15777-70-5|4-Hydroxy-3-methylbenzonitrile| Ambeed

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Quality Control of [ 15777-70-5 ] Purity: 98% SDS Specification

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Product Details of [ 15777-70-5 ]

CAS No. :	15777-70-5
Formula :	C₈H₇NO
M.W :	133.15
SMILES Code :	N#CC1=CC=C(O)C(C)=C1
MDL No. :	MFCD11848762
InChI Key :	WTTADDGUHFYGEH-UHFFFAOYSA-N
Pubchem ID :	10964560

Safety of [ 15777-70-5 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 15777-70-5 ] Show Less

Physicochemical Properties

Num. heavy atoms	10
Num. arom. heavy atoms	6
Fraction Csp3	0.12
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	38.15
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	44.02 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.43
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.98
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.57
Log P_o/w (MLOGP)? MLOGP: Topological method implemented from Moriguchi I. et al. 1992 Chem. Pharm. Bull. Moriguchi I. et al. 1994 Chem. Pharm. Bull. Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.	1.12
Log P_o/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	1.78
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.38

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.73
Solubility	2.5 mg/ml ; 0.0188 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.49
Solubility	4.28 mg/ml ; 0.0322 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com	-2.26
Solubility	0.73 mg/ml ; 0.00548 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble

Pharmacokinetics

GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg	High
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg	Yes
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) and tested on 415 molecules (test set) 10-fold CV: ACC=0.72 / AUC=0.77 External: ACC=0.88 / AUC=0.94	No
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.83 / AUC=0.90 External: ACC=0.84 / AUC=0.91	Yes
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) and tested on 3000 molecules (test set) 10-fold CV: ACC=0.80 / AUC=0.86 External: ACC=0.80 / AUC=0.87	No
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) and tested on 2075 molecules (test set) 10-fold CV: ACC=0.78 / AUC=0.85 External: ACC=0.71 / AUC=0.81	No
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) and tested on 1068 molecules (test set) 10-fold CV: ACC=0.79 / AUC=0.85 External: ACC=0.81 / AUC=0.87	No
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) and tested on 2579 molecules (test set) 10-fold CV: ACC=0.77 / AUC=0.85 External: ACC=0.78 / AUC=0.86	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.42 cm/s

Druglikeness

Lipinski? Lipinski (Pfizer) filter: implemented from Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev. MW ≤ 500 MLOGP ≤ 4.15 N or O ≤ 10 NH or OH ≤ 5	0.0
Ghose? Ghose filter: implemented from Ghose AK. et al. 1999 J. Comb. Chem. 160 ≤ MW ≤ 480 -0.4 ≤ WLOGP ≤ 5.6 40 ≤ MR ≤ 130 20 ≤ atoms ≤ 70	None
Veber? Veber (GSK) filter: implemented from Veber DF. et al. 2002 J. Med. Chem. Rotatable bonds ≤ 10 TPSA ≤ 140	0.0
Egan? Egan (Pharmacia) filter: implemented from Egan WJ. et al. 2000 J. Med. Chem. WLOGP ≤ 5.88 TPSA ≤ 131.6	0.0
Muegge? Muegge (Bayer) filter: implemented from Muegge I. et al. 2001 J. Med. Chem. 200 ≤ MW ≤ 600 -2 ≤ XLOGP ≤ 5 TPSA ≤ 150 Num. rings ≤ 7 Num. carbon > 4 Num. heteroatoms > 1 Num. rotatable bonds ≤ 15 H-bond acc. ≤ 10 H-bond don. ≤ 5	1.0
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat implemented from Martin YC. 2005 J. Med. Chem.	0.55

Medicinal Chemistry

PAINS? Pan Assay Interference Structures: implemented from Baell JB. & Holloway GA. 2010 J. Med. Chem.	0.0 alert
Brenk? Structural Alert: implemented from Brenk R. et al. 2008 ChemMedChem	0.0 alert: heavy_metal
Leadlikeness? Leadlikeness: implemented from Teague SJ. 1999 Angew. Chem. Int. Ed. 250 ≤ MW ≤ 350 XLOGP ≤ 3.5 Num. rotatable bonds ≤ 7	No; 1 violation:MW<1.0
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties, trained on 12'782'590 molecules and tested on 40 external molecules (r² = 0.94)	1.2

Application In Synthesis of [ 15777-70-5 ]

* 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.

