Structure of 197376-47-9
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CAS No. : | 197376-47-9 |
Formula : | C9H10ClNO2 |
M.W : | 199.63 |
SMILES Code : | O=C(OCC)CC1=CC=C(Cl)N=C1 |
MDL No. : | MFCD03092921 |
InChI Key : | HNMKCAOYIPYXRD-UHFFFAOYSA-N |
Pubchem ID : | 15661146 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 13 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 4 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 49.92 |
TPSA ? Topological Polar Surface Area: Calculated from |
39.19 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.28 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.97 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.84 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.28 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.5 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.97 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.4 |
Solubility | 0.801 mg/ml ; 0.00401 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.42 |
Solubility | 0.762 mg/ml ; 0.00382 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-3.53 |
Solubility | 0.0586 mg/ml ; 0.000294 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 |
-6.12 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) |
1.9 |
* 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 |
---|---|---|
With sulfuric acid; In ethanol; water; | (6-Chloro-pyridin-3-yl)-acetic acid ethyl ester To a solution of EtOH (27 mL), concentrated H2SO4 (10 mL) was added dropwise and 2-chloropyridine-5-acetonitrile (2.00 g, 13.1 mmol) was added portionwise. The solution was stirred at 100C for three hours. The mixture was added dropwise to a solution of NaHCO3 (30.00 g) in H2O (100 mL) and it was extracted twice with DCM. The organic layer were collected, dried and evaporated to give the title compound (2.60 g, quant.) C9H10ClNO2 Mass (calculated) [199]; (found) [M+H]+ = 200. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In diethyl ether; | To a solution at-5 C of 44 mL of absolute ethanol in 155 mL of chloroform under nitrogen was added dropwise 45 mL of acetyl chloride. After 0.5 hours a solution of 8.46 g (55.4 MMOL) of Preparatory Compound E in 71 mL of chloroform was added dropwise keeping the temperature at 0 C or below. The mixture was then kept at 0 C for 4 hours and was then allowed to warm to room temperature overnight (about 22 C). Ethyl ether was added (350 mL) with cooling and the mixture was stirred for several minutes and was then filtered through a medium porosity sintered glass funnel always careful to keep a layer of ether over the white solid. After washing with an ample amount of ether, the solid/ether mixture was washed into a 1 L three-neck round-bottomed flask fitted with a mechanical stirrer and was then diluted with 400 mL of ether and was treated dropwise with 12.34 g (122 mmol, 2.2 equiv. ) of triethylamine in ether while cooling. The contents were stirred overnight under nitrogen. The mixture was filtered, the filtrate was dried over sodium sulfate and was concentrated to give 9.91 g (90%) of Preparatory Compound K, ethyl 2- (6-CHLORO-3-PYRIDINYL) ethanimidoate, as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
442 mg (yield; 84.4%) | In methanol; hexane; chloroform; water; toluene; | 2-(6-chloro-3-pyridyl)methyl-1,4,5,6-tetrahydropyrimidine [Compound 8] To a stirred solution of 20 ml of toluene were added 3.75 ml of 1M trimethylaluminum/hexane solution and 315 mul (3.77 mmol) of trimethylenediamine under argon atmosphere at room temperature, and to this mixture was further added 500 mg (2.5 mmol) of ethyl (6-chloro-3-pyridyl)acetate in toluene solution. The mixture was stirred for 22 hours at 100 C. under refluxing. After cooling the reaction mixture to room temperature, 5 