Structure of 848366-28-9
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CAS No. : | 848366-28-9 |
Formula : | C6H5BrClNO |
M.W : | 222.47 |
SMILES Code : | BrC1=CN=C(C(=C1)Cl)OC |
MDL No. : | MFCD04972382 |
InChI Key : | XCHXNAQRMMXBGN-UHFFFAOYSA-N |
Pubchem ID : | 40427004 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H332-H335 |
Precautionary Statements: | P261-P280-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.17 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 43.44 |
TPSA ? Topological Polar Surface Area: Calculated from |
22.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.33 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
2.48 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.51 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.92 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.67 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.38 |
Log S (ESOL):? ESOL: Topological method implemented from |
-3.16 |
Solubility | 0.154 mg/ml ; 0.000692 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.59 |
Solubility | 0.573 mg/ml ; 0.00258 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.63 |
Solubility | 0.0524 mg/ml ; 0.000236 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) |
Yes |
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 |
-5.9 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 |
0.0 |
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) |
1.89 |
* 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 |
---|---|---|
78% | With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 80℃; | AF. 3-Chloro-2-methoxy-5-(4A5,5-tetramethyl-l,3,2-dioxaborolan-2- vDpyridine; To a dry flask was added <strong>[848366-28-9]5-bromo-3-chloro-2-methoxypyridine</strong> (0.5 g, 2.2 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.70 g, 2.7 mmol), and Pd(dppf)Cl2 (82 mg, 0.10 mmol). Potassium acetate (0.6 g, 6.0 mmol) was weighed directly into the flask. The flask was then evacuated and back filled with N2. Anhydrous N,N- dimethylformamide (DMF) (13.0 mL) was added and the reaction was heated at 80 0C in an oil bath overnight. The reaction mixture was evaporated to dryness. The residue was dissolved in ethyl acetate (10 mL) and washed with water (1OmL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting material was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (0.47 g, 78%). ESI-MS m/z calc. 269.53, found 270.3 (MW+1)+. Retention time 2.07 minutes. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With sodium t-butanolate;palladium diacetate; XPhos; In toluene; tert-butyl alcohol; at 20 - 110℃; for 122.0h;Inert atmosphere; | Intermediate 15: 6-(5-Chloro-6-methoxy-pyridin-3-yl)-4-methoxy-5,6,7,8-tetrahydro- pyrido[4,3-d]pyrimidine; To a glass vial was added 4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (WO2008/130481 , p 47) (0.273 g, 1 .65 mmol), <strong>[848366-28-9]5-bromo-3-chloro-2-methoxypyridine</strong> (0.368 g, 1.65 mmol), sodium ferf-butoxide (318 mg, 3.31 mmol), diacetoxypalladium (0.037 g, 0.17 mmol), X-Phos (0.079 g, 0.17 mmol) and anhydrous toluene / ferf-butanol, 5 /1 (6 mL). The vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 2h at 1 10C then allowed to cool to room temperature and stirred at rt for 5 days. Diluted with CH2CI2 (10 mL) and water (2 mL), filtered through a celite pad. The organic phase was separated by filtering through a phase separation tube and concentrated in vacuo. Purified by flash chromatography on silica gel with heptane / EtOAc 100 / 0 to 0/ 100 to give 6-(5-chloro-6-methoxy-pyridin-3-yl)-4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3- d]pyrimidine as a yellow solid (95 mg, 19% yield) LCMS: [M+H]+=307.0 / 308.9, Rt (3)= 1 .62 mm. |
19% | With palladium diacetate; sodium t-butanolate; XPhos; In toluene; tert-butyl alcohol; at 20 - 110℃; for 122.0h;Inert atmosphere; | To a glass vial was added 4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (WO 2008/130481 , p 47) (0.273 g, 1.65 mmol), <strong>[848366-28-9]5-bromo-3-chloro-2-methoxypyridine</strong> (0.368 g, 1.65 mmol), sodium ferf-butoxide (318 mg, 3.31 mmol), diacetoxypalladium (0.037 g, 0.17 mmol), X-Phos (0.079 g, 0.17 mmol) and anhydrous toluene / ferf-butanol, 5 /1 (6 mL). The vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 2h at 1 10C then allowed to cool to room temperature and stirred at rt for 5 days. Diluted with CH2CI2 (10 mL) and water (2 mL), filtered through a celite pad. The organic phase was separated by filtering through a phase separation tube and concentrated in vacuo. Purified by flash chromatography on silica gel with heptane / EtOAc 100 / 0 to 0/ 100 to give 6-(5-chloro-6-methoxy-pyridin-3-yl)-4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine as a yellow solid (95 mg, 19% yield) LCMS: [M+H]+=307.0 / 308.9, Rt (3)= 1.62 mm. |
