872422-15-6|1-(4-Bromo-2-fluorophenyl)cyclopropanecarboxylic acid| Ambeed

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Quality Control of [ 872422-15-6 ] Purity: 97% SDS Specification

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Product Details of [ 872422-15-6 ]

CAS No. :	872422-15-6
Formula :	C₁₀H₈BrFO₂
M.W :	259.07
SMILES Code :	O=C(C1(C2=CC=C(Br)C=C2F)CC1)O
MDL No. :	MFCD12405622
InChI Key :	UPADMCJEKQAEKT-UHFFFAOYSA-N
Pubchem ID :	66662682

Safety of [ 872422-15-6 ]

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

Computational Chemistry of [ 872422-15-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	14
Num. arom. heavy atoms	6
Fraction Csp3	0.3
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	53.03
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	37.3 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.06
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	2.52
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	3.06
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.	3.0
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	3.31
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.79

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.22
Solubility	0.156 mg/ml ; 0.000604 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.	-2.95
Solubility	0.291 mg/ml ; 0.00112 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	-3.72
Solubility	0.0489 mg/ml ; 0.000189 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.	-6.09 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.	0.56

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<0.0
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)	1.73

Application In Synthesis of [ 872422-15-6 ]

* 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 [ 872422-15-6 ]

[ 872422-15-6 ] Synthesis Path-Downstream 1~31

1
[ 114897-91-5 ]
[ 107-04-0 ]
[ 872422-15-6 ]

Yield	Reaction Conditions	Operation in experiment
70%		Step 1. 1-(4-Bromo-2-fluorophenyl)cyclopropanecarboxylic acid Sodium hydroxide, 50% aqueous solution (5.71 mL, 0.149 mol), was added to a mixture of (4-bromo-2-fluorophenyl)acetonitrile (3.16 g, 0.0145 mol), benzyltriethylammonium chloride (0.26 g, 0.0011 mol), and 1-bromo-2-chloro-ethane (2.51 mL, 0.0302 mol) at 50 C. for 10 h. The mixture was poured into ice-water (50 mL) and was extracted with ethyl ether (250 mL). The combined organic phase was washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give 2.88 g of brown solid. 1H-NMR confirmed that desired nitrile intermediate was isolated. To the resulting residue was added 50% NaOH aqueous solution (3.8 mL) and ethylene glycol (20 mL) and the solution was heated to 100 C. and stirred overnight. The reaction mixture was poured into 50 mL of water and washed with ether (250 mL). The aqueous layer was cooled with an ice bath and then acidified by the slow addition of 6 N HCl. to pH=2. The product was extracted with EtOAc (2*100 mL), dried over MgSO4 and concentrated to give 1.634 g. (70%) of the desired product. 1H NMR confirmed that the desired product was isolated.
		To a stirred mixture of the (4-bromo-2-fluorophenyl)acetonitrile (12.53 g, 0.05854 mol), benzyltriethylammonium chloride (0.9 g, 0.004 mol), and l-bromo-2-chloro-ethane (9.70 mL, 0.117 mol) was added dropwise sodium hydroxide, 50% aqueous solution (21.00 mL, 0.5484 mol) at 50 C. After stirring for 16 h, the reaction mixture was diluted with water, 1,2-ethanediol (65.00 mL, 1.166 mol), and sodium hydroxide, 50% aqueous solution (5 mL). The resulting mixture was heated at 100C for 16 h. The reaction mixture was extracted with diethyl ether and the aqueous layer was acidified to pH~2 and the product precipitated out and was collected by filtration and used in the subsequent reaction without further purification.

References: [1]Patent: US2005/288338,2005,A1 .Location in patent: Page/Page column 34.
[2]Patent: WO2006/20598,2006,A2 .Location in patent: Example 145.1.

