[ CAS No. 2836-44-4 ] {[proInfo.proName]}

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Quality Control of [ 2836-44-4 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 2836-44-4 ]

SDS Specification

Alternatived Products of [ 2836-44-4 ]

Product Details of [ 2836-44-4 ]

CAS No. :	2836-44-4	MDL No. :	MFCD03265321
Formula :	C₆H₅F₃N₂O	Boiling Point :	No data available
Linear Structure Formula :	-	InChI Key :	DBDRDWKBAGNHHS-UHFFFAOYSA-N
M.W :	178.11	Pubchem ID :	135416727
Synonyms :

Calculated chemistry of [ 2836-44-4 ] Expand+

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	6
Fraction Csp3 :	0.33
Num. rotatable bonds :	1
Num. H-bond acceptors :	5.0
Num. H-bond donors :	1.0
Molar Refractivity :	34.83
TPSA :	45.75 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) :	-7.27 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.01
Log Po/w (XLOGP3) :	0.17
Log Po/w (WLOGP) :	2.25
Log Po/w (MLOGP) :	0.5
Log Po/w (SILICOS-IT) :	2.5
Consensus Log Po/w :	1.29

Druglikeness

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

Water Solubility

Log S (ESOL) :	-1.36
Solubility :	7.86 mg/ml ; 0.0441 mol/l
Class :	Very soluble
Log S (Ali) :	-0.69
Solubility :	36.5 mg/ml ; 0.205 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-2.83
Solubility :	0.263 mg/ml ; 0.00148 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.84

Safety of [ 2836-44-4 ]

Signal Word:	Warning	Class:
Precautionary Statements:	P261-P305+P351+P338	UN#:
Hazard Statements:	H315-H319-H335	Packing Group:
GHS Pictogram:

Application In Synthesis of [ 2836-44-4 ]

* 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 [ 2836-44-4 ]

[ 2836-44-4 ] Synthesis Path-Downstream 1~8

1
[ 124-42-5 ]
[ 372-31-6 ]
[ 2836-44-4 ]

Yield	Reaction Conditions	Operation in experiment
85.7%		As shown in Scheme 1, to a 250 mL round-bottomflask, trifluoroacetoacetate (0.05 mol), acetamidine hydrochloride (0.05 mol), sodium methoxide (0.075 mol),and ethanol (100 mL) were added and refluxed for 10 h. After that, the mixture was acidified with 1 mol/L HCl to pH 7. The crude products were extracted using ethylacetate to produce intermediate 1. Then, intermediate 1(0.05 mol), POCl3(0.1 mol), and CH3CN(120 mL) wereadded to a 250 mL round-bottom flask to react for 0.5 hat a reflux temperature, and then, diisopropylethylamine(0.06 mol) was added dropwise. After continuously refluxingfor 8 h, excess POCl3and CH3CNwere distilled, andthen, ice water mixture (60 mL) was added. Finally, themixture was alkalify with 5 mol/L to pH 9 and extractedusing CH2Cl2to give intermediate 2 (Xie et al. 2013).2-Methyl-6-(trifluoromethyl)pyrimidin-4-ol (1) White crystals;yield 85.7%; m.p. 140-142 C; 1H NMR (DMSO-d6,500 MHz, ppm) delta: 13.03 (s, 1H, pyrimidine-OH), 6.68 (s,1H, pyrimidine-H), 2.36 (s, 3H); 13C NMR (DMSO-d6,125 MHz, ppm) delta: 162.78, 162.16, 152.03 (q, J = 35.5 Hz),122.33, 120.15, 111.12, 21.74.
	With sodium methylate; In ethanol; water;	(1) To a suspension of ethyl trifluoroacetoacetate (18.4g, 0.1mol) and acetamidine hydrochloride (9.5g, 0.1mol) in ethanol (100ml) was dropwise added 28% sodium methylate (19.3g, 0.1mol) under cooling with ice. The resulting mixture was stirred at room temperature for 1 hour, and further refluxed for 12 hours. After cooling, the reaction mixture was evaporated, water (150ml) was added to the residue, then the mixture was neutralized with concentrated hydrochloric acid. The crystal separated was collected by filtration, washed with water, and dried to give 4-hydroxy-2-methyl-6-trifluoromethylpyrimidine (9.8g). m.p.:141-143 ØC 1H-NMR(CDCl3) delta 2.57(3H, s), 6.72(1H, s), 13.4(1H, br s). 1H-NMR(DMSO-d6) delta 2.36(3H, s), 6.67(1H, s). 19F-NMR(DMSO-d6) delta -72.13.
		To 12.6 g of sodium methoxide (28% methanol solution), 3.1 g of acetoamidine hydrochloride and 3 g of 4,4,4- trifluoro-3-oxo-butanoic acid ethyl ester were added. This mixture was stirred at 800C for 20 hours. The reaction mixture was left standing to cool and then concentrated. To the residue, 10% hydrochloric acid was added, followed by extraction three times with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was washed with hexane to obtain 2.4 g of 2-methyl-6-trifluoromethylpyrimidin-4-ol . 2-methyl-6-trifluoromethylpyrimidin-4-ol1H-NMR (DMSO-d6): 2.35(s,3H), 6.68(s,lH), 13.02(bs,lH)

