2991-28-8|2,5-Difluorobenzoic acid| Ambeed

CAS No. :	2991-28-8
Formula :	C₇H₄F₂O₂
M.W :	158.10
SMILES Code :	O=C(O)C1=CC(F)=CC=C1F
MDL No. :	MFCD00002410
InChI Key :	LBQMIAVIGLLBGW-UHFFFAOYSA-N
Pubchem ID :	76339

Safety of [ 2991-28-8 ]

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

Computational Chemistry of [ 2991-28-8 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	33.32
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.	1.22
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	2.07
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.5
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.	2.47
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	2.06
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.06

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.46
Solubility	0.546 mg/ml ; 0.00345 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.	-2.48
Solubility	0.52 mg/ml ; 0.00329 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	-2.32
Solubility	0.764 mg/ml ; 0.00483 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	No
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.	-5.79 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.	0.56

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<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)	1.15

Application In Synthesis of [ 2991-28-8 ]

* 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 [ 2991-28-8 ]

[ 2991-28-8 ] Synthesis Path-Downstream 1~54

1
[ 16867-03-1 ]
[ 2991-28-8 ]
[ 52333-66-1 ]

References: [1]Journal of Medicinal Chemistry,1978,vol. 21,p. 1158 - 1162.

2
[ 399-94-0 ]
[ 124-38-9 ]
[ 2991-28-8 ]

References: [1]Journal of Organic Chemistry,1990,vol. 55,p. 773 - 775.

3
[ 124-38-9 ]
[ 540-36-3 ]
[ 2991-28-8 ]

References: [1]Journal of Organic Chemistry,1987,vol. 52,p. 713 - 719.

4
[ 75-65-0 ]
[ 2991-28-8 ]
[ 129589-71-5 ]

References: [1]Synthesis,1990,p. 295 - 299.

5
[ 2991-28-8 ]
[ 35730-09-7 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; for 3h;Reflux;	General procedure: A mixture of <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> (1.58 g, 10 mmol) and thionyl chloride (7 mL) was refluxed for 3 h. The excess thionyl chloride was removed by distillation under reduced pressure to give an oil residue
	With thionyl chloride; In dichloromethane; toluene; for 5h;Reflux;	General procedure: Benzoic acid (1 mmol) was reacted with a solution of thionyl chloride in CH2Cl2 (1 M, 6 mL) in refluxing toluene (3 mL) for 5 h. After cooling to room temperature, the solvent was evaporated under reduced pressure. The obtained benzoyl chloride was dissolved in dry CH2Cl2 (5 mL), and the resultant solution was cooled to 0 C. To this solution, TEA (4.4 mmol, 0.444 g), 1-(9H-fluoren-9-yl)-piperazine (3) (1.1 mmol, 0.275 g) or 1-(diphenylmethyl)-piperazine (9) (1.1 mmol, 0.277 g) in dry CH2Cl2 (5 mL) was added dropwise. After the addition, the reaction mixture was stirred for 16 h at room temperature. Subsequently, the solution was washed with aqueous HCl (10%, v/v, 3 x 15 mL), a saturated NaHCO3 solution (1 x 15 mL), and aqueous NaCl (5%, w/v, 1 x 15 mL). Finally, the organic layer was dried over anhydrous magnesium sulfate. The mixture was filtered, and the solvent was evaporated under reduce pressure. When necessary, the products were purified using silica gel chromatography with CH2Cl2/methanol (20:5, v/v) as the mobile phase. This protocol was used for the synthesis of 9H-fluoren-9-yl-piperazines 2, 4a, 4c-e, 4h-i and 1-(diphenylmethyl)-piperazines 10a-b and 10d-e. The crystal used for the data collection was obtained by recrystallization of compound 4d from hexane followed by slow evaporation at room temperature.
	With thionyl chloride;Reflux;	General procedure: The corresponding acid compound 5 (10 mmol) was completely dissolved in 30 mL of SOCl2. The reaction was stirred at reflux temperature for 12 h. The mixture was evaporated under vacuum, the residue was dissolved in 10 mL of dry DCM and used in next step without purification.

