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[ CAS No. 500577-99-1 ] {[proInfo.proName]}

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Chemical Structure| 500577-99-1

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Quality Control of [ 500577-99-1 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 500577-99-1 ]

Product Details of [ 500577-99-1 ]

CAS No. :	500577-99-1	MDL No. :	MFCD03407440
Formula :	C₇H₅F₂NO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MJHZRTJMDQYAHN-UHFFFAOYSA-N
M.W :	173.12	Pubchem ID :	282133
Synonyms :

Calculated chemistry of [ 500577-99-1 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.0
Num. rotatable bonds :	1
Num. H-bond acceptors :	4.0
Num. H-bond donors :	2.0
Molar Refractivity :	37.72
TPSA :	63.32 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) :	-6.67 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.98
Log Po/w (XLOGP3) :	0.97
Log Po/w (WLOGP) :	2.09
Log Po/w (MLOGP) :	0.75
Log Po/w (SILICOS-IT) :	1.36
Consensus Log Po/w :	1.23

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.83
Solubility :	2.57 mg/ml ; 0.0148 mol/l
Class :	Very soluble
Log S (Ali) :	-1.89
Solubility :	2.24 mg/ml ; 0.013 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-1.97
Solubility :	1.87 mg/ml ; 0.0108 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.17

Safety of [ 500577-99-1 ]

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 [ 500577-99-1 ]

* 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 [ 500577-99-1 ]
Downstream synthetic route of [ 500577-99-1 ]

[ 500577-99-1 ] Synthesis Path-Upstream 1~3

1
[ 110301-23-0 ]
[ 500577-99-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	at 110℃; for 16 h;	4-amino-3,5-difluorobenzonitrile (354.3 mg, 2.3 mmol) was suspended in 1M aqueous sodium hydroxide (12 mL) and the resulting suspension was heated at 110 °C for 16 h. After cooling, the mixture was washed with ether. The aqueous phase was acidified to pH = 2 with 10percent KHS04/Na2S04 buffer and extracted with EtOAc (2X). The combined EtOAc extracts were washed with water, and then brine, dried over anhydrous sodium sulfate and concentrated in vacuo to provide 4-amino-3,5-difluorobenzoic acid (335 mg, 84percent yield) as a yellow solid. 1H NMR (300 MHz, Chloroform-d) δ 7.66 - 7.58 (m, 2H).

Reference： [1] Journal of Materials Chemistry C, 2016, vol. 4, # 23, p. 5326 - 5333
[2] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 3, p. 250 - 255
[3] Patent: WO2018/136935, 2018, A1, . Location in patent: Paragraph 00408
[4] Bioconjugate Chemistry, 2018, vol. 29, # 2, p. 324 - 334
[5] Journal of the American Chemical Society, 2012, vol. 134, # 51, p. 20597 - 20600

2
[ 67567-26-4 ]
[ 500577-99-1 ]

Reference： [1] Bioconjugate Chemistry, 2018, vol. 29, # 2, p. 324 - 334
[2] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 3, p. 250 - 255
[3] Patent: WO2018/136935, 2018, A1,

3
[ 64-17-5 ]
[ 500577-99-1 ]
[ 1415920-00-1 ]

Reference： [1] Journal of the American Chemical Society, 2012, vol. 134, # 51, p. 20597 - 20600

[ 500577-99-1 ] Synthesis Path-Downstream 1~48

1
[ 500577-99-1 ]
[ 1124212-41-4 ]
[ 1124213-40-6 ]

Yield	Reaction Conditions	Operation in experiment
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; for 2h;	To a stirred solution of 4-ammo-3,5-difluorobenzoic acid (1 g, 5.78 mmoles), N-tert-butyl-3-(piperazin-1-ylmethyl)benzamide (1.59 g, 5.78 mmoles) and triethylamine (4 mL) in dichloromethane (30 mL) was added 1-propanephosphonic acid cyclic anhydride (8 mL, 50% solution in ethyl acetate). After 2 hours stirring, the reaction mixture was diluted with ethyl acetate and washed with sodium carbonate (aqueous) (3*), dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound (2.24 g) as an off-white foam. MS (ESI) m/z 431.9 [M+H]+
	With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In dichloromethane; ethyl acetate; for 2h;	To a stirred solution of <strong>[500577-99-1]4-amino-3,5-difluorobenzoic acid</strong> (1g, 5.78mmoles), N-tert-butyl- 3-(piperazin-1-ylmethyl)benzamide (1.59g, 5.78mmoles) and triethylamine (4mL) in dichloromethane (3OmL) was added 1-propanephosphonic acid cyclic anhydride (8ml_, 50% solution in ethyl acetate). After 2 hours stirring, the reaction mixture was diluted with ethyl acetate and washed with sodium carbonate (aqueous) (3x), dried (magnesium sulfate) and concentrated under reduced pressure to give the title compound (2.24g) as an off-white foam. MS (ESI) m/z 431.9 [M+H]+

