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Structure of 623-47-2
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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. : | 623-47-2 |
Formula : | C5H6O2 |
M.W : | 98.10 |
SMILES Code : | C#CC(OCC)=O |
MDL No. : | MFCD00009184 |
InChI Key : | FMVJYQGSRWVMQV-UHFFFAOYSA-N |
Pubchem ID : | 12182 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H225-H315-H319-H335 |
Precautionary Statements: | P501-P240-P210-P233-P243-P241-P242-P264-P280-P370+P378-P337+P313-P305+P351+P338-P362+P364-P303+P361+P353-P332+P313-P403+P235 |
Class: | 3 |
UN#: | 3272 |
Packing Group: | Ⅲ |
Num. heavy atoms | 7 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.4 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 25.6 |
TPSA ? Topological Polar Surface Area: Calculated from |
26.3 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.84 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.96 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.26 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.79 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.5 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.87 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.92 |
Solubility | 11.8 mg/ml ; 0.12 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.1 |
Solubility | 7.8 mg/ml ; 0.0795 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.36 |
Solubility | 42.7 mg/ml ; 0.436 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 |
-6.22 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 |
2.0 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) |
2.13 |
* 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 |
---|---|---|
59.8% | Stage #1: With N-hydroxy-2,4-dinitrobenzenamine In acetonitrile at 20℃; for 12 h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 10 h; |
2,4-Dinitrophenylhydroxylamine (13.00 g, 65.3 mmol) was added to a 500 mL vial, dissolved in 200 mL of acetonitrile, and 4-methylpyridine (9.12 g, 97.9 mmol) was added at room temperature for 12 h at room temperature. The solution was spun dry, 200 mL of DMF and potassium carbonate (27.07 g, 195.9 mmol) were added, ethyl propiolate (9.60 g, 97.9 mmol) was added in one portion, and reacted at room temperature for 10 h. The reaction was completed by TLC, and 300 mL of water and EA, liquid separation, water layer was extracted with 300 mL of EA, and the organic phase was combined, washed with 300 mL of brine, dried over anhydrous sodium sulfate, filtered and evaporatedElution with PE/EA=20/1-10/1 gave 7.97 g of pale yellow solid, yield 59.8percent. |
53% | Stage #1: With mesitylenesulfonylhydroxylamine In dichloromethane at 0℃; for 2 h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h; |
General procedure: These were made using MSH or DNPH as detailed below, unless otherwise stated. A fresh solution of MSH23 in CH2Cl2 (1 equiv) was added to the substituted pyridine (1 equiv) in CH2Cl2 (10 mL) at 0 °C. After 2 h, the solvent was removed in vacuo. Alternatively, a solution of DNPH12 (1 equiv) and the substituted pyridine (1 equiv) in MeCN (40 mL) was heated at 40 °C for 18 h. The solvent was removed in vacuo. The method continues by taking the residue from either method in dry DMF (8 mL), and then ethyl propiolate (1 equiv) and K2CO3 (2 equiv) were added, and the suspension stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed three times with water then with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (eluting with a hexanes: EtOAc gradient, unless otherwise stated) gave the pyrazolo[1,5-a]pyridine. |
53% | Stage #1: With mesitylenesulfonylhydroxylamine In dichloromethane at 0℃; for 2 h; Stage #2: With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18 h; |