References: [1]Journal of Medicinal Chemistry,1982,vol. 25,p. 84 - 86.
[2]Journal of Organic Chemistry,1987,vol. 52,p. 713 - 719.
[3]Journal of Medicinal Chemistry,2006,vol. 49,p. 4512 - 4516.
[4]Bioorganic and Medicinal Chemistry,2014,vol. 22,p. 3670 - 3683.
[5]European Journal of Medicinal Chemistry,2014,vol. 90,p. 436 - 447.
[6]Natural Product Research,2019,vol. 33,p. 2453 - 2460.

6
[ 162459-94-1 ]
[ 2991-28-8 ]
[ 1053624-65-9 ]

References: [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 3715 - 3726.

7
[ 59-49-4 ]
[ 2991-28-8 ]
[ 230628-46-3 ]

References: [1]Il Farmaco,1999,vol. 54,p. 112 - 115.
[2]Il Farmaco,2002,vol. 57,p. 535 - 538.
[3]Arzneimittel-Forschung/Drug Research,2003,vol. 53,p. 114 - 120.

8
[ 95-25-0 ]
[ 2991-28-8 ]
[ 230628-47-4 ]

References: [1]Il Farmaco,1999,vol. 54,p. 112 - 115.

9
[ 2358-29-4 ]
[ 455-38-9 ]
[ 65-85-0 ]
[ 2991-28-8 ]

References: [1]Journal of Physical Chemistry A,2000,vol. 104,p. 352 - 361.

10
[ 1979-36-8 ]
[ 2991-28-8 ]

References: [1]Journal of Physical Chemistry A,2000,vol. 104,p. 352 - 361.

11
[ 2991-28-8 ]
[ 455-38-9 ]
[ 65-85-0 ]

References: [1]Journal of Physical Chemistry A,2000,vol. 104,p. 352 - 361.

14
[ 123066-64-8 ]
[ 2991-28-8 ]
N-[4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-2,5-difluorobenzamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2000,vol. 43,p. 2975 - 2981.

15
[ 2991-28-8 ]
N^α-Fmoc-N^im-tert-butyloxycarbonyl-L-tryptophan 4-hydroxymethylphenoxy resin [ No CAS ]
2-(2,5-difluoro-benzoylamino)-3-(1H-indol-3-yl)-propionic acid [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2004,vol. 14,p. 2055 - 2059.

16
[ 2991-28-8 ]
[ 741721-49-3 ]

Yield	Reaction Conditions	Operation in experiment
31.3%	With sulfuric acid; nitric acid; at 0 - 20℃; for 1h;	[00205] Step A: <strong>[2991-28-8]2,5-Difluorobenzoic acid</strong> (2.01 g, 9.90 mmol, 31.3percent yield) was dissolved in concentrated sulfuric acid (25 mL) and cooled to 00C. Nitric Acid (1.46 mL, 34.8 mmol) was added, and the reaction mixture was stirred at room temperature for one hour. The solution was extracted with DCM (3 X), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (1:1 hexanes:lpercentHCOOH/EtOAc) giving 2,5-difluoro-3-nitrobenzoic acid (2.01 g, 31.3percent) as a solid.
31.3%	With sulfuric acid; nitric acid; In water; at 0 - 20℃;	<strong>[2991-28-8]2,5-Difluorobenzoic acid</strong> (2.01 g, 9.90 mmol, 31.3percent yield) was dissolved in concentrated sulfuric acid (25 mL) and cooled to 0°C. Nitric Acid (1.46 mL, 34.8 mmol) was added, and the reaction mixture was stirred at room temperature for one hour. The solution was extracted with DCM (3 X), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (1:1 hexanes:lpercentHCOOH/EtOAc) giving 2,5-difluoro-3-nitrobenzoic acid (2.01 g, 31.3percent) as a solid.
31.3%	With sulfuric acid; nitric acid; at 0 - 20℃;	Step A: <strong>[2991-28-8]2,5-Difluorobenzoic acid</strong> (2.01 g, 9.90 mmol, 31.3percent yield) was dissolved in concentrated sulfuric acid (25 mL) and cooled to 0°C. Nitric Acid (1.46 mL, 34.8 mmol) was added, and the reaction mixture was stirred at room temperature for one hour. The solution was extracted with DCM (3 X), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (1:1 hexanes:lpercentHCOOH/EtOAc) giving 2,5-difluoro-3-nitrobenzoic acid (2.01 g, 31.3percent) as a solid.