Reference： [1]Patent: US2009/264416,2009,A1 .Location in patent: Page/Page column 20
[2]Patent: WO2009/24550,2009,A1 .Location in patent: Page/Page column 34-35

2
[ 500577-99-1 ]
[ 1196693-61-4 ]
[ 1196693-74-9 ]

Yield	Reaction Conditions	Operation in experiment
		4-Amino-3,5-difluorobenzoic acid (1.899mmol, 329mg), 1 ,1 , 1 ,3,3, 3-hexafluoro-2- (4-(piperazin-1-ylmethyl)phenyl)propan-2-ol (1.899mmol, 650mg) and triethylamine (5.70mmol, 0.792ml_, 576mg) were combined and stirred at room temperature in dichloromethane (5ml_). 1-Propanephosphonic acid cyclic anhydride (2.85mmol,1.696mL, 1813mg; 50% solution in ethyl acetate) was added and the reaction stirred for 2 hours. Saturated sodium hydrogen carbonate solution was added to the reaction mixture and the layers separated. The organic layer was dried over magnesium sulfate and concentrated under vacuum to afford the title compound (340mg) as a pale pink solid. MS (ESI) m/z 498.7 [M+H]+

Reference： [1]Patent: WO2009/138438,2009,A1 .Location in patent: Page/Page column 69-70

3
[ 96-50-4 ]
[ 500577-99-1 ]
[ 851202-82-9 ]

Reference： [1]Journal of Medicinal Chemistry,2011,vol. 54,p. 751 - 764

4
[ 64-17-5 ]
[ 500577-99-1 ]
[ 1415920-00-1 ]

Reference： [1]Organic and Biomolecular Chemistry,2019,vol. 17,p. 1827 - 1833
[2]Journal of the American Chemical Society,2012,vol. 134,p. 20597 - 20600

5
[ 110301-23-0 ]
[ 500577-99-1 ]

Yield	Reaction Conditions	Operation in experiment
84%	With water; sodium hydroxide; at 110℃; for 16h;	4-amino-3,5-difluorobenzonitrile (354.3 mg, 2.3 mmol) was suspended in 1M aqueous sodium hydroxide (12 mL) and the resulting suspension was heated at 110 C for 16 h. After cooling, the mixture was washed with ether. The aqueous phase was acidified to pH = 2 with 10% KHS04/Na2S04 buffer and extracted with EtOAc (2X). The combined EtOAc extracts were washed with water, and then brine, dried over anhydrous sodium sulfate and concentrated in vacuo to provide 4-amino-3,5-difluorobenzoic acid (335 mg, 84% yield) as a yellow solid. 1H NMR (300 MHz, Chloroform-d) delta 7.66 - 7.58 (m, 2H).
83%	With sodium hydroxide; In water; at 100℃;	4-Amino-3,5-difluorobenzonitrile (1.00 g, 6.49 mmol, 1.00 equiv) was suspended in 1 M NaOH aqueous solution (80 mL) and heated to reflux for 4 h. The reaction mixture was cooled to room temperature and acidified with 1 M HCl aqueous solution (50 mL). The resulting precipitate was filtered, washed with distilled water (200 mL) and dried to yield the desired product (0.93 g, 5.39 mmol, 83%) as a white solid. The characterization is in agreement with the literature.[2]
71.4%	With sodium hydroxide; for 18h;Reflux;	Step S2: 25 g of 2,6-difluoro-4-cyanoaniline is dissolved in 800 mL of 1 M sodium hydroxide solution.After refluxing for 18 h, the reaction was completed by TLC thin layer chromatography and cooled to room temperature.Adjust the system to pH=8 with 1N hydrochloric acid, precipitate a large amount of solid, and filter by suction.The solid was dissolved in 500 mL of ethyl acetate and dried over anhydrous sodium sulfate (20 g).The product was concentrated to give a pale yellow solid (20.2 g).The yield was 71.4%.

Reference： [1]Journal of Materials Chemistry C,2016,vol. 4,p. 5326 - 5333
[2]Organic and Biomolecular Chemistry,2019,vol. 17,p. 1827 - 1833
[3]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 250 - 255
[4]Patent: WO2018/136935,2018,A1 .Location in patent: Paragraph 00408
[5]Beilstein Journal of Organic Chemistry,2019,vol. 15,p. 2500 - 2508
[6]Bioconjugate Chemistry,2018,vol. 29,p. 324 - 334
[7]Patent: CN108947782,2018,A .Location in patent: Paragraph 0019; 0023; 0030; 0037; 0042; 0044
[8]Journal of the American Chemical Society,2012,vol. 134,p. 20597 - 20600

