[ CAS No. 2991-28-8 ] {[proInfo.proName]}

Name: 2991-28-8|2,5-Difluorobenzoic acid|98%
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SKU: A318013
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3d Animation Molecule Structure of 2991-28-8

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Quality Control of [ 2991-28-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 2991-28-8 ]

Product Details of [ 2991-28-8 ]

CAS No. :	2991-28-8	MDL No. :	MFCD00002410
Formula :	C₇H₄F₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	LBQMIAVIGLLBGW-UHFFFAOYSA-N
M.W :	158.10	Pubchem ID :	76339
Synonyms :

Calculated chemistry of [ 2991-28-8 ]

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 :	37.3 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	No
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.79 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.22
Log Po/w (XLOGP3) :	2.07
Log Po/w (WLOGP) :	2.5
Log Po/w (MLOGP) :	2.47
Log Po/w (SILICOS-IT) :	2.06
Consensus Log Po/w :	2.06

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.56

Water Solubility

Log S (ESOL) :	-2.46
Solubility :	0.546 mg/ml ; 0.00345 mol/l
Class :	Soluble
Log S (Ali) :	-2.48
Solubility :	0.52 mg/ml ; 0.00329 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-2.32
Solubility :	0.764 mg/ml ; 0.00483 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.15

Safety of [ 2991-28-8 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

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.

Upstream synthesis route of [ 2991-28-8 ]
Downstream synthetic route of [ 2991-28-8 ]

[ 2991-28-8 ] Synthesis Path-Upstream 1~12

1
[ 2367-82-0 ]
[ 2991-28-8 ]

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

2
[ 367-23-7 ]
[ 2991-28-8 ]

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

3
[ 2358-29-4 ]
[ 455-38-9 ]
[ 65-85-0 ]
[ 2991-28-8 ]

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

4
[ 399-94-0 ]
[ 124-38-9 ]
[ 2991-28-8 ]

Reference： [1] Journal of Organic Chemistry, 1990, vol. 55, # 2, p. 773 - 775

5
[ 124-38-9 ]
[ 540-36-3 ]
[ 2991-28-8 ]

Reference： [1] Journal of Organic Chemistry, 1987, vol. 52, # 5, p. 713 - 719

6
[ 32890-92-9 ]
[ 2991-28-8 ]

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

7
[ 1979-36-8 ]
[ 2991-28-8 ]

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

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

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

9
[ 64-17-5 ]
[ 2991-28-8 ]
[ 708-25-8 ]

Reference： [1] Journal of the American Chemical Society, 2017, vol. 139, # 23, p. 7745 - 7748
[2] Asian Journal of Chemistry, 2015, vol. 27, # 10, p. 3605 - 3608
[3] Asian Journal of Chemistry, 2016, vol. 28, # 3, p. 639 - 643
[4] Oriental Journal of Chemistry, 2016, vol. 32, # 4, p. 2155 - 2161
[5] Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 2016, vol. 55B, # 2, p. 207 - 212
[6] Oriental Journal of Chemistry, 2017, vol. 33, # 6, p. 2930 - 2936

10
[ 2991-28-8 ]
[ 741721-51-7 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 20, p. 5392 - 5397

11
[ 2991-28-8 ]
[ 241479-74-3 ]

Reference： [1] Patent: CN105732605, 2016, A,

12
[ 870-46-2 ]
[ 2991-28-8 ]
[ 1079843-62-1 ]

Reference： [1] Tetrahedron Letters, 2010, vol. 51, # 48, 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

[ 2991-28-8 ] Synthesis Path-Downstream 1~88

1
[ 399-94-0 ]
[ 124-38-9 ]
[ 2991-28-8 ]

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

2
[ 124-38-9 ]
[ 540-36-3 ]
[ 2991-28-8 ]

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

3
[ 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.