31.3%

With sulfuric acid; nitric acid; at 0 - 20℃;

[2991-28-8]2,5-Difluorobenzoic acid (2.01 g, 9.90 mmol, 31.3percent yield) was dissolved in concentrated sulfuric acid (25 mL) and cooled to 0°C. Nitric Acid (1.46 mL, 34.8 mmol) was added, and the reaction mixture was stirred at room temperature for one hour. The solution was extracted with DCM (3 X), and the combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (1:1 hexanes:lpercentHCOOH/EtOAc) giving 2,5-difluoro-3-nitrobenzoic acid (2.01 g, 31.3percent) as a solid.

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 5392 - 5397.
[2]Patent: WO2011/25951,2011,A1 .Location in patent: Page/Page column 40.
[3]Patent: WO2009/111277,2009,A1 .Location in patent: Page/Page column 48.
[4]Patent: WO2009/111280,2009,A1 .Location in patent: Page/Page column 48.
[5]Patent: WO2009/111279,2009,A1 .Location in patent: Page/Page column 75.

17
[ 2991-28-8 ]
[ 741721-51-7 ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2006,vol. 16,p. 5392 - 5397.

18
[ 2991-28-8 ]
8,11-dichloro-2-fluoro-dibenzo[b,f][1,4]oxazepine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 4512 - 4516.

19
[ 2991-28-8 ]
[ 908336-77-6 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 4512 - 4516.

20
[ 2991-28-8 ]
[ 908336-70-9 ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 4512 - 4516.

21
[ 2991-28-8 ]
8-chloro-2-fluoro-11-(4-methylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 4512 - 4516.

22
[ 2991-28-8 ]
6-(2,5-difluoro-benzoyl)-3-(4-pyridin-2-yl-piperazin-1-ylmethyl)-3H-benzooxazol-2-one [ No CAS ]

References: [1]Arzneimittel-Forschung/Drug Research,2003,vol. 53,p. 114 - 120.

23
[ 2991-28-8 ]
3-[4-(4-acetyl-phenyl)-piperazin-1-ylmethyl]-6-(2,5-difluoro-benzoyl)-3H-benzooxazol-2-one [ No CAS ]

References: [1]Arzneimittel-Forschung/Drug Research,2003,vol. 53,p. 114 - 120.

24
[ 2991-28-8 ]
6-(2,5-difluoro-benzoyl)-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-3H-benzooxazol-2-one [ No CAS ]

References: [1]Arzneimittel-Forschung/Drug Research,2003,vol. 53,p. 114 - 120.

25
[ 2991-28-8 ]
3-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-ylmethyl)-6-(2,5-difluoro-benzoyl)-3H-benzooxazol-2-one [ No CAS ]

References: [1]Arzneimittel-Forschung/Drug Research,2003,vol. 53,p. 114 - 120.

26
[ 2991-28-8 ]
6-(2,5-difluoro-benzoyl)-3-(2-oxo-2-phenyl-ethyl)-3H-benzooxazol-2-one [ No CAS ]

References: [1]Il Farmaco,2002,vol. 57,p. 535 - 538.

