150 C and the solution solidified. The solid was placed onto ice and brought to a pH of 12 followed by extraction with chloroform. The solid was recrystallized from methanol-water to yield 7.343 g of 4,7-bis(4-fluorophenyl)-1,10-phenanthroline as a colorless crystalline solid.

References: [1]Journal of the Chemical Society. Perkin transactions II,1985,p. 705 - 710.
[2]Journal of Fluorine Chemistry,2015,vol. 173,p. 63 - 68.
[3]Journal of Chemical Crystallography,2015,vol. 45,p. 453 - 460.

4
[ 31736-73-9 ]
[ 95815-83-1 ]
[ 97802-13-6 ]

References: [1]Journal of the Chemical Society. Perkin transactions II,1985,p. 705 - 710.

5
[ 31736-73-9 ]
[ 88-74-4 ]
[ 97802-09-0 ]

Yield	Reaction Conditions	Operation in experiment
	With phosphoric acid; orthoarsenic acid; at 100 - 150℃;Inert atmosphere;	General procedure: o-Nitroaminobenzene (5.00 g, 36.200 mmol), arsenic acid (20.00 g, 52.000 mmol) and o-phosphoric acid (60 mL) were added to a round bottom flask with stir bar and purged with nitrogen. The solution was heated to 100 C and a melt of 3-chloro-1-(4-fluoro-phenyl)-propan-1-one (12.376 g, 66.320 mmol), was added drop wise while maintaining the solution at 100 C. The solution was heated to 140-150 C for 1.5 h and then cooled to 80 C and poured onto ice. The solution was then brought to a pH of 12 using K2CO3 and the organics were extracted from the aqueous phase using methylene chloride. The contents were purified on basic alumina (methylene chloride) to yield 9.890 g (36.870 mmol) of 4-(4-fluorophenyl)-8-nitro-quinoline which was used without further purification.

6
[ 31736-73-9 ]
[ 25574-19-0 ]

Yield	Reaction Conditions	Operation in experiment
100%	With sodium tetrahydroborate; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere;	To a solution of sodium borohydride (3.8 g, 100 mmol) in tetrahydrofuran (100 mL) was added a solution of l-(4-bromo-phenyl)"3-chloro-propan-l-one (25 g, 100 mmol) dropwise at 0C under nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated to about 50 mL under reduced pressure and diluted with water. Extractive workup was performed with ethyl acetate and the extracts were dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography on silica gel (hexane/ethyl acetate=3/l as an eluant) to yield l-(4-bromo-phenyl)- 3-chloro-propan-l-ol (25 g, lOOmmol, 100%) as yellow oil.
	With sodium tetrahydroborate; In tetrahydrofuran; water; at 20℃; for 2h;	EXAMPLE 59; {3- (3-Chloro-phenoxy)-3- [4- (lH-pyrazol-4-vl)-phenYl]-propyl}-methyl-amine; 59A. 1-f4-Bromo-phenyl)-3-chloro-propan-1-ol; (J. Med. Chem, 2004, 47, 3924-3926) To a solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-one (1g, 4. 04mmol) in tetrahydrofuran (9ml) and water (0. 58ml) was added sodium borohydride (0. 16g, 4. 28mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with careful addition of water and extracted with ethyl acetate. The organic layers were separated, dried (MgS04), filtered and concentrated to afford the title compound, which was used in the next step without further purification. LC/MS : (PS-A2) Rt 3.07 [M+H] +No Ionization.
	With sodium tetrahydroborate; In methanol; for 1h;Cooling with ice;	To a solution of Compound 89 (1.00 g, 4.04 mmol) in methanol (20 ml) was added sodium borohydride (306 mg, 8.08 mmol) under ice cooling, and the reaction mixture was stirred under ice cooling for 1 hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and then extracted with ethyl acetate, which was then dried over sodium sulfate. The solvent was removed under reduced pressure, the obtained residue was dissolved in THF (20 ml), to which was then added KOt-Bu (1.43 g, 12.8 mmol) under ice cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and then extracted with ethyl acetate, which was then washed with saturated aqueous NaCl. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain Compound 91 (376 mg, 1.77 mmol, 44% in 2 steps) as a yellow oil. To Compound 91 (100 mg, 0.469 mmol) were added dioxane (1 ml), Compound 54 (179 mg, 0.704 mmol), PdCl2(dppf)CH2Cl2 (38.3 mg, 0.047 mmol), and potassium acetate (184 mg, 1.88 mmol), and the reaction mixture was stirred at 100C for 2 hours. The reaction mixture was purified by silica gel column chromatography to obtain Compound 92 (104 mg, 0.400 mmol, 85%). Compound 92; 1H-NMR (CDCl3)delta: 1.35 (s, 12H), 2.61-2.65 (m, 1H), 3.00-3.08 (m, 1H), 4.65-4.68 (m, 1H), 4.82-4.84 (m, 1H), 5.83 (t, J = 7.5 Hz, 1H), 7.43 (d, J = 7.8 Hz, 2H), 7.84 (d, J = 7.9 Hz, 2H).