ml of chloroform, 5 ml of methanol and 1 ml of water were added. Then precipitated gel was removed off by filtration and washed with a mixture of chloroform and methanol (9:1), and the filtrate was concentrated under reduced pressure. The resulting residue was purified by aminopropyl-coated silica gel (Chromatorex NH-type; Fuji Silysia Chemical Ltd.) column chromatography (eluent; dichloromethane:ethyl acetate=30:1, then dichloromethane:methanol=50:1) to give 442 mg (yield; 84.4%) of 2-(6-chloro-3-pyridyl)methyl-1,4,5,6-tetrahydropyrimidine as crystalline. This product was dissolved in methanol and to this solution was added 245 mg (2.11 mmol) of fumaric acid, and the mixture was concentrated under reduced pressure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sulfuric acid; at 100℃; for 3h; | To a solution of EtOH (27 mL), concentrated H2SO4 (10 mL) was added dropwise and 2-chloropyridine-5-acetonitrile (2.00 g, 13.1 mmol) was added portionwise. The solution was stirred at 100 C. for three hours. The mixture was added dropwise to a solution of NaHCO3 (30.00 g) in H2O (100 mL) and it was extracted twice with DCM. The organic layer were collected, dried and evaporated to give the title compound (2.60 g, quant.) (0395) C9H10ClNO2 Mass (calculated) [199]; (found) [M+H]+=200. |
75% | Step 2. Synthesis of (6-chloropyridin-3-yl) acetic acid ethyl ester. 10 g (65 5 mmol) (6-chloropyriotadiotan-3-yl)acetoniotatriotale were added to a mixture of 122 mL ethanol and 46 mL cone sulfuric acid and the mixture stirred under reflux for 5 h After cooling to ambient temperature, the reaction mixture was slowly added dropwise. while stirring, to a mixture of 161 g sodium bicarbonate and 450 mL water The aqueous phase was extracted with DCM (three times with 300 mL each time) The combined organic phases were dried over sodium sulfate, filtered and concentrated on a rotary evaporator The crude oil was purified by silica gei chromatography, eluted using a gradient of 2/98(v/v) EtOAc/hexanes to 9/91 (v/v) EtOAc/hexanes to afford 9 8 g (75%) of product as clear oil ESI-MS m/z 200 (MH)f | |
To a solution at-5 C of 44 mL of absolute ethanol in 155 mL of chloroform under nitrogen was added dropwise 45 mL of acetyl chloride. After 0.5 hours a solution of 8.46 g (55.4 MMOL) of Preparatory Compound E in 71 mL of chloroform was added dropwise keeping the temperature at 0 C or below. The mixture was then kept at 0 C for 4 hours and was then allowed to warm to room temperature overnight (about 22 C). Ethyl ether was added (350 mL) with cooling and the mixture was stirred for several minutes and was then filtered through a medium porosity sintered glass funnel always careful to keep a layer of ether over the white solid. After washing with an ample amount of ether, the solid/ether mixture was washed into a 1 L three-neck round-bottomed flask fitted with a mechanical stirrer and was then diluted with 400 mL of ether and was treated dropwise with 12.34 g (122 mmol, 2.2 equiv. ) of triethylamine in ether while cooling. The contents were stirred overnight under nitrogen. The mixture was filtered, the filtrate was dried over sodium sulfate and was concentrated to give 9.91 g (90%) of Preparatory Compound K, ethyl 2- (6-CHLORO-3-PYRIDINYL) ethanimidoate, as an oil. |
22.0 g (144 mmol) of (6-chloropyridin-3-yl)acetonitrile are added to a mixture of 270 ml of ethanol and 101 ml conc. sulfuric acid, and the mixture is stirred under reflux for 24 h. With stirring, the reaction mixture is then slowly added dropwise to a mixture of 350 g of sodium bicarbonate and 1 liter of water. The aqueous phase is extracted with dichloromethane (five times 400 ml each). The combined organic phases are dried over sodium sulfate, filtered and freed from the solvent using a rotary evaporator. This gives 23.1 g (80% of theory) of the title compound, which is reacted without further purification.1H-NMR (400 MHz, DMSO-d6): delta=8.32 (d, 1H), 7.78 (dd, 1H), 7.49 (d, 1H), 4.10 (q, 2H), 3.77 (s, 2H), 1.19 (t, 3H).LC-MS (Method 3): Rt=1.91 min; MS (ESIpos): m/z=200 [M+H]+. | ||
