496863-48-0|1-(2-(Methylthio)pyrimidin-4-yl)ethanone| Ambeed

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Quality Control of [ 496863-48-0 ] Purity: 95% SDS Specification

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Product Details of [ 496863-48-0 ]

CAS No. :	496863-48-0
Formula :	C₇H₈N₂OS
M.W :	168.22
SMILES Code :	CC(C1=NC(SC)=NC=C1)=O
MDL No. :	MFCD09263472
InChI Key :	WXQMROLQWGTVBM-UHFFFAOYSA-N
Pubchem ID :	11658348

Safety of [ 496863-48-0 ]

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

Computational Chemistry of [ 496863-48-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.29
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	43.95
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	68.15 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.81
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	1.06
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.4
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.	-0.08
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	1.71
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.18

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.82
Solubility	2.53 mg/ml ; 0.0151 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.	-2.08
Solubility	1.39 mg/ml ; 0.00827 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-2.48
Solubility	0.558 mg/ml ; 0.00332 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.	-6.57 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)	1.61

Application In Synthesis of [ 496863-48-0 ]

* 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 [ 496863-48-0 ]

[ 496863-48-0 ] Synthesis Path-Downstream 1~35

1
[ 521092-35-3 ]
[ 496863-48-0 ]

Yield	Reaction Conditions	Operation in experiment
	With hydrogenchloride; In water; ethyl acetate; for 1h;Product distribution / selectivity;	Example 12 1-(2-methylsulfanyl-pyrimidin-4-yl)-ethanone 4-(1,1-Dimethoxy-ethyl)-2-methylsulfanyl-pyrimidine (500 mg, 2.33 mmol) was dissolved in ethyl acetate (7 ml), 1M hydrochloric acid (5 ml) was added, and the mixture was stirred for 1 hr. The mixture was partitioned, and the obtained organic layer was washed with saturated brine and concentrated under reduced pressure. Hexane (5 ml) was added to the concentrate to allow stirring for 3 hrs in an ice bath. The precipitate was filtrated, and dried under reduced pressure to give the title compound (254 mg, 1.52 mmol) as crystals. melting point 35C 1H-NMR(CDCl3) delta 2.63(3H, s), 2.69(3H, s), 7.50(1H, d, J=4.9Hz), 8.73(1H, d, J=4.9Hz) The powder X-ray diffraction pattern of the thus-obtained crystals was measured under the following conditions. As a result, characteristic peaks were found at diffraction angles (2theta+/-0.1) of about 12.3, about 12.6, about 17.4, about 24.7 and about 26.5. The X-ray powder diffraction pattern is shown in Fig. 1. For the measurement of powder X-ray diffraction, a powder X-ray diffraction apparatus X'Pert (manufactured by PANalytical) equipped with semiconductor array detector X'Celerator was used under the conditions of tube:Cu, tube electric current: 55 mA, tube voltage: 40 kV, sampling width:0.017, scanning rate: 0.269/sec, wavelength: 1.54056A, measurement diffraction angle range (2theta): 5 - 45C.; Example 13: 1-(2-methylsulfanyl-pyrimidin-4-yl)-ethanone ; 4-(1,1-Dimethoxy-ethyl)-2-methylsulfanyl-pyrimidine (1.50, 7.0 mmol) was dissolved in ethyl acetate (5 mL), 2M hydrochloric acid (5 ml) was added thereto, and the mixture was stirred for 1 hr. The reaction mixture was partitioned, and the obtained organic layer was washed with saturated brine and concentrated under reduced pressure. Acetone (1.5 mL) was added to the residue, and water (12 mL) was added dropwise. The mixture was stirred overnight in an ice bath, and the precipitate was filtrated, and dried under reduced pressure to give the title compound (1.00 g, 5.95 mmol) as crystals. melting point 37C The powder X-ray diffraction pattern of the thus-obtained crystals was measured under the same conditions as in Example 12. As a result, characteristic peaks were found at diffraction angles (2theta+/-0.1) of about 13.7, about 14.8, about 17.9, about 21.2 and about 36.1. The X-ray powder diffraction pattern is shown in Fig. 2.
		Example 14: 1-(2-methylsulfanyl-pyrimidin-4-yl)-ethanone; To 1-hydroxy-4,4-dimethoxy-pent-1-en-3-one-sodium salt (10.38 g, 57.0 mmol) were added ethyl acetate (110 mL) and methyl sulfate (7.40 g, 58.7 mmol), and the mixture was stirred at 80C overnight. The mixture was analyzed by HPLC under the same conditions as in the above-mentioned Example 3, and the reaction yield was confirmed to be 99%. The reaction mixture was cooled, the precipitate was filtered off under nitrogen, methylisothiourea sulfate (9.30 g, 33.4mmol) and sodium carbonate (7.65 g, 72.2 mmol) were added, and the mixture was stirred at 80C overnight (cyclization yield: 90% by HPLC analysis under the same conditions as in the above-mentioned Example 3). After the reaction, the mixture was washed successively with water and 1M hydrochloric acid, and the solvent was evaporated. To the residue was added acetone (7 ml), then 1M hydrochloric acid (22 ml) was added, and the mixture was stirred at room temperature for 1 hr. The mixture was neutralized to pH 6 with an aqueous sodium hydroxide solution and stirred overnight in an ice bath. The precipitate was filtrated, and dried under reduced pressure to give the title compound (7.18 g, 42.7 mmol).
	In water; acetone; at 0 - 20℃; for 3h;	(3) In 570 ml of acetone was dissolved 142 g of the compound obtained in (2), and under ice-cooling, 114 ml of 6M hydrochloric acid was added to the solution and the mixture was stirred at room temperature for 3 hours.. After adding 450 ml of water to the mixture, the solvent was removed and the residue was extracted with ethyl acetate.. The organic layer was washed, dried and concentrated to give 107 g of 1-(2-methylsulfanylpyrimidin-4-yl)ethanone.