6
[ 500577-99-1 ]
4-azido-3,5-difluorobenzoic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		Example 4. Synthesis of l i?ido-2>6-difiuoro-4-(n-propylcarboxamido)benzene (18c), prepared according to Figure 3. First, <strong>[500577-99-1]4-amino-3,5-difluorobenzoic acid</strong> (23) was prepared according literature procedure: Bleger et al., J. Am. Chem. Soc. 2012, 134, 20597. Then, to a solution of 4- amino-3,5-difluorobenzoic acid (23, 1 g, 4.77 mmol) in TFA (25 mL) was added slowly at 0 C NaN02 (658 mg, 9.54 mmol). The mixture was stirred for 1 h at 0 C. NaN3 (3.10 g, 47.7 mmol) was added in small portions to keep the temperature below 5 C. Et20 (20 mL) was added and the solution was stirred 2 h at rt. The reaction mixture was quenched with H20 (30 mL) and extracted with Et20. T he organic layer was washed with sat. NaCi, dried (Na2SG4), filtered and concentrated in vacuo. The product 24 was used without further purification in the next step. 1H NMR (CDC13, 400 MHz): delta 7.70-7.63 (m, 2H).
		Example 7. Synthesis of J~azido~2, 6~difltioro~4-(n-propylcarboxamido)benzene (3p), depicted in Figure 4 (top) First, <strong>[500577-99-1]4-amino-3,5-difluorobenzoic acid</strong> (17) was prepared according literature procedure: Bleger et a/. , J. Am. Chem. Soc. 2012, 134, 20597. Then, to a solution of 4- amino-3,5-difluorobenzoic acid (17, 1 g, 4.77 mmol) in TFA (25 mL) was added slowly at 0 C NaN02 (658 mg, 9.54 mmol). The mixture was stirred for 1 h at 0 C. NaN3 (3.10 g, 47.7 mmol) was added in small portions to keep the temperature below 5 C. Et20 (20 mL) was added and the solution was stirred 2 h at rt. The reaction mixture was quenched with H20 (30 mL) and extracted with Et20. The organic layer was washed with sat. NaCl, dried (Na2S04), filtered and concentrated in vacuo. The product 18 was used without further purification in the next step. 1H NMR (CDCI3, 400 MHz): delta 7.70-7.63 (m, 2H) ppm.
		(0295) First, <strong>[500577-99-1]4-amino-3,5-difluorobenzoic acid</strong> (23) was prepared according literature procedure: Blger et al., J Am. Chem. Soc. 2012, 134, 20597. Then, to a solution of <strong>[500577-99-1]4-amino-3,5-difluorobenzoic acid</strong> (23, 1 g, 4.77 mmol) in TFA (25 mL) was added slowly at 0 C. NaNO2 (658 mg, 9.54 mmol). The mixture was stirred for 1 h at 0 C. NaN3 (3.10 g, 47.7 mmol) was added in small portions to keep the temperature below 5 C. Et2O (20 mL) was added and the solution was stirred 2 h at rt. The reaction mixture was quenched with H2O (30 mL) and extracted with Et2O. The organic layer was washed with sat. NaCl, dried (Na2SO4), filtered and concentrated in vacuo. The product 24 was used without further purification in the next step. (0296) 1H NMR (CDCl3, 400 MHz): delta 7.70-7.63 (m, 2H).

First, <strong>[500577-99-1]4-amino-3,5-difluorobenzoic acid</strong> (17) was prepared according literature procedure: Blger et al., J. Am. Chem. Soc. 2012, 134, 20597. Then, to a solution of <strong>[500577-99-1]4-amino-3,5-difluorobenzoic acid</strong> (17, 1 g, 4.77 mmol) in TFA (25 mL) was added slowly at 0 C. NaNO2 (658 mg, 9.54 mmol). The mixture was stirred for 1 h at 0 C. NaN3 (3.10 g, 47.7 mmol) was added in small portions to keep the temperature below 5 C. Et2O (20 mL) was added and the solution was stirred 2 h at rt. The reaction mixture was quenched with H2O (30 mL) and extracted with Et2O. The organic layer was washed with sat. NaCl, dried (Na2SO4), filtered and concentrated in vacuo. The product 18 was used without further purification in the next step.

Reference： [1]Patent: WO2015/112016,2015,A1 .Location in patent: Page/Page column 83
[2]Patent: WO2015/112014,2015,A1 .Location in patent: Page/Page column 91
[3]Patent: US2017/8858,2017,A1 .Location in patent: Paragraph 0295-0296
[4]Patent: US2017/2012,2017,A1 .Location in patent: Paragraph 0349; 0350

7
[ 500577-99-1 ]
4-azido-N-benzyl-3,5-difluorobenzamide [ No CAS ]

Reference： [1]Patent: WO2015/112014,2015,A1
[2]Patent: US2017/2012,2017,A1

8
[ 500577-99-1 ]
4-azido-3,5-difluorobenzoic acid N-hydroxysuccinimide ester [ No CAS ]

Reference： [1]Patent: WO2015/112014,2015,A1
[2]Patent: US2017/2012,2017,A1

9
[ 500577-99-1 ]
α-UDP-N-(4‘-azido-3‘,5‘-difluorobenzoyl)-D-galactosamine [ No CAS ]