19% | With palladium diacetate; sodium t-butanolate; XPhos; In toluene; tert-butyl alcohol; at 20 - 110℃; for 122.0h;Inert atmosphere; | Intermediate 15 6-(5-Chloro-6-methoxy-pyridin-3-yl)-4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine To a glass vial was added 4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine (WO 2008/130481, p 47) (0.273 g, 1.65 mmol), <strong>[848366-28-9]5-bromo-3-chloro-2-methoxypyridine</strong> (0.368 g, 1.65 mmol), sodium tert-butoxide (318 mg, 3.31 mmol), diacetoxypalladium (0.037 g, 0.17 mmol), X-Phos (0.079 g, 0.17 mmol) and anhydrous toluene/tert-butanol, 5/1 (6 mL). The vial was flushed with a stream of argon for 15 sec and capped. The mixture was heated with stirring for 2 h at 110 C. then allowed to cool to room temperature and stirred at rt for 5 days. Diluted with CH2Cl2 (10 mL) and water (2 mL), filtered through a celite pad. The organic phase was separated by filtering through a phase separation tube and concentrated in vacuo. Purified by flash chromatography on silica gel with heptane/EtOAc 100/0 to 0/100 to give 6-(5-chloro-6-methoxy-pyridin-3-yl)-4-methoxy-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine as a yellow solid (95 mg, 19% yield) LCMS: [M+H]+=307.0/308.9, Rt(3)=1.62 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With sodium t-butanolate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In tetrahydrofuran; at 90℃; for 3.0h;Inert atmosphere; | (S)-3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5fi ,8-tetrahydro-pyrido[4,3-d]pyripyrrolidine-1 -carboxylic acid tert-butyl ester; X-Phos (0.073 g, 0.154 mmol), Pd2(dba)3 (0.100 g, 0.1 10 mmol), NaOtBu (0.395 g, 4.1 1 mmol) and 5-bromo-3-chloro-2-methoxy-pyridine (0.732 g, 3.29 mmol) were combined and flushed under a stream of argon for 10 min. To this mixture, a solution of (S)-3-(5,6,7,8- tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1 -carboxylic acid tert-butyl ester (Intermediate 7) (2.15 g, 6.72 mmol) in THF (6 mL) was added at rt and the reaction mixture was stirred at 90C for 3h. The reaction was cooled down to rt, EtOAc was added, the mixture filtered through a celite pad and concentrated under vacuum. Purification by flash chromatography on silica gel (CH2CI2 /MeOH 99/1 to 95/5) gave (S)-3-[6-(5-chloro-6- methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1- carboxylic acid tert-butyl ester as yellow foam (0.766 g, 60% yield). LCMS: [M+H]+=462.1 , Rt (3)= 1.84 min |
60% | With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; XPhos; In tetrahydrofuran; at 90℃; for 3.0h;Inert atmosphere; | (S)-3-[6-(5-Chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester X-Phos (0.073 g, 0.154 mmol), Pd2(dba)3 (0.100 g, 0.110 mmol), NaOtBu (0.395 g, 4.11 mmol) and 5-bromo-3-chloro-2-methoxy-pyridine (0.732 g, 3.29 mmol) were combined and flushed under a stream of argon for 10 min. To this mixture, a solution of (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (Intermediate 7) (2.15 g, 6.72 mmol) in THF (6 mL) was added at rt and the reaction mixture was stirred at 90 C. for 3 h. The reaction was cooled down to rt, EtOAc was added, the mixture filtered through a celite pad and concentrated under vacuum. Purification by flash chromatography on silica gel (CH2Cl2/MeOH 99/1 to 95/5) gave (S)-3-[6-(5-chloro-6-methoxy-pyridin-3-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylic acid tert-butyl ester as yellow foam (0.766 g, 60% yield). LCMS: [M+H]+=462.1, Rt(3)=1.84 min |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.0 g | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃; | Step 3 To a 250 mL RBF was added <strong>[848366-28-9]5-bromo-3-chloro-2-methoxypyridine</strong> (1.5 g), tribasic potassium phosphate (2.86 g, 13.5 mmol), bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.275 g, 6.74 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.27 g, 7.13 mmol), dioxane (50 mL) and water (3 mL). The flask was sealed and was stirred at 80 C. overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, filtered and concentrated. The resultant residue was purified by column chromatography to yield tert-butyl 4-(5-chloro-6-methoxypyridin-3-yl)-3-methylbenzoate (2.0 g, 5.99 mmol). MS ESI calc'd. for C18H21ClNO3 [M+H]+ 334.1. found 334.0. |