References: [1]Patent: EP1849761,2007,A1 .Location in patent: Page/Page column 12.
[2]Patent: EP1849761,2007,A1 .Location in patent: Page/Page column 12-13.
[3]Patent: EP1439174,2004,A1 .Location in patent: Page 89.

2
[ 496863-48-0 ]
[ 521092-43-3 ]

Yield	Reaction Conditions	Operation in experiment
	With hydroxylamine hydrochloride; sodium acetate; In methanol; for 0.5h;Heating / reflux;	(1) In 180 ml of methanol was dissolved 17.6 g of the compound obtained in Reference example 3 (3) or Reference example 4 (2), 14.5 g of hydroxylamine hydrochloride and 17.2 g of sodium acetate were added to the solution, and the mixture was refluxed under heating for 30 minutes.. After cooling the reaction mixture, the solvent was removed, water was added to the residue and the mixture was extracted with ethyl acetate.. The organic layer was washed, dried and concentrated.. To the residue was added hexane and the precipitated crystals were collected by filtration to give 18.3 g of <strong>[496863-48-0]1-(2-methylsulfanylpyrimidin-4-yl)ethanone</strong> oxime.. Melting point: 150-152C.

References: [1]Patent: EP1439174,2004,A1 .Location in patent: Page 90.

3
[ 521092-40-0 ]
[ 496863-48-0 ]

Yield	Reaction Conditions	Operation in experiment
		(2) In 200 ml of acetone was dissolved 18.9 g of the compound obtained in (1), 60 ml of 4M hydrochloric acid was added to the solution and the mixture was stirred at room temperature for an hour.. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate.. The organic layer was washed, dried and concentrated to give 15.9 g of 1-(2-methylsulfanylpyrimidin-4-yl)ethanone.

References: [1]Patent: EP1439174,2004,A1 .Location in patent: Page 90.

4
[ 75-97-8 ]
[ 4637-24-5 ]
[ 17356-08-0 ]
[ 74-88-4 ]
[ 496863-48-0 ]

Yield	Reaction Conditions	Operation in experiment
82%		1) 4-Acetyl-2-methylthiopyrimidine A mixture of 3, 3-dimethylbutan-2-one (25.15 g) and N, N-dimethylformamide dimethylacetal (126 mL) was stirred at an external temperature of 100C for 48 hours. After air cooling, the low boiling point components generated during the reaction were evaporated under reduced pressure, and methanol (400 mL), thiourea (28.92 g) and sodium methoxide (15.39 g) were added to the residue thus obtained. The mixture was heated to reflux for 118 hours. After air cooling, sodium methoxide (10.26 g) was added to the reaction solution, methyl iodide (17.8 mL) was added dropwise to the mixture over 5 minutes under ice cooling, and the mixture was stirred for 5 hours. Water and ethyl acetate were added to a residue obtained by evaporating the reaction solvent under reduced pressure, and the mixture was partitioned. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and an aqueous 3 N hydrochloric acid solution (400 mL) was added to the residue thus obtained and stirred for 15 hours at room temperature. Ethyl acetate was added to the reaction solution and the mixture was partitioned, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane), to obtain 4-acetyl-2-methylthiopyrimidine (26.34 g, 82%) as a solid. 1H-NMR(400MHz, CDCl3)delta: 2.63(3H, s), 2.70(3H, s), 7.51(1H, d, J=4.9Hz), 8.74(1H, d, J=4.9Hz). ESI-MSm/z: 169(M+H)+.

References: [1]Patent: EP1785418,2007,A1 .Location in patent: Page/Page column 39.

5
[ 496863-48-0 ]
[ 4637-24-5 ]
[ 496863-64-0 ]

Yield	Reaction Conditions	Operation in experiment
97%		Step 1 : A flask was charged with l-(2-(methylthio)pyrimidin-4-yl)ethanone(23.7 mmol, 4 g) and DMF-DMA (40 mmol, 4.7 g. 5.33 mL). The reaction mixture was stirred at 80 C for 2 hours, then it was cooled and concentrated in vacuo to a dark orange solid. The solid was dissolved in absolute EtOH (20 mL) and hydrazine monohydrate (1.26 mL, 26 mmol) was added. The reaction mixture was stirred at 80 C overnight, then it was cooled and concentrated in vacuo. The residue was dissolved in EtOAc, washed with brine (3x), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 4.42 g of 4- (4-bromo-l-ethyl-lH-pyrazol-3-yl)-2-(methylthio)pyrimidine as a yellow solid (97% yield): 1H NMR (CDC13, ppm) delta 8.67 (d, 1H), 8.46 (d, 1H), 7.62 (s, 1H), 6.89 (s, 1H), 2.51 (s, 3H).