Reference： [1]Chemical Papers,2019,vol. 73,p. 719 - 729
[2]Patent: EP1333029,2003,A1
[3]Patent: WO2010/134478,2010,A1 .Location in patent: Page/Page column 175; 176

2
[ 2836-44-4 ]
[ 5993-98-6 ]

Yield	Reaction Conditions	Operation in experiment
54.6%		2-Methyl-6-trifluoromethyl-4-hydroxypyrimidine (0.05 mol) and acetonitrile (50 mL) were added to a three-necked flask and stirred in an ice bath.Slowly add phosphorus oxychloride (0.75 mol),After the dropwise addition is completed, the mixture is stirred at room temperature for 0.5 hours.Add acetonitrile to dissolve N,N-isopropylethylamine (0.0005 mol),After the completion of the dropwise addition, the reaction was stopped after heating and refluxing for 10 hours.Spin dry, pour into ice water, adjust the pH to 10 with alkali, extract with dichloromethane, separate the layers, combine the organic layers, dry over anhydrous sodium sulfate, filter, and dissolve.The mass of the brown liquid was 5.37 g (theoretical value 9.83 g) in a yield of 54.6%.
51.7%		As shown in Scheme 1, to a 250 mL round-bottomflask, trifluoroacetoacetate (0.05 mol), acetamidine hydrochloride (0.05 mol), sodium methoxide (0.075 mol),and ethanol (100 mL) were added and refluxed for 10 h. After that, the mixture was acidified with 1 mol/L HCl to pH 7. The crude products were extracted using ethylacetate to produce intermediate 1. Then, intermediate 1(0.05 mol), POCl3(0.1 mol), and CH3CN(120 mL) wereadded to a 250 mL round-bottom flask to react for 0.5 hat a reflux temperature, and then, diisopropylethylamine(0.06 mol) was added dropwise. After continuously refluxingfor 8 h, excess POCl3and CH3CNwere distilled, andthen, ice water mixture (60 mL) was added. Finally, themixture was alkalify with 5 mol/L to pH 9 and extractedusing CH2Cl2to give intermediate 2 (Xie et al. 2013)
	With thionyl chloride;N,N-dimethyl-formamide; In toluene; at 80.0℃; for 2h;	To a mixture of 20 ml of toluene, 2.2 g of 2-methyl-6- trifluoromethylpyrimidin-4-ol and 0.19 g of N, N- dimethylformamide, 2.94 g of thionyl chloride was slowly added dropwise at 800C. This mixture was stirred at 80C for 2 hours. The reaction mixture was left standing to cool to room temperature, poured into water and then extracted three times with tert-butyl methyl ether. The organic layer was washed in turn with an aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and then concentrated to obtain a crude product. This crude product was used in the next step without purification.

Reference： [1]Patent: CN110003117,2019,A .Location in patent: Paragraph 0020; 0024-0025
[2]Chemical Papers,2019,vol. 73,p. 719 - 729
[3]Patent: WO2010/134478,2010,A1 .Location in patent: Page/Page column 176

3
[ 2836-44-4 ]
4-bromo-2-methyl-6-(trifluoromethyl)pyrimidine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
62.5%	With phosphorus(V) oxybromide; In acetonitrile; at 80.0℃; for 6h;	A suspension of 6-methyl-2-(trifluoromethyl)pyrimidin-4-ol (3.Og, 16.8 mmol) and phosphorous oxybromide (19.3g, 67.3 mmol) in acetonitrile (30 mL) was stined at 80C for 6h.The volatiles were concentrated under reduced pressure to get the residue. The residue was neutralized with 10% sodium bicarbonate solution and extracted ethyl acetate. Then the organic portion was washed with water, brine and dried over anhydrous sodium sulphate and evaporated under reduced pressure to get 4-bromo-2-methyl-6-(trifluoromethyl)pyrimidine (2.5g, 62.5%).LC-MS: 243.2 [M+H].

Reference： [1]Patent: WO2016/185342,2016,A1 .Location in patent: Page/Page column 50

4
[ 2836-44-4 ]
4-chloro-N-(4-((2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)oxy)phenyl)benzamide [ No CAS ]