1333240-17-7|2-Chloro-4,5-dimethoxypyrimidine| Ambeed

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Quality Control of [ 1333240-17-7 ] Purity: 95% SDS Specification

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Product Details of [ 1333240-17-7 ]

CAS No. :	1333240-17-7
Formula :	C₆H₇ClN₂O₂
M.W :	174.59
SMILES Code :	COC1=CN=C(Cl)N=C1OC
MDL No. :	MFCD21098377
InChI Key :	KIIOOCFFMSRIHK-UHFFFAOYSA-N
Pubchem ID :	66569546

Safety of [ 1333240-17-7 ]

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

Computational Chemistry of [ 1333240-17-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.33
Num. rotatable bonds	2
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	40.03
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	44.24 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.22
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	1.44
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.15
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.	0.1
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	1.5
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.28

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.1
Solubility	1.38 mg/ml ; 0.00792 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.97
Solubility	1.85 mg/ml ; 0.0106 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	-2.52
Solubility	0.527 mg/ml ; 0.00302 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	No
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-6.34 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)	2.22

Application In Synthesis of [ 1333240-17-7 ]

* 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 [ 1333240-17-7 ]

[ 1333240-17-7 ] Synthesis Path-Downstream 1~18

1
[ 1333240-17-7 ]
[ 128796-39-4 ]
[ 1333240-16-6 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;(diphenylphosphin)ferrocene; In tetrahydrofuran; water; at 150.0℃; for 0.166667h;Microwave irradiation;	5-Hydroxy-2-(4-trifluoromethyl-phenyI)-3H-pyrimidin-4-one (6)6To a mixture of 0.05 g (0.26 mmol) 4-trifluoromethylphenylboronic acid, 0.02 g (0.009 mmol Pd EN Cat 30, and 0.65 mL 1 M aq Cs2C03, was added a solution of 0.005 g (0.009 mmol) Iota ,Gamma- (bisdiphenylphosphino)ferrocene and 0.03 g (0.17 mmol) 2-chloro-4,5-dimethoxy-pyrirnidine in 1 mL THF, The resulting mixture was heated by microwave to 150 C for 10 minutes. After cooling, the aq layer was removed and the organic phase was filtered and concentrated, To the resulting residue was added 1 mL 33%> HBr in AcOH, and the resulting mixture was heated by microwave to 160 C for 5 min. The resulting solution was diluted with water (2 mL) and loaded onto an SCX column. After washing with MeOH (5 mL), the crude product was eluted off with 2 M ammonia in MeOH. Purification by automated mass-guided HPLC afforded 1 ,7 mg (4%) 5-hydroxy-2-(4-trifluoromethyl-phenyl)-3H- pyrimidin-4-one. 'H NMR (499 MHz, DMSO-de ): delta 9.85 (br s, 1 H); 8.22 (d, J = 7.93 Hz, 2 H); 7.85 (d, J = 8.12 Hz, 2 H); 7.63 (br s, 1 H). High resolution mass spec (FT/ICR) calc (M+H)+ - 257.0533 found 257.0532.

References: [1]Patent: WO2011/109267,2011,A1 .Location in patent: Page/Page column 47.