27
[ 2991-28-8 ]
6-(2,5-difluoro-benzoyl)-3-(2-oxo-2-p-tolyl-ethyl)-3H-benzooxazol-2-one [ No CAS ]

References: [1]Il Farmaco,2002,vol. 57,p. 535 - 538.

28
[ 2991-28-8 ]
3-[2-(4-bromo-phenyl)-2-oxo-ethyl]-6-(2,5-difluoro-benzoyl)-3H-benzooxazol-2-one [ No CAS ]

References: [1]Il Farmaco,2002,vol. 57,p. 535 - 538.

29
[ 2991-28-8 ]
3-[2-(4-chloro-phenyl)-2-oxo-ethyl]-6-(2,5-difluoro-benzoyl)-3H-benzooxazol-2-one [ No CAS ]

References: [1]Il Farmaco,2002,vol. 57,p. 535 - 538.

30
[ 540-36-3 ]
[ 2991-28-8 ]

References: [1]Journal of Physical Chemistry A,2000,vol. 104,p. 352 - 361.

31
[ 2367-82-0 ]
[ 2991-28-8 ]

References: [1]Journal of Physical Chemistry A,2000,vol. 104,p. 352 - 361.
[2]Journal of Physical Chemistry A,2000,vol. 104,p. 352 - 361.

32
[ 367-23-7 ]
[ 2991-28-8 ]

References: [1]Journal of Physical Chemistry A,2000,vol. 104,p. 352 - 361.

33
[ 32890-92-9 ]
[ 2991-28-8 ]

References: [1]Journal of Physical Chemistry A,2000,vol. 104,p. 352 - 361.
[2]Journal of Physical Chemistry A,2000,vol. 104,p. 352 - 361.

34
[ 2991-28-8 ]
[ 111608-81-2 ]

Yield	Reaction Conditions	Operation in experiment
93%	With sec-BuLi; In tetrahydrofuran; hydrogenchloride; N,N-dimethyl-formamide;	a. 4,7-Difluoro-3-hydroxy-1(3H)-isobenzofuranone. To a -78° C. solution of the oxazoline derivative (7.95 g, 37.7 mmol), prepared from <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> in the usual manner, in THF (50 mL) was added over 15 min sec-BuLi (29 mL of 1.3 M solution). After 30 min, DMF (6.0 mL) was added, and the reaction was stirred at -78° C. for 2 hr. The reaction was then quenched with concentrated HCl (5 mL). The solvents were removed in vacuo, and the residue was taken up in 5 N HCl (5 mL) and heated on the steam bath overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc (3*200 mL). Standard workup gave a light brown solid (6.5 g, 93percent, mp 125°-128° C.).
93%	With sec-BuLi; In tetrahydrofuran; hydrogenchloride; N,N-dimethyl-formamide;	a. 4,7-Difluoro-3-hydroxy-1(3H)-isobenzofuranone To a -78° C. solution of the oxazoline derivative (7.95 g, 37.7 mmol), prepared from <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> in the usual manner, in THF (50 mL) was added over 15 min sec-BuLi (29 mL of 1.3 M solution). After 30 min, DMF (6.0 mL) was added, and the reaction was stirred at -78° C. for 2 hr. The reaction was tnen quenched with concentrated HCl (5 mL). Tne solvents were removed in vacuo, and the residue was taken up in 5 N HCl (5 mL) and heated on the steam bath overnight. After cooling to room temperature, the reaction mixture was extracted with EtOAc (3*200 mL). Standard workup gave a light brown solid (6.5 g, 93percent, mp 125°-128° C.).

References: [1]Patent: US4663445,1987,A .
[2]Patent: US4697005,1987,A .
[3]Journal of Organic Chemistry,1987,vol. 52,p. 713 - 719.

35
[ 2991-28-8 ]
2-[(2,5-Difluoro-phenyl)-hydroxy-methyl]-amino}-2-methyl-propan-1-ol [ No CAS ]

References: [1]Journal of Organic Chemistry,1987,vol. 52,p. 713 - 719.