13 g | With sulfuric acid; for 4h;Reflux; | 15.2 g 2-chloropyridin-5-ylacetonitrile was added to a 250 ml four-mouthed flask. Add 150 ml ethanol. 10ml 98% concentrated sulfuric acid. Heat to reflux. Reflux reaction for 4 hours, reaction finishes, prolapsed ethanol, add 100 g water to stir, is neutral pH the sodium carbonate is used to regulate, filter, to obtain 2-chloro pyridine ethyl acetate 13 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With copper(II) bis(trifluoromethanesulfonate); triethylamine; In N,N-dimethyl acetamide; at 20℃;Sealed tube; | General procedure: General Procedure A: Cu(OTf)2 (54.3 mg, 0.150 mmol, 0.30 equiv.) and arylboronic ester (1.00 mmol, 1.20 to 2.00 equiv.) were added sequentially to a 1 dram vial charged with a stirbar. The carboxylic acid (0.500 mmol, 1.00 equiv.) was added as a solution in anhydrous DMA (0.6 mL). Additional DMA (2×0.3 mL) was used to quantitatively transfer the solution to the reaction mixture. The solution was stirred until a homogeneous pale blue solution was formed (approximately 2 minutes, partially heterogeneous mixtures obtained when using increased Cu loadings), followed by the addition of triethylamine (0.42 mL, 3.0 mmol, 6.0 equiv.). The vial was sealed with a PTFE-lined cap, exposed to air via a needle, and gently stirred at room temperature. Upon completion of the reaction (24 to 72 h), the reaction mixture was diluted with EtOAc (40 mL), and washed sequentially with NH4Cl (15 mL), 0.5 M NaOH (2×20 mL), and brine (15 mL). The organic layer was dried with Na2SO4, concentrated in vacuo, and purified by silica gel chromatography. No difference was observed if reactions were prepared in an atmosphere-controlled glovebox, then exposed to ambient air. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; triphenylphosphine;palladium diacetate; In water; at 80℃; for 4h; | [6'-(4-[2-(Trifluoromethyl')phenyl]oxy}-l-piperidinyl)-2,3'-bipyridin-5-yl]acetic acid Step 1 : 6 '-(4- ( r2-(Trifluoromethyl)phenyl1oxyl - 1 -piperidinvO-2.3 '-bipyridin-5-yll acetic acid Ethyl (6-chloro-pyridin-3-yl)-acetate (1.5 eq) was treated with a mixture of 5- (4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2-{4-[2-(trifluoromethyl)phenoxy]piperidin-l- yl}pyridine (from step 3 of example 1), Pd(OAc)2 (0.017 equiv.), Ph3P (0.05 equiv.), and 2M Na2CO3 (4.5 equiv.), and the mixture was heated at 80 0C. After a period of 4 h, the reaction mixture was hydro lyzed with 2M aqueous LiOH (5 eq) for 3 h at 22 C. The solution was neutralized with the addition of formic acid (30 eq) and concentrated. The residue was suspended in DMSO (0.04 M) and centrifuged. The supernatant was purified by reverse phase HPLC using a C18 CombiPrep ODS-AM column (gradient: 60% H2O in CH3CN to 5% H2O in CH3CN over 8 min) to obtain the title compound. MS: m/z 458.5 (ESI+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | Lithium bromide (3.2 g, 37 mmol) and acetyl bromide (1.3 mL, 17 mmol) were added to a solution of (2-chloro-pyridin-5-yl)acetic acid ethyl ester (1.08 g, 5.42 mmol) in acetonitrile (7.2 mL), and the mixture was heated under reflux at an external temperature of 86 to 94C for 31 hours. The reaction mixture was dissolved in water. The solution was neutralized with a sodium hydroxide aqueous solution, followed by extraction with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate = 4/1) to give the title compound (655 mg, 53%). 