2
[ 67-56-1 ]
[ 19646-07-2 ]
[ 1333240-17-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	With potassium carbonate; at 20.0℃; for 19.0h;	a. Preparation of Compound 2-Chloro-4,5-dimethoxypyrimidine 2,4-Dichloro-5-methoxypyrimidine (2.37 g, 13.2 mmol) and K2C03 (1.8 g, 13.2 mmol) were dissolved in MeOH (50 mL) and stirred for 19 hours at room temperature. The solvent was removed under reduced pressure. The resulting residue was dissolved in EtOAc and washed with distilled water followed by brine. The organic layer was dried over Na2S04 and concentrated. It was then flash chromatographed on silica gel eluting with 0 to 20% EtOAc/Hexane to give 2-chloro-4,5-dimethoxypyrimidine as a white solid (1.70 g, 73%); m.p.65-67 C; NMR (400 MHz, CDC13) delta 7.84 (s, 1H), 4.03 (s, 3H), 3.88 (s, 3H); 13C NMR (100 MHz, CDC13) delta 161.2, 150.0, 141.7, 138.2, 56.6, 55.0.
	With potassium carbonate; at 20.0℃; for 24.0h;	2-Chloro-4,5-dimethoxy-pyrimidine To a solution of 10 g (55.9 mmol) 2,4-dich.oro-5-methoxy-pyrimidine in 200 mL MeOH was added 7.7 g (55.9 mmo.) K2CO3. The reaction mixture was stirred at room temperature for 24 h, then the volatiles were removed in vacuo. The residue was diluted with EtOAc (200 mL) and water (100 mL). The organic layer was separated, dried (Na2S04), and evaporated affording 9,0 g (92%) 2-chioro-4,5- dimethoxy-pyrimidine as a fluffy white solid which was used in subsequent steps without further purification. LCMS [M+H]+ =175.0.

References: [1]Patent: WO2014/43252,2014,A2 .Location in patent: Page/Page column 64.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 8086 - 8098.
[3]Patent: WO2011/109267,2011,A1 .Location in patent: Page/Page column 46-47.

3
[ 1333240-17-7 ]
[ 1581767-51-2 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8086 - 8098.
[2]Patent: WO2014/43252,2014,A2 .

4
[ 1333240-17-7 ]
[ 1581767-53-4 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8086 - 8098.
[2]Patent: WO2014/43252,2014,A2 .

5
[ 1333240-17-7 ]
[ 1581767-55-6 ]

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8086 - 8098.
[2]Patent: WO2014/43252,2014,A2 .

6
[ 1333240-17-7 ]
[ 126747-14-6 ]
[ 1581767-52-3 ]

Yield	Reaction Conditions	Operation in experiment
74%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 4.0h;Reflux; Inert atmosphere;	a. Preparation of Compound 4-(4,5-dimethoxypyrimidin-2-yl)benzonitrile 2-Chloro-4,5-dimethoxypyrimidine (100 mg, 0.57 mmol), (4-cyanophenyl)boronic acid (126 mg, 0.86 mmol), Pd(PPh3)4 (66 mg, 0.06 mmol) and Na2C03(182 mg, 1.72 mmol) were dissolved in a mixture of dioxane (9 mL) and water (3 mL). The air was evacuated and replaced with N2. Then, the reaction mixture was refluxed for 4 hours. After the reaction was completed, it was cooled to room temperature and it was diluted with EtOAc and washed with sat. NH4CI followed by brine. The organic layer was dried over Na2S04 and concentrated in vacuo and the resulting residue was flash chromatographed on silica gel eluting with 0 to 20 % EtOAc/hexaiie. This afforded 4-(4,5-dimethoxypyrimidin-2-yl)benzonitrile as a white solid (69 mg, 74%); m.p.170-172 C; 1H NMR (400 MHz, CDC13) delta 8.49 (d, J= 9 Hz, 2H), 8.18 (s, 1H), 7.76 (d, J = 9 Hz, 2H), 4.20 (s, 3H), 4.02 (s, 3H); ,3C NMR (100 MHz, CDC13) delta 159.8, 154.0, 141.8, 141.5, 137.0, 132.3, 128.0, 119.0, 113.0, 56.4, 54.2.

References: [1]Patent: WO2014/43252,2014,A2 .Location in patent: Page/Page column 66-67.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 8086 - 8098.