Reference： [1]Patent: WO2015/112016,2015,A1
[2]Patent: WO2015/112014,2015,A1
[3]Patent: US2017/8858,2017,A1
[4]Patent: US2017/2012,2017,A1

10
[ 500577-99-1 ]
1-azido-2,6-difluoro-4-(n-propylcarboxamido)benzene [ No CAS ]

Reference： [1]Patent: WO2015/112016,2015,A1

11
[ 500577-99-1 ]
C₇H₃F₂NO₃ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
60%	With oxone; In dichloromethane; water; acetone; at 20℃; for 2h;	Oxone monopersulfate (2.13 g, 3.46 mmol) was dissolved in 14 mL of DI H2O and added to a solution of<strong>[500577-99-1]4-amino-3,5-difluorobenzoic acid</strong> (300 mg, 1.73 mmol) in 6 mL of DCM/acetone (2:1). The mixture wasvigorously stirred at rt. After 2 h, 40 mL of DI H2O were added and the mixture was extracted with EtOAc(3 × 10 mL). The pooled organic layers were dried over Na2SO4 and the solvent was evaporated at reducedpressure. The resulting beige solid (nitrosobenzoic acid) was suspended in 12 mL of AcOH/toluene/TFA(6:6:1) and p-methoxyaniline (135 mg, 0.64 mmol) was added. The mixture was stirred at rt for 3 days. 60mL of DI H2O were added and the mixture was extracted with EtOAc (3 × 35 mL). The pooled organiclayers were dried over Na2SO4 and the solvent was evaporated at reduced pressure. The residue was purifiedby column chromatography [SiO2, DCM/MeOH (90:10, v/v)] to afford MeO-2FAB (90 mg, 18%) as abrownish solid
	With Oxone; In dichloromethane; water; acetone; at 20℃;	4-Amino-3,5-difluorobenzoic acid (500 mg, 2.89 mmol, 1.00 equiv) was dissolved in CH2Cl2/acetone (20 mL, 5:1, v/v), a solution of Oxone (3.56 g, 5.78 mmol, 2.00 equiv) in distilled water (10.0 mL) was added and the resulting mixture was stirred at room temperature for 4 h. The organic layer was washed with distilled water (100 mL), and brine (100 mL), dried over anhydrous MgSO4. Solvents were removed under reduced pressure.

Reference： [1]Beilstein Journal of Organic Chemistry,2019,vol. 15,p. 2812 - 2821
[2]Chemistry - A European Journal,2014,vol. 20,p. 16492 - 16501
[3]Beilstein Journal of Organic Chemistry,2019,vol. 15,p. 2500 - 2508

12
[ 500577-99-1 ]
C₁₃H₆F₄N₂O₂ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2014,vol. 20,p. 16492 - 16501
[2]Beilstein Journal of Organic Chemistry,2019,vol. 15,p. 2500 - 2508

13
[ 500577-99-1 ]
C₁₃H₈F₂N₂O₂ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2014,vol. 20,p. 16492 - 16501

14
[ 500577-99-1 ]
C₁₆H₁₂F₂N₂O₄ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2014,vol. 20,p. 16492 - 16501

15
[ 500577-99-1 ]
ethyl-4-((2,6-difluorophenyl)diazenyl)-3,5-difluorobenzoate [ No CAS ]

Reference： [1]Chemistry - A European Journal,2014,vol. 20,p. 16492 - 16501
[2]Chemistry - A European Journal,2014,vol. 20,p. 16492 - 16501

16
[ 500577-99-1 ]
C₁₅H₁₂F₂N₂O₂ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2014,vol. 20,p. 16492 - 16501
[2]Chemistry - A European Journal,2014,vol. 20,p. 16492 - 16501

17
[ 500577-99-1 ]
C₁₈H₁₆F₂N₂O₄ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2014,vol. 20,p. 16492 - 16501
[2]Chemistry - A European Journal,2014,vol. 20,p. 16492 - 16501

18
[ 500577-99-1 ]
C₁₅H₁₀F₄N₂O₂ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2014,vol. 20,p. 16492 - 16501

19
[ 500577-99-1 ]
C₁₅H₁₂F₂N₂O₂ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2014,vol. 20,p. 16492 - 16501

20
[ 500577-99-1 ]
C₁₈H₁₆F₂N₂O₄ [ No CAS ]

Reference： [1]Chemistry - A European Journal,2014,vol. 20,p. 16492 - 16501

21
[ 500577-99-1 ]
[ 108-95-2 ]
2',6'-difluoro-4-hydroxyazobenzene-4'-carboxylic acid [ No CAS ]

Reference： [1]Journal of Materials Chemistry C,2016,vol. 4,p. 5326 - 5333

22
[ 500577-99-1 ]
1-azido-2,6-difluoro-4-(n-propylcarboxamido)benzene [ No CAS ]

Reference： [1]Patent: US2017/8858,2017,A1
[2]Patent: US2017/2012,2017,A1

23
[ 67567-26-4 ]
[ 500577-99-1 ]

