[ CAS No. 146137-80-6 ] {[proInfo.proName]}

Name: 146137-80-6|2-Fluoro-4-methylbenzaldehyde|98%
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Quality Control of [ 146137-80-6 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 146137-80-6 ]

Product Details of [ 146137-80-6 ]

CAS No. :	146137-80-6	MDL No. :	MFCD03094325
Formula :	C₈H₇FO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	MVDRIMBGRZBWPE-UHFFFAOYSA-N
M.W :	138.14	Pubchem ID :	2778471
Synonyms :

Calculated chemistry of [ 146137-80-6 ]

Physicochemical Properties

Num. heavy atoms :	10
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.12
Num. rotatable bonds :	1
Num. H-bond acceptors :	2.0
Num. H-bond donors :	0.0
Molar Refractivity :	36.75
TPSA :	17.07 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.83 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.78
Log Po/w (XLOGP3) :	1.85
Log Po/w (WLOGP) :	2.37
Log Po/w (MLOGP) :	2.21
Log Po/w (SILICOS-IT) :	2.86
Consensus Log Po/w :	2.21

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	2.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-2.24
Solubility :	0.795 mg/ml ; 0.00575 mol/l
Class :	Soluble
Log S (Ali) :	-1.83
Solubility :	2.05 mg/ml ; 0.0148 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.98
Solubility :	0.144 mg/ml ; 0.00104 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	1.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.06

Safety of [ 146137-80-6 ]

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 [ 146137-80-6 ]

* 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 [ 146137-80-6 ]
Downstream synthetic route of [ 146137-80-6 ]

[ 146137-80-6 ] Synthesis Path-Upstream 1~8

1
[ 95-52-3 ]
[ 201230-82-2 ]
[ 63082-45-1 ]
[ 146137-80-6 ]

Reference： [1] Patent: EP1544189, 2005, A1, . Location in patent: Page/Page column 6

2
[ 452-74-4 ]
[ 146137-80-6 ]

Reference： [1] Patent: US6462242, 2002, B1,

3
[ 95-52-3 ]
[ 201230-82-2 ]
[ 63082-45-1 ]
[ 146137-80-6 ]

Reference： [1] Patent: EP1544189, 2005, A1, . Location in patent: Page/Page column 6

4
[ 3030-47-5 ]
[ 352-70-5 ]
[ 146137-80-6 ]

Reference： [1] Patent: US2002/156081, 2002, A1,
[2] Patent: US6921763, 2005, B2,

5
[ 50-00-0 ]
[ 452-80-2 ]
[ 146137-80-6 ]

Reference： [1] Journal of Medicinal Chemistry, 2010, vol. 53, # 21, p. 7879 - 7882
[2] Patent: US2012/16158, 2012, A1, . Location in patent: Page/Page column 3-4

6
[ 104-87-0 ]
[ 146137-80-6 ]
[ 177756-62-6 ]

Reference： [1] Organic Process Research and Development, 2008, vol. 12, # 2, p. 339 - 344

7
[ 352-70-5 ]
[ 68-12-2 ]
[ 146137-80-6 ]

Reference： [1] Tetrahedron Letters, 1992, vol. 33, # 49, p. 7499 - 7502

8
[ 104-87-0 ]
[ 146137-80-6 ]
[ 177756-62-6 ]

Reference： [1] Organic Process Research and Development, 2008, vol. 12, # 2, p. 339 - 344

[ 146137-80-6 ] Synthesis Path-Downstream 1~88

1
[ 2365-48-2 ]
[ 146137-80-6 ]
[ 82787-72-2 ]

Reference： [1]Tetrahedron Letters,1992,vol. 33,p. 7499 - 7502
[2]Journal of Medicinal Chemistry,2007,vol. 50,p. 4793 - 4807

2
[ 352-70-5 ]
[ 68-12-2 ]
[ 146137-80-6 ]