Downstream synthetic route of [ 15777-70-5 ]

[ 15777-70-5 ] Synthesis Path-Downstream 1~35

1
[ 15777-70-5 ]
(Z)-N',4-dihydroxy-3-methylbenzimidamide [ No CAS ]

References: [1]ACS Medicinal Chemistry Letters,2018,vol. 9,p. 667 - 672.
[2]Chemische Berichte,1891,vol. 24,p. 3671.

2
[ 103264-03-5 ]
[ 15777-70-5 ]

Yield	Reaction Conditions	Operation in experiment
78%	With potassium carbonate; In methanol; water; at 20℃; for 0.5h;	An ice-cold solution of 4-bromo-2-methylphenol (5.6 g, 30 mmol) and pyridine (6.1 mL, 75 mmol) in 50 mL of anhydrous dichloromethane was treated with a solution of acetyl chloride (2. 8 mL, 26 mmol) in 5 ML of anhydrous dichloromethane. After 2 hours, the reaction mixture was concentrated IN VACUO. The resulting residue was treated with crushed ice, diluted with 150 mL of dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 6.9 g of 4-BROMO-2-METHYLPHENYL acetate as a light brown oil (quantitative yield). A solution of 4-bromo-2-methylphenyl acetate (6.9 g, 30 mol) in 75 ML of anhydrous dimethyl acetamide was treated with zinc cyanide (3 g, 25.6 mmol) and tetrakis (triphenylphosphine) palladium (0) (4.5 g, 3.9 mmol). The reaction mixture was heated at 100 C for 2 hours, cooled to room temperature, and treated with 300 mL of cold water. The resulting precipitate was filtered, washed with water, and air dried. Chromatography on SI02 (100% dichloromethane) afforded 5.2 g of 4-cyano-2-methylphenyl acetate as a colorless oil (99% yield), which solidified on standing. A stirred solution OF 4-CYANO-2-METHYLPHENYL acetate (5.2 g, 29.7 mmol) in 75 mL of methanol was treated with a solution of potassium carbonate (30 mmol, 4.15 g) in 25 mL of water at room temperature. After 30 minutes, the mixture was concentrated in vacuo and treated with 1 N sulfuric acid. The resulting precipitate was filtered, washed with water, and dried to give 3.1 g of 4-hydroxy-3-methylbenzonitrile as a white solid (78% yield). A stirred solution of 4-hydroxy-3-methylbenzonitrile (3.1 g, 23.3 mmol) in 60 mL of anhydrous acetonitrile was cooled to-30 C and treated with nitronium tetrafluoroborate (3.4 g, 25.6 mmol) in portions. After 60 minutes, the reaction mixture was diluted with 100 mL of water. The resulting light yellow precipitate was filtered, washed with water, and dried to give 3.9 g of 4-hydroxy-3-methyl-5-nitrobenzonitrile (94% yield). 4-Hydroxy-3-methyl-5-nitrobenzonitrile was converted to the title product according to the procedure described for the preparation of trifluoromethanesulfonic acid 3-fluoro-2-nitrophenyl ester.

References: [1]Patent: WO2005/30213,2005,A1 .Location in patent: Page/Page column 184.
[2]Chemische Berichte,1891,vol. 24,p. 3671.

3
[ 15777-70-5 ]
[ 2219-66-1 ]
[ 108839-34-5 ]

References: [1]Journal of the Chemical Society,1957,p. 1668,1670.

4
[ 589-57-1 ]
[ 15777-70-5 ]
[ 76211-49-9 ]

References: [1]Journal of general chemistry of the USSR,1980,vol. 50,p. 1561 - 1568.
Zhurnal Obshchei Khimii,1980,vol. 50,p. 1937 - 1946.

5
[ 15777-70-5 ]
[ 813-77-4 ]
[ 76216-77-8 ]

References: [1]Journal of general chemistry of the USSR,1980,vol. 50,p. 1561 - 1568.
Zhurnal Obshchei Khimii,1980,vol. 50,p. 1937 - 1946.

6
[ 7677-24-9 ]
[ 553-97-9 ]
[ 15777-70-5 ]
[ 14143-26-1 ]

References: [1]Tetrahedron Letters,1994,vol. 35,p. 7901 - 7904.