1H-NMR (chloroform-d): 1.26 (t, 3H, J=7.2Hz), 3.58 (s, 2H), 4.16 (q, 2H, J=7.2Hz), 7.44 (d, 1H, J=8.4Hz), 7.51 (dd, 1H, J=8.4, 2.4Hz), 8.26 (d, 1H, J=2.4Hz); MS (ESI+) : 244 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 140℃; for 0.116667h;Irradiation; | N,N-Dimethylformamide (0.7 mL) was added to 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2] dioxaborolan-2-yl)-phenyl] -propyl} -2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-butan-2-ol (Example 27-(2); 60 mg, 0.105 mmol), (6-chloro-pyridin-3-yl)acetic acid ethyl ester (40 mg, 0.201 mmol), tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) and potassium phosphate (63.9 mg, 0.30 mmol). The mixture was stirred with microwave heating at 140C for seven minutes in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate = 5/1) to give the title compound (26 mg, 41%). 1H-NMR (chloroform-d): 0.62 (t, 6H, J=7.0Hz), 1.26 (t, 3H, J=6.9Hz), 2.11 (q, 4H, J=7.0Hz), 2.18 (m, 3H), 2.23 (m, 3H), 2.70 (m, 2H), 3.66 (s, 2H), 4.14 (q, 2H, J=6.9Hz), 6.82-7.05 (m, 5H), 7.14 (d, 1H, J=8.1Hz), 7.35 (d, 1H, J=7.9Hz), 7.69 (d, 1H, J=8.1Hz), 8.52 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
22% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 140℃; for 0.166667h;Irradiation; | (6-Chloro-pyridin-3-yl)-acetic acid ethyl ester (30 mg, 0.149 mmol), tetrakis(triphenylphosphine)palladium (0) (16 mg, 0.014 mmol) and potassium phosphate (32 mg, 0.149 mmol) were added to a solution of (E)-1-(4-{1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-1-penten-3-ol (Example 38-(6); 50 mg, 0.099 mmol) in N,N-dimethylformamide (0.5 mL). After replacement with nitrogen, the mixture was stirred with microwave heating at 140C for 10 minutes. Then, ethyl acetate was added to the reaction mixture, which was washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate = 4:1) to give the target compound as a colorless oil (11.6 mg, 22%). 1H-NMR (chloroform-d): 0.65 (6H, t, J=7.25Hz), 0.93 (6H, t, J=7.25Hz), 1.29 (3H, t, J=7.26Hz), 1.65 (4H, q, J=7.26Hz), 1.99 (6H, s), 2.09 (4H, q, J=7.26Hz), 2.33 (3H, s), 3.67 (2H, s), 4.21 (2H, q, J=7.25Hz), 6.02 (1H, d, J=15.99Hz), 6.75 (1H, d, J=15.82Hz), 6.89 (2H, s), 6.98-7.01 (2H, m), 7.22 (1H, d, J=8.08Hz), 7.31 (1H, d, J=8.90Hz), 7.71 (1H, dd, J=8.08, 2.31Hz), 8.59 (1H, d, J=1.82Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With potassium phosphate;tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 140℃; for 0.166667h;Irradiation; | A solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1, 3, 2] dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 50.0 mg, 0.10 mmol), (6-chloro-pyridin-3-yl)acetic acid ethyl ester (31.4 mg, 0.15 mmol), tetrakistriphenylphosphine palladium (16.9 mg, 0.0146 mmol) and potassium phosphate (33.4 mg, 0.15 mmol) in N,N-dimethylformamide (0.30 mL) was stirred with microwave heating at 140C for 10 minutes. The reaction mixture was filtered through cotton plug, and the residue was purified by silica gel chromatography (30 to 40% ethyl acetate/hexane) to give the title compound (37.6 mg, 69%). 1H-NMR (chloroform-d): 0.65 (t, 6H, J=7.3Hz), 0.92 (t, 6H, J=7.3Hz), 1.26 (t, 3H, J=7.1Hz), 1.64 (q, 4H, J=7.5Hz), 2.13 (q, 4H, J=7.2Hz), 2.30 (s, 3H), 3.64 (s, 2H), 4.18 (q, 2H, J=7.1Hz), 6.01 (d, 1H, J=16.1Hz), 6.75 (d, 1H, J=16.1Hz), 6.96-6.99 (m, 2H), 7.26-7.32 (m, 3H), 7.68 (s, 2H), 7.85 (d, 2H, J=8.4Hz), 8.56 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With sodium carbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 76 - 84℃; for 7.5h; | A solution of t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 13 mg, 0.021 mmol) in N,N-dimethylformamide (0.2 mL) was added to 2-chloropyridine-5-acetic acid ethyl ester (7.4 mg, 0.037 mmol) and a [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II), dichloromethane complex (1:1) (2.0 mg, 0.0024 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 76 to 84C for seven hours and 30 minutes. Water was added to the reaction mixture, followed by extraction with ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate = 10/1) to give the title compound (2.1 mg, 16%). 