2
[ 872422-15-6 ]
[ 1056998-46-9 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; at 0 - 20℃; for 2.5h;	Step 1. 1-(4-Bromo-2-fluorophenyl)cyclopropanecarbonyl chloride To <strong>[872422-15-6]1-(4-bromo-2-fluorophenyl)cyclopropanecarboxylic acid</strong> (2.50 g, 0.00965 mol, prepared as an intermediate in the preparation of example 62, step 1) was added thionyl chloride (20 mL, 0.3 mol) at 0 C. and the resulting solution was stirred for 2.5 h at rt.

References: [1]Patent: US2005/288338,2005,A1 .Location in patent: Page/Page column 48.

3
[ 872422-15-6 ]
[ 57260-71-6 ]
[ 869979-17-9 ]

Yield	Reaction Conditions	Operation in experiment
52%		A mixture of l-(4-bromo-2-fluorophenyl)cyclopropanecarboxylic acid (2.390 g, 0.009225 mol), tert-buty piperazine-1-carboxylate (2.126 g, 0.01107 mol), sodium tert-butoxidQ (2.194 g, 0.02214 mol), palladium acetate (62 mg, 0.00028 mol) and 2-(di-£-butylphosphino)biphenyl (165 mg, 0.000554 mol) in anhydrous 1,4-dioxane (30.0 mL, 0.384 mol) was refluxed (oil bath temperature 110 C) overnight. The reaction mixture was poured into cold saturated NH4CI (60 mL), acidified to pH = 6 with 1 N HC1, and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated in-vacuo. The residue was purified by CombiFlash eluting with 0-10% methanol in methylene chloride to give the product (1.762 g, 52% in yield). LCMS: (M-t-Bu+H)+ = 309.1.
	With sodium t-butanolate;palladium diacetate; johnphos; In 1,4-dioxane;Heating / reflux;	Step 2. 1-{4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-2-fluorophenyl}cyclopropane carboxylic acid A mixture of <strong>[872422-15-6]1-(4-bromo-2-fluorophenyl)cyclopropanecarboxylic acid</strong> (5.0 g, 0.019 mol), tert-butyl piperazine-1-carboxylate (4.3 g, 0.023 mol), sodium tert-butoxide (4.4 g, 0.046 mol), palladium acetate (100 mg, 0.0006 mol) and 2-(di-t-butylphosphino)biphenyl (200 mg, 0.0006 mol) was evacuated and then charged with nitrogen. To the mixture was added 1,4-dioxane (60 mL, 0.8 mol) and the resulting mixture was refluxed overnight. The reaction mixture was poured into cold saturated. NH4Cl and then extracted with ethyl acetate and the combined extracts were washed with brine, dried, and concentrated. The product was purified by CombiFlash using 6% methanol in methylene chloride. LCMS: (M-t-Bu+H)=309.1.

References: [1]Patent: WO2006/20598,2006,A2 .Location in patent: Example 145.2.
[2]Patent: US2005/288338,2005,A1 .Location in patent: Page/Page column 34.

4
[ 872422-15-6 ]
C₁₀H₇ClFIO [ No CAS ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 314 - 318.

5
[ 872422-15-6 ]
[ 1268444-95-6 ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 314 - 318.

6
[ 872422-15-6 ]
[ 1268445-03-9 ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 314 - 318.

7
[ 872422-15-6 ]
[ 1268444-96-7 ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 314 - 318.

8
[ 872422-15-6 ]
[ 1252638-10-0 ]
[ 1268444-92-3 ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 314 - 318.

9
[ 872422-15-6 ]
[ 1252634-04-0 ]
[ 1268445-02-8 ]

References: [1]Angewandte Chemie - International Edition,2011,vol. 50,p. 314 - 318.

