[ CAS No. 532967-21-8 ]

Name: 532967-21-8|2,6-Difluoro-4-hydroxybenzaldehyde|98%
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SKU: A194628
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Quality Control of [ 532967-21-8 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 532967-21-8 ]

Product Details of [ 532967-21-8 ]

CAS No. :	532967-21-8	MDL No. :	MFCD07772042
Formula :	C₇H₄F₂O₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	ROAQMGJHSNIROA-UHFFFAOYSA-N
M.W :	158.10 g/mol	Pubchem ID :	24903548
Synonyms :

Calculated chemistry of [ 532967-21-8 ]

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 :	33.77
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) :	-6.39 cm/s

Lipophilicity

Log Po/w (iLOGP) :	0.95
Log Po/w (XLOGP3) :	1.23
Log Po/w (WLOGP) :	2.32
Log Po/w (MLOGP) :	1.66
Log Po/w (SILICOS-IT) :	2.35
Consensus Log Po/w :	1.7

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	1.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-1.93
Solubility :	1.85 mg/ml ; 0.0117 mol/l
Class :	Very soluble
Log S (Ali) :	-1.61
Solubility :	3.87 mg/ml ; 0.0245 mol/l
Class :	Very 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 :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.09

Safety of [ 532967-21-8 ]

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 [ 532967-21-8 ]

* 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 [ 532967-21-8 ]
Downstream synthetic route of [ 532967-21-8 ]

[ 532967-21-8 ] Synthesis Path-Upstream 1~1

1
[ 68-12-2 ]
[ 532967-21-8 ]

Yield	Reaction Conditions	Operation in experiment
97%	Stage #1: With N,N,N,N,-tetramethylethylenediamine; sec.-butyllithium In tetrahydrofuran; cyclohexane at -78℃; for 0.5 h; Stage #2: at -78℃; for 1.5 h; Stage #3: With hydrogenchloride; water In tetrahydrofuran; cyclohexane at 20℃; for 12 h;	Intermediate 20; 4-hydroxy-2,6-difluorobenzaldehyde. Sec-BuLi (1.3M solution in cyclohexane, 53 mL, 69.3 mmol) was added slowly at -78⁰C to a solution of intermediate 19, 1-(ferf- butyldimethylsilyl)oxy-3,5-difluorobenzene (15.3 g, 62.6 mmol) and TMEDA (10.5 mL, 69.3 mmol) in THF (200 mL) and the mixture was stirred at the same temperature for 30 min. DMF (5.33 mL, 69.3 mmol) was added to the mixture at -78⁰C, and the mixture was stirred at the same temperature for 1.5h. Then 10percent aqueous HCI was added to attain pH~4-5 (200 mL),USERS\\DOCS\\LA21952\\LPJWA\\5D2T011.DOC / 250229 / PC32528.JWA Foreign Filing 04-27-06 EPO <DP n="138"/>and then the reaction mixture was stirred at RT for 12h. The aqueous layer was extracted with EtOAc (200 mL). The organic layer was separated. The organic layer was washed with sat. NaHCO₃, then H₂O was added, HCI was added to attain pH~3-4, the organic layer was separated, washed with brine, dried with Na₂SO₄ and evaporated in vacuo to give the title compound (9.7 g, 97percent, 61.3 mmol) as a white solid. 1 H NMR data (dmso-d6): 11.54 (br.s, 1 H, OH), 10.00 (s, 1H, CHO), 6.50 - 6.57 (m, 2H, H-Ar).

Reference： [1] Patent: WO2006/136924, 2006, A1, . Location in patent: Page/Page column 136-137

[ 532967-21-8 ] Synthesis Path-Downstream 1~59

1
[ 123-75-1 ]
[ 532967-21-8 ]
[ 917828-00-3 ]

Yield	Reaction Conditions	Operation in experiment
20%		Intermediate 21; 3,5-Difluoro-4-(pyrrolidin-1-ylmethyl)phenol. Pyrrolidine (6.6 mL, 80 mmol) was added to a solution of intermediate 20, <strong>[532967-21-8]4-hydroxy-2,6-difluorobenzaldehyde</strong> (9.7 g, 61.3 mmol) in dichloromethane (100 mL). The reaction mixture was cooled on ice bath, and sodium triacetoxyborohydride (19.5 g, 925 mmol) was added in portions under stirring. The reaction mixture was intensively stirred for 24 h at RT. Water (100 mL) and concentrated HCI were added to attain pH~2. The organic layer was separated. The aqueous one was extracted with CH2CI2 (2 * 100 mL), then with EtOAc (100 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH~10, the obtained crystals were separated by filtration, dried in vacuo, dissolved in small amount of water, HCI was added to attain pH~7, and water layer was extracted with CHCI3 (2 * 100 mL). The organic layer was separated, washed with brine, dried with Na2SO4 and evaporated in vacuo to give the title compound (2.6 g, 20%, 12 mmol). LCMS data: 215 and 214 (M+H)+ (calculated for C11H13F2NO 213.23). 1H NMR data (DMSO-d6): 10.26 (br.s, 1H, OH), 6.38 - 6.46 (m, 2H, H- Ar), 3.52 (s, 2H, Ar-CH2); 2.35 - 2.44 (m, 4H), 1.58 - 1.68 (m, 4H).

