[ CAS No. 4519-39-5 ] {[proInfo.proName]}

Name: 4519-39-5|2,3-Difluorobenzoic acid|97%
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SKU: A138736
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2D 3D

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Quality Control of [ 4519-39-5 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 4519-39-5 ]

SDS Specification

Alternatived Products of [ 4519-39-5 ]

Product Details of [ 4519-39-5 ]

CAS No. :	4519-39-5	MDL No. :	MFCD00010267
Formula :	C₇H₄F₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	JLZVIWSFUPLSOR-UHFFFAOYSA-N
M.W :	158.10	Pubchem ID :	370590
Synonyms :

Calculated chemistry of [ 4519-39-5 ]

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) :	-5.94 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.06
Log Po/w (XLOGP3) :	1.87
Log Po/w (WLOGP) :	2.5
Log Po/w (MLOGP) :	2.47
Log Po/w (SILICOS-IT) :	2.06
Consensus Log Po/w :	1.99

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.34
Solubility :	0.729 mg/ml ; 0.00461 mol/l
Class :	Soluble
Log S (Ali) :	-2.27
Solubility :	0.839 mg/ml ; 0.00531 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 :	1.18

Safety of [ 4519-39-5 ]

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 [ 4519-39-5 ]

* 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 [ 4519-39-5 ]
Downstream synthetic route of [ 4519-39-5 ]

[ 4519-39-5 ] Synthesis Path-Upstream 1~9

1
[ 2646-91-5 ]
[ 6418-38-8 ]
[ 4519-39-5 ]

Reference： [1] Advanced Synthesis and Catalysis, 2005, vol. 347, # 7-8, p. 1027 - 1034

2
[ 61079-72-9 ]
[ 455-38-9 ]
[ 455-86-7 ]
[ 4519-39-5 ]
[ 65-85-0 ]

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

3
[ 124-38-9 ]
[ 126163-64-2 ]
[ 4519-39-5 ]

Yield	Reaction Conditions	Operation in experiment
91%	at -65 - -60℃; for 6 h;	General procedure: Temperature control -65 ~ -60 ° C,Passing carbon dioxide into the reaction solution containing lithium 2,3-difluorobenzene,The molar ratio of carbon dioxide to metal substitution reagent is 1.5:1,The incubation time was 4 hours.Add water to hydrolyze,The mass ratio of the added water to the reaction liquid containing lithium 2,3-difluorobenzene is 1.5:1.The hydrolysis temperature is 15 to 20 °C.The organic solvent is then separated by heat distillation and concentrated and recovered.The temperature is controlled at 20 to 22 ° C and acidified with 10percent hydrochloric acid.The molar ratio of acid to metal-substituted reagent is 2:1.After the addition of the hydrochloric acid solution, the reaction was kept for 3 hours. Cool down to 0 ° C,The crystal obtained by suction filtration was washed with a buffer solution of pH=2.Then wash,Dry to obtain 2,3-difluorobenzoic acid.The product obtained has a purity of 99.5percent and a product yield of 90percent.

Reference： [1] Patent: CN108658759, 2018, A, . Location in patent: Paragraph 0032; 0037

4
[ 124-38-9 ]
[ 367-11-3 ]
[ 4519-39-5 ]

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

5
[ 1489-53-8 ]
[ 4519-39-5 ]

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

6
[ 61079-72-9 ]
[ 455-38-9 ]
[ 455-86-7 ]
[ 4519-39-5 ]
[ 65-85-0 ]

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

7
[ 2646-91-5 ]
[ 6418-38-8 ]
[ 4519-39-5 ]

Reference： [1] Advanced Synthesis and Catalysis, 2005, vol. 347, # 7-8, p. 1027 - 1034

8
[ 4519-39-5 ]
[ 75853-18-8 ]

Reference： [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 5, p. 1005 - 1009

9
[ 4519-39-5 ]
[ 113211-94-2 ]

Reference： [1] Journal of Medicinal Chemistry, 1988, vol. 31, # 5, p. 1005 - 1009