1H-NMR (chloroform-d): 0.08 (s, 3H), 0.12 (s, 3H), 0.65 (t, 6H), 0.89 (s, 9H), 0.94 (s, 9H), 1.30 (t, 3H), 1.57 (m, 1H), 1.79 (m, 1H), 2.12 (q, 4H), 2.25 (s, 3H), 2.34 (s, 3H), 2.41 (m, 1H), 2.78 (m, 1H), 3.35 (dd, 1H), 3.67 (s, 2H), 4.20 (q, 2H), 6. 93-7.09 (m, 5H), 7.28 (d, 1H), 7.39 (d, 1H), 7.69 (dd, 1H), 8.56 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 20℃; for 23h; | Reference Example 74 ethyl [6-(methylsulfanyl)pyridin-3-yl]acetate To a solution of <strong>[197376-47-9]ethyl (6-chloropyridin-3-yl)acetate</strong> (10.7 g) in N,N-dimethylformamide (100 mL) was added sodium methanethiolate (11.3 g), and the mixture was stirred at room temperature for 23 hr. The reaction mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane =5:95 - 50:50, volume ratio) to give the title compound (4.55 g, yield 40%) as a colorless oil. MS:212(MH+). _ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate;dicyclohexyl-(2',6'-dimethoxybiphenyl-2-yl)-phosphane; palladium diacetate; In iso-butanol; at 100℃; for 10h;Inert atmosphere; | To a flask containing <strong>[197376-47-9]ethyl 2-(6-chloropyridin-3-yl)acetate</strong> 208-1 (300 mg, 1.5 mmol), 2-fluoropyridin-4-ylboronic acid 205-4 (318 mg, 2.25 mmol), Pd(OAc)2 (17 mg, 0.075 mmoL), 2-dicyclohexylphosphino-2',6'-dimethoxyybiphenyl (62 mg, 0.15 mmol), K3PO4 (800 mg, 9 mmol) under argon was added 2-butanol (1.5 rnL). The reaction mixture was stirred at 100 0C for 10 hours. After cooled to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, and concentrated to dryness by rotary evaporation. The crude was purified by silica gel flash chromatography, eluted with 40% ethyl acetate in dichloromethane to give ethyl 2-(2'-fluoro-2,4'-bipyridin-5-yl)acetate 208-2 as a yellow solid. MS m/z 261.1 (M + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.4% | With 1,8-diazabicyclo[5.4.0]undec-7-ene; In dimethyl sulfoxide; at 150℃; | Step 1: ethyl 2-(6-(pyrrolidin-1-yl)pyridin-3-yl)acetate A reaction mixture of <strong>[197376-47-9]ethyl (6-chloropyridin-3-yl)acetate</strong> (0.30 g, 1.5 mmol) (Asymchem, Cat. #110112), pyrrolidine (0.14 mL, 1.6 mmol and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL, 1.6 mmol) in dimethyl sulfoxide (2.0 mL) was stirred at 150 C. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3*10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-40%) to afford the desired product (0.10 g, 28.4%). Analytic LCMS (M+H)+: m/z=235.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; In tetrahydrofuran; for 20h;Heating; Inert atmosphere; Reflux; | Step 3. Synthesis of (beta-tert-butoxycarbonylamino-pyrjdin-S-yO-acetic acid ethyl ester. A 500 ml round-bottom-flask was charged with 2-chloropyndiotan- 3-yl) acetic acid ethyl ester (6 8 g, 34 0 mmol), tert-butyl carbamate (12 4 g, 105 mmol), 9,9-diotamethyl-4,5-biotas(diotaphenylphosphiotano)xanthene (4 2 g, 7 25 mmol), triotas(diotabenzyliotadeneacetone)diotapal.adiotaum (3 29 g, 3 59 mmol) cesium carbonate (16 9 g 51 87 mmol) and THF (165 mL) The mixture was heated and refluxed under argon for 20 hours Upon cooling, the reaction was quenched with 10% ammonium acetate solution and extracted with ethyl acetate The combined organic extracts were washed with water, brine dried and concentrated The residue was purified by silica gel chromatography eluted using a gradient of 2/98(v/v) EtOAc/hexanes to 10/90 (v/v) EtOAc/hexanes to afford 14 g of crude product ESI-MS m/z 225 (MH-C4He)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