36
[ 2991-28-8 ]
[ 106588-52-7 ]

References: [1]Journal of Organic Chemistry,1987,vol. 52,p. 713 - 719.

37
[ 2991-28-8 ]
[ 111608-80-1 ]

References: [1]Journal of Organic Chemistry,1987,vol. 52,p. 713 - 719.

38
[ 2991-28-8 ]
4,7-Difluoro-1-hydroxy-3-oxo-1,3-dihydro-isobenzofuran-1-carbonitrile [ No CAS ]

References: [1]Journal of Organic Chemistry,1987,vol. 52,p. 713 - 719.

39
[ 2991-28-8 ]
2-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-3,6-difluoro-N,N-dimethyl-benzamide [ No CAS ]

References: [1]Journal of Organic Chemistry,1987,vol. 52,p. 713 - 719.

40
[ 2991-28-8 ]
(S)-1-(2,5-Difluoro-benzoyl)-pyrrolidine-2-carboxylic acid [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1982,vol. 25,p. 84 - 86.

41
[ 2991-28-8 ]
[ 79787-20-5 ]

References: [1]Journal of Medicinal Chemistry,1982,vol. 25,p. 84 - 86.

42
[ 2991-28-8 ]
[ 79787-15-8 ]

References: [1]Journal of Medicinal Chemistry,1982,vol. 25,p. 84 - 86.

43
[ 2991-28-8 ]
[ 129589-74-8 ]

References: [1]Synthesis,1990,p. 295 - 299.

44
[ 2991-28-8 ]
[ 129589-72-6 ]

References: [1]Synthesis,1990,p. 295 - 299.

45
[ 2991-28-8 ]
[ 129589-73-7 ]

References: [1]Synthesis,1990,p. 295 - 299.

46
[ 221164-29-0 ]
[ 2991-28-8 ]
C₂₄H₂₀F₂N₆O₇ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1H-NMR(CDCl3,delta):1.47(3H,t,J=7.3 Hz),1.53(3H,t,J=6.9 Hz), 4.55(2H,q,J=7.3 Hz),4.67(2H,q,J=6.9 Hz),5.26(2H,s), 6.63-6.69(1H,m),6.97-7.06(2H,m),7.26(1H,d,J=2.0 Hz), 7.71(1H,d,J=1.0 Hz),7.90-8.10(1H,br),8.16(1H,s),8.45(1H,s).

References: [1]Patent: US6348461,2002,B1 .Location in patent: Page column 127.

47
[ 2991-28-8 ]
[ 741721-49-3 ]
[ 741721-50-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; nitric acid; at 0℃; for 2h;	To a solution of 2, 5-difluoro-benzoic acid (3.66 g, 23 mmol) in concentrated sulfuric acid (10 mL) was added a mixture of 3 mL of nitric acid (90percent, fuming) and 3 mL of concentrated sulfuric acid dropwise at 0 °C. The reaction mixture was stirred at 0 C for 2 hours. The resulting mixture was then poured onto ice and extracted with ethyl acetate (3 X 30 mL). After removal of the solvent, the residue was purified by chromatography using 5percent of methanol in chloroform as eluent. A mixture of 2,5-difluoro-3-nitro-benzoic acid and 3,6- DIFLUORO-2-NITRO-BENZOIC acid was obtained. Yield 2.48 G. LH NMR (400 MHZ, CDC13) : 2, 5-difluoro-3-nitro-benzoic acid: 8 8.36 (ddd, 1H), 8.07 (ddd, 1H).

References: [1]Patent: WO2004/69832,2004,A2 .Location in patent: Page 134.