References: [1]Patent: WO2012/125981,2012,A2 .Location in patent: Page/Page column 137.

6
[ 496863-48-0 ]
[ 1400220-97-4 ]

References: [1]Patent: WO2012/125981,2012,A2 .

7
[ 496863-48-0 ]
[ 1400221-00-2 ]
4-(1-ethyl-1H-pyrazol-5-yl)-2-(methylthio)pyrimidine [ No CAS ]

References: [1]Patent: WO2012/125981,2012,A2 .

8
[ 496863-48-0 ]
[ 1400221-02-4 ]

References: [1]Patent: WO2012/125981,2012,A2 .

9
[ 496863-48-0 ]
[ 1400221-04-6 ]

References: [1]Patent: WO2012/125981,2012,A2 .

10
[ 496863-48-0 ]
[ 1400215-54-4 ]

References: [1]Patent: WO2012/125981,2012,A2 .

11
[ 496863-48-0 ]
[ 95-92-1 ]
[ 1403333-53-8 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation JEthyl 4-[2-(methylsulfanyl)pyrimidin-4-yl] -2,4-dioxobutanoate [(X) R1 = Me, X= -S-, R4 = H, R3 = COOEt)] step 7In a 250 mL, three-necked, round-bottomed flask equipped with a thermometer, magnetic stirrer, under nitrogen atmosphere, cooled to -7 C with an ice/NaCI bath, anhydrous THF (10 mL) was loaded and sodium tert-butoxide 1.26 g (13.1 mmol, 2.2 eq.) was added in small portions. The addition was slightly exothermic. The solid dissolved completely within 15 min yielding a white, turbid solution. Diethyl oxalate 2.41 mL (17.83 mmol, 3 eq.) diluted in 10 mL of THF was loaded into the addition funnel and added dropwise to the solution at -7 C. The addition was again slightly exothermic and took about 20 min, meanwhile the solution color changed to light yellow. Once the addition was complete the mixture was stirred at the same temperature for 30 min. and then cooled to -11 C. 1-(2- Methylsulfanyl-pyrimidin-4-yl)-ethanone 1 g (5.94 mmol) was dissolved in 14 mL of THF, loaded into the addition funnel and added dropwise to the cooled mixture. The temperature was kept below -8 C throughout the addition, which took 20 min. The mixture was stirred for 1 h in the cold and then for 1 further h at r.L The reaction mass was poured into an ice cooled biphasic mixture made of 50 mL 5% citric acid and 50 mL AcOEt under vigorous stirring. The aqueous layer was separated and extracted again with 50 mL of AcOEt. The combined organic extracts were then concentrated to a dark yellow oil which contained a variable amount of diethyl oxalate. This raw material was used as such in the following step.LC/MS (254 nm) HPLC method 3: Rt 3,13 min
		[0559] In a 250 mL, three-necked, round-bottomed flask equipped with a thermometer, magnetic stirrer, under nitrogen atmosphere, cooled to -7 C. with an ice/NaCl bath, anhydrous THF (10 mL) was loaded and sodium tert-butoxide 1.26 g (13.1 mmol, 2.2 eq.) was added in small portions. The addition was slightly exothermic. The solid dissolved completely within 15 min yielding a white, turbid solution. Diethyl oxalate 2.41 mL (17.83 mmol, 3 eq.) diluted in 10 mL of THF was loaded into the addition funnel and added dropwise to the solution at -7 C. The addition was again slightly exothermic and took about 20 min, meanwhile the solution color changed to light yellow. Once the addition was complete the mixture was stirred at the same temperature for 30 min. and then cooled to -11 C. 1-(2-Methylsulfanyl-pyrimidin-4-yl)-ethanone 1 g (5.94 mmol) was dissolved in 14 mL of THF, loaded into the addition funnel and added dropwise to the cooled mixture. The temperature was kept below -8 C. throughout the addition, which took 20 min. The mixture was stirred for 1 h in the cold and then for 1 further h at r.t. The reaction mass was poured into an ice cooled biphasic mixture made of 50 mL 5% citric acid and 50 mL AcOEt under vigorous stirring. The aqueous layer was separated and extracted again with 50 mL of AcOEt. The combined organic extracts were then concentrated to a dark yellow oil which contained a variable amount of diethyl oxalate. This raw material was used as such in the following step. [0560] LC/MS (254 nm) HPLC method 3: Rt 3.13 min

References: [1]Patent: WO2012/139930,2012,A1 .Location in patent: Page/Page column 57.
[2]Patent: US2014/51708,2014,A1 .Location in patent: Paragraph 0557-0560.

12
[ 496863-48-0 ]
[ 1403333-55-0 ]