[ 4519-39-5 ] Synthesis Path-Downstream 1~88

1
[ 4519-39-5 ]
[ 18355-73-2 ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride; In toluene; for 3h;Heating / reflux;	2,3-Difiuorobenzoic acid (11.6 g, 0.07 mol), thionyl chloride (37.5 ml, 61.1 g, 0.5 mol) and toluene (80 ml) were heated at reflux for 3 h. The solution was cooled and the volatiles were removed in vacuo. The residue was azeotroped with toluene (2 x 30 ml) to give the product (10.8 g) as a clear yellow oil.
	With thionyl chloride; for 2h;Reflux;	A mixture of <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (1 g, 6.32 mmol) and thionyl chloride (9 mL, 123.53 mmol) is stirred and heated at reflux for 2h. The solvent is evaporated in vacuo and the residue is coevaporated with toluene. Once dried, the residue is dissolved in 5 mL of tetrahydrofuran, chilled at 0C and monomethylamine (6.32 mL, 12.65 mmol) is added. After 20 min the reaction is quenched with water and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate and the solvent evaporated in vacuo to yield 790 mg of the title compound. MS (m/z): 172 (M+l)
	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 0 - 20℃; for 2h;	General procedure: Analogs 6a-o were synthesized as outlined in Scheme 1: Acid(1.2 eq) was dissolved in anhydrous DCM, oxalyl chloride (1.44eq) was added dropwise at 0C and then one drop DMF was added.The reaction mixture stirred at room temperature for 2 h. The excess oxalyl chloride was removed under reduced pressure, andthe residue dissolved in THF for next transformation.Intermediate 5 (1eq) and triethylamine (1.5 eq) were added sequent to a 25 ml three-neck-bottom flask under a nitrogen atmosphere. Acyl chloride in THF was added dropwise to flask at 0C.The reaction mixture was stirred at 0C. After pale yellow solid appeared, the mixture reacted at room temperature until TLC showed 5 disappeared. Ice water was added to reaction mixtureat 0C, and stirred for another 30 min until no insoluble solid generated.The solid was filtered to get crude product. The crude product further purified by medium pressure column chromatography(C18 padding, ACN: H2O (containing 0.05% TFA) =1:99-99:1) to getproduct as a solid.

Reference： [1]Journal of Medicinal Chemistry,1982,vol. 25,p. 84 - 86
[2]Journal of the Chemical Society. Perkin transactions I,1998,p. 3661 - 3671
[3]Journal of Medicinal Chemistry,2006,vol. 49,p. 4512 - 4516
[4]Journal of Fluorine Chemistry,2007,vol. 128,p. 641 - 646
[5]Patent: WO2008/7149,2008,A2 .Location in patent: Page/Page column 26
[6]Patent: WO2011/60217,2011,A1 .Location in patent: Page/Page column 25
[7]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 481 - 484
[8]Bioorganic and Medicinal Chemistry,2018,vol. 26,p. 1740 - 1750

2
[ 4519-39-5 ]
[ 75853-18-8 ]

Reference： [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 1005 - 1009

3
[ 4519-39-5 ]
[ 902524-15-6 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 641 - 646

4
[ 4519-39-5 ]
[ 902524-19-0 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 641 - 646

5
[ 4519-39-5 ]
[ 1011493-54-1 ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 641 - 646

6
[ 4519-39-5 ]
(DL)-3-(2',3'-difluorophenyl)-3,4-dihydroisocoumarin [ No CAS ]

Reference： [1]Journal of Fluorine Chemistry,2007,vol. 128,p. 641 - 646

7
[ 4519-39-5 ]
7,11-dichloro-4-fluoro-dibenzo[b,f][1,4]oxazepine [ No CAS ]

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

8
[ 4519-39-5 ]
8,11-dichloro-4-fluoro-dibenzo[b,f][1,4]oxazepine [ No CAS ]

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

9
[ 4519-39-5 ]
[ 908336-81-2 ]

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

10
[ 4519-39-5 ]
[ 908336-79-8 ]

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

11
[ 4519-39-5 ]
[ 908336-75-4 ]

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

12
[ 4519-39-5 ]
[ 908336-72-1 ]

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

13
[ 4519-39-5 ]
7-chloro-4-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

14
[ 4519-39-5 ]
8-chloro-4-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

15
[ 4519-39-5 ]
N^α-Fmoc-N^im-tert-butyloxycarbonyl-L-tryptophan 4-hydroxymethylphenoxy resin [ No CAS ]
6-(2,3-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

16
[ 4519-39-5 ]
N^α-Fmoc-N^im-tert-butyloxycarbonyl-L-tryptophan 4-hydroxymethylphenoxy resin [ No CAS ]
3-[4-(4-acetyl-phenyl)-piperazin-1-ylmethyl]-6-(2,3-difluoro-benzoyl)-3H-benzooxazol-2-one [ No CAS ]

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

17
[ 4519-39-5 ]
N^α-Fmoc-N^im-tert-butyloxycarbonyl-L-tryptophan 4-hydroxymethylphenoxy resin [ No CAS ]
3-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-ylmethyl)-6-(2,3-difluoro-benzoyl)-3H-benzooxazol-2-one [ No CAS ]

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

18
[ 4519-39-5 ]
N^α-Fmoc-N^im-tert-butyloxycarbonyl-L-tryptophan 4-hydroxymethylphenoxy resin [ No CAS ]
6-(2,3-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

19
[ 1489-53-8 ]
[ 4519-39-5 ]

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

20
[ 4519-39-5 ]
3-Fluoro-2-hydroxy-benzoic acid 2,6-di-tert-butyl-4-methoxy-phenyl ester [ No CAS ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1998,p. 3661 - 3671
[2]Journal of the Chemical Society. Perkin transactions I,1998,p. 3661 - 3671

21
[ 4519-39-5 ]
[ 219636-59-6 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1998,p. 3661 - 3671

22
[ 4519-39-5 ]
[ 219636-37-0 ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1998,p. 3661 - 3671