Reference： [1]Bioconjugate Chemistry,2018,vol. 29,p. 324 - 334
[2]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 250 - 255
[3]Patent: WO2018/136935,2018,A1
[4]Patent: CN108947782,2018,A
[5]Organic and Biomolecular Chemistry,2019,vol. 17,p. 1827 - 1833
[6]Beilstein Journal of Organic Chemistry,2019,vol. 15,p. 2500 - 2508

24
[ 500577-99-1 ]
4-amino-3,5-difluorophenylmethanol [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2018,vol. 29,p. 324 - 334

25
[ 500577-99-1 ]
C₁₄H₈F₂N₄O₅ [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2018,vol. 29,p. 324 - 334

26
[ 500577-99-1 ]
C₁₇H₉F₂N₃O₅ [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2018,vol. 29,p. 324 - 334

27
[ 500577-99-1 ]
C₃₅H₃₂F₂N₄O₁₃ [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2018,vol. 29,p. 324 - 334

28
[ 500577-99-1 ]
C₂₅H₂₃F₂NO₆ [ No CAS ]
C₂₅H₂₃F₂NO₆ [ No CAS ]

Reference： [1]Bioconjugate Chemistry,2018,vol. 29,p. 324 - 334

29
[ 500577-99-1 ]
[ 100-39-0 ]
benzyl 4-amino-3,5-difluorobenzoate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
84%		To a stirred solution of <strong>[500577-99-1]4-amino-3,5-difluorobenzoic acid</strong> (332.2 mg, 1.92 mmol) in DMF (9.7mL) was added potassium carbonate (0.29 g, 2.11 mmol) under nitrogen. Stirring continued at room temperature for 10 min before addition of benzyl bromide (0.22 mL, 1.82 mmol). The resulting reaction mixture was stirred at room temperature for 3 h, then poured onto cold water and extracted with EtOAc (2X). The combined organic extracts were washed with water (2X), then brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford benzyl 4-amino-3,5-difluorobenzoate (423 mg, 84% yield) as a pink solid. 1H NMR (300 MHz, Chloroform-d) delta 7.62 - 7.55 (m, 2H), 7.49 - 7.32 (m, 5H), 5.34 (s, 2H), 4.16 (br. s, 2H).

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 250 - 255
[2]Patent: WO2018/136935,2018,A1 .Location in patent: Paragraph 00409

30
[ 500577-99-1 ]
benzyl 4-((4-cyclohexylbenzyl)amino)-3,5-difluorobenzoate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 250 - 255
[2]Patent: WO2018/136935,2018,A1

31
[ 500577-99-1 ]
benzyl (R)-4-(N-(4-cyclohexylbenzyl)-2-((2,3,4,5,6-pentafluorophenyl)-N-methylsulfonamido)-propanamido)-3,5-difluorobenzoate [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 250 - 255
[2]Patent: WO2018/136935,2018,A1

32
[ 500577-99-1 ]
(R)-4-(N-(4-cyclohexylbenzyl)-2-((2,3,4,5,6-pentafluorophenyl)-N-methylsulfonamido)-propanamido)-3,5-difluorobenzoic acid [ No CAS ]

Reference： [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 250 - 255
[2]Patent: WO2018/136935,2018,A1

33
[ 500577-99-1 ]
[ 62-53-3 ]
2,6-difluoro-4-phenylcarbamoylaniline [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		1.73 g (10 mmol) of <strong>[500577-99-1]3,5-difluoro-p-aminobenzoic acid</strong>,2.108 g (11 mmol) EDC and 0.148 g (1.1 mmol) HOBT Add 30ml of dichloromethane,The reaction was stirred at room temperature.The reaction was followed by TLC, and the reaction was completed with <strong>[500577-99-1]3,5-difluoro-p-aminobenzoic acid</strong>, and 0.99 g (10 mmol) of aniline was added.The reaction was continued at room temperature. After the reaction is over, filter,1.773 g of a light gray solid was obtained and used in the next step without purification.
1.773 g		1.73 g (10 mmol) of <strong>[500577-99-1]3,5-difluoro-p-aminobenzoic acid</strong>,2.108 g (11 mmol) of EDC and 0.148 g (1.1 mmol) of HOBT were added to 30 ml of dichloromethane, and the reaction was stirred at room temperature.The reaction was followed by TLC, and the reaction was completed with <strong>[500577-99-1]3,5-difluoro-p-aminobenzoic acid</strong>. 0.99 g (10 mmol) of aniline was added and the reaction was continued at room temperature.After completion of the reaction, filtration gave 1.773 g of pale-yellow solid.