48
(RS) 3-(4-fluorobenzoyl)pyrrolidine hydrochloride [ No CAS ]
[ 2991-28-8 ]
[ 852290-07-4 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); for 16h;	To a solution of the appropriate acid component (0.5 mmol) in DMF (1 ml) was added sequentially a solution of HATU (209 mgs) in DMF (1 ml), PS-DIEA (273mgs of 3.66 mmol/g) and a sonicated solution of (RS) 3- (4-fluorobenzoyl) pyrrolidine hydrochloride (prepared according to J Med. Chem. , 13 (1), 1-6, (1970); 139 mgs, 0. 57mmol) and diisopropylethylamine (DIEA) (50.5 mgs, 0. 07ml, 0.5 mmol) in DMF (1-2 ml), and the reaction mixture was aged for approximately 16 hours. The products were purified by purification technique (a), (b) or (c) described below: a) The reaction mixture was poured onto an Isolute SCX-2 column (1 g, 0. 4mmol/g) aligned over an Isolute-NH2 column (1 g, 0. 6mmol/g) transferring with DCM (0. 5ml). The columns were then eluted under atmospheric pressure with DCM. The bulk of the solvent was removed using a Genevac HT4 and then if necessary purified using the Isco CombiFlash Optix-10 parallel flash chromatography Optics-10 system (12g silica column, Gradient of isohexane/EtOAc, Flow rate 30 ml/min). b) The bulk of the solvent was removed using a Genevac HT4 and then purified using the Isco CombiFlash Optix-10 parallel flash chromatography system Optics-10 system (12g silica column, Gradient of isohexane/EtOAc, Flow rate 30 ml/min). c) Preparative LC-MS. Conditions: Column: 19x50mm Xterra CIS 5Rm with guard Time (mins) Apercent Bpercent 0 95 5 1. 02 95 5 6. 50 0 100 6. 60 0 100 8*5 100 9 95 5 A: water containing 1percent ammonia B: MeCN far UV grade It will be appreciated that various orders of addition, and various purification methods, or combinations of methods, can be employed to prepare the compounds exemplified below, and their congeners

References: [1]Patent: WO2005/47250,2005,A1 .Location in patent: Page/Page column 34-35.

49
[ 870-46-2 ]
[ 2991-28-8 ]
[ 1079843-62-1 ]

Yield	Reaction Conditions	Operation in experiment
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 3h;	To a solution of 5.Og (31.6 mmol) of <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> (1-1) in 2OmL of 1: 1 THF/DMF was added 4.39g (33.2 mmol) of t-butylcarbazate, 6.67g (34.8 mmol) of EDCI, and 50 mg of DMAP. After stirring for 3h at room temperature, the reaction was dumped into ice water and extracted three times with ether. The combined organic phases were washed two times with 10percent citric acid, two times with saturated NaHCO3, once with water, once with brine, and then dried over MgSO4. Concentration by rotary evaporation provided the BOC-protected acyl hydrazine as a white solid. To a solution of 1.5g (5.5 mmol) of this material in 20 mL of CH2Cl2, cooled to 00C, was added 10 mL of trifluoroacetic acid, and the resultant mixture was allowed to stir for 2 h at that temperature. The volatiles were removed by rotary evaporation, the residue was partitioned between EtOAc and aqueous NaHCO3, the layers were separated, and the aqueous phase was extracted two more times with EtOAc. The combined organic phases were washed twice with saturated NaHCO3, brine, dried over Na2SO4, and concentrated to provide 663mg (3.85 mmol) of 2,5-difluorobenzohydrazide (1-2) as a white solid. This material was dissolved in 30 mL of EtOH, and then 1.5 mL of HOAc was added, followed by 390 muL (3.85 mmol) of benzaldehyde. After stirring for Ih at room temperature, the solvents were removed by rotary evaporation, and the residue was triturated with Et2O to provide the imine as a white powder. A portion of this imine (225mg, 0.86 mmol) was dissolved in 3 mL of acetic anhydride and heated at 125 0C for 2h After cooling to room temperature, the volatiles were removed by rotary evaporation, the residue was dissolve in EtOAc, washed twice with saturated NaHCO3, water, dried over Na2SO4, and concentrated. The residue was then purified by column chromatography with a gradient of EtOAc in hexanes to provide (1-3) as a white solid. IH NMR (500 MHz, CDC13): delta 7.6 -7.4 (m, 6H), 7.2 (m, 2H), 7.1 (s, IH), 2.4 (s, 3H) ppm. HRMS (ES) calc'd M + H for C16H12F2N2O2: 303.0940; found 303.0926.
	With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride;dmap; In tetrahydrofuran; N,N-dimethyl-formamide; for 16h;	Step B: Preparation of <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> hydrazide: To a solution of<strong>[2991-28-8]2,5-difluorobenzoic acid</strong> (3.5 g, 22 mmol) in THF/DMF (20 mL/20 mL) was added EDCI (4.7 g, 24 mmol), DMAP (50 mg) and NH2NHBoC (3.07 g, 23.2 mmol). After stirring for 16 hours, the reaction was quenched with water (30 mL) and diluted with EtOAc (30 mL). The organic layer was then washed with HCl (0.5 M, 20 mL), saturated NaHCO3 (20 mL), and brine (20 mL). The organic layer was then dried over Na2SO4, filtered and concentrated under reduced pressure to afford the crude Boc-protected product, which was then dissolved in DCM (60 mL) at 0 °C. TFA (50 mL) was added to the above DCM solution. After stirring for 2 hours, the reaction mixture was concentrated and the residue was dissolved in DCM (60 mL). The solution was washed with saturated NaHCO3 (40 mL) and dried over Na2SO4, filtered and concentrated under reduced pressure to afford the desired crude product.