7
[ 67-56-1 ]
[ 15777-70-5 ]
[ 42113-13-3 ]

References: [1]Bulletin of the Chemical Society of Japan,1975,vol. 48,p. 2127 - 2133.

8
[ 78881-21-7 ]
[ 15777-70-5 ]

References: [1]Bulletin of the Chemical Society of Japan,1975,vol. 48,p. 2127 - 2133.

9
[ 15777-70-5 ]
[ 96-32-2 ]
[ 186552-02-3 ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3572 - 3587.

11
[ 41963-20-6 ]
[ 15777-70-5 ]

References: [1]Angewandte Chemie - International Edition,2009,vol. 48,p. 7595 - 7599.
[2]Angewandte Chemie - International Edition,2009,vol. 48,p. 918 - 921.
[3]Journal of Medicinal Chemistry,1999,vol. 42,p. 3572 - 3587.
[4]Organic Letters,2016,vol. 18,p. 5248 - 5251.

12
[ 15777-70-5 ]
[ 75-26-3 ]
[ 610797-50-7 ]

References: [1]Tetrahedron,2003,vol. 59,p. 6545 - 6558.

13
[ 15777-70-5 ]
[ 190270-92-9 ]

References: [1]Tetrahedron,2003,vol. 59,p. 6545 - 6558.

14
[ 15777-70-5 ]
[ 956257-34-4 ]

References: [1]Tetrahedron,2003,vol. 59,p. 6545 - 6558.

15
[ 15777-70-5 ]
3-dibromomethyl-4-isopropoxy-benzonitrile [ No CAS ]

References: [1]Tetrahedron,2003,vol. 59,p. 6545 - 6558.

16
[ 15777-70-5 ]
[ 186552-03-4 ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3572 - 3587.

17
[ 15777-70-5 ]
[2-((S)-3-Amino-2-oxo-pyrrolidin-1-ylmethyl)-4-cyano-phenoxy]-acetic acid methyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3572 - 3587.

18
[ 15777-70-5 ]
[ 245761-08-4 ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3572 - 3587.

19
[ 15777-70-5 ]
[ 245761-11-9 ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3572 - 3587.

20
[ 15777-70-5 ]
{2-[(S)-3-(7-Methoxy-naphthalene-2-sulfonylamino)-2-oxo-pyrrolidin-1-ylmethyl]-4-thiocarbamoyl-phenoxy}-acetic acid methyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3572 - 3587.

21
[ 15777-70-5 ]
{4-Carbamimidoyl-2-[(S)-3-(7-methoxy-naphthalene-2-sulfonylamino)-2-oxo-pyrrolidin-1-ylmethyl]-phenoxy}-acetic acid methyl ester [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3572 - 3587.

22
[ 15777-70-5 ]
{2-[(S)-3-(7-Methoxy-naphthalene-2-sulfonylamino)-2-oxo-pyrrolidin-1-ylmethyl]-4-methylsulfanylcarbonimidoyl-phenoxy}-acetic acid methyl ester; hydriodide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,1999,vol. 42,p. 3572 - 3587.

23
[ 15777-70-5 ]
[ 76211-55-7 ]

References: [1]Journal of general chemistry of the USSR,1980,vol. 50,p. 1561 - 1568.
Zhurnal Obshchei Khimii,1980,vol. 50,p. 1937 - 1946.

24
[ 15777-70-5 ]
[ 76211-51-3 ]

References: [1]Journal of general chemistry of the USSR,1980,vol. 50,p. 1561 - 1568.
Zhurnal Obshchei Khimii,1980,vol. 50,p. 1937 - 1946.

25
[ 15777-70-5 ]
[ 110571-06-7 ]

References: [1]Journal of the Chemical Society,1957,p. 1668,1670.

26
[ 15777-70-5 ]
2-methyl-4-(methyl-[1,2,4]oxadiazol-3-yl)-phenol [ No CAS ]

References: [1]Chemische Berichte,1891,vol. 24,p. 3671.