Reference： [1]Tetrahedron Letters,1992,vol. 33,p. 7499 - 7502

3
[ 3030-47-5 ]
[ 352-70-5 ]
[ 146137-80-6 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; n-butyllithium; In tetrahydrofuran; n-heptane; ethyl acetate; N,N-dimethyl-formamide;	a 2-fluoro-4-methylbenzaldehyde The solution of 3-fluorotoluene (2.91 g, 0.0266 mol) in anhydrous tetrahydrofuran was cooled to -78 C. and a 1.4M solution of n-butyllithium in hexanes (19 mL, 0.0266 mol) was added dropwise keeping the reaction mixture temperature below -75 C. Upon the completion of the addition, N,N,N',N',N"-pentamethyldiethylenetriamine was added dropwise and the stirring at -78 C. was continued under an atmosphere of nitrogen for an additional 2 hours. N,N-dimethylformamide (3.89 g, 0.0532 mol) was added dropwise and the reaction mixture was slowly warmed up while stirring for 0.5 hours. It was quenched by dropwise addition of 1N hydrochloric acid and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2x 150 mL) and the combined organic extracts were dried with magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield 2-fluoro-4-methylbenzaldehyde (0.83 g, 0.006 mol) as a white solid. 1H NMR (DMSO-d6, 400 MHz) delta 10.17 (s, 1H), 7.74 (d, 1H), 7.23 (m, 2H), 2.41 (s, 3H). TLC (ethyl acetate/heptane 5:95) Rf 0.18
	With hydrogenchloride; n-butyllithium; In tetrahydrofuran; n-heptane; ethyl acetate; N,N-dimethyl-formamide;	a) 2-fluoro-4-methylbenzaldehyde The solution of 3-fluorotoluene (2.91 g, 0.0266 mol) in anhydrous tetrahydrofuran was cooled to -78 C. and a 1.4M solution of n-butyllithium in hexanes (19 mL, 0.0266 mol) was added dropwise keeping the reaction mixture temperature below -75 C. Upon the completion of the addition, N,N,N',N',N"-pentamethyldiethylenetriamine was added dropwise and the stirring at -78 C. was continued under an atmosphere of nitrogen for an additional 2 hours. N,N-dimethylformamide (3.89 g, 0.0532 mol) was added dropwise and the reaction mixture was slowly warmed up while stirring for 0.5 hours. It was quenched by dropwise addition of 1N hydrochloric acid and the layers were separated. The aqueous phase was further extracted with ethyl acetate (2*150 mL) and the combined organic extracts were dried with magnesium sulfate. The organic phase was concentrated under reduced pressure and the residue was purified by flash chromatography on silica using ethyl acetate/n-heptane (5:95) as mobile phase to yield 2-fluoro-4-methylbenzaldehyde (0.83 g, 0.006 mol) as a white solid. 1H NMR (DMSO-d6, 400 MHz) delta 10.17 (s, 1H), 7.74 (d, 1H), 7.23 (m, 2H), 2.41 (s, 3H).

Reference： [1]Patent: US2002/156081,2002,A1
[2]Patent: US6921763,2005,B2

4
[ 452-74-4 ]
[ 146137-80-6 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium formate;bis(triphenylphosphine)palladium(II) dichloride; In CO; N,N-dimethyl-formamide;	Example 4 2-Fluoro-4-methylbenzaldehyde 2.84 g of 2-fluoro-4-methylbromobenzene, 0.21 g of bis(triphenylphosphine)palladium dichloride and 1.53 g of sodium formate were placed in a flask fitted with a reflux condenser and a gas inlet tube, 15 ml of DMF were added and the mixture was stirred and heated at 110 C. while passing in CO. After conversion was complete (GC monitoring), the reaction mixture was allowed to cool to 21 C. and the catalyst was separated off by filtration through silica gel. This gave a crude product which contained >95% of 2-fluoro-4-methylbenzaldehyde and <1% of 2-fluoro-4-methylbenzyl alcohol (percentages are based on the areas in the GC).

