Structure of 475275-69-5
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CAS No. : | 475275-69-5 |
Formula : | C6H7BClNO3 |
M.W : | 187.39 |
SMILES Code : | COC1=NC=C(Cl)C(B(O)O)=C1 |
MDL No. : | MFCD06658398 |
InChI Key : | ONFAPGPPGOLJST-UHFFFAOYSA-N |
Pubchem ID : | 11030558 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 45.56 |
TPSA ? Topological Polar Surface Area: Calculated from |
62.58 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.69 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.58 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.57 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.55 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.2 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.67 |
Solubility | 3.96 mg/ml ; 0.0212 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.58 |
Solubility | 4.91 mg/ml ; 0.0262 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.66 |
Solubility | 4.09 mg/ml ; 0.0218 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 |
No |
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 |
-6.95 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 |
1.0 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) |
2.12 |
* 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 |
---|---|---|
General procedure: [0548] At -78 C., LDA (2 molar in THFheptane/ethylbenzene)was added to a solution of the appropriate pyridinederivative in THF (3 ml/mmol), the mixture was stirred for2-4 h and triisopropyl borate was then added quickly. Thereaction mixture was maintained at -7S C. for a further 2-3hand then slowly thawed to RT overnight. After addition ofwater, the THF was removed under reduced pressure and theaqueous phase was extracted twice with ethyl acetate Theaqueous phase was acidified with 2M hydrochloric acid, generallyresulting in formation of a precipitate which was filteredoff, washed with water and dried. The aqueous phasewas extracted three times with ethyl acetate. The combinedorganic phases were dried (sodium sulphate), filtered andconcentrated under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; copper diacetate; caesium carbonate; In 1,4-dioxane; at 80℃; | INTERMEDIATE 29 5-Chloro-4-(3-iodo-lH-pyrazol-l-yl)-2-methoxypyridine A solution of 3-iodo-lH-pyrazole (0.3 g, 1.547 mmol), 5-chloro-2-methoxypyridine- 4-boronic acid (0.377 g, 2.011 mmol), DMAP (0.756 g, 6.19 mmol), copper(II)acetate (0.281 g, 1.547 mmol), and cesium carbonate (1.26 g, 3.87 mmol) in 1,4-dioxane (7.73 mL) was heated at 80 C overnight. The reaction was allowed to warm to room temperature and filtered. The filtrate was diluted with EtOAc and water, and the seperated aq. layer was extracted with EtOAc. The combined organics were dried over MgS04, filtered and concentrated. The residue was purified with flash chromatography (ISCO Combiflash, 24 g, 0-10 % EtOAc in hexanes) to give 5- chloro-4-(3-iodo-lH-pyrazol-l-yl)-2-methoxypyridine, as a white solid. LCMS calc. = 335.93; found = 335.82 (M+H)+. 1H NMR (500 MHz, CDC13): delta 8.25 (s, 1 H); 8.01 (d, J= 2.6 Hz, 1 H); 7.14 (s, 1 H); 6.66 (d, J= 2.5 Hz, 1 H); 3.96 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium dihydrogenphosphate; chloro(2-dicyclohexylphosphino-2?,4?,6?-triisopropyl-1,1?-biphenyl)[2-(2?-amino-1,1?-biphenyl?)]palladium(II); In tetrahydrofuran; water; at 60℃;Inert atmosphere; Sonication; | General procedure: [0550] In a flask which had been dried by heating andflushed with argon, 1.0 eq. of the appropriate boronic acids,1.0 eq. of the aryl bromide or aryl iodide and 0.05 eq. ofXPhos precatalyst [(2'-aminobiphenyl-2-yl)( chloro )palladium/dicyclohexyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphane(1:1)], J. Am. Chern. Soc. 2010, 132, 14073-14075]were initially charged. The flask was then evacuated threetimes and in each case vented with argon. THF (about 12ml/mmol) which had been degassed in an ultrasonic bath and3.0 eq. of