Reference： [1]Patent: WO2006/136924,2006,A1 .Location in patent: Page/Page column 137

2
[ 68-12-2 ]
[ 532967-21-8 ]

Yield	Reaction Conditions	Operation in experiment
97%		Intermediate 20; 4-hydroxy-2,6-difluorobenzaldehyde. Sec-BuLi (1.3M solution in cyclohexane, 53 mL, 69.3 mmol) was added slowly at -780C to a solution of intermediate 19, 1-(ferf- butyldimethylsilyl)oxy-3,5-difluorobenzene (15.3 g, 62.6 mmol) and TMEDA (10.5 mL, 69.3 mmol) in THF (200 mL) and the mixture was stirred at the same temperature for 30 min. DMF (5.33 mL, 69.3 mmol) was added to the mixture at -780C, and the mixture was stirred at the same temperature for 1.5h. Then 10% aqueous HCI was added to attain pH~4-5 (200 mL),USERSDOCSLA21952LPJWA5D2T011.DOC / 250229 / PC32528.JWA Foreign Filing 04-27-06 EPO <DP n="138"/>and then the reaction mixture was stirred at RT for 12h. The aqueous layer was extracted with EtOAc (200 mL). The organic layer was separated. The organic layer was washed with sat. NaHCO3, then H2O was added, HCI was added to attain pH~3-4, the organic layer was separated, washed with brine, dried with Na2SO4 and evaporated in vacuo to give the title compound (9.7 g, 97%, 61.3 mmol) as a white solid. 1 H NMR data (dmso-d6): 11.54 (br.s, 1 H, OH), 10.00 (s, 1H, CHO), 6.50 - 6.57 (m, 2H, H-Ar).

Reference： [1]Patent: WO2006/136924,2006,A1 .Location in patent: Page/Page column 136-137

4
[ 532967-21-8 ]
[ 86864-60-0 ]
[ 1239964-34-1 ]

Yield	Reaction Conditions	Operation in experiment
100%	With potassium carbonate; In N,N-dimethyl-formamide; at 85℃; for 3h;	To a solution of <strong>[532967-21-8]2,6-difluoro-4-hydroxybenzaldehyde</strong> (5.00 g, 31.60 mmol) in DMF (80 mL) were added K2CO3 (6.50 g, 47.40 mmol) and (2-bromoethoxy)-tert- butyldimethylsilane (8.90 mL, 41.10 mmol). The reaction mixture was heated to 85 0C for 3h and was complete by LCMS analysis. The cooled mixture was combined with water and extracted with EtOAc (3 x 100 mL). The combined extracts were washed with brine, dried over anhyd Na2SO4, concentrated and purified by flash chromatography (20% EtO Ac/Hex) to achieve 4-(2-(fert-butyldimethylsilyloxy)ethoxy)-2,6-difluorobenzaldehyde as a while solid (10.00 g, 100%). MS (EI) m/z 317.3 (MH+).

Reference： [1]Patent: WO2010/93845,2010,A1 .Location in patent: Page/Page column 158

5
[ 15159-40-7 ]
[ 532967-21-8 ]
[ 1296131-13-9 ]

Yield	Reaction Conditions	Operation in experiment
94%	With pyridine; In dichloromethane; at 0 - 20℃;Cooling with ice;	To a 250 mL dry round bottom flask were added <strong>[532967-21-8]2,6-difluoro-4-hydroxybenzaldehyde</strong> (5.53 g, 35.0 mmol), anhydrous CH2Cl2 (40 mL) and pyridine (3.68 mL, 45.5 mmol). The mixture was stirred in an ice-water bath, then 4-morpholinecarbonyl chloride (4.4 mL, 37.4 mmol) was added. After stirring at 0 C. for 1 hour, the mixture was stirred at room temperature overnight. Water (80 mL) and CH2Cl2 (50 mL) were added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (50 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 3,5-difluoro-4-formylphenyl morpholine-4-carboxylate (8.90 g) as white solid. Yield: 94%. 1H NMR (CDCl3, 300 MHz): delta=10.28 (s, 1H), 6.91 (dd, J=10.8, 1.5 Hz, 2H), 3.77-3.58 (m, 8H). 13C NMR (CDCl3, 75.5 MHz, mixture of two isomers): delta=183.7, 163.8 (dd, J=263.1, 8.53 Hz), 157.0 (t, J=15.3 Hz), 151.8, 111.7 (t, J=11.5 Hz), 106.6 (dd, J=25.1, 3.70 Hz), 66.6, 66.5, 45.2, 44.5.