27
[ 15777-70-5 ]
[ 849353-44-2 ]

Yield	Reaction Conditions	Operation in experiment
94%	With nitronium tetrafluoborate; In acetonitrile; at -30℃; for 1h;	An ice-cold solution of 4-bromo-2-methylphenol (5.6 g, 30 mmol) and pyridine (6.1 mL, 75 mmol) in 50 mL of anhydrous dichloromethane was treated with a solution of acetyl chloride (2. 8 mL, 26 mmol) in 5 ML of anhydrous dichloromethane. After 2 hours, the reaction mixture was concentrated IN VACUO. The resulting residue was treated with crushed ice, diluted with 150 mL of dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to give 6.9 g of 4-BROMO-2-METHYLPHENYL acetate as a light brown oil (quantitative yield). A solution of 4-bromo-2-methylphenyl acetate (6.9 g, 30 mol) in 75 ML of anhydrous dimethyl acetamide was treated with zinc cyanide (3 g, 25.6 mmol) and tetrakis (triphenylphosphine) palladium (0) (4.5 g, 3.9 mmol). The reaction mixture was heated at 100 C for 2 hours, cooled to room temperature, and treated with 300 mL of cold water. The resulting precipitate was filtered, washed with water, and air dried. Chromatography on SI02 (100% dichloromethane) afforded 5.2 g of 4-cyano-2-methylphenyl acetate as a colorless oil (99% yield), which solidified on standing. A stirred solution OF 4-CYANO-2-METHYLPHENYL acetate (5.2 g, 29.7 mmol) in 75 mL of methanol was treated with a solution of potassium carbonate (30 mmol, 4.15 g) in 25 mL of water at room temperature. After 30 minutes, the mixture was concentrated in vacuo and treated with 1 N sulfuric acid. The resulting precipitate was filtered, washed with water, and dried to give 3.1 g of <strong>[15777-70-5]4-hydroxy-3-methylbenzonitrile</strong> as a white solid (78% yield). A stirred solution of <strong>[15777-70-5]4-hydroxy-3-methylbenzonitrile</strong> (3.1 g, 23.3 mmol) in 60 mL of anhydrous acetonitrile was cooled to-30 C and treated with nitronium tetrafluoroborate (3.4 g, 25.6 mmol) in portions. After 60 minutes, the reaction mixture was diluted with 100 mL of water. The resulting light yellow precipitate was filtered, washed with water, and dried to give 3.9 g of 4-hydroxy-3-methyl-5-nitrobenzonitrile (94% yield). 4-Hydroxy-3-methyl-5-nitrobenzonitrile was converted to the title product according to the procedure described for the preparation of trifluoromethanesulfonic acid 3-fluoro-2-nitrophenyl ester.

References: [1]Patent: WO2005/30213,2005,A1 .Location in patent: Page/Page column 184.

28
[ 15174-69-3 ]
[ 15777-70-5 ]

Yield	Reaction Conditions	Operation in experiment
66%	With hydroxylamine hydrochloride; acetic acid; for 1.5h;Heating / reflux;	Preparation 70: 4-Hydroxy-3-methylbenzonitrile A mixture of 4-hydroxy-3-methylbenzaldehyde (530 mg, 3.91 mmol) and hydroxyl ammonium chloride (406 mg, 5.81 mmol) in acetic acid (5 mL) was heated under reflux for 90 minutes. The cooled reaction mixture was then diluted with diethyl ether (30 mL) and washed with water (30 mL). The combined organic solution was washed with brine, dried over magnesium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel, eluting with dichloromethane:methanol, 100:0 to 97.5:2.5, to afford the title compound as a pale yellow oil in 66% yield, 345 mg. 1H NMR(400 MHz, CDCl3) δ: 2.25(s, 3H), 6.84(d, 1H), 7.37(d, 1H), 7.40(s, 1H)

References: [1]Patent: US2006/160786,2006,A1 .Location in patent: Page/Page column 36.

29
BF₃OEt₂ (200 UL) [ No CAS ]
[ 352616-29-6 ]
[ 13589-71-4 ]
[ 15777-70-5 ]

Yield	Reaction Conditions	Operation in experiment
		A solution of 3-methylhydroxy-benzonitrile (1.44 g, 10.8 mmol) in solvent (CH2Cl2: cyclohexane 1:2, 60 mL) was treated with t-butyl trichloroimmidate (8.65 g, 4.0 eq) (Ref: Tetrahedron Letter, 29, 2483, 1988). To the solution was added BF3OEt2 (200 uL) and the resulting solution was stirred overnight. Conventional workup followed by flash chromatography gave 0.96 g of 3-methyl-4-hydroxy-benzonitrile and 0.64 g (31%) of the title compound. 1H-NMR (500 MHz, CDCl3) δ7.43 (s, 1H0, 7.39 (d, J=8.7 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 2.20 (s, 3H), 1.45 (s, 9H).