Step 2.1 : A fresh solution of O-(mesitylsulfonyl)hydroxylamine in CH2CI2 (6.0 ml_, 0.44 mol L"1, 2.6 mmol) [T. Eichenberger et al., HeIv. Chim. Acta 1986, 69(6), 1521] was added to 4-methylpyridine (1: X = Me) (248 mg, 2.66 mmol) in CH2CI2 (10 mL) at 0 0C. After 2 h, the solvent was removed in vacuo. The residue was taken up in dry DMF (8 mL), then ethyl propiolate (0.25 mL, 2.5 mmol) and K2CO3 (450 mg, 3.26 mmol) were added, and the suspension stirred at room temperature for 18 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic phases were washed three times with water then with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (eluting with hexanes: EtOAc 97:3 to 95:5 to 9:1) gave ethyl 5-methyl- pyrazolo[1 ,5-a]pyridine-3-carboxyIate (4: X = Me) as a pale brown solid (175 mg, 53percent). 1H NMR δ (400 MHz, CDCI3) 8.39 (d, J 7.1 Hz, 1 H)1 8.34 (s, 1H), 7.93 (s, 1H), 6.76 (dd, J 7.1 , 1.9 Hz, 1 H), 4.38 (q, J 7.1 Hz, 2H), 2.47 (s, 3H), 1.41 (t, J 7.1 Hz, 3H). LCMS (APCI+) 205 (MH+, 100percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | In xylene; for 6h;Reflux; | Ethyl propiolate (2.4 ml_, 23.7 mmol) was slowly added to a solution of reference example 14 (2.99 g, 21.3 mmol) in xylene (mixture of isomers, 40 ml_). The mixture was heated to reflux for 6 hours and the solvent was distilled off. The residue was purified by chromatography over silica gel using hexane/EtOAc mixtures of increasing polarity as eluent, to afford 2.3 g of the desired compound (yield: 56%). LC-MS (Method 2): tR = 1.63 min; m/z = 195 (MH+). |
40.4% | In 5,5-dimethyl-1,3-cyclohexadiene; at 125℃; for 12h; | 4,5,6,7-tetrahydro-3-oxo-[1,2,3]oxadiazolo[3,4-a]pyridin-8-indole (17.00 g, 121.3 mmol), Xylene (80 mL) and ethyl propiolate (18.7 mL, 185 mmol) were placed in a 250 mL round bottom flask, and reacted under nitrogen for 12 h at 125 C. The reaction was complete by TLC. The mixture was spin-dried, and subjected to silica gel column chromatography, gradient elution of PE:EA=20:1-2:1 to obtain 9.52 g of a yellow liquid, the yield was 40.4%. |
32% | In 5,5-dimethyl-1,3-cyclohexadiene; for 2h;Reflux; | General procedure: A mixture of 22a (13.0 g, 93 mmol), and ethyl propiolate (28.5 mL, 278 mmol), in xylene (250 mL) was heated under reflux for 2 h. The cooled mixture was evaporated under reduced pressure. The residual oil was purified by column chromatography (diethylether), to afford the title compound as an oil, (5.82 g, 32%). 1H NMR (CDCl3) delta: 1.39 (t, 3H), 1.88 (m, 2H), 2.06 (m, 2H), 2.82 (t, 2H), 4.20 (t, 2H), 4.39 (q, 2H), 6.55 (s, 1H). LRMS (Thermospray) m/z: 195.2 (M+1)+. |
26% | In o-xylene; for 16h;Heating / reflux; | Step 2: 4, 5, 6, 7-TetrahYdropYrazolof1 5-alpvridine-2-carboxvlic acid ethylester :; Ethyl propiolate (804 mg) was added to the o-xylene (15 mL) solution of tetrahydropyridino [1,2-c] [1, 2,3] oxadiazolone (1.04 g) under a nitrogen atmosphere and refluxed for 16 h. The solution was concentrated under a reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (2/1-1/1). The titled compound was obtained as yellow oil (871 mg, 65%), and 4,5, 6, 7-tetrahydropyrazolo [1,5-a] pyridine-3-carboxylic acid ethyl ester was obtained as yellow oil (345 mg, 26%). 'H NMR (CDCI3) 61. 39 (t, 3H, J = 7.1 Hz), 1.84-1. 91 (m, 2H), 2.02-2. 09 (m, 2H), 2.82 (t, 2H, J = 6.4 Hz), 4.22 (t, 2H, J = 6.2 Hz), 4.39 (q, 2H, J = 7.1 Hz), 6.53 (s, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In o-xylene; for 16h;Heating / reflux; | Step 2: 4, 5, 6, 7-Tetrahvdropvrazolof1, 5-alpvridine-2-carboxylic ; acid ethvlester : Ethyl propiolate (804 mg) was added to the o-xylene (15 mL) solution of tetrahydropyridino [1, 2-c] [1,2, 3] oxadiazolone (1.04 g) under a nitrogen atmosphere and refluxed for 16 h. The solution was concentrated under a reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (2/1-1/1). The titled compound was obtained as yellow oil (871 mg, 65%), and 4,5, 6, 7-tetrahydropyrazolo [1,5-a] pyridine-3-carboxylic acid ethyl ester was obtained as yellow oil (345 mg, 26%). 'H NMR (CDCI3) 8 1. 39 (t, 3H, J = 7.1 Hz), 1.84-1. 91 (m, 2H), 2.02-2. 09 (m, 2H), 2.82 (t, 2H, J = 6.4 Hz), 4.22 (t, 2H, J = 6.2 Hz), 4.39 (q, 2H, J = 7.1 Hz), 6.53 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65%; 26% | In o-xylene; for 16h;Heating / reflux; | Ethyl propiolate (804 mg) was added to the oxylene (15 mL) solution of tetrahydropyridino[1,2-c][1,2,3]oxadiazolone (1.04 g) under a nitrogen atmosphere and refluxed for 16 h. The solution was concentrated under a reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (2/1-1/1). The titled compound was obtained as yellow oil (871 mg, 65%), and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester was obtained as yellow oil (345 mg, 26%). 