Reference： [1]Patent: US6462242,2002,B1

5
[ 867-13-0 ]
[ 146137-80-6 ]
[ 1030846-76-4 ]

Yield	Reaction Conditions	Operation in experiment
		Production Example 1 Under ice-cooling, sodium hydride (about 40% mineral oil was added, 7.0 g) was added to a THF (120 ml) solution of ethyl diethylphosphonoacetate (38 ml) and stirred under ice-cooling for 30 minutes. A THF (200 ml) solution of <strong>[146137-80-6]2-fluoro-4-methylbenzaldehyde</strong> (20 g) was added dropwise under ice-cooling to the reaction mixture and stirred under ice-cooling for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and then dried with anhydrous magnesium sulfate. The desiccant was removed, the solvent was evaporated under a reduced pressure, and then the residue was purified by a silica gel column chromatography (hexane-ethyl acetate) to obtain ethyl (2E)-3-(2-fluoro-4-methylphenyl)acrylate (30 g) as a colorless oil.

Reference： [1]Patent: EP2096109,2009,A1 .Location in patent: Page/Page column 19

6
[ 1231308-52-3 ]
[ 146137-80-6 ]
[ 1231308-55-6 ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of terf-butyl l-(((ls,4s)-4-(benzyloxymethyl)cyclohexyl)methyl)hydrazinecarboxylate (1.0 g, 2.87 mmol) in CH2Cl2 (5 mL), was added TFA (5.0 mL) at room temperature. After stirring for 3 h at the same temperature, the reaction was concentrated under reduced pressure. The residue was dissolved in THF (10 mL) and <strong>[146137-80-6]2-fluoro-4-methylbenzaldehyde</strong> (0.40 g, 2.87 mmol) was added. After stirring for 30 min, the reaction was washed with saturated NaHCO3. The organics were dried over MgSO4 and concentrated under reduced pressure to give the title compound (0.96 g). LCMS mlz = 369.3 [M+H]+.

Reference： [1]Patent: WO2010/68242,2010,A1 .Location in patent: Page/Page column 142

7
[ 146137-80-6 ]
[ 109-77-3 ]
[ 771570-09-3 ]

Reference： [1]Tetrahedron Letters,2010,vol. 51,p. 4991 - 4994
[2]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2741 - 2745
[3]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 6296 - 6299

8
[ 50-00-0 ]
[ 452-80-2 ]
[ 146137-80-6 ]

Yield	Reaction Conditions	Operation in experiment
		First, commercially available tri-substituted aromatic compounds (1a to 1d) including different halogens were used as a starting material and converted to aldehyde compounds (2a to 2d) by subjecting their amino group ends to a formylation reaction.Such conversion can be performed, for example, in accordance with the following steps: In step i, a diazotization reaction is performed by using hydrochloric acid/sodium nitrate/copper sulfate/sodium sulfite/sodium acetate. Then, in step ii, the resulting product is treated with hydroximic amine hydrochloride in the presence of paraformaldehyde. Then, in step iii, the resulting product is degraded by using hydrochloric acid to obtain the aldehyde compound of interest.

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 7879 - 7882
[2]Patent: US2012/16158,2012,A1 .Location in patent: Page/Page column 3-4
[3]Patent: CN109134262,2019,A .Location in patent: Paragraph 0035-0036; 0038

9
[ 4009-98-7 ]
[ 146137-80-6 ]
C₁₀H₁₁FO [ No CAS ]

Reference： [1]Journal of Medicinal Chemistry,2010,vol. 53,p. 7879 - 7882

10
[ 146137-80-6 ]
[ 57260-71-6 ]
[ 1285444-20-3 ]

Reference： [1]Synthesis,2010,p. 4287 - 4299

11
[ 352-24-9 ]
[ 146137-80-6 ]
[ 57-13-6 ]
[ 1293388-61-0 ]

