2836-44-4|2-Methyl-6-(trifluoromethyl)pyrimidin-4-ol| Ambeed

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Quality Control of [ 2836-44-4 ] Purity: 97% SDS Specification

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Product Details of [ 2836-44-4 ]

CAS No. :	2836-44-4
Formula :	C₆H₅F₃N₂O
M.W :	178.11
SMILES Code :	CC1=NC(C=C(C(F)(F)F)N1)=O
MDL No. :	MFCD03265321
InChI Key :	DBDRDWKBAGNHHS-UHFFFAOYSA-N
Pubchem ID :	135416727

Safety of [ 2836-44-4 ]

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

Computational Chemistry of [ 2836-44-4 ] Show Less

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 ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	45.75 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.01
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	0.17
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.25
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.	0.5
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	2.5
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.29

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.36
Solubility	7.86 mg/ml ; 0.0441 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.	-0.69
Solubility	36.5 mg/ml ; 0.205 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	-2.83
Solubility	0.263 mg/ml ; 0.00148 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	No
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	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-7.27 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)	1.84

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 1~35

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)

References: [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.

References: [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].

References: [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 ]