23
[ 4519-39-5 ]
2-Allyl-3-fluoro-benzoic acid 2,6-di-tert-butyl-4-methoxy-phenyl ester [ No CAS ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1998,p. 3661 - 3671
[2]Journal of the Chemical Society. Perkin transactions I,1998,p. 3661 - 3671

24
[ 4519-39-5 ]
6-Fluoro-biphenyl-2-carboxylic acid 2,6-di-tert-butyl-4-methoxy-phenyl ester [ No CAS ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1998,p. 3661 - 3671
[2]Journal of the Chemical Society. Perkin transactions I,1998,p. 3661 - 3671

25
[ 4519-39-5 ]
2-Benzyl-3-fluoro-benzoic acid 2,6-di-tert-butyl-4-methoxy-phenyl ester [ No CAS ]

Reference： [1]Journal of the Chemical Society. Perkin transactions I,1998,p. 3661 - 3671
[2]Journal of the Chemical Society. Perkin transactions I,1998,p. 3661 - 3671
[3]Journal of the Chemical Society. Perkin transactions I,1998,p. 3661 - 3671

26
[ 4519-39-5 ]
[ 113211-94-2 ]

Reference： [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 1005 - 1009

27
[ 4519-39-5 ]
6-Chloro-9-(2,3-difluoro-benzyl)-9H-purine [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 1005 - 1009

28
[ 4519-39-5 ]
[9-(2,3-Difluoro-benzyl)-9H-purin-6-yl]-methyl-amine; hydrochloride [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,1988,vol. 31,p. 1005 - 1009

29
[ 4519-39-5 ]
(S)-1-(2,3-Difluoro-benzoyl)-pyrrolidine-2-carboxylic acid [ No CAS ]

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

30
[ 4519-39-5 ]
[ 79787-18-1 ]

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

31
[ 4519-39-5 ]
[ 79787-13-6 ]

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

32
[ 4519-39-5 ]
[ 129589-66-8 ]

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

33
[ 4519-39-5 ]
[ 129589-69-1 ]

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

34
[ 4519-39-5 ]
[ 129589-67-9 ]

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

35
[ 4519-39-5 ]
[ 129589-70-4 ]

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

36
[ 4519-39-5 ]
[ 129589-68-0 ]

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

37
[ 4519-39-5 ]
[ 847972-30-9 ]

Yield	Reaction Conditions	Operation in experiment
	With chlorosulfonic acid; at 20℃; for 2h;	To 2, 3-DIFLUORO-BENZOIC acid (3g) was added to a solution of chlorosulfonic acid and the reaction mixture was stirred for 2 hours at room temperature. After such time, the reaction mixture was poured onto ice. The resulting solid precipitate was then filtered off and dried in vacuo to yield the title compound as a light grey solid (4. 8 g, mp = 109- 114C, MS (EI) : 256.0 (MT) and was used directly in the next step without any further purification

Reference： [1]Patent: WO2005/23260,2005,A1 .Location in patent: Page/Page column 144
[2]Bioorganic and Medicinal Chemistry,2010,vol. 18,p. 3307 - 3319

38
[ 4519-39-5 ]
[ 13958-86-6 ]
[ 858939-32-9 ]

Yield	Reaction Conditions	Operation in experiment
22.2%	With 3-methyl-1-phenyl-1H-pyrazole;	The cyclization with 2,3-difluorbenzoic acid in PPA was performed as described above. Purified by column chromatography (silica gel, eluent: dichloromethan/methanol = 12/1). Yield: 22.2%.

Reference： [1]Patent: WO2005/63744,2005,A2 .Location in patent: Page/Page column 232

39
[ 54-96-6 ]
[ 4519-39-5 ]
[ 858935-15-6 ]

Yield	Reaction Conditions	Operation in experiment
88%	With PPA; at 180℃; for 4h;	A mixture of 3, 4-diaminopyridine (2.00 g), <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (1 equivalent) and polyphosphoric acid (50 g) was heated at 180 C for 4 h with stirring. Then the mixture was cooled to ambient temperature and poured into ice/water. The resulting mixture was neutralized by addition of solid NaOH. The crude 2- (2, 3- difluorophenyl)-1 (3) H-imidazo [4,5-c] pyridine was collected by filtration, washed with water and dried. It was used in the next step without further purification. Yield: 88%.
	With phosphorus pentoxide; In methanesulfonic acid; at 50 - 190℃; for 3h;	Phosphorous pentoxide (24.56g) was dissolved in methanesulfonic acid (165. 8mL) at 50 C with stirring. To the solution, 3,4-diaminopyridine (12.3g, 0 lmoles) and <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (19.4g, 0.12moles) were added. The reaction mixture was heated to 190 C for 3 hours. The reaction was done three times. The reaction mixtures was cooled to 50 C and poured into ice with stirring. At this stage, all three batches were combined. The reaction mixture was neutralized by the addition of NaOH with stirring until the pH is 8. Solid material precipitated out of solution, was collected by filtration and air-dried. The final product was re-crystallized from ethanol/water twice to yield 36g of 2- (2, 3-difluorophenyl) -3H-imidazo [4,5- c] pyridine. 1H 300Mhz (CD30D) sigma 7.3-7. 42 (m, lp) ; 7.43-7. 58 (m, lp) ; 7.70 (d, lp) ; 8.0 (m, lp) ; 8.34 (d, lp) ; and 8.95 (s, lp). LC/MS data M/z = 232.