Reference： [1]Patent: CN103965133,2018,B .Location in patent: Paragraph 0239-0242
[2]Patent: CN103965134,2019,B .Location in patent: Paragraph 0231-0234

34
[ 500577-99-1 ]
[ 1562995-70-3 ]

Reference： [1]Patent: CN108947782,2018,A

35
[ 500577-99-1 ]
3,5-difluoro-4-bromobenzyl alcohol [ No CAS ]

Reference： [1]Patent: CN108947782,2018,A

36
[ 500577-99-1 ]
4-bromo-3,5-difluorobenzaldehyde [ No CAS ]

Reference： [1]Patent: CN108947782,2018,A

37
[ 500577-99-1 ]
[ 1415920-00-1 ]

Yield	Reaction Conditions	Operation in experiment
86%	With sulfuric acid; In ethanol; for 5h;Reflux;	Step S3: adding 20 g of 3,5-difluoro-4-aminobenzoic acid to 400 mL of ethanol,Then, 10 mL of concentrated sulfuric acid was added dropwise, and refluxed for 5 hours. The reaction was completed by TLC thin layer chromatography, and the system was cooled.Then concentrated, the residue was dissolved in 300 mL of water, then the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and 200 mL of X3 was extracted with dichloromethane.Dry over anhydrous sodium sulfate and concentrate.The product was obtained in an amount of 19.9 g, and the yield was 86%.

Reference： [1]Patent: CN108947782,2018,A .Location in patent: Paragraph 0019; 0024; 0031; 0038; 0042; 0045

38
[ 500577-99-1 ]
[ 1415919-94-6 ]
[ 1415919-99-1 ]

Reference： [1]Organic and Biomolecular Chemistry,2019,vol. 17,p. 1827 - 1833

39
[ 500577-99-1 ]
C₂₀H₂₇F₂N₃O₃ [ No CAS ]

Reference： [1]Patent: WO2019/120209,2019,A1

40
[ 500577-99-1 ]
C₁₅H₁₉F₂N₃O*(x)ClH [ No CAS ]

Reference： [1]Patent: WO2019/120209,2019,A1

41
[ 500577-99-1 ]
C₂₃H₂₂F₅N₅OS [ No CAS ]
C₂₃H₂₂F₅N₅OS [ No CAS ]

Reference： [1]Patent: WO2019/120209,2019,A1

42
[ 500577-99-1 ]
[ 593-51-1 ]
C₈H₈F₂N₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
74%	With triethylamine; HATU; In tetrahydrofuran; at 20℃;	A mixture of <strong>[500577-99-1]4-amino-3,5-difluorobenzoic acid</strong> (CAS: 500577-99-1) (500 mg, 2.89 mmol), methylamine hydrochloride (393 mg, 5.78 mmol), HATU (1098 mg, 2.89 mmol) and Et3N(875 mg, 8.67 mmol) in THF (10 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (50 mL X 3). The combined organic extracts were washed with brine, dried over anhydrous Na,SOy,andfiltered. The filrate was concentrated and the residue was purified by chromatographyonsilica gel eluted with PE/EtOAc (3/1, v/v) to give intermediate 157 (400 mg, 74%) as a white solid.

Reference： [1]Patent: WO2019/120209,2019,A1 .Location in patent: Page/Page column 190

43
[ 500577-99-1 ]
methyl 3,5-difluoro-4-nitrosobenzoate [ No CAS ]

Reference： [1]Patent: WO2019/222635,2019,A1

44
[ 500577-99-1 ]
C₂₀H₂₁BF₂N₂O₄ [ No CAS ]

Reference： [1]Patent: WO2019/222635,2019,A1

45
[ 500577-99-1 ]
(E)-(2-((2,6-difluoro-4-(methoxycarbonyl)phenyl)diazenyl)phenyl)boronic acid [ No CAS ]

Reference： [1]Patent: WO2019/222635,2019,A1

46
[ 500577-99-1 ]
(E)-4-((2-boronophenyl)diazenyl)-3,5-difluorobenzoic acid [ No CAS ]

Reference： [1]Patent: WO2019/222635,2019,A1

47
[ 67-56-1 ]
[ 500577-99-1 ]
[ 1162676-00-7 ]

Yield	Reaction Conditions	Operation in experiment
77%	With sulfuric acid; for 14h;Reflux;	[4- Amino-3, 5-difluorobenzoic acid (500 mg, 2.89 mmol) was dissolved in 20 mL of MeOH, to which 1.75 mL of concentrated sulfuric acid was added. The reaction was heated to reflux for 14 hours. After the reaction, the solvent was removed in vacuo and 20 mL of water was added, leading to the precipitation of the product, which was collected and dried on a funnel to provide the title product (417 mg, 77%) as a white solid, which was used in the next reaction without further purification. *H NMR (500 MHz, CDCh) d 7.58 - 7.46 (m, 2H), 4.14 (s, 2H), 3.87 (s, 3H).