References: [1]Patent: US2003/65176,2003,A1 .

30
[ 23382-09-4 ]
[ 15777-70-5 ]
[ 130800-76-9 ]
[ 173900-31-7 ]

Yield	Reaction Conditions	Operation in experiment
2.88 g (99.3%)	With potassium iodide; potassium carbonate; In 1-methyl-pyrrolidin-2-one; hexane; ethyl acetate;	d) 3-Methyl-4-[3-(3-methylisoxazol-5yl)propyloxy]phenylcyanide. 3-(3-Methylisoxazol-5yl) propyl chloride (2.7 g, 16.9 mmol) and 0.2 g (60 mmol) of potassium iodide, 3.89 g (28.2 mmol) of potassium carbonate (milled, 80%), 2.7 g g (16.9 mmol) of 2-methyl-4-cyanophenol were combined in 15 ml of N-methyl-2-pyrrolidinone with stirring and the mixture was heated to 60 C. overnight. The mixture was diluted with water, extracted with ethyl acetate (3x), and the organic layer was washed with 10% NaOH solution, water, and brine, and dried over magnesium sulfate. The ethyl acetate solution was filtered through Florisil and concentrated in vacuo to provide 3.64 g of a pale yellow solid. The solid was repurified by MPLC (430 g Silica Gel 60, 20% ethyl acetate in hexane, 25 ml/min) to provide 2.88 g (99.3%) of the title compound as a crystalline solid; m.p. 65-66 C.

References: [1]Patent: US5464848,1995,A .

31
[ 53078-71-0 ]
[ 15777-70-5 ]

Yield	Reaction Conditions	Operation in experiment
	With boron tribromide; In methanol; dichloromethane; water;	c) 4-Hydroxy-3-methylphenylcyanide. To a solution of 4-methoxy-3-methylphenylcyanide (11b, 44.8 g, 0.3044 mol) in 150 ml of methylene chloride, chilled to 0 C. with stirring under nitrogen, was added 575 ml (0.575 mol) of boron tribromide (1M in methylene chloride) in a steady stream, and the mixture was stirred at room temperature for 24 h. The reaction mixture was refluxed overnight, additional boron tribromide (44.7 ml) was added at 25 C. and the mixture was stirred at room temperature for 30 min, refluxed for 3 h, and then stirred at room temperature for 48 h. The indicated the presence of the starting nitrile, and therefore, the third addition of boron tribromide (60.88 ml) was made and the mixture was refluxed overnight. The reaction mixture was chilled to 0 C. in an ice bath, 175 ml of methanol was added dropwise, and 600 ml of water was added. The resulting mixture was stirred overnight. The aqueous layer was extracted with methylene chloride (2x), the organic layer was washed with 10% NaOH solution (3x). The basic aqueous layer was acidified to pH=5 with 6N HCl solution (product oiled out), the mixture was extracted with methylene chloride(3x), and the organic layer was washed with brine and dried over magnesium sulfate. The methylene chloride solution was filtered through Florisil and concentrated in vacuo to provide 38.2 g of the title compound as a pale yellow solid, m.p. 95.5-97 C.

References: [1]Patent: US5464848,1995,A .

32
[ 2362-12-1 ]
[ 15777-70-5 ]

Yield	Reaction Conditions	Operation in experiment
		(a) 2-Methyl-4-cyanophenol The sub-title compound was prepared according to the method described in Example 10(b) above from 2-methyl-4-bromophenol.

References: [1]Patent: US6291475,2001,B1 .

33
[ 15777-70-5 ]
1-(2-methyl-4-cyanophenoxy)-2,3-epoxy-propane [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		(b) 3-Methyl-4-(2-oxiranylmethoxy)benzonitrile The sub-title compound was prepared according to the method described in Example A above from 2-methyl-4-cyanophenol (from step (a) above).

References: [1]Patent: US6291475,2001,B1 .