Reference： [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

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

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

5
[ 2991-28-8 ]
[ 908336-77-6 ]

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

6
[ 2991-28-8 ]
[ 908336-70-9 ]

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

7
[ 2991-28-8 ]
8-chloro-2-fluoro-11-(4-methylpiperazin-1-yl)-dibenzo[b,f][1,4]oxazepine [ No CAS ]

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

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

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

9
[ 2991-28-8 ]
3-[4-(4-acetyl-phenyl)-piperazin-1-ylmethyl]-6-(2,5-difluoro-benzoyl)-3H-benzooxazol-2-one [ No CAS ]

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

10
[ 2991-28-8 ]
6-(2,5-difluoro-benzoyl)-3-[4-(4-trifluoromethyl-phenyl)-piperazin-1-ylmethyl]-3H-benzooxazol-2-one [ No CAS ]

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

11
[ 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 ]

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

12
[ 2991-28-8 ]
6-(2,5-difluoro-benzoyl)-3-(2-oxo-2-phenyl-ethyl)-3H-benzooxazol-2-one [ No CAS ]

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

13
[ 2991-28-8 ]
6-(2,5-difluoro-benzoyl)-3-(2-oxo-2-p-tolyl-ethyl)-3H-benzooxazol-2-one [ No CAS ]

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

14
[ 2991-28-8 ]
3-[2-(4-bromo-phenyl)-2-oxo-ethyl]-6-(2,5-difluoro-benzoyl)-3H-benzooxazol-2-one [ No CAS ]

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

15
[ 2991-28-8 ]
3-[2-(4-chloro-phenyl)-2-oxo-ethyl]-6-(2,5-difluoro-benzoyl)-3H-benzooxazol-2-one [ No CAS ]

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

16
[ 540-36-3 ]
[ 2991-28-8 ]

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

17
[ 2367-82-0 ]
[ 2991-28-8 ]

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

18
[ 367-23-7 ]
[ 2991-28-8 ]

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

19
[ 32890-92-9 ]
[ 2991-28-8 ]

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

20
[ 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.).

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

21
[ 2991-28-8 ]
2-[(2,5-Difluoro-phenyl)-hydroxy-methyl]-amino}-2-methyl-propan-1-ol [ No CAS ]

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

22
[ 2991-28-8 ]
[ 106588-52-7 ]

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

23
[ 2991-28-8 ]
[ 111608-80-1 ]

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

24
[ 2991-28-8 ]
4,7-Difluoro-1-hydroxy-3-oxo-1,3-dihydro-isobenzofuran-1-carbonitrile [ No CAS ]

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

25
[ 2991-28-8 ]
2-(4,4-Dimethyl-4,5-dihydro-oxazol-2-yl)-3,6-difluoro-N,N-dimethyl-benzamide [ No CAS ]

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

26
[ 2991-28-8 ]
(S)-1-(2,5-Difluoro-benzoyl)-pyrrolidine-2-carboxylic acid [ No CAS ]

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

27
[ 2991-28-8 ]
[ 79787-20-5 ]

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

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

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

29
[ 2991-28-8 ]
[ 129589-74-8 ]

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

30
[ 2991-28-8 ]
[ 129589-72-6 ]

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

31
[ 2991-28-8 ]
[ 129589-73-7 ]

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

32
[ 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).

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

33
[ 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).

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

34
(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

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

35
[ 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.

Reference： [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

36
[ 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]+.

Reference： [1]Patent: US2002/37907,2002,A1

37
[ 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)

Reference： [1]Patent: US6384033,2002,B1

38
(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>.

Reference： [1]Patent: US2002/128262,2002,A1

39
[ 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.

Reference： [1]Patent: US5998470,1999,A

40
[ 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.