Reference： [1]Patent: WO2005/63744,2005,A2 .Location in patent: Page/Page column 210
[2]Bioorganic and Medicinal Chemistry Letters,2007,vol. 17,p. 5111 - 5114
[3]Patent: WO2005/63744,2005,A2 .Location in patent: Page/Page column 72-73

40
[ 4519-39-5 ]
[ 333780-74-8 ]

Yield	Reaction Conditions	Operation in experiment
84%	With N-iodo-succinimide; trifluorormethanesulfonic acid; at 0 - 20℃; for 3h;	Reference Example 3: Synthesis of 6-(2,3-dichlorobenzyl)-1,4- dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinolinecarboxylic acid; Step 1 Synthesis of 2,3-difluoro-5-iodobenzoic acid; <strong>[4519-39-5]2,3-Difluorobenzoic acid</strong> (5.0 g, 31.6 mmol) was dissolved in trifluoromethanesulfonic acid (25 ml) and N-iodosuccinimide (8.55 g, 38.0 mmol) was cast by portions under an argon stream at 0C. After stirring at room temperature for 3 hr, the reaction mixture was poured into sodium sulfite in ice water and stirred. The precipitated solid was collected by filtration, washed with water, and vacuum dried to give the object product (7.5 g, yield 84%) as a pale-pink solid. ¹H NMR(CDC13 300MHz) (No.) ppm: 7.74 (lH, m) , 8.11 (lH, m) MS (ESI) : M- 283
84%	With N-iodo-succinimide; In trifluorormethanesulfonic acid; at 0 - 20℃; for 3h;	<strong>[4519-39-5]2,3-Difluorobenzoic acid</strong> (5.0 g, 31.6 mmol) was dissolved in trifluoromethanesulfonic acid (25 ml), and N-iodosuccinimide (8.55 g, 38.0 mmol) was added by portions at 0C under an argon stream. The mixture was stirred at room temperature for 3 hrs., and the reaction solution was poured into sodium sulfite in ice water. The mixture was stirred and the precipitate was collected by filtration, washed with water and vacuum-dried to give an object product (7.5 g, yield 84%) as a pale-pink solid.1H NMR(CDCl3 300MHz) (delta) ppm: 7.74 (1H,m), 8.11 (1H,m) MS(ESI): M- 283
50%	With N-Iodosuccinamide; sulfuric acid; at 0 - 5℃; for 5h;	To an ice cooled and stirred solution of 2,3 <strong>[4519-39-5]difluorobenzoic acid</strong> (10.0 g, 63.2 mmol) in concentrated sulfuric acid (50 mL), was added N-iodosuccinamide (14.2 g, 63.2 mmol) in portions, and the mixture stirred 0-5 0C for 5 hours during which time TLC showed the disappearance of the starting material. The reaction mixture was poured into crushed ice with vigorous stirring. The precipitate thus formed was filtered, washed with cold water (5x 50 mL), and dried under reduced pressure to give the title compound as a white solid. Yield: 9.O g (50%).

	With N-iodo-succinimide; trifluorormethanesulfonic acid; sodium sulfite;	PREPARATION 19 2,3-Difluoro-5-iodobenzoic acid [J.2] A 500 mL, 3 neck round bottom flask, equipped with an overhead stirrer is charged with trifluoromethanesulfonic acid (100 g), cooled to 0-5 C. in an ice bath, and treated with <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (18.96 g). To this mixture is added N-iodosuccinimide (32.4 g) portion-wise over a 10 min period. After an additional 3 min, the cooling bath is removed and the reaction mixture is allowed to warm to room temperature. After a total of 5 h, the reaction mixture is poured into 600 mL of vigorously stirred crushed ice/water containing 100 mL of 10% sodium sulfite solution. The beige colored precipitate is collected, washed with ice water and dried at 50 C. in a vacuum oven overnight to produce 28.2 g (83%) of the title compound. Physical characteristics: 1H NMR (CDCl3) delta10.35, 8.12, 7.76; MS (ESI-) m/z 283 (M-H)-.
	With sodium hydrogensulfite; In N-iodo-succinimide; trifluorormethanesulfonic acid;	Preparation 29 2,3-Difluoro-5-iodobenzoic acid (Formula H-2 of Chart H) To a cold (0 C.), stirred solution of 4.74 g of <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> in 15.0 mL of trifluoromethanesulfonic acid is added in portions 8.1 g of powdered N-iodosuccinimide. Following the addition, the mixture is allowed to warm to room temperature, stirred for 5 h, then poured onto 200 mL of cracked ice containing 5 g of sodium bisulfite. The mixture is stirred well for 15 m, then filtered, and the solid washed well with water and dried under vacuum to provide 6.78 g of the title compound as a solid. 1H NMR (CDCl3) delta7.81, 8.09. IR 3082, 1713, 1473, 1280 cm-1 MS (ES-) m/z 282.8.
	With sodium periodate; sulfuric acid; iodine; at 20℃; for 0.666667h;	Sodium periodate (193.0 g, 901.0 mmol) and iodine (602.0 g, 2371.0 mmol) were suspended in conc. sulfuric acid (2500 mL) and heated in a 40 oC bath for 20 min. The mixture was cooled to RT and <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (ChemPure Chemicals, Plymouth, MI, USA) (750.0 g, 4744.0 mmol) was added in one portion and additional conc. sulfuric acid (100 mL) was added. The reaction mixture was stirred for 40 min at RT. The reaction was poured into a rapidly stirred mixture of water (5000 mL), ice (~3000 g) and ethyl acetate (5000 mL). Sodium sulfite (500 g) was added and layers were separated. The organic layer was washed with hydrochloric acid (500 mL of 0.5 N aqueous solution) followed by brine (500 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give 25a (1020.0 g, 76% yield). The crude solid was used without further purification. MS (ESI, positive ion) m/z: no ionization. 1H NMR (400 MHz, DMSO-d6) _ 8.06- 8.00 (m, 1H), 7.80 (d, J = 5.7 Hz, 1H).