aqueous potassium phosphate solution (0.5 molar)were added, and the reaction mixture was stirred at 60 C.Water and ethyl acetate were then added to the reaction mixture.After phase separation, the aqueous phase was extractedonce with ethyl acetate. The combined organic phases weredried (sodium sulphate), filtered and concentrated underreduced pressure. The crude product was then purified eitherby flash chromatography (silica gel 60, mobile phase: cyclohexane/ethyl acetate mixtures or dichloromethane/methanolmixtures) or by preparative HPLC (Reprosil CIS, water/acetonitrilegradient or water/methanol gradient). | |
193 mg | With potassium phosphate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tetrahydrofuran; water; at 60℃;Inert atmosphere; Sonication; | General procedure: General Method 2B: Suzuki coupling In a flask whichhad been dried by heating and flushed with argon, 1.0 eq. of the appropriateboronic acids, 1.0 eq. of the aryl bromide or aryl iodide and 0.05 eq. of XPhosprecatalyst[(2'-aminobipheny1-2-y1)(chloro)palladium/dicyclohexyl(2',4',61-triisopropylbipheny1-2-yl)phosphane(1:1)], J. Am. Chem. Soc. 2010, 132, 14073-14075] were initially charged. Theflask was then evacuated three times and in each case vented with argon. THF(about 12 ml/mmol) which had been degassed in an ultrasonic bath and 3.0 eq. ofaqueous potassium phosphate solution (0.5 molar) were added, and the reactionmixture was stirred at 60 C. Water and ethyl acetate were then I uiu fore=countries added to the reaction mixture. After phase separation, the aqueousphase was extracted once with ethyl acetate. The combined organic phases weredried (sodium sulphate), filtered and concentrated = under reduced pressure.The crude product was then purified either by flash chromatography (silica gel60, mobile phase: cyclohexane/ethyl acetate mixtures ordichloromethane/methanol mixtures) or by preparative HPLC (Reprosil C18,water/acetonitrile gradient or water/methanol gradient).443 mg (2.20 mmol) of5-chloro-2-methoxypyridin-4-ylboronic acid and 571 mg (2.20 mmol) of2-bromo-4-chloro-1-(trifluoromethyl)benzene in the presence of XPhosprecatalyst were reacted according to General Method 2B.Yield: 193 mg (purity 93%, 25% of theory) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
10.44 g | With lithium hexamethyldisilazane; In tetrahydrofuran; n-heptane; ethylbenzene; at -78 - 20℃; | General procedure: General Method 1A: Preparation of a boronic acid At-78C, LDA (2 molar in THF/heptane/ethylbenzene) was added to a solution of theappropriate pyridine derivative in THF (3 ml/mmol), the mixture was stirred for2-4 h and triisopropyl borate was then added quickly. The reaction mixture wasmaintained at -78 C for a further 2-3 h and then slowly thawed to RT overnight.After addition of water, the THF was removed under reduced pressure and theaqueous phase was extracted twice with ethyl acetate The aqueous phase wasacidified with 2M hydrochloric acid, generally resulting in formation of aprecipitate which was filtered off, washed with water and dried. The aqueousphase was extracted three times with ethyl acetate. The combined organic phaseswere dried (sodium sulphate), filtered and concentrated under reduced pressure.10.0 g (69.65 mmol) of 5-chloro-2-methoxypyridine werereacted according to General Method 1A.The desired product precipitated on acidification with hydrochloric acid (2N).Yield: 10.44 g (purity 91%, 73% of theory) |