Reference： [1]Patent: US5272163,1993,A

41
2,5-difluoro-α,α-dichloroacetophenone [ No CAS ]
sodium disulfite [ No CAS ]
[ 2991-28-8 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In sodium hypobromide; water;	EXAMPLE 18 2,5-Difluorobenzoic acid 96 g of 2,5-difluoro-alpha,alpha-dichloroacetophenone from Example 17 are added dropwise at 30° C. and with stirring in the course of about 11/4 h to 1258 g of sodium hypobromite solution (9.5percent strength). The mixture is subsequently stirred at 30° C. for 45 min and then at 50° C. for 3 h. After diluting with 250 ml of water, the mixture is brought to pH 6 using 75 ml of hydrochloric acid (32percent) with the addition of sodium disulphite and the organic phase is separated off. It is then brought to pH 1 using 50 ml of hydrochloric acid (32percent) with the addition of sodium disulphite. 63.6 g of 2,5-difluorobenzoic acid are obtained, which corresponds to 80.5percent of theory, relative to 0.5 mol of 1,4-difluorobenzene employed in Example 17.

Reference： [1]Patent: US5093529,1992,A

42
C₇H₃F₂O₂^(1-)*C₂₅H₃₀N₃⁽¹⁺⁾ [ No CAS ]
[ 467-63-0 ]
[ 2991-28-8 ]

Reference： [1]Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical and Analytical,2008,vol. 47,p. 369 - 373

43
[ 467-63-0 ]
[ 2991-28-8 ]
C₇H₃F₂O₂^(1-)*C₂₅H₃₀N₃⁽¹⁺⁾ [ No CAS ]

Reference： [1]Indian Journal of Chemistry, Section A: Inorganic, Physical, Theoretical and Analytical,2008,vol. 47,p. 369 - 373

44
[ 54-96-6 ]
[ 2991-28-8 ]
[ 1275249-07-4 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5111 - 5114

45
[ 110-91-8 ]
[ 2991-28-8 ]
[ 948794-61-4 ]

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 4579 - 4581

46
[ 124-40-3 ]
[ 2991-28-8 ]
[ 1046468-37-4 ]

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 4579 - 4581

47
[ 62-53-3 ]
[ 2991-28-8 ]
[ 923228-82-4 ]

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 4579 - 4581

48
[ 100-46-9 ]
[ 2991-28-8 ]
[ 948671-28-1 ]

Reference： [1]Tetrahedron Letters,2008,vol. 49,p. 4579 - 4581

49
[ 56-36-0 ]
[ 2991-28-8 ]
tri-n-butyltin 2,5-difluorobenzoate [ No CAS ]

Reference： [1]Organometallics,1994,vol. 13,p. 2849 - 2854

50
[ 888720-37-4 ]
[ 2991-28-8 ]
[ 888717-41-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 1945 - 1951

51
[ 1130849-59-0 ]
[ 2991-28-8 ]
[ 1130849-36-3 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 654 - 657

52
[ 1130849-60-3 ]
[ 2991-28-8 ]
[ 1130849-30-7 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 654 - 657

53
[ 104799-67-9 ]
[ 2991-28-8 ]
[ 313676-69-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 654 - 657

54
[ 104800-02-4 ]
[ 2991-28-8 ]
[ 1130849-05-6 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2009,vol. 19,p. 654 - 657

55
[ 13194-68-8 ]
[ 2991-28-8 ]
5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 6501 - 6504

56
[ 1187890-09-0 ]
[ 2991-28-8 ]
[ 1187889-55-9 ]

Yield	Reaction Conditions	Operation in experiment
37%	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 10 - 20℃;	Example 6 Synthesis of N-Biphenyl-4-yl-3-[4-(2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> (34 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide.hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water. The resulting precipitate was filtered, then purified by column chromatography using silica gel 60-120 mesh (70percent ethyl acetate in hexane) to 36 mg (37percent) of N-Biphenyl-4-yl-3-[4-(2,5-difluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 464.17 (M+1)+, 97.6percent, 1H NMR: (CDCl3): delta 9.6 (d, 1H), 7.6 (m, 6H), 7.42 (t, 2H), 7.34 (t, 1H), 7.12 (m, 3H), 3.85 (d, 3H), 3.7 (m, 3H), 3.55 (d, 2H), 3.4 (m, 2H).