Reference： [1]Patent: US2011/98251,2011,A1 .Location in patent: Page/Page column 64

6
[ 497-25-6 ]
[ 532967-21-8 ]
[ 32315-10-9 ]
[ 1296131-09-3 ]

Yield	Reaction Conditions	Operation in experiment
33%		To a 250 mL dry round bottom flask were added 2-oxazolidinone (4.35 g, 50.0 mmol), triphosgene (5.49 g, 18.5 mmol) and anhydrous THF (80 mL). The mixture was stirred in an ice-water bath, then triethylamine (9.8 mL, 70.0 mmol) was added slowly. After stirring at 0 C. for 1 hour, the mixture was stirred continually at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in 20 mL of CH2Cl2, and this solution was added slowly to a stirring mixture of <strong>[532967-21-8]2,6-difluoro-4-hydroxybenzaldehyde</strong> (5.93 g, 27.5 mmol) and pyridine (4.44 mL, 55.0 mmol) in 30 mL of anhydrous CH2Cl2 at 0 C. After stirring at room temperature for 10 hours, water (100 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (50 mL×4). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 3,5-difluoro-4-formylphenyl 2-oxooxazolidine-3-carboxylate (4.92 g) as a white solid. Yield: 33%. 1H NMR (CDCl3, 300 MHz): delta=10.29 (s, 1H), 6.98 (dd, J=10.8, 2.1 Hz, 2H), 4.51 (t, J=7.8 Hz, 2H), 4.18 (t, J=7.6 Hz, 2H). 13C NMR (CDCl3, 75.5 MHz): delta=183.5, 163.7 (dd, J=263.6, 8.00 Hz), 151.2, 148.0, 112.6, 106.8 (dd, J=25.7, 3.70 Hz), 62.1, 43.7.

Reference： [1]Patent: US2011/98251,2011,A1 .Location in patent: Page/Page column 61-62

7
[ 1121-83-1 ]
[ 532967-21-8 ]
[ 32315-10-9 ]
[ 1296131-20-8 ]

Yield	Reaction Conditions	Operation in experiment
52%		The synthesis of 5,5-Dimethyl-oxazolidin-2-one as depicted in the above scheme followed the procedures disclosed in: Bull, S. D.; Davies, S. G.; Jones, S.; Sanganee, H. J. J. Chem. Soc. Perkin Trans. 1 1999, 4, 387.To a 250 mL dry round bottom flask were added 5,5-dimethyl-oxazolidin-2-one (5.10 g, 44.3 mmol), triphosgene (5.26 g, 17.7 mmol) and anhydrous THF (80 mL). The mixture was stirred in an ice-water bath, then triethylamine (8.6 mL, 62.0 mmol) was added slowly. The resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate was concentrated. To the residue was added <strong>[532967-21-8]2,6-difluoro-4-hydroxybenzaldehyde</strong> (5.03 g, 31.9 mmol) and 80 mL of CH2Cl2. The resulting solution was cooled in an ice-water bath, then triethylamine (6.0 mL, 42.5 mmol) was added. After stirring at room temperature for 7 hours, water (100 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (50 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 3,5-difluoro-4-formylphenyl 5,5-dimethyl-2-oxooxazolidine-3-carboxylate (6.9 g) as a pale yellow crystal. Yield: 52%. 1H NMR (CDCl3, 300 MHz): delta=10.39 (s, 1H), 7.09 (d, J=9.0 Hz, 2H), 3.97 (s, 2H), 1.67 (s, 6H).

Reference： [1]Patent: US2011/98251,2011,A1 .Location in patent: Page/Page column 66

8
[ 532967-21-8 ]
[ 108-23-6 ]
[ 1296131-16-2 ]