Reference： [1]Patent: WO2005/113509,2005,A1 .Location in patent: Page/Page column 84
[2]Patent: EP1564210,2005,A1 .Location in patent: Page/Page column 42
[3]Patent: WO2009/4382,2009,A2 .Location in patent: Page/Page column 75
[4]Patent: US2002/25959,2002,A1
[5]Patent: US2002/103170,2002,A1
[6]Journal of Medicinal Chemistry,2009,vol. 52,p. 4869 - 4882
[7]Patent: WO2006/50942,2006,A1 .Location in patent: Page/Page column 41
[8]Patent: WO2018/112094,2018,A1 .Location in patent: Page/Page column 101-102

41
[ 4519-39-5 ]
[ 223444-56-2 ]

Yield	Reaction Conditions	Operation in experiment
91%		Example 22 N-t-Butyl-2,3-difluorobenzamide The title compound (0.3873 g; 91%) was prepared by the same method as that described in Example 14, using <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (0.3159 g, 2.00 mmol). 1H-NMR(270 MHz, CDCl3) 7.76 (ddd, 1H, J=8.1, 6.6, 1.6 Hz), 7,33-7.22 (m, 1H), 7.17 (tdd, 1H, J=8.1, 4.8, 1.6 Hz), 6.43 (br, 1H), 1.48 (s, 9H)

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

42
[ 4519-39-5 ]
[ 147696-82-0 ]

Yield	Reaction Conditions	Operation in experiment
10%	With hydrogenchloride; PPA; aniline; In water;	a. 4'-Amino-2,3-difluorobenzophenone To stirred polyphosphoric acid (125 g) heated to 90 C. was added <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (10.00 g, 63.3 mmol) followed by aniline (5.72 g, 61.7 mmol). The reaction mixture was heated at 180-185 C. for 1 hour (solid dissolved at 135 C.), then the oil bath was removed and distilled water (35 mL) was cautiously added in small portions through the condenser. The oil bath was returned, and the reaction mixture heated at 135-145 C. for 1 hour. The oil bath was again removed, 3N HCl (55 mL) was added to the solution, the reaction mixture was then poured into water (750 mL) and stirred for one hour. The aqueous solution was filtered through Celite and the filtrate basified with 15% NaOH to a pH of 8. A green solid was collected by filtration and purified by flash column chromatography (methylene chloride). Trituration with hexane yielded the title benzophenone (1.43 g, 10%) as a yellow solid; mp 104-106 C. 1 H--NMR (250 MHz, d6 --DMSO): 6.41 (s, 2H, NH2) 6.60 (d, 2H, J=8.7 Hz, aromatic) 7.22-7.37 (m, 2H, aromatic) 7.50 (d, 2H, J=8.6 Hz, aromatic) 7.53-7.64 (m, 1H, aromatic). MS (CI, CH4): 234 (M+1). Analysis for C13 H9 F2 NO: Calculated: C, 66.94; H, 3.90; N, 6.00. Found: C, 66.87; H, 3.80; N, 5.91.