Reference： [1]Patent: US2009/239848,2009,A1 .Location in patent: Page/Page column 15; 16

57
[ 1229293-88-2 ]
[ 2991-28-8 ]
C₃₁H₃₉F₂N₃O₇ [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 4545 - 4549

58
[ 67-56-1 ]
[ 2991-28-8 ]
methyl 2,5-difluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90.7%	With thionyl chloride;Reflux;	Difluorobenzoic acid (31.6 g, 0.2 mol) and thionyl chloride (35.7 g, 0.3 mol) were dissolved in 500 mL of methanol,The reaction was heated to reflux until the end of the reaction. After cooling, ice water was added, extracted with ethyl acetate, and the organic phase was dried and concentrated to give 31.2 g of product,Yield 90.7percent.
	With thionyl chloride; at 60℃; for 3h;Cooling with ice;	Example 17: Synthesis of 4-(2-carboxy-4-fluoro-phenyl)-piperazine-l-carboxylic acid tert-butyl ester 0C, 48 h To a stirred solution of <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> (20 g, 126 mmol) in MeOH (250 rnL) is added thionyl chloride (22.5g, 190 mmol) dropwise at ice-cold conditions. After complete addition the reaction mixture is heated at 60 0C for 3 h. The reaction mixture is concentrated and the residue neutralized with aqueous Na2CO3 solution. It is extracted with CH2Cl2 (3 x 100 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to afford the desired <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> methyl ester as a thick liquid (22 g)-

Reference： [1]Patent: CN105732605,2016,A .Location in patent: Paragraph 0067; 0068; 0069
[2]Letters in drug design and discovery,2013,vol. 10,p. 620 - 624
[3]Patent: WO2010/126851,2010,A1 .Location in patent: Page/Page column 114-115

59
[ 2991-28-8 ]
[ 265644-03-9 ]

Yield	Reaction Conditions	Operation in experiment
56%		To a solution of 2,5- difluorobenzoic acid (5.0 g, 31.6 mmol) in CH2Cl2 (60 mL) was added SOCl2 (23 mL) slowly at rt. The mixture was refiuxed for 3h, allowed to cool and concentrated in vacuo. The residue was treated with toluene and concentrated in vacuo. A solution of the crude acid chloride in CH2Cl2 (100 mL) was treated with anhydrous hydrazine (5.0 g) and heated at reflux for 4h. Once at rt, the reaction was washed with brine, dried over Na2SO4, filtered and evaporated. The resulting solid was recrystallized from MeOH (20 mL). The colorless crystals were collected by filtration and dried to give 1.99 g (56percent yield) of the hydrazide. 1H NMR (DMSO-dbeta) delta 4.52 (2H, s), 7.29- 7.33 (3H, m), 9.53 (IH, s). MS m/e 173 (M + if); Calculated MW: 172 for C7H6F2N2O.

Reference： [1]Patent: WO2010/104843,2010,A2 .Location in patent: Page/Page column 18
[2]Asian Journal of Chemistry,2015,vol. 27,p. 3605 - 3608
[3]Asian Journal of Chemistry,2016,vol. 28,p. 639 - 643
[4]Oriental Journal of Chemistry,2016,vol. 32,p. 2155 - 2161
[5]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,2016,vol. 55B,p. 207 - 212
[6]Oriental Journal of Chemistry,2017,vol. 33,p. 2930 - 2936

60
[ 1258008-63-7 ]
[ 2991-28-8 ]
[ 1258009-49-2 ]