10.0 g of 5-chloro-2-methoxypyridine were initially charged in 225 ml of THF, and 41.8 ml (83.6 mmol) of lithium diisopropylamide (2M in THF/heptane/ethylbenzene) were added at -78 C. The mixture was stirred at -78 C. for 4 h, and 32.6 ml (141 mmol) of triisopropyl borate were then added rapidly. The reaction mixture was stirred at-78 C. for 3 h and then warmed to room temperature overnight. The procedure was then repeated, and a further 20.9 ml (41.8 mmol) of lithium diisopropylamide (2M in THF/heptane/ethylbenzene) and 16.1 ml (69.7 mmol) of triisopropyl borate were added. The reaction mixture was poured into 500 ml of water and THF was removed under reduced pressure. The aqueous phase was extracted three times with ethyl acetate. The aqueous phase was acidified with hydrochloric acid (2N) and the precipitate was filtered oil. The filtrate was extracted twice with ethyl acetate, the organic phase was dried and filtered, the solvent was removed under reduced pressure and the residue, together with the precipitate, was dried under high vacuum. Yield:10.4 g (91% pure, 73% of theory).j0675] LC/MS [Method 1]: R=0.50 mm; MS (ESIpos):mlz=188 (M+H), j0676] ?H-NMR (400 MHz, DMSO-d5): oe [ppm]=8.64(br. s, 2H), 8.12 (s, 1H), 6.81 (s, 1H), 3.82 (s, 3H). | ||
16 g | Under a nitrogen atmosphere, 300 g of anhydrous tetrahydrofuran was added to the reaction flask, stirring was continued, 17 g of 5-chloro-2-methoxypyridine was added and cooled to -30C.A solution of 70 mL of 2.0 M of n-BuLi was slowly added dropwise, and after stirring for 30 minutes, 1,3 g of 1,4,7,10-tetramethyl-1,4,7,10-tetraazacyclododecane was slowly added dropwise.After 2 hours of incubation, 41 mL of triisopropyl borate was slowly added dropwise at -30 C, stirred for 1 hr, slowly raised to room temperature and stirred for 1 hour.And 400 g of concentrated hydrochloric acid was added thereto, followed by stirring for 1 hour to carry out a hydrolysis reaction.The layers were allowed to stand, and the organic layer was washed three times with water (3 x 100 g).The aqueous layers were combined and the aqueous layer was extracted once with 100 ml of petroleum ether. The combined organic layers were dried over 50 g of anhydrous sodium sulfate and filtered.The filtrate was concentrated to dryness to give 6-chloro-2-methoxy-4-pyridine boronic acid 16 g, |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With catacxium A; In tetrahydrofuran; water; at 60℃; for 1h; | At 60 C., 4.17 g (16.2 mmol) of 2-bromo-4- chioro-1 -(difluoromethoxy)benzene, 3.04 g (16.2 mmol) of <strong>[475275-69-5](5-chloro-2-methoxypyridin-4-yl)boronic acid</strong>, 561 mg (486 tmol) of CATAXCium A precatalyst and 133 ml of aqueous potassium phosphate solution (0.5N) were stirred in 73 ml of THF for 1 h. The reaction mixture was then diluted with 125 ml of water and 125 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted with 125 mlof ethyl acetate. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulphate and filtered, and the solvent was removed under reduced pressure. Purification by colunm chromatography of the crude product (100 g silica cartridge, flow rate:50 ml/min, cyclohexane/ethyl acetate gradient) gave the title compound. Yield: 2.80 g (86% pure, 46% of theory).10679] LC/MS [Method 1]: R=1.20 mm; MS (ESIpos):mlz=320 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16 g | Under a nitrogen atmosphere, 300 g of anhydrous tetrahydrofuran was added to the reaction flask, stirring was continued, 17 g of 5-chloro-2-methoxypyridine was added and cooled to -30C.Sulfur was added dropwise to 70 mL of 2.0 M of n-BuLi. After stirring for 30 minutes, 26 g of 1,4,7-trimethyl-1,4,7-triazacyclononane was slowly added dropwise.After incubation for 2 hours, 26 mL of trimethyl borate was slowly added dropwise at -30 C, stirred for 1 hr, slowly rose to room temperature and stirred for 1 hour.And 400 g of concentrated hydrochloric acid was added thereto, followed by stirring for 1 hour to carry out a hydrolysis reaction.The layers were allowed to stand, and the organic layer was washed three times with water (3 x 100 g).The aqueous layers were combined and the aqueous layer was extracted once with 100 ml of petroleum ether. The combined organic layers were dried over 50 g of anhydrous sodium sulfate and filtered.The filtrate was concentrated to dryness to give 16 g of product 5-chloro-2-methoxy-4-pyridine