Structure of 2-Chloro-4-methoxypyrimidine
CAS No.: 22536-63-6
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 22536-63-6 |
Formula : | C5H5ClN2O |
M.W : | 144.56 |
SMILES Code : | COC1=NC(Cl)=NC=C1 |
MDL No. : | MFCD00194055 |
InChI Key : | BDXYNMVQMBCTDB-UHFFFAOYSA-N |
Pubchem ID : | 588935 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.2 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 33.53 |
TPSA ? Topological Polar Surface Area: Calculated from |
35.01 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.64 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.77 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.14 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.33 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.56 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.29 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.28 |
Solubility | 0.761 mg/ml ; 0.00526 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.12 |
Solubility | 1.09 mg/ml ; 0.00753 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.37 |
Solubility | 0.612 mg/ml ; 0.00424 mol/l |
Class? Solubility class: Log S scale |
Soluble |
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) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.93 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
1.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.74 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | 2-chloro-4-methoxypyrimidine (500 mg, 3.45 mmol) was combined with zinc cyanide (242 mg, 2.07 mmol) and tetrakis (triphenylphosphne)palladium (0) (159 mg, 0.14 mmol) in DMF (10 mL) and the slurry was heated at 800C under nitrogen for 6h. The mixture was cooled to rt, diluted with EtOAc (50 mL) and washed twice with 2N ammonium hydroxide (50 mL). The EtOAc solution was washed with brine (20 mL) and concentrated in vacuo to provide the crude mixture. The crude was then purified by column chromatography (10% EtOAc in hexanes) to afford 4-methoxypyrimidine-2-carbonitrile in 50% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 3-quinuclidinol; In dimethyl sulfoxide; at 60℃; for 2.5h; | General procedure: A mixture of 2-chloropyrimidines(10 mmol), potassium cyanide (13-15 mmol), water (20 mmol), and DMSO(20 mL) was heated to 60 C. A solution of 3-quinuclidinol (0.1-0.2 mmol) inDMSO(5 mL) was added to the reaction mixture over 0.5 h. The reaction mixturewas stirred at 50-70 C for additional hours as specified in Table 1. Uponcompletion, the mixture was cooled to room temperature and water (50 mL) wasadded. The resulting mixture was extracted with isopropyl acetate (3 40 mL)(product 7a precipitated out after water addition and was collected by filtration).The combined organic layers were washed with water (2 30 mL), dried overMgSO4, filtered, and concentrated under vacuum to give crude 2-cyanopyrimidines, which were purified by column chromatography (SiO2) to afford pureproducts. |
4.361 g | With 3-quinuclidinol; In water; acetonitrile; at 50℃; for 2.0h; | To a solution of potassium cyanide (2.70 g, 41.5 mmol) in water (5 mL) was added 2- chloro-4-methoxypyrimidine (4.99 g, 34.5 mmol), 3-quinuclidinol (1.10 g, 8.65 mmol) and acetonitrile (70 mL). The mixture was heated at 50 C for two hours, brought to room temperature and filtered with an acetonitrile rinse. The filtrate was concentrated, and the residue extracted first with tert-butyl methyl ether and then with 1:1 ethyl acetate/tert-butyl methyl ether. Extracts were sequentially filtered through a short plug of silica (10 g) to give the titled compound (4.361 g). 1H NMR (400 MHz, CDCl3) δ ppm 4.05 (s, 3H), 6.92 (d, J = 5.8 Hz, 1H), 8.49 (d, J = 5.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ ppm 54.9, 111.8, 115.6, 144.2, 157.7, 169.8; MS (DCI) m/z 153 (M+NH4)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere; | General procedure: To a solution of 2-chloro-4-methoxypyrimidine (120 g, 0.83 mol) in dioxane (2 L) was added 1-methyl-1H-pyazol-4-amine hydrochloride (111 g, 0.83 mol), Cs2co3(0.83 kg, 2.5 mol), S-Phos (13.3 g, 0.03 mol) and Pd2(dba)3(16.7 g, 0.02 mol). The reaction mixture was stirred at 120oC under N2for 4 h. The reaction mixture was cooled to room temperature and water (4 L) was added. The layers were separated and the aqueous phase was extracted with EtOAc (3x2 L). The combined organic layers were washed with brine (3L), dried (Na2SO4) and concentrated. The crude material was purified by silica gel chromatography (PE : EtOAc = 5 : 1 to 1 : 1) to give 4-methoxy-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (73 g, yield: 43percent) as a tan solid. ESI-MS (M+H)+: 205.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1-methyl-pyrrolidin-2-one; at 140℃; for 1.0h;Sealed tube; Microwave irradiation; | 2-chloro-4-methoxy-pyrimidine (600 mg, 4.15 mmol) and Zn(CN)2(292 mg, 2.49 mmol) and Pd(dppf)CI2(607 mg, 0.83 mmol) were taken up into a microwave tube in NMP (3 mL). The sealed tube was heated at 140C for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature, filtered through celite and washed with ethyl acetate (20 mL). The reaction mixture was extracted with ethyl acetate (20 mL x 3) and the organic layers were washed with water (20 x 3mL), brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate) to give 4- methoxypyrimidine-2-carbonitrile. | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1-methyl-pyrrolidin-2-one; at 140℃; for 1.0h;Sealed tube; Microwave irradiation; | 2-chloro-4-methoxy-pyrimidine (600 mg, 4.15 mmol) and Zn(CN)2 (292 mg, 2.49 mmol) andPd(dppf)C12 (607 mg, 0.83 mmol) were taken up into a microwave tube in NMP (3 mL). The sealed tube was heated at 140C for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature, filtered through celite and washed with ethyl acetate (20 mL). The reaction mixture was extracted with ethyl acetate (20 mL x 3) and the organic layers were washed with water (20 x 3mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reducedpressure to give a residue. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate) to give 4-methoxypyrimidine-2-carbonitrile. | |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1-methyl-pyrrolidin-2-one; at 140℃; for 1.0h;Sealed tube; Microwave irradiation; | 2-chloro-4-methoxy-pyrimidine (600 mg, 4.15 mmol) and 423 Zn(CN)2 (292 mg, 2.49 mmol) and Pd(dppf)Cl2 (607 mg, 0.83 mmol) were taken up into a microwave tube in NMP (3 mL). The sealed tube was heated at 140 C. for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature, filtered through celite and washed with ethyl acetate (20 mL). The reaction mixture was extracted with ethyl acetate (20 mL×3) and the organic layers were washed with water (20×3 mL), brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate) to give 438 4-methoxypyrimidine-2-carbonitrile. |
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1-methyl-pyrrolidin-2-one; at 140℃; for 1.0h;Sealed tube; Microwave irradiation; | 2-chloro-4-methoxy-pyrimidine (600 mg, 4.15 mmol) and Zn(CN)2 (292 mg, 2.49 mmol) and (1068) Pd(dppf)Cl2 (607 mg, 0.83 mmol) were taken up into a microwave tube in NMP (3 mL). The sealed tube was heated at 140C for 1 hour under microwave irradiation. The reaction mixture was cooled to room temperature, filtered through celite and washed with ethyl acetate (20 mL). The reaction mixture was extracted with ethyl acetate (20 mL x 3) and the organic layers were washed with water (20 x 3mL), brine (20 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash chromatography on silica gel (petroleum ether/ethyl acetate) to give 4-methoxypyrimidine-2-carbonitrile. |
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