34
[ 123-75-1 ]
[ 15777-70-5 ]
4-[imino(pyrrolidin-1-yl)methyl]-2-methylphenol hydrochloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
78%		Step 1 Synthesis of 4-[imino(pyrrolidin-1-yl)methyl]-2-methylphenol hydrochloride To a solution of <strong>[15777-70-5]4-hydroxy-3-methylbenzonitrile</strong> (1.53 g, 11.5 mmol) in ethanol (8 mL) was added 4N hydrochloric acid-dioxane (58 mL), and the mixture was stirred at room temperature for 1 day. The reaction mixture was concentrated under reduced pressure to remove ethanol to a certain level, and the solid was collected by filtration. To the obtained solid were added toluene (8 mL) and pyrrolidine (1.9 mL) and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and concentrated hydrochloric acid and water were added and the mixture was stirred with heating. When the solution became uniform, it was concentrated under reduced pressure, and the obtained residue was recrystallized from acetone to give the title compound. yield: 1.87 g (7.78 mmol) yield: 78% MS (ESI, m/z) 205 [M+H]+

References: [1]Patent: US2013/23563,2013,A1 .Location in patent: Paragraph 0428-0430.

35
[ 15777-70-5 ]
[ 220000-87-3 ]
[ 1573056-19-5 ]