10
[ 872422-15-6 ]
[ 74-88-4 ]
1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarboxylic acid methyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.5%		In a 1 L round-bottomed flask, l-(4-bromo-2-fluorophenyl)cyclopropanecarboxylic acid (10.8 g, 41.7 mmol) was combined with DMF (180 mL) to give a yellow solution and to this magnetically stirred solution was added K2C03 (17.3 g, 125 mmol). To this was dripped in over 1 h, methyl iodide (47.3 g, 20.9 ml, 333 mmol) dissolved in DMF (20 ml). The yellow suspension was stirred at RT overnight. The reaction was concentrated, diluted with water (500 mL), and extracted with EtOAc (2 x 500 ml). The EtOAc layers were washed with water brine (250 ml), combined, dried over MgS04, filtered, and concentrated yielding l-(4- bromo-2-fluoro-phenyl)-cyclopropanecarboxylic acid methyl ester (10.3 g, 90.5%> yield) as light brown oil. LC/MS calcd. for CnHi0BrFO2 (m/e) 272/274, obsd. 273/275 (M+H, ES+).

References: [1]Patent: WO2013/189865,2013,A1 .Location in patent: Page/Page column 54.

11
[ 114897-91-5 ]
[ 872422-15-6 ]

References: [1]Patent: WO2013/189865,2013,A1 .
[2]Patent: EP2700643,2014,A1 .

12
[ 749928-88-9 ]
[ 872422-15-6 ]

Yield	Reaction Conditions	Operation in experiment
100%	With water; potassium hydroxide; In ethanol; for 7h;Reflux;	A solution of the compound (24.6 g, 102 mmol) obtained in Example 14-2) and potassium hydroxide (46 g, 820 mmol) in ethanol (200 ml) and water (40 ml) was heated to reflux for 7 h. The reaction mixture was cooled to room temperature, and then 5 N hydrochloric acid was added until the reaction mixture was rendered acidic. The deposited solid was collected by filtration, washed with water, and then dried to obtain the title compound (28.7 g, quant.) as a colorless solid. 1H-NMR (400 Hz, CDCl3) delta: 1.23 (2H, m), 1.72 (2H, m), 7.10-7.15 (1H, m), 7.22-7.25 (2H, m)
10.87 g	With water; lithium hydroxide; at 100℃;	In a 1 L round-bottomed flask, l-(4-bromo-2-fluorophenyl)cyclopropanecarbonitrile (1 1.2 g, 46.7 mmol) and LiOH (58 g, 1.38 mol) were combined with water (230 mL) to give a yellow suspension. The mixture was heated in an oil bath at 100 C overnight. The mixture was diluted to 1 L with water and ice and extracted with ethyl ether (3 x 300 mL). There was some white insoluble material between phases that was not included in aqueous layer. The aqueous layer was acidified with concentrated HC1 (ca. 1 10 mL) slowly with addition of ice. A very fine precipitate formed and the milky solution was not filtered but extracted with DCM (4 x 250 ml). The organic layers were combined, dried over MgS04, filtered, and concentrated yielding l-(4-bromo-2-fluorophenyl)cyclopropanecarboxylic acid (10.87 g, 89.9% yield) as a yellow solid. LC/MS calcd. for Ci0H8BrFO2 (m/e) 258/260, obsd. 259/261 (M+H, ES+).

References: [1]Patent: EP2700643,2014,A1 .Location in patent: Paragraph 0190.
[2]Patent: WO2013/189865,2013,A1 .Location in patent: Page/Page column 54.

13
[ 872422-15-6 ]
1-[2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid methyl ester [ No CAS ]

References: [1]Patent: WO2013/189865,2013,A1 .

14
[ 872422-15-6 ]
1-{3-fluoro-4'-[4-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-[1,2,3]triazol-1-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid methyl ester [ No CAS ]

References: [1]Patent: WO2013/189865,2013,A1 .

15
[ 872422-15-6 ]
1-{3-fluoro-4'-[4-methyl-5-((R)-1-phenyl-ethoxycarbonylamino)-[1,2,3]triazol-1-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid [ No CAS ]

References: [1]Patent: WO2013/189865,2013,A1 .

16
[ 76283-09-5 ]
[ 872422-15-6 ]