Reference： [1]Patent: WO2019/222635,2019,A1 .Location in patent: Paragraph 0082-0083

48
[ 500577-99-1 ]
(E)-3,5-difluoro-4-((4-methoxyphenyl)diazenyl)benzoic acid [ No CAS ]

Reference： [1]Beilstein Journal of Organic Chemistry,2019,vol. 15,p. 2812 - 2821

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Ghs Precautionary Statements

Precautionary Statements-General
Code	Phrase
P101	If medical advice is needed,have product container or label at hand.
P102	Keep out of reach of children.
P103	Read label before use
Prevention
Code	Phrase
P201	Obtain special instructions before use.
P202	Do not handle until all safety precautions have been read and understood.
P210	Keep away from heat/sparks/open flames/hot surfaces. - No smoking.
P211	Do not spray on an open flame or other ignition source.
P220	Keep/Store away from clothing/combustible materials.
P221	Take any precaution to avoid mixing with combustibles
P222	Do not allow contact with air.
P223	Keep away from any possible contact with water, because of violent reaction and possible flash fire.
P230	Keep wetted
P231	Handle under inert gas.
P232	Protect from moisture.
P233	Keep container tightly closed.
P234	Keep only in original container.
P235	Keep cool
P240	Ground/bond container and receiving equipment.
P241	Use explosion-proof electrical/ventilating/lighting/equipment.
P242	Use only non-sparking tools.
P243	Take precautionary measures against static discharge.
P244	Keep reduction valves free from grease and oil.
P250	Do not subject to grinding/shock/friction.
P251	Pressurized container: Do not pierce or burn, even after use.
P260	Do not breathe dust/fume/gas/mist/vapours/spray.
P261	Avoid breathing dust/fume/gas/mist/vapours/spray.
P262	Do not get in eyes, on skin, or on clothing.
P263	Avoid contact during pregnancy/while nursing.
P264	Wash hands thoroughly after handling.
P265	Wash skin thouroughly after handling.
P270	Do not eat, drink or smoke when using this product.
P271	Use only outdoors or in a well-ventilated area.
P272	Contaminated work clothing should not be allowed out of the workplace.
P273	Avoid release to the environment.
P280	Wear protective gloves/protective clothing/eye protection/face protection.
P281	Use personal protective equipment as required.
P282	Wear cold insulating gloves/face shield/eye protection.
P283	Wear fire/flame resistant/retardant clothing.
P284	Wear respiratory protection.
P285	In case of inadequate ventilation wear respiratory protection.
P231 + P232	Handle under inert gas. Protect from moisture.
P235 + P410	Keep cool. Protect from sunlight.
Response
Code	Phrase
P301	IF SWALLOWED:
P304	IF INHALED:
P305	IF IN EYES:
P306	IF ON CLOTHING:
P307	IF exposed:
P308	IF exposed or concerned:
P309	IF exposed or if you feel unwell:
P310	Immediately call a POISON CENTER or doctor/physician.
P311	Call a POISON CENTER or doctor/physician.
P312	Call a POISON CENTER or doctor/physician if you feel unwell.
P313	Get medical advice/attention.
P314	Get medical advice/attention if you feel unwell.
P315	Get immediate medical advice/attention.
P320
P302 + P352	IF ON SKIN: wash with plenty of soap and water.
P321
P322
P330	Rinse mouth.
P331	Do NOT induce vomiting.
P332	IF SKIN irritation occurs:
P333	If skin irritation or rash occurs:
P334	Immerse in cool water/wrap n wet bandages.
P335	Brush off loose particles from skin.
P336	Thaw frosted parts with lukewarm water. Do not rub affected area.
P337	If eye irritation persists:
P338	Remove contact lenses, if present and easy to do. Continue rinsing.
P340	Remove victim to fresh air and keep at rest in a position comfortable for breathing.
P341	If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P342	If experiencing respiratory symptoms:
P350	Gently wash with plenty of soap and water.
P351	Rinse cautiously with water for several minutes.
P352	Wash with plenty of soap and water.
P353	Rinse skin with water/shower.
P360	Rinse immediately contaminated clothing and skin with plenty of water before removing clothes.
P361	Remove/Take off immediately all contaminated clothing.
P362	Take off contaminated clothing and wash before reuse.
P363	Wash contaminated clothing before reuse.
P370	In case of fire:
P371	In case of major fire and large quantities:
P372	Explosion risk in case of fire.
P373	DO NOT fight fire when fire reaches explosives.
P374	Fight fire with normal precautions from a reasonable distance.
P376	Stop leak if safe to do so. Oxidising gases (section 2.4) 1
P377	Leaking gas fire: Do not extinguish, unless leak can be stopped safely.
P378
P380	Evacuate area.
P381	Eliminate all ignition sources if safe to do so.
P390	Absorb spillage to prevent material damage.
P391	Collect spillage. Hazardous to the aquatic environment
P301 + P310	IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician.
P301 + P312	IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.
P301 + P330 + P331	IF SWALLOWED: Rinse mouth. Do NOT induce vomiting.
P302 + P334	IF ON SKIN: Immerse in cool water/wrap in wet bandages.
P302 + P350	IF ON SKIN: Gently wash with plenty of soap and water.
P303 + P361 + P353	IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower.
P304 + P312	IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell.
P304 + P340	IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.
P304 + P341	IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing.
P305 + P351 + P338	IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing.
P306 + P360	IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes.
P307 + P311	IF exposed: call a POISON CENTER or doctor/physician.
P308 + P313	IF exposed or concerned: Get medical advice/attention.
P309 + P311	IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician.
P332 + P313	IF SKIN irritation occurs: Get medical advice/attention.
P333 + P313	IF SKIN irritation or rash occurs: Get medical advice/attention.
P335 + P334	Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages.
P337 + P313	IF eye irritation persists: Get medical advice/attention.
P342 + P311	IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician.
P370 + P376	In case of fire: Stop leak if safe to Do so.
P370 + P378	In case of fire:
P370 + P380	In case of fire: Evacuate area.
P370 + P380 + P375	In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion.
P371 + P380 + P375	In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion.
Storage
Code	Phrase
P401
P402	Store in a dry place.
P403	Store in a well-ventilated place.
P404	Store in a closed container.
P405	Store locked up.
P406	Store in corrosive resistant/ container with a resistant inner liner.
P407	Maintain air gap between stacks/pallets.
P410	Protect from sunlight.
P411
P412	Do not expose to temperatures exceeding 50 oC/ 122 oF.
P413
P420	Store away from other materials.
P422
P402 + P404	Store in a dry place. Store in a closed container.
P403 + P233	Store in a well-ventilated place. Keep container tightly closed.
P403 + P235	Store in a well-ventilated place. Keep cool.
P410 + P403	Protect from sunlight. Store in a well-ventilated place.
P410 + P412	Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF.
P411 + P235	Keep cool.
Disposal
Code	Phrase
P501	Dispose of contents/container to ...
P502	Refer to manufacturer/supplier for information on recovery/recycling