Yield	Reaction Conditions	Operation in experiment
136 mg		Example 2.2.: Synthesis of 4-{2- ethyl-4-[3-(1-methyl-2-oxo-5- trifluoromethyl-1,2-dihydro-pyridin-3-yl)-ureidomethyl]-phenoxy}- pyridine-2-carboxylic acid methyl amide 1) Synthesis of 4-(4-Cvano-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide A solution of 4-Hydroxy-3-methyl-benzonitrile (0,100 g; 0,717 mmol) in dry DMF (3 ml_) was treated with potassium-terf-butylat (0,088 g; 0,788 mmol). The reaction mixture was stirred at RT for 2 h and 4-Chloro-pyridine-2- carboxylic acid methylamide (0,130 g; 0,717 mmol) and potassium carbonat (0,020 ml; 0,358 mmol) were added. The resulting suspension was then heated to 130C for 4 days. For purification the reaction mixture was allowed to cool down to RT and it was washed with 1 N NaOH-solution (5 ml_) and water (5 ml_). The solid, that precipitated while washing, was filtrated and added into the organic layer. The aqueous phase was extracted with DCM (2 x 15 mL) and the combined organic layers were evaporated to dryness. The resulting solid was dissolved in DCM (20 mL), dried with Na2S04 and concentrated to afford the crude product. The product was purified with flash column chromatography (Combi Flash RF, Si-60, 24 g-column, gradient PE/EE 95:5 to 50:50 in 12 min then for 7 min isocratic 50:50, flow 35 ml/min, UV 254 nM) resulting in 4-(4-Cyano-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (136,000 mg; 0,443 mmol) as yellow solid. 2) Synthesis of 4-(4-Aminomethyl-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide A solution of 4-(4-Cyano-2-methyl-phenoxy)-pyridine-2-carboxylic acid methylamide (0,690 g; 0,836 mmol) in methanol (5 mL) and NH3 in methanol (20%, 5 mL) was treated with nickel sponge (0.5 g Johnson Matthey, A- 7000) and purged with H2. The reaction mixture was stirred at RT for 17.5 h with a pressure of five bar. The catalyst was filtrated off and the solvent was evaporated. The crude product was then purified by flash column chromatography (Flashmaster, UV 240 nM, 70g silica gel column, flow 20 ml/min, DCM/MeOH 9:1) yielding 4-(4-Aminomethyl-2-methyl-phenoxy)- pyridine-2-carboxylic acid methylamide (0,182 g; 0,584 mmol) as yellow resin. 3) Synthesis of 1-Methyl-3-nitro-5-trifluoromethyl-1 H-pyridin-2-one To a solution of 3-Nitro-5-(trifluoromethyl)pyridin-2-ol (60,0 g; 288,33 mmol) in DMF (500 ml) was added potassium carbonat (120,0 g; 864,99 mmol) and iodomethan (19,7 ml; 317,16 mmol). The resulting suspension was stirred for about 16 h at 80C. The reaction mixture was diluted with EtOAc and extracted 3x with water, dried over Na2SO4, filtrated and the solution evaporated to dryness. The residue was treated with THF/ petroleum ether (PE). The precipitated product was filtered off, rinsed with PE and dried in vacuo to yield a brown solid. 4) Synthesis of 3-Amino-1-methyl-5-trifluoromethyl-1H-pyridin-2-one To a solution of 1-Methyl-3-nitro-5-trifluoromethyl-1 H-pyridin-2-one (9.40 g, 42.32 mmol) in THF (100 ml) and MeOH (10 ml) was added 5% Pd/C (54% H20, 2 g). The reaction was stirred under an atmosphere of hydrogen at room temperature. After 16h additional Pd/C (4g) were added and stirring was continued under hydrogen (1 atm) for 23 hours. The solids were removed via filtration and the filtrate reduced in vacuo to yield 3-Amino-1- methyl-5-trifluoromethyl-1H-pyridin-2-one (7.9 g, 41.1 mmol). 5) Synthesis of 4-f2-Methyl-4-r3-(1-methyl-2-oxo-5-trifluoromethyl-1 ,2- dihvdro-pyridin-3-yl)-ureidomethyll-phenoxy -pyridine-2-carboxylic acid methyl amide 3-Amino-1-methyl-5-trifluoromethyl-1H-pyridin-2-one (1,64 g, 8,55 mmol) was dissolved in DCM (50 ml), 4-nitro-phenyl-chloro-formiate (1 ,90 g, 9,437 mmol) and pyridine (0,76 ml) were added. The mixture was stirred for 2 h at room temperature. Then were added 4-(4-Aminomethyl-2-methyl-phenoxy)- pyridine-2-carboxylic acid methylamide (2,32 mg, 8,55 mmol) and N-ethyl- diisopropyl-amine (2,91 ml, 17,10 mmol). The mixture was stirred for about 16 h at room temperature. To the mixture was added DCM. The organic layer was washed once with 1 N NaOH and twice with water, it was dried over Na2S04, filtrated and the solvent removed in vacuo. The residual mixture was taken up with MTBE, the resulting white precipitate was filtered off and dried in vacuo. 4-{2-Methyl-4-[3-(1-methyl-2-oxo-5-trifluoromethyl-1 ,2-dihydro-pyhdin-3-yl)- ureidomethyl]-phenoxy}-pyridine-2-carboxylic acid methylamide was obtained as white solid (HPLC/MS: Rt=2,184 min, M+H 490.2). 1H NMR (500 MHz, DMSO-d6) ppm = 8.74 (q, J=4.6, 1H), 8.65 (s, 1 H), 8.50 (d, J=5.6, 1 H), 8.22 (d, J=2.5, 1 H), 7.96 - 7.92 (m, 1 H), 7.76 (t, J=5.9, 1 H), 7.34 - 7.31 (m, 1H), 7.29 (d, J=2.6, 1 H), 7.25 (dd, J=8.2, 2.2, 1 H), 7.15 - 7.11 (m, 1H), 7.10 (dd, J=5.6, 2.6, 1H), 4.33 (d, J=5.8, 2H), 3.57 (s, 3H), 2.79 (d, J=4.9, 3H), 2.10 (s, 3H). Method Info: HPLC/MS A: H20 + 0,05% HCOOH \| B: MeCN + 0,04% HCOOH T: 30 C I Flow: 2 ml/min \| Column: Chromolith RP-18e 50-4,6 mm \| MS: 85- 800 amu 1% -> 00% B: 0 -> 2,8 min \| 100% B: 2,8 -> 3,3 min

References: [1]Patent: WO2014/32755,2014,A2 .Location in patent: Page/Page column 141-143.

Historical Records

Technical Information

• Acidity of Phenols • Alkyl Halide Occurrence • Blaise Reaction • Catalytic Hydrogenation • Chan-Lam Coupling Reaction • Complex Metal Hydride Reductions • Electrophilic Substitution of the Phenol Aromatic Ring • Etherification Reaction of Phenolic Hydroxyl Group • Halogenation of Phenols • Hydride Reductions • Oxidation of Phenols • Pechmann Coumarin Synthesis • Preparation of Aldehydes and Ketones • Preparation of Amines • Reactions of Benzene and Substituted Benzenes • Reimer-Tiemann Reaction • Ritter Reaction • Thorpe-Ziegler Reaction

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[ 15777-70-5 ]

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CAS No.: 15777-70-5

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