at 90℃; for 0.5h;Microwave irradiation; | 3.99 g (20.0 mmol) of the compound from Example 1A are dissolved in 13.7 ml of dimethylformamide diethyl acetal, and the mixture is stirred with microwave irradiation at 90 C. for 30 min. The mixture is then concentrated on a rotary evaporator, and the residue is chromatographed on silica gel 60 (mobile phase: dichloromethane?dichloromethane/methanol 20:1).Yield: 5.06 g (99% of theory)1H-NMR (300 MHz, DMSO-d6): delta=8.13 (d, 1H), 7.61 (s, 1H), 7.58 (dd, 1H), 7.41 (d, 1H), 4.01 (q, 2H), 2.70 (s, 6H), 1.12 (t, 3H).LC-MS (Method 3): Rt=1.98 min; MS (ESIpos): m/z=255 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodium hydride; In N,N-dimethyl-formamide; at 0℃; for 1h; | To a solution of <strong>[197376-47-9]ethyl 2-(6-chloropyridin-3-yl)acetate</strong> (1.1 g, 5.51 mmol) in dimethylformamide was added slowly sodium hydride (242 mg, 6.06 mmol) at 0 C, followed by iodomethane (821 mg, 5.79 mmol). The mixture was stirred at same degree for 1 hour, and then quenched with water. The resulting mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over MgS04 and concentrated under reduced pressure to afford crude which was purified by column chromatography to afford ethyl 2-(6-chloropyridin-3-yl)propanoate (790 mg, 67 %). |
67% | With sodium hydride; In N,N-dimethyl-formamide; at 0℃; for 1h; | To a solution of <strong>[197376-47-9]ethyl 2-(6-chloropyridin-3-yl)acetate</strong> (1.1 g, 5.51 mmol) in dimethylformamide was added slowly sodium hydride (242 mg, 6.06 mmol) at 0 C, followed by iodomethane (821 mg, 5.79 mmol). The mixture was stirred at same degree for 1 hour, and then quenched with water. The resulting mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulphate and concentrated under reduced pressure to afford crude which was purified by column chromatography to afford ethyl 2-(6-chloropyridin-3-yl)propanoate (790 mg, 67 %). |
67% | With sodium hydride; In N,N-dimethyl-formamide; at 0℃; for 1h; | Step 2: To a solution of <strong>[197376-47-9]ethyl 2-(6-chloropyridin-3-yl)acetate</strong> (1.1 g, 5.51 mmol) in dimethylformamide was added slowly sodium hydride (242 mg, 6.06 mmol) at 0 C., followed by iodomethane (821 mg, 5.79 mmol). The mixture was stirred at same degree for 1 hour, and then quenched with water. The resulting mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over MgSO4 and concentrated under reduced pressure to afford crude which was purified by column chromatography to afford ethyl 2-(6-chloropyridin-3-yl)propanoate (790 mg, 67%). |
67% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0℃; for 1h; | Step 2 To a solution of <strong>[197376-47-9]ethyl 2-(6-chloropyridin-3-yl)acetate</strong> (1.1 g, 5.51 mmol) in dimethylformamide was added slowly sodium hydride (242 mg, 6.06 mmol) at 0 C., followed by iodomethane (821 mg, 5.79 mmol). The mixture was stirred at same degree for 1 hour, and then quenched with water. The resulting mixture was diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to afford crude which was purified by column chromatography to afford ethyl 2-(6-chloropyridin-3-yl)propanoate (790 mg, 67%). |
A solution of lithium bis(trimethylsilyl)amide in THF (1 M, 14 mL, 14.0 mmol) was added to a solution of <strong>[197376-47-9]ethyl 2-(6-chloropyridin-3-yl)acetate</strong> (2.5 g, 12.5 mmol) in THF at -78 C under nitrogen. After stirred at -78 C for 2 h, methyl iodide (1.94 g, 13.7 mmol) was added. The mixture was stirred at 20 C for another 8 h. Worked up, concentrated and purified with silica gelcolumn chromatography, eluting with 0%-40% EA/PE, to give the title compound (1.5 g, 83% purity in LCMS, yield 46%) as yellow oil. MS (ES+) C10H12C1N02 requires: 213, 215, found:214, 216 [M+H]. |
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