7
[ 1333240-17-7 ]
[ 150255-96-2 ]
[ 1581767-54-5 ]

Yield	Reaction Conditions	Operation in experiment
100%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 5.0h;Reflux; Inert atmosphere;	a. Preparation of Compound 3-(4,5-Dimethoxypyrimidin-2-yl)benzonitrile 2-Chloro-4,5-dimethoxypyrimidine (100 mg, 0.57 mmol), (3-cyanophenyl)boronic acid (126 mg, 0.86 mmol), Pd(PPh3)4 (66 mg, 0.06 mmol) and Na2C03(182 mg, 1.72 mmol) were dissolved in a mixture of dioxane (9 mL) and water (3 mL). The air was evacuated and replaced with N2. Then, the reaction mixture was refluxed for 5 hours. After the reaction was completed, it was cooled to room temperature and it was diluted with EtOAc and washed with sat. NH4CI followed by brine. The organic layer was dried over Na2S04 and concentrated in vacuo and the resulting residue was flash chromatographed on silica gel eluting with 0 to 20% EtOAc/Hexane. This afforded 3-(4,5-dimethoxypyrimidin-2-yl)benzonitrile as a white solid (138 mg, 100%); m.p.134-136 C; H NMR (400 MHz, CDC13) delta 8.61 (s, 1H), 8.54 (d, J= 8 Hz, 1H), 8.09 (s, 1H), 7.65 (d, J= 8 Hz, 1H), 7.51 (t, J= 8 Hz, 1H), 4.13 (s, 3H), 3.95 (s, 3H); 13C NMR (100 MHz, CDC13) 6 159.8, 153.6, 141.7, 138.5, 137.0, 132.8, 131.6, 131.3, 129.2, 1 18.9, 1 12.6, 56.4, 54.2

References: [1]Patent: WO2014/43252,2014,A2 .Location in patent: Page/Page column 68-69.
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 8086 - 8098.

8
[ 1333240-17-7 ]
[ 1765-93-1 ]
[ 1581767-50-1 ]

Yield	Reaction Conditions	Operation in experiment
77%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 5.0h;Reflux; Inert atmosphere;	b. Preparation of Compound 2-(4-Fluorophenyl)-4,5-dimethoxypyrimidine 2-Chloro-4,5-dimethoxypyrimidine (500 mg, 2.86 mmol), (4-fluorophenyl)boronic acid (601 mg, 4.30 mmol), Pd(PPh3)4 (330 mg, 0.29 mmol) and Na2CO3(910 mg, 8.59 mmol) were dissolved in a mixture of dioxane (12 mL) and water (4 niL). The air was evacuated and replaced with N2. Then, the reaction mixture was refluxed for 5 hours. After the reaction was completed, it was cooled to room temperature and it was diluted with EtOAc and washed with sat. NH4CI followed by brine. The organic layer was dried over Na2S04 and concentrated under reduced pressure and the resulting residue was flash chromatographed on silica gel eluting with 0 to 10% EtOAc/Hexane. This afforded 2-(4-fluorophenyl)-4,5-dimethoxypyrimidine as a white solid (123 mg, 77%); m.p.l 14-116 C; LH NMR (400 MHz, CDC13) delta 8.37 (dd, J= 9 Hz, J= 6 Hz, 2H), 8.12 (s, 1H), 7.16 - 7. 12 (m, 2H), 4.17 (s, 3H), 3.98 (s, 3H); 13C NMR (100 MHz, CDCI3) delta 163.1 (JQF= 248 Hz), 159.7, 155.3, 141.0, 137.2, 133.6 (JCIF= 3 Hz), 129.6 (J F= 8 Hz), 115.3 (JC,F= 22 Hz), 56.4, 54.0; 19F NMR (376 MHz, CDC13) delta -11 1.9.

References: [1]Journal of Medicinal Chemistry,2014,vol. 57,p. 8086 - 8098.
[2]Patent: WO2014/43252,2014,A2 .Location in patent: Page/Page column 65.

9
[ 1333240-17-7 ]
2-(3-fluorophenyl)-5-methoxypyrimidin-4(3H)-one [ No CAS ]