References: [1]Tetrahedron Letters,2010,vol. 51,p. 6236 - 6239.
[2]Patent: WO2006/31348,2006,A2 .Location in patent: Page/Page column 28.
[3]Patent: WO2006/44825,2006,A2 .Location in patent: Page/Page column 55.

50
[ 75-31-0 ]
[ 2991-28-8 ]
2,5-Difluoro-N-isopropyl-benzamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Step A 2,5-Difluoro-N-isopropyl-benzamide The title compound was prepared from <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> (10 g, 63.2 mmol), carbonyidiimidazole (9.57 g, 61 mmol) and isopropyl amine (5.15 mL, 60.5 mmol) according to the procedure used for example 84 (Step A) to give near quantitative yield of the title compound. NMR (DMSO-d6, 400 MHz): delta 1.12-1.13 (d, 6H), 3.99-4.04 (m, 1H), 7.31-7.36 (m, 3H), 8.24-8.26 (broad s, 1H). MS (ESI+, m/z): 200 [M+H]+.

References: [1]Patent: US2002/37907,2002,A1 .

51
[ 2991-28-8 ]
[ 223444-58-4 ]

Yield	Reaction Conditions	Operation in experiment
91%		Example 25 N-t-Butyl-2,5-difluorobenzamide The title compound (0.3921 g; 91percent) was prepared by the same method as that described in Example 14, using <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> (0.3173 g, 2.01 mmol). 1H-NMR (270 MHz, CDCl3) 7.78-7.71 (m, 1H), 7.14-7.03 (m, 2H), 6.60 (br, 1H), 1.47 (s, 9H)

References: [1]Patent: US6384033,2002,B1 .

52
(E)-5-(3,4-difluorostyryl)-2,3-dihydro-1-methyl-1H-1,4-benzodiazepine dihydrochloride [ No CAS ]
[ 2991-28-8 ]
(7-fluoro-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In (1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester;	The starting material was prepared as follows: (7-fluoro-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester was prepared in an analogous fashion to (1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepin-5-ylidenemethyl)phosphonic acid diethyl ester, prepared in Example 1, by replacing 2-fluorobenzoic acid with <strong>[2991-28-8]2,5-difluorobenzoic acid</strong>.