2.0 g | With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃;Sealed tube; | Step C: tert-Butyl 4-(5-chloro-6-methoxypyridin-3-yl-3-methylbenzoate: To a 250 mL roundbottomed flask was added <strong>[848366-28-9]5-bromo-3-chloro-2-methoxypyridine</strong> (1.5 g), tribasic potassium phosphate (2.86 g, 13.5 mmol), bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane adduct (0.275 g, 6.74 mmol), tert-butyl 3 -methyl-4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)benzoate (Step B, 2.27 g, 7.13 mmol), dioxane (50 mL) and water (3 mL). The flask was sealed and was stirred at 80C overnight. The reaction was cooled to roomtemperature, diluted with ethyl acetate, washed with water, filtered and the filtrate concentrated.The resultant residue was purified by silica gel chromatography to yield tert-butyl 4-(5-chloro-6-methoxypyridin-3-yl)-3-methylbenzoate (2.0 g, 5.99 mmol). LCMS (M+H)*: 334.0 |
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃;Sealed tube; | Step 3: To a 250 mL RBF was added <strong>[848366-28-9]5-bromo-3-chloro-2-methoxypyridine</strong> (1.5g, 6.74 mmol), tribasic potassium phosphate (2.86 g, 13.5 mmol), [1,1 '-20 bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.275 g, 0.337 mmol),tert-butyl 3-methyl-4-( 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoate (2.27 g, 7.13 mmol),dioxane (50 mL) and water (3 mL). The flask was sealed and was stirred at 80 C overnight. Thereaction was cooled to room temperature, diluted with ethyl acetate, washed with water, filteredand concentrated. The resultant residue was purified by column chromatography to yield tert-25 butyl4-(5-chloro-6-methoxypyridin-3-yl)-3-methylbenzoate. MS ESI calc'd. for C18H21ClN03[M + H]+ 334.1, found 334.0. |
With potassium phosphate; dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; water; at 80℃;Sealed tube; | Step 3: To a 250 mL RBF was added <strong>[848366-28-9]5-bromo-3-chloro-2-methoxypyridine</strong> (1.5 g), tribasic potassium phosphate (2.86 g, 13.5 mmol), bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.275 g, 6.74 mmol), tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoate (2.27 g, 7.13 mmol), dioxane (50 mL) and water (3 mL). The flask was sealed and was stirred at 80 C overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water, filtered and concentrated. The resultant residue was purified by column chromatography to yield tert-butyl 4-(5-chloro-6-methoxypyridin-3-yl)-3-methylbenzoate. MS ESI calc'd. for C18H21CINO3 [M + H]+ 334.1, found 334.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium tert-butylate; In tetrahydrofuran; at 20℃; for 16.0h;Cooling with ice; | General procedure: Intermediate A (Method 20) ch loro-2-isobutoxypyrid ine To a solution of 5-bromo-3-chloro-2-fluoropyridine (Aldrich) (105 g, 0.5 mol) and 2- methylpropan-1-ol (44 g, 0.6 mol) in dry THF(1 I) was added f-BuOK(1 12 g, 1 mol) dropwise with ice-bath, and then the mixture was stirred at room temperature for 16 hrs. The reaction was quenched with saturated NH4CI aqueous solution, extracted with EtOAc (x2). The separated organic phase was washed with brine (x2), dried over anhydrous Na2S04 and filtered. The filtration solution was concentrated under reduced pressure to give the title compound. LC-MS m/z Rt = 1.16 mins; [M+H]+ 264, Method 5-95AB 1.5minLC_v003 1H NMR (400 MHz, DMSO-d6) delta 8.17 (1 H, d), 7.88 (1 H, d), 4.18 (2H, d), 2.06 (1 H, m), 0.99 (6H, d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With tetrakis(triphenylphosphine) palladium(0); potassium carbonate; In 1,4-dioxane; water; at 90℃; for 16.0h;Inert atmosphere; | [0153] To a solution of <strong>[848366-28-9]5-bromo-3-chloro-2-methoxypyridine</strong> (5.0 g, 22.5 mmol), and 3,5-dimethylisoxazole-4-boronic acid pinacol ester (6.0 g, 27.0 mmol) in 1,4-dioxane (188 mL) and water (19 mL) was added potassium carbonate (6.2 g, 44.9 mmol). The mixture was purged with nitrogen for 10 min, and tetrakis(triphenylphosphine)palladium(0) was added (1.3 g, 1.12 mmoi). The mixture was heated to 90 C for 16 h, then diluted with ethyl acetate (100 mL) and washed with brine (100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (silica gel, 0- 30% ethyl acetate/hexanes) to afford 4 as a white solid (4.2 g, 78%): JH NMR (300 MHz, DMSO-d6) delta 8.18 (d, J = 2.1 Hz, 1H), 8.01 (d, J - 2.1 Hz, 1H), 3.99 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H); ESI m/z 239 [M + H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; palladium diacetate; tricyclohexylphosphine; In water; toluene; at 100℃;Inert atmosphere; | To a mixture of cyclopropylboronic acid (1.26 g) , 5- bromo-3-chloro-2-methoxypyridine (2.50 g) , toluene (30 ml) and water (3 ml) were added palladium(II) acetate (126 mg) , tricyclohexylphosphine (315 mg) and tripotassium phosphate (7.16 g) , and the mixture was stirred under a nitrogen (1052) atmosphere at 100C overnight. Water was added to the mixture and the mixture was extracted with^ ethyl acejtate . The._organic . layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.20 g) . (1053) MS: [M+H]+ 184.3. |
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