With sodium tetrahydroborate; water; In tetrahydrofuran; at 20℃; for 2h;

EXAMPLE 59; {3-(3-Chloro-phenoxy)-3-[4-(1H-pyrazol-4-yl')-phenv?-propyl}-methyl-amine; 59A. 1-(4-Bromo-phenyl)-3-chloro-propan-1-ol; (J.Med.Chem, 2004,47,3924-3926); To a solution of 1-(4-Bromo-phenyl)-3-chloro-propan-1-one (1g, 4.04mmol) in tetrahydrofuran (9ml) and water (0.58ml) was added sodium borohydride (0.16g, 4.28mmol). The reaction mixture was stirred at room temperature for 2 hours, quenched with careful addition of water and extracted with ethyl acetate. The organic layers were separated, dried (MgStheta4), filtered and concentrated to afford the title compound, which was used in the next step without further purification. LC/MS: (PS-A2) Rt 3.07 [M+H]+ No Ionization.

References: [1]Patent: WO2010/114179,2010,A1 .Location in patent: Page/Page column 49.
[2]Journal of Heterocyclic Chemistry,1995,vol. 32,p. 1493 - 1498.
[3]Bulletin de la Societe Chimique de France,1969,p. 3648 - 3652.
[4]Patent: WO2005/61463,2005,A1 .Location in patent: Page/Page column 153.
[5]Patent: EP3187498,2017,A1 .Location in patent: Paragraph 0282; 0283.
[6]Patent: WO2006/136821,2006,A1 .Location in patent: Page/Page column 116.

7
[ 15715-41-0 ]
[ 31736-73-9 ]
[ 1003316-36-6 ]

Yield	Reaction Conditions	Operation in experiment
	In toluene; for 5h;Heating / reflux;	l-(4-bromophenyl)-3- chloropropan-1-one (4.5 g, 18.18 mmol) and diethyl methylphosphonite (6 g, 44.1 mmol) were stirred in refluxing toluene (9 mL) for 5 hours. Room temperature was attained and the solvent removed in vacuo. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave ethyl [3- (4-bromophenyl)-3-oxopropyl]methylphosphinate as a pale yellow oil that crystallised on standing.

References: [1]Patent: WO2008/10985,2008,A2 .Location in patent: Page/Page column 174.

8
[ 31736-73-9 ]
[ 873-55-2 ]
C₁₅H₁₃O₃SBr [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry,2007,vol. 15,p. 4396 - 4405.

9
[ 31736-73-9 ]
[ 674283-20-6 ]

References: [1]European Journal of Inorganic Chemistry,2003,p. 3752 - 3758.

10
[ 31736-73-9 ]
[ 173037-26-8 ]