References: [1]Patent: US2002/128262,2002,A1 .

53
[ 85-48-3 ]
[ 2991-28-8 ]
[ 190660-28-7 ]

Yield	Reaction Conditions	Operation in experiment
		EXAMPLE 265 Preparation of 1-N-(N-2,5-difluoro-benzoyl-leucinyl)-amino-3-N-(8-quinoline-sulfonyl)-amino-propan-2-one Following the procedure of Example 250(a)-(c), except substituting "<strong>[2991-28-8]2,5-difluoro-benzoic acid</strong>" for "4-pyridyl acetic acid" and "8-quinoline sulfonic acid" for "2-benzyloxy phenyl sulphonyl chloride" the title compound was prepared: MS(ES) M+H+ =535.

References: [1]Patent: US5998470,1999,A .

54
[ 2991-28-8 ]
[ 147696-81-9 ]

Yield	Reaction Conditions	Operation in experiment
21%	With hydrogenchloride; PPA; aniline; In water;	a. 4'-Amino-2,5-difluorobenzophenone To stirred 90° C. polyphosphoric acid (125 g) was added <strong>[2991-28-8]2,5-difluoro-benzoic acid</strong> (10.0 g, 6.32 mmol) and aniline (5.87 g 6.3 mmol) and the bath temperature raised to 180°-190° C. and held there for 1 hour. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 50 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 45 mL of 3N HCl added, the mixture poured into 650 mL of water and filtered through a pad of Celite. The filtrate was basified with 15percent sodium hydroxide and the mixture filtered through a pad of Celite. The Celite pad was washed well with methylene chloride, the methylene chloride dried (MgSO4), filtered and the solvent removed in vacuo. Purification by flash column chromatography (methylene chloride) followed by recrystallization twice from 50percent ethanol (80 mL) yielded the aniline as a yellow solid (3.08 g, 21percent); mp 101°-103° C. 1 H--NMR (300 MHz, CDCl3): 4.27 (s, 2H, NH2) 6.63-6.67 (m, 2H, aromatic) 7.09-7.19 (m, 3H, aromatic) 7.68-7.71 (m, 2H, aromatic). MS (CI, CH4): 234 (M+1). Analysis for C13 H9 F2 NO: Calculated: C, 66.95; H, 3.89; N, 6.01. Found: C, 66.86; H, 4.04; N, 5.95.

References: [1]Patent: US5272163,1993,A .

Historical Records

Technical Information

• Alkyl Halide Occurrence • Arndt-Eistert Homologation • Baeyer-Villiger Oxidation • Barbier Coupling Reaction • Baylis-Hillman Reaction • Bucherer-Bergs Reaction • Clemmensen Reduction • Corey-Bakshi-Shibata (CBS) Reduction • Corey-Chaykovsky Reaction • Fischer Indole Synthesis • Grignard Reaction • Henry Nitroaldol Reaction • Horner-Wadsworth-Emmons Reaction • Hunsdiecker-Borodin Reaction • Hydride Reductions • Lawesson's Reagent • Leuckart-Wallach Reaction • McMurry Coupling • Meerwein-Ponndorf-Verley Reduction • Passerini Reaction • Paternò-Büchi Reaction • Petasis Reaction • Peterson Olefination • Pictet-Spengler Tetrahydroisoquinoline Synthesis • Preparation of Aldehydes and Ketones • Preparation of Amines • Preparation of Carboxylic Acids • Prins Reaction • Reactions of Aldehydes and Ketones • Reactions of Amines • Reactions of Benzene and Substituted Benzenes • Reactions of Carboxylic Acids • Reformatsky Reaction • Robinson Annulation • Schlosser Modification of the Wittig Reaction • Schmidt Reaction • Specialized Acylation Reagents-Ketenes • Stobbe Condensation • Tebbe Olefination • Ugi Reaction • Wittig Reaction • Wolff-Kishner Reduction

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[ 2991-28-8 ]

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