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

43
[ 13754-19-3 ]
[ 4519-39-5 ]
8-(2,3-difluorophenyl)-purine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		4,5-Diaminopyrimidine (1) (4.5 g, 0.04 moles) and 2,3-difluorobenzoic acid (2) (6.95 g, 0.044 moles) were suspended in 100 mL of Eaton's Acid. The reaction mixture was heated in an oil bath at 190 C. for 2 hours and then poured into 800 mL ice/water. Solid sodium hydroxide was added (59 g, 1.5 moles) to adjust to pH 5, which resulted in the product precipitating from solution. The product was filtered and washed twice with deionized water and air dried. The crude product was recrystallized from water/ethanol resulting in 8 g of pure product (3) (M+1=233). Purine (3) (500 mg, 2.15 mmoles) was dissolved in 10 mL of anhydrous DMF and 1.1 mL of sodium hydroxide solution (10% w/v) was added. 5-(Chloromethyl)-3-(4-chlorophenyl)isoxazole (4) (587 mg, 2.6 mmoles) was added to the above reaction mixture and the solution was stirred at room temperature overnight. The crude product was triturated from water followed by recrystallization from hot ethyl acetate. The precipitate was filtered to yield 30 mg of the gold colored solid 1-((3-(4-chlorophenyl)isoxazol-5-yl)methyl)-8-(2,3-difluorophenyl)-1H-purine 5) in high purity as determined by analytical LC/MS (M+1=429) and 1H NMR (400 MHz, DMSO-d6) delta 5.99 (s, 2H), 7.17 (s, 1H), 7.34 (m, 1H), 7.55 (s, 1H), 7.56 (d, 2H), 7.87 (d, 2H), 8.14 (m, 1H), 9.14 (s, 1H), 9.32 (s, 1H).

Reference： [1]Patent: US2006/52602,2006,A1 .Location in patent: Page/Page column 53-54

44
C₇H₃F₂O₂^(1-)*C₂₅H₃₀N₃⁽¹⁺⁾ [ No CAS ]
[ 467-63-0 ]
[ 4519-39-5 ]

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

45
[ 467-63-0 ]
[ 4519-39-5 ]
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

46
[ 4519-39-5 ]
[ 56-36-0 ]
tri-n-butyltin 2,3-difluorobenzoate [ No CAS ]

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

47
[ 4519-39-5 ]
[ 5680-79-5 ]
[ 1072833-88-5 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (0.190 g, 1.2 ?unol) in tetrahydrofuran (5 mL) were added glycine methyl ester hydrochloride (0.150 g, 1.2 mmol), HOBt (0.162 g, 1.2 mmol), DIEA (0.209 mL, 1.2 mmol) and EDCI (0.252 g, 1.3 mmol). The reaction mixture was allowed to stir overnight. The reaction mixture was quenched with a saturated solution of sodium bicarbonate and the product partitioned into DCM. Separation of the organic layer followed by removal of the solvent gave methyl [(2,3- difluorobenzoyl)amino]acetate which was used in the next step without purification.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;	glycine methyl ester hydrochloride (0.150 g, 1.2 mmol), HOBt(0.162 g, 1 .2 mmol), DIEA (0.209mL, 1.2 mmol) and EDCI (0.252g, 1.3 mmol) wereadded to solution of <strong>[4519-39-5]2,3-difluoro-benzoic acid</strong> (0.190 g, 1.2 mmol) intetrahydrofuran (5 mL). The reaction mixture was stirred overnight. Thereaction was stopped by quenching the reaction mixture in a saturated solutionof sodium bicarbonate and the product was separated in DCM. The organic layerwas separated, and by removing the solvent, methyl [(2,3-difluorobenzoyl)amino] acetate was obtained and that was used in the next step without purification.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;	In tetrahydrofuran (5 mL) of <strong>[4519-39-5]2,3-difluoro-benzoic acid</strong> (0.190 g, 1.2 mmol) to a solution of glycine methyl ester hydrochloride (0.150 g, 1.2 mmol), HOBt (0.162 g, 1.2 mmol), DIEA ( 0.209 mL, 1.2 mmol) and EDCI (was added 0.252 g, 1.3 mmol). The reaction mixture was stirred overnight. The reaction mixture was quenched with a saturated solution of sodium bicarbonate and was partitioned with DCM and the product. The organic layer was separated and then, the solvent was removed I got a [(2,3-difluoro-benzoyl) amino] methyl acetate, which was used in the next step without further purification.