boronic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of the appropriate pyridine derivative in tetrahydrofuran (about 3 ml/mmol) at -78 C. was added lithium diisopropylamide (2 M in tetrahydrofuran/heptane/ethylbenzene), the mixture was stirred for 2 to 4 h and then triisopropyl borate was then added quickly. The reaction mixture was maintained at -78 C. for a further 2 to 3 h and then slowly thawed to RT overnight. After addition of water, the tetrahydrofuran was removed under reduced pressure and the aqueous phase was extracted twice with ethyl acetate. The aqueous phase was acidified with aqueous hydrochloric acid (2M), generally resulting in formation of a precipitate which was filtered off, washed with water and dried. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried (sodium sulphate or magnesium sulphate), filtered and concentrated under reduced pressure. | ||
General procedure: [0471] To a solution of the appropriate pyridine derivativein tetrahydroffiran (about 3 ml/mmol) at -78 C. was added lithium diisopropylamide (2 M in tetrahydrofuranlheptane/ ethylbenzene), the mixture was stirred for 2 to 4 h and then triisopropyl borate was then added quickly. The reaction mixture was maintained at -78 C. for a further 2 to 3 h and then slowly thawed to RT overnight. Afier addition of water, the tetrahydroffiran was removed under reduced pressure and the aqueous phase was extracted twice with ethyl acetate. The aqueous phase was acidified with aqueous hydrochloric acid (2M), generally resulting in formation of a precipitate which was filtered off, washed with water and dried. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried (sodium sulphate or magnesium sulphate), filtered and concentrated under reduced pressure.; According to General Method 1A, 11.53 g (82.9 mmol) of 2,5-dimethoxypyridine were reacted. The desired product precipitated out after acidification of the aqueous phase. | ||
General procedure: To a solution of the appropriate pyridine derivative in tetrahydrofuran (about 3 ml/mmol) at -78 C. was added lithium diisopropylamide (2 M in tetrahydrofuran/heptane/ethylbenzene), the mixture was stirred for 2 to 4 h and then triisopropyl borate was then added quickly. The reaction mixture was maintained at -78 C. for a further 2 to 3 h and then slowly thawed to RT overnight. After addition of water, the tetrahydrofuran was removed under reduced pressure and the aqueous phase was extracted twice with ethyl acetate. The aqueous phase was acidified with aqueous hydrochloric acid (2M), generally resulting in formation of a precipitate which was filtered off, washed with water and dried. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried (sodium sulphate or magnesium sulphate), filtered and concentrated under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium phosphate; In tetrahydrofuran; water; at 100℃; for 2h;Inert atmosphere; | To a nitrogen-purged solution of methyl 5-bromo-3-methylpyrazine-2-carboxylate (Intermediate 1, 18 g, 78 mmol), <strong>[475275-69-5](5-chloro-2-methoxypyridin-4-yl)boronic acid</strong> (17.52 g, 93 mmol) and PdCl2(dppf) (5.70 g, 7.79 mmol) in THF (200 ml) and water (40.0 ml) was added K3PO4 (49.6 g, 234 mmol) under a nitrogen atmosphere. The reaction mixture was heated to a vigorous reflux at 100 C for 2 h. Then the reaction was allowed to slowly cool to room temperature overnight with stirring. The reaction was stirred at room temperature for 72h, then partitioned between ethyl acetate (150 ml) and water (150 ml) and stirred for 30 min. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous Na2S04, filtered and evaporated to afford a crude residue. The residue was purified via column chromatography on silica gel (ISCO RediSep Gold 220g silica gel column, gradient elution with 0% to 100% EtOAc in hexanes) to give the title compound. |
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