Yield	Reaction Conditions	Operation in experiment
84%	With pyridine; In dichloromethane; toluene; at 0 - 20℃;Cooling with ice;	To a 250 mL dry round bottom flask were added <strong>[532967-21-8]2,6-difluoro-4-hydroxy-benzaldehyde</strong> (4.80 g, 30.4 mmol), anhydrous CH2Cl2 (30 mL) and pyridine (3.0 mL, 36.5 mmol). The mixture was stirred in an ice-water bath, then a solution of isopropyl chloroformate in toluene (1.0 M, 33.4 mL) was added. After stirring at 0 C. for 2 hours, the mixture was stirred at room temperature overnight. Water (80 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (80 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 3,5-difluoro-4-formylphenyl isopropyl carbonate (6.20 g) as a colorless oil. Yield: 84%. 1H NMR (CDCl3, 300 MHz): delta=10.30 (s, 1H), 7.02-6.96 (m, 2H), 5.03 (seventet, J=6.3 Hz, 1H), 1.43 (d, J=6.3 Hz, 6H). 13C NMR (CDCl3, 75.5 MHz): delta=183.3, 163.6 (dd, J=262.5, 7.92 Hz), 156.3 (t, J=15.2 Hz), 151.1, 111.9 (t, J=11.5 Hz), 106.0 (dd, J=25.1, 3.62 Hz), 74.5, 21.5. 19F NMR (CDCl3, 282.3 MHz): delta=-113.0 (d, J=9.0 Hz).

Reference： [1]Patent: US2011/98251,2011,A1 .Location in patent: Page/Page column 65

9
[ 1296132-58-5 ]
[ 532967-21-8 ]
[ 1296131-21-9 ]

Yield	Reaction Conditions	Operation in experiment
46%	With triethylamine; In dichloromethane; at 20℃; for 48h;	To a 250 mL dry round bottom flask were added (S)-(1-(chlorocarbonyl)pyrrolidin-2-yl)methyl acetate (6.79 g, 33.0 mmol), <strong>[532967-21-8]2,6-difluoro-4-hydroxybenzaldehyde</strong> (4.74 g, 30 mmol), triethylamine (5.40 mL, 39.0 mmol) and anhydrous CH2Cl2 (40 mL). The resulting mixture was stirred at room temperature for 2 days, then water (80 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (80 mL×2). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give (S)-3,5-difluoro-4-formylphenyl 2-(acetoxymethyl)pyrrolidine-1-carboxylate (4.92 g) as a colorless oil. Yield: 46%. 1H NMR (CDCl3, 300 MHz, mixture of two isomers): delta=10.28 (s, 1H), 6.97 (t, J=11.4 Hz, 2H), 4.33-4.12 (m, 3H), 3.65-3.55 (m, 2H), 2.10-2.01 (m, 7H). 13C NMR (CDCl3, 75.5 MHz, mixture of two isomers): delta=183.5, 170.7 (d, J=7.3 Hz), 163.6 (dd, J=262.5, 8.6 Hz), 157.0, 150.8 (d, J=14.6 Hz), 112.6, 106.2 (d, J=25.0 Hz), 64.4, 63.8, 56.8, 56.4, 47.4, 47.3, 28.7, 27.8, 23.8, 22.9, 20.8.

Reference： [1]Patent: US2011/98251,2011,A1 .Location in patent: Page/Page column 67

10
[ 532967-21-8 ]
[ 4128-31-8 ]
[ 32315-10-9 ]
[ 1296131-17-3 ]

Yield	Reaction Conditions	Operation in experiment
46%		To a 250 mL dry round bottom flask were added 2-octanol (4.51 g, 34.6 mmol), triphosgene (3.44 g, 11.6 mmol) and anhydrous THF (100 mL). The mixture was stirred in an ice-water bath, then pyridine (5.6 mL, 69.2 mmol) was injected slowly. After stirring at room temperature for 30 minutes, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in 15 mL of CH2Cl2 and cooled in an ice-water bath. To this stirring solution, a solution of <strong>[532967-21-8]2,6-difluoro-4-hydroxybenzaldehyde</strong> (4.2 g, 26.6 mmol) and pyridine (2.80 mL, 34.6 mmol) in 20 mL of anhydrous CH2Cl2 was added slowly. After stirring at room temperature for 2 hours, water (80 mL) was added to the reaction mixture. The CH2Cl2 layer was separated, and the aqueous layer was extracted continually with CH2Cl2 (100 mL×3). The combined CH2Cl2 solution was dried over Na2SO4. After removal of the solvent, the residue was purified with a silica gel chromatography (heptane/ethyl acetate, gradient eluting) to give 3,5-difluoro-4-formylphenyl octan-2-yl carbonate (5.0 g) as a colorless oil. Yield: 46%. 13C NMR (CDCl3, 75.5 MHz): delta=183.2, 163.4 (dd, J=263.0, 8.53 Hz), 156.3 (t, J=15.2 Hz), 151.2, 111.8 (t, J=11.0 Hz), 105.9 (dd, J=25.7, 3.62 Hz), 78.0, 35.6, 31.6, 28.9, 25.1, 22.4, 19.6, 13.9.

Reference： [1]Patent: US2011/98251,2011,A1 .Location in patent: Page/Page column 65

11
[ 532967-21-8 ]
[ 1239964-35-2 ]