	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;	To a solution of <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (0.190 g, 1.2 mmol) in tetrahydrofuran (5 mL) were added glycine methyl ester hydrochloride (0.150 g,1.2 mmol), HOBt (0.162 g, 1.2 mmol), DIEA (0.209 mL, 1.2 mmol) and EDCI (0.252 g, 1.3 mmol). The reaction mixture was allowed to stir overnight. The reaction mixture was quenched with a saturated solution of sodium bicarbonate and the product partitioned into DCM. Separation of the organic layer followed by removal of the solvent gave methyl [(2,3-difluorobenzoyl)amino]acetate which was used in the next step without purification.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;	To a solution of <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (0.190 g, 1.2 mmol) in tetrahydrofuran (5 mL) was added glycine methyl ester hydrochloride (0.150 g, 1.2 mmol), HOBt (0.162 g, 1 , 2 mmol), DIEA (0.209 mL, 1.2 mmol), and EDCI (0.252 g, 1.3 mmol)Was added. The reaction mixture was stirred overnight.The reaction mixture was quenched with a saturated solution of sodium bicarbonate,The product was separated in DCM. By separating the organic layer and removing the solvent,Methyl [(2,3-difluorobenzoyl) amino] acetate was obtained,It was used in the next step without purification.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;	To a solution of <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (0.190 g, 1.2 mmol) in tetrahydrofuran (5 mL) was added glycine methyl ester hydrochloride (0.150 g, 1.2 mmol), HOBt (0.162 g, 1 , 2 mmol), DIEA (0.209 mL, 1.2 mmol), and EDCI (0.252 g, 1.3 mmol)Was added. The reaction mixture was stirred overnight. The reaction mixture was quenched with a saturated solution of sodium bicarbonate and the product was separated in DCM. The organic layer was separated and the solvent was removed to give methyl [(2,3-difluorobenzoyl) amino] acetate which was used in the next step without purification.
	With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran;	Step 1: methyl [(2,3-difluorobenzoyl)amino]acetate To a solution of <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (0.190 g, 1.2 mmol) in tetrahydrofuran (5 mL) were added glycine methyl ester hydrochloride (0.150 g, 1.2 mmol), HOBt (0.162 g, 1.2 mmol), DIEA (0.209 mL, 1.2 mmol) and EDCI (0.252 g, 1.3 mmol). The reaction mixture was allowed to stir overnight. The reaction mixture was quenched with a saturated solution of sodium bicarbonate and the product partitioned into DCM. Separation of the organic layer followed by removal of the solvent gave methyl [(2,3-difluorobenzoyl)amino]acetate which was used in the next step without purification.

Reference： [1]Patent: WO2009/20448,2009,A1 .Location in patent: Page/Page column 23
[2]Patent: JP2016/14038,2016,A .Location in patent: Paragraph 0079
[3]Patent: KR2016/40735,2016,A .Location in patent: Paragraph 0105-0107
[4]Patent: ,2016, .Location in patent: Paragraph 0105; 0106; 0107
[5]Patent: JP2016/172768,2016,A .Location in patent: Paragraph 0079
[6]Patent: JP2018/24694,2018,A .Location in patent: Paragraph 0078; 0079
[7]Patent: US7442830,2008,B1 .Location in patent: Page/Page column 19-21
[8]Patent: JP2020/79299,2020,A .Location in patent: Paragraph 0078-0079

48
[ 960249-80-3 ]
[ 4519-39-5 ]
[ 1034141-34-8 ]

Yield	Reaction Conditions	Operation in experiment
	With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 18h;	Example 5: 5-Amino-N-(2-[[(2,3-difluorophenyl)carbonyl1(ethyl)amino1methyl)-3,3,3- trifluoro-2-hvdroxypropyl)-1-(4-fluorophenyl)-1 H-pyrazole-4-carboxamide. A solution of <strong>[4519-39-5]2,3-<strong>[4519-39-5]difluorobenzoic acid</strong></strong> (0.088mmol) and O-(7-azabenzotriazol-1-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (0.088mmol) in dimethylformamide (0.2ml) and N,N-diisopropylethylamine (30mul) was shaken for 1 min before a solution of 5-amino-N-{2-[(ethylamino)methyl]-3,3,3-trifluoro-2- hydroxypropyl}-1-(4-fluorophenyl)-1 H-pyrazole-4-carboxamide (0.07mmol) in dimethylformamide (0.1 ml) was added and then shaken for a further minute. After standing at room temperature for 18hrs, dimethylsulphoxide (0.3ml) was added and this solution was purified via the CAT MDAP (2 times, by cat_gr method and then by catjipo uv method) to give the title compound (10.5mg).1H NMR (400 MHz, CHLOROFORM-d) delta ppm 7.71 - 7.75 (m, 1 H) 7.49 - 7.55 (m, 2 H) 7.25 - 7.30 (m, 2 H) 7.17 - 7.25 (m, 4 H) 7.06 - 7.11 (m, 1 H) 5.47 (br. s., 2 H) 3.98 - 4.10 (m, 2 H) 3.62 - 3.72 (m, 1 H) 3.51 - 3.57 (m, 1 H) 3.43 - 3.49 (m, 1 H) 3.25 - 3.36 (m, 1 H) 1.07 (t, 3 H) LC-MS Retention Time 3.25mins, MH+ 530.A sample of Example 5 was further separated into its enantiomers (Enantiomer 1 and 2) using a Chiralpak AD column eluting with 70% ethanol in heptane at a flow rate of 15ml/min.

Reference： [1]Patent: WO2008/74814,2008,A1 .Location in patent: Page/Page column 66-67

49
[ 4519-39-5 ]
[ 61070-98-2 ]
[ 1105062-83-6 ]