Reference： [1]Journal of Fluorine Chemistry,2011,vol. 132,p. 155 - 159

12
[ 101336-63-4 ]
[ 146137-80-6 ]
[ 109-77-3 ]
[ 1204654-01-2 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2741 - 2745

13
[ 146137-80-6 ]
[ 1204654-01-2 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 2741 - 2745

14
[ 146137-80-6 ]
[ 1227682-53-2 ]

Reference： [1]Journal of Agricultural and Food Chemistry,2010,vol. 58,p. 6296 - 6299

15
[ 146137-80-6 ]
[ 60-34-4 ]
[ 34879-87-3 ]

Reference： [1]Organic process research and development,2011,vol. 15,p. 565 - 569

16
[ 4009-98-7 ]
[ 146137-80-6 ]
[ 1241405-22-0 ]

Yield	Reaction Conditions	Operation in experiment
		Then, the obtained aldehyde compounds (2a to 2d) are subjected to, for example, a Wittig reaction using MeOCH2 P(Ph3)Cl and C6H18KNSi2 in toluene (step iv), and furthermore, for example, to acid treatment using hydrochloric acid in acetone (step v), thereby obtaining phenyl aldehyde compounds (3a to 3d) that have an extended carbon chain. The phenyl aldehyde compounds (3a to 3d) are converted to phenylacetic acid compounds (4a to 4d) by the oxidation reaction using periodic acid in the presence of 2% by mole of PFC (step vi).

Reference： [1]Patent: US2012/16158,2012,A1 .Location in patent: Page/Page column 3-4
[2]Patent: CN109134262,2019,A .Location in patent: Paragraph 0035-0036; 0039

17
[ 146137-80-6 ]
[ 518070-28-5 ]

Reference： [1]Patent: CN109134262,2019,A

18
[ 146137-80-6 ]
[ 1241405-26-4 ]

Reference： [1]Patent: US2012/16158,2012,A1

19
[ 146137-80-6 ]
[ 1241405-27-5 ]

Reference： [1]Patent: US2012/16158,2012,A1

20
[ 146137-80-6 ]
[ 1241405-31-1 ]

Reference： [1]Patent: US2012/16158,2012,A1

21
[ 146137-80-6 ]
[ 1241405-35-5 ]

Reference： [1]Patent: US2012/16158,2012,A1

22
[ 146137-80-6 ]
[ 1241405-00-4 ]

Reference： [1]Patent: US2012/16158,2012,A1

23
[ 104-87-0 ]
[ 146137-80-6 ]
[ 177756-62-6 ]

Reference： [1]Organic Process Research and Development,2008,vol. 12,p. 339 - 344

24
[ 4926-28-7 ]
[ 146137-80-6 ]
(2-fluoro-4-methylphenyl)(4-methylpyridin-2-yl)methanol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		7B To a solution of 2-bromo-4-methylpyridine (600 mg) in diethyl ether (20 mL) at -78 C. is added a 2.3M solution of butyllithium in hexanes (1.52 mL). After stirring at this temperature for 1 hour <strong>[146137-80-6]2-fluoro-4-methylbenzaldehyde</strong> is added and the mixture allowed to warm at room temperature. The reaction mixture is then hydrolyzed with diluted aqueous hydrochloric acid, washed with diethyl ether, basified with concentrated sodium hydroxide and extracted with diethyl ether. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (heptane/ethyl acetate 2/1) to afford (2-fluoro-4-methylphenyl)(4-methyl-pyridin-2-yl)methanol as a pale yellow oil which solidifies on standing. Further examples can be prepared according to example 7. As regards the etherification step it can be advantageous to rise the temperature progressively after having mixed the different reagents and to observe when etherification occurs. Once the right temperature has been found, reaction may be continued up to adequate conversion.

Reference： [1]Patent: US2013/324507,2013,A1 .Location in patent: Paragraph 0238

25
[ 6272-38-4 ]
[ 146137-80-6 ]
2-(2-(benzyloxy)phenoxy)-4-methylbenzaldehyde [ No CAS ]