Yield	Reaction Conditions	Operation in experiment
		Example 57: 3-(1 -cvclohexyl-5-phenyl-i H-pyrazol-4-yl)-5-(2,5-difluorophenyl)-1 ,2,4- oxadiazole; FTo a solution of <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> (Fluorochem; 48 mg; 0.3 mmol) in anhydrous MeCN (2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (80.5 mg; 0.42 mmol) followed by Intermediate 9 (102 mg; 0.36 mmol) in a Microwave vial and the mixture stirred at RT for 18 h. Anhydrous pyridine (2 mL) was added and the reaction vessel was sealed and heated at 150 0C for 45 min in the microwave. This reaction was performed twice, and the reaction mixtures were combined for workup. The solvents were removed in vacuo and H2O (10 mL) and DCM (10 mL) were added. The mixture was passed through a hydrophobic frit and the solvent removed in vacuo. The residue was triturated with isopropanol and dried to give Example 57 as a white solid. 1H NMR: (CDCI3, 400MHz) delta 8.17 (1 H, s), 7.75-7.69 (1 H, m), 7.54-7.51 (3H, m), 7.45-7.41 (2H, m), 7.27-7.14 (2H, m), 4.02- 3.92 (1 H, m), 2.12-1.98 (2H, m), 1.96-1.79 (4H, m), 1.71-1.61 (1 H, m), 1.32-1.14 (3H, m). LC/MS: 407 (M+H)+. HPLC (Method F) Rt 4.63 min (Purity: 97.6percent).

Reference： [1]Patent: WO2010/142628,2010,A1 .Location in patent: Page/Page column 119-120

61
[ 2991-28-8 ]
[ 1154278-08-6 ]

Reference： [1]Patent: WO2011/25951,2011,A1
[2]Patent: WO2009/111277,2009,A1
[3]Patent: WO2009/111280,2009,A1
[4]Patent: WO2009/111279,2009,A1

62
[ 280110-63-6 ]
[ 2991-28-8 ]
[ 1205637-32-6 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation Example 27To a solution of <strong>[2991-28-8]2,5-difluorobenzoic acid</strong> (1.95 g) in THF (40 mL) were added oxalyl chloride (1.5 mL) and a catalytic amount of DMF, followed by stirring at room temperature for 1 hour.The reaction liquid was concentrated under reduced pressure, and to the residue was added THF (40 mL).Under ice-cooling, tert-butyl 4-[amino(hydroxyimino)methyl]piperidine-1-carboxylate (2.5 g) and triethylamine (3.0 mL) were added thereto, followed by stirring at room temperature for 2 hours.To the reaction liquid were added ethyl acetate and water, and the organic phase was separated.The organic phase was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.To a solution of the residue in THF (20 mL) was added a 1 M tetrabutylammonium fluoride/THF solution (10.3 mL), followed by stirring at 50°C for 30 minutes.The reaction liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform).To the purified product was added 4 M hydrogen chloride/dioxane (40 mL), followed by stirring at room temperature for 2 hours.The reaction liquid was concentrated under reduced pressure, then to the residue was added THF, and the resulting solid was collected by filtration.The solid was washed with THF and ethyl acetate in this order, and dried under reduced pressure to obtain 4-[5-(2,5-difluorophenyl)-1,2,4-oxadiazol-3-yl]piperidine hydrochloride (2.58 g).

Reference： [1]Patent: EP2308869,2011,A1 .Location in patent: Page/Page column 17-18

63
[ 1094435-24-1 ]
[ 2991-28-8 ]
[ 1394137-57-5 ]

Reference： [1]Journal of the Brazilian Chemical Society,2012,vol. 23,p. 854 - 860

64
[ 1038304-53-8 ]
[ 2991-28-8 ]
[ 1394137-59-7 ]

Reference： [1]Journal of the Brazilian Chemical Society,2012,vol. 23,p. 854 - 860

65
[ 93073-14-4 ]
[ 2991-28-8 ]
[ 1394137-60-0 ]

Reference： [1]Journal of the Brazilian Chemical Society,2012,vol. 23,p. 854 - 860

66
[ 1038379-52-0 ]
[ 2991-28-8 ]
[ 1394137-55-3 ]

Reference： [1]Journal of the Brazilian Chemical Society,2012,vol. 23,p. 854 - 860

67
[ 1394137-54-2 ]
[ 2991-28-8 ]
[ 1394137-61-1 ]

Reference： [1]Journal of the Brazilian Chemical Society,2012,vol. 23,p. 854 - 860

68
[ 2991-28-8 ]
[ 800406-59-1 ]