Yield	Reaction Conditions	Operation in experiment
		2,3-Difluoro-benzoic acid (lOOmg), HATU (345.6 mg), and diisopropylethylamine (3 eq.) were added to DMF (90OuL) and stirred for 15 minutes. Pyridazine-3,4-diamine was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated, partitioned between water and ethyl acetate. The organic fraction was dried with sodium sulfate and concentrated in vacuo. The residue was then heated in acetic acid at reflux for one day. The mixture was evaporated and purified via reverse-phase HPLC to give 136 mg of 6-(2,3-difluoro-phenyl)-2H- imidazo[4,5-c]pyridazine. MS: 233.1 (M+H+) H'-NMR (DMSOd6): £(prhom) 9.04 (d, IH, 5.8Hz), 8.08 (m, IH), 7.96 (d, IH, 5.3 Hz) 7.70 (m, IH) 7.44 (m, IH)
		General Procedure JSynthesis of Compounds 245-2476-(2,3-difluoro-phenyl)-2H-imidazo[4,5-c]pyridazinePyridazine-3,4-diamine was synthesized as described by Kuraishi et al. in J. Het. Chem. 1964, 1, 42-47. MS: 111.1 (M+H+); H1-NMR (DMSO-d6): delta (ppm) 8.2-8.3 (m, 3H), 7.31 (s, 2H), 6.73 (d, 1H, 6.1 Hz).2,3-Difluoro-benzoic acid (100 mg), HATU (345.6 mg), and diisopropylethylamine (3 eq.) were added to DMF (900 uL) and stirred for 15 minutes. Pyridazine-3,4-diamine was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated, partitioned between water and ethyl acetate. The organic fraction was dried with sodium sulfate and concentrated in vacuo. The residue was then heated in acetic acid at reflux for one day. The mixture was evaporated and purified via reverse-phase HPLC to give 136 mg of 6-(2,3-difluoro-phenyl)-2H-imidazo[4,5-c]pyridazine. MS: 233.1 (M+H+) H1-NMR (DMSO-d6): delta (ppm) 9.04 (d, 1H, 5.8 Hz), 8.08 (m, 1H), 7.96 (d, 1H, 5.3 Hz) 7.70 (m, 1H) 7.44 (m, 1H)

Reference： [1]Patent: WO2009/11787,2009,A1 .Location in patent: Page/Page column 208
[2]Patent: US2010/29655,2010,A1 .Location in patent: Page/Page column 85

50
(S)-1-(2-azido-ethyl)-4-{4-methoxy-3-[(R)-(tetrahydro-furan-3-yl)oxy]-phenyl}-pyrrolidin-2-one [ No CAS ]
[ 4519-39-5 ]
[ 790297-80-2 ]

Yield	Reaction Conditions	Operation in experiment
		Into a flask containing 100 mg (0.63 mmol) of 2, 3-<strong>[4519-39-5]difluorobenzoic acid</strong> and 85 mg (0.63 mmol) of HOBt was added 6.5 mL of THF. This was cooled to 0 C under argon and 0.10 mL (0.63 mmol) OF DIC was added and stirring continued for 30 minutes. This solution was then added to a flask containing 55 mg (0.16 mmol) of (S)-L- (2-AZIDO- ETHYL)-4- {4-METHOXY-3-[(R)-(TETRAHYDRO-FURAN-3-YL) OXY]-PHENYL}-PYRROLIDIN-2-ONE in 3 mL of THF at room temperature. Then, 0.12 mL of PBu3 was added and the reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in 10 mL of ethyl acetate. The organic layer was washed with 10 mL of IN HC1, 10 mL OF K2C03, 10 mL of water, and 10 mL of brine, dried over NA2S04, filtered and concentrated. Purification was accomplished by silica gel column chromatography using a gradient elution from 0% to 10% methanol in dichloromethane to yield 27 mg (4S)-2, 3-DIFLUORO-4- [4-METHOXY-3- (3R)-TETRAHYDROFURANYLOXYPHENYL]-N- [2-(2-OXOPYRROLIDIN-1-YL) ETHYL]-BENZAMIDE. LH-NMR 6 (CDC13) 7.7 (t, 1H), 7.3 (M, 1H), 7.2 (m, 2H), 6.8 (s, 2H), 6.7 (s, 1H), 4.9 (M, 1H), 4.0 (M, 3H), 3. 8 (M, 5H), 3.7 (M, 2H), 3.0 (M, 2H), 2.3 (M, 2H), 2.7 (dd, 1H), 2.5 (dd, 1H), 2.1 (M, 2H). M+1=461. 0

Reference： [1]Patent: WO2004/94375,2004,A2 .Location in patent: Page 135-136

51
[ 4519-39-5 ]
[ 1250397-72-8 ]

Reference： [1]Patent: WO2011/60217,2011,A1

52
[ 4519-39-5 ]
[ 56-17-7 ]
C₁₈H₁₆F₄N₂O₂S₂ [ No CAS ]

Reference： [1]ACS Combinatorial Science,2011,vol. 13,p. 205 - 208

53
[ 4519-39-5 ]
[ 1251919-44-4 ]

Reference： [1]ACS Medicinal Chemistry Letters,2011,vol. 2,p. 481 - 484

54
[ 4519-39-5 ]
[ 21907-22-2 ]
Sb₄O₄(OH)2(C₆H₅)8(OOCC₆H₃F₂)2 [ No CAS ]

Reference： [1]Zeitschrift fur Anorganische und Allgemeine Chemie,2012,vol. 638,p. 725 - 729

55
[ 4519-39-5 ]
[ 1314230-89-1 ]