Ghs Hazard Statements

Physical hazards
Code	Phrase
H200	Unstable explosive
H201	Explosive; mass explosion hazard
H202	Explosive; severe projection hazard
H203	Explosive; fire, blast or projection hazard
H204	Fire or projection hazard
H205	May mass explode in fire
H220	Extremely flammable gas
H221	Flammable gas
H222	Extremely flammable aerosol
H223	Flammable aerosol
H224	Extremely flammable liquid and vapour
H225	Highly flammable liquid and vapour
H226	Flammable liquid and vapour
H227	Combustible liquid
H228	Flammable solid
H229	Pressurized container: may burst if heated
H230	May react explosively even in the absence of air
H231	May react explosively even in the absence of air at elevated pressure and/or temperature
H240	Heating may cause an explosion
H241	Heating may cause a fire or explosion
H242	Heating may cause a fire
H250	Catches fire spontaneously if exposed to air
H251	Self-heating; may catch fire
H252	Self-heating in large quantities; may catch fire
H260	In contact with water releases flammable gases which may ignite spontaneously
H261	In contact with water releases flammable gas
H270	May cause or intensify fire; oxidizer
H271	May cause fire or explosion; strong oxidizer
H272	May intensify fire; oxidizer
H280	Contains gas under pressure; may explode if heated
H281	Contains refrigerated gas; may cause cryogenic burns or injury
H290	May be corrosive to metals
Health hazards
Code	Phrase
H300	Fatal if swallowed
H301	Toxic if swallowed
H302	Harmful if swallowed
H303	May be harmful if swallowed
H304	May be fatal if swallowed and enters airways
H305	May be harmful if swallowed and enters airways
H310	Fatal in contact with skin
H311	Toxic in contact with skin
H312	Harmful in contact with skin
H313	May be harmful in contact with skin
H314	Causes severe skin burns and eye damage
H315	Causes skin irritation
H316	Causes mild skin irritation
H317	May cause an allergic skin reaction
H318	Causes serious eye damage
H319	Causes serious eye irritation
H320	Causes eye irritation
H330	Fatal if inhaled
H331	Toxic if inhaled
H332	Harmful if inhaled
H333	May be harmful if inhaled
H334	May cause allergy or asthma symptoms or breathing difficulties if inhaled
H335	May cause respiratory irritation
H336	May cause drowsiness or dizziness
H340	May cause genetic defects
H341	Suspected of causing genetic defects
H350	May cause cancer
H351	Suspected of causing cancer
H360	May damage fertility or the unborn child
H361	Suspected of damaging fertility or the unborn child
H361d	Suspected of damaging the unborn child
H362	May cause harm to breast-fed children
H370	Causes damage to organs
H371	May cause damage to organs
H372	Causes damage to organs through prolonged or repeated exposure
H373	May cause damage to organs through prolonged or repeated exposure
Environmental hazards
Code	Phrase
H400	Very toxic to aquatic life
H401	Toxic to aquatic life
H402	Harmful to aquatic life
H410	Very toxic to aquatic life with long-lasting effects
H411	Toxic to aquatic life with long-lasting effects
H412	Harmful to aquatic life with long-lasting effects
H413	May cause long-lasting harmful effects to aquatic life
H420	Harms public health and the environment by destroying ozone in the upper atmosphere