1H NMR (CDCl3) delta1.39 (t, 3H, J=7.1 Hz), 1.84-1.91 (m, 2H), 2.02-2.09 (m, 2H), 2.82 (t, 2H, J=6.4 Hz), 4.22 (t, 2H, J=6.2 Hz), 4.39 (q, 2H, J=7.1 Hz), 6.53 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26% | In o-xylene; | Step 2 4,5,6,7-Tetrahydropyrazolo[1,5-a]pyridine-2-carboxylic acid ethylester Ethyl propiolate (804 mg) was added to the o-xylene (15 mL) solution of tetrahydropyridino[1,2-c][1,2,3]oxadiazolone (1.04 g) under a nitrogen atmosphere and refluxed for 16 h. The solution was concentrated under a reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with n-hexane-AcOEt (2/1-1/1). The titled compound was obtained as yellow oil (871 mg, 65%), and 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylic acid ethyl ester was obtained as yellow oil (345 mg, 26%). 1H NMR (CDCl3) delta 1.39 (t, 3H, J=7.1 Hz), 1.84-1.91 (m, 2H), 2.02-2.09 (m, 2H), 2.82 (t, 2H, J=6.4 Hz), 4.22 (t, 2H, J=6.2 Hz), 4.39 (q, 2H, J=7.1 Hz), 6.53 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In tetrahydrofuran; at 20 - 30℃; for 4h; | a. 1H-Pyrazole-3-carboxylic acid ethyl ester (Intermediate 74a) A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated dropwise with (trimethylsilyl)diazomethane (51 mL, 0.10 mol) maintaining the temperature between 20-30° C. with ice bath cooling. The mixture was stirred at RT for 4 h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94percent). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+]. |
94% | In tetrahydrofuran; at 20 - 30℃; for 4h; | A solution of ethyl propiolate (10.0 g, 0.10 mol) in THF (67 mL) was treated drop wise with (trimethylsilyl)diazo methane (51 mL, 0.10 mol) maintaining the temperature between 20-30 °C with ice bath cooling. The mixture was stirred at RT for 4h then treated cautiously with water (250 mL) with cooling in an ice bath. The organics were evaporated in vacuo and the resulting precipitate was collected by filtration, washed with water and dried at RT in vacuo to give the title compound (13.5 g, 94percent). LCMS (Method 3): Rt 2.22 min, m/z 141 [MH+]. |
90% | In tetrahydrofuran; at 20 - 30℃; for 3h; | Example 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 mL) was added dropwise trimethylsilyldiazomethane (153 mL, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid. |
90% | In hexane; at 20℃; for 3h; | Example 15.[00151] Example 15 presents the preparation of Cmpd 15, N-(5-fluoropyrimidin-2-yl)- 6,7-dihydro-4H-pyrazolo[4',3':5,6]oxepino[4,3-d][1 ,3]thiazol-2-amine (Table II,Compound No. 15). Cmpd 15Example 15, Step A[00152] To a solution of ethyl propiolate (30 g, 306 mmol) in THF (200 ml.) was added dropwise trimethylsilyldiazomethane (153 ml_, 2M in hexanes, 306 mmol) at 20-30°C with ice bath cooling (delayed exotherm observed). The reaction mixture was stirred for 3 hours at r.t. Water was then added (750 mL) and the organic solvents evaporated. The white precipitate was filtered and dried under vacuum to afford compound 15b (38.5 g, 90percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | <strong>[144649-99-0]5-Bromo-2-methoxy-benzonitrile</strong> (25.00 mmol, 5.73 g) was dissolved in ethanol (35 mL) and treated with ethyl propiolate (28.75 mmol, 2.93 g). The reaction mixture was heated at 60° C. for 30 minutes and then treated with a solution of potassium hydroxide (28.75 mmol, 1.63 g) in ethanol (35 mL). The reaction mixture was then heated at reflux for 3 hours and then allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure and taken up in water 300 mL. The mixture was adjusted to pH 4 with conc hydrochloric acid and the resultant solid was filtered off and washed with water. The solid was transferred to a round bottom flask, suspended in toluene and evaporated to dryness twice to provide the title compound as an off white solid. Yield=4.4 g, 63percent. Analytical LCMS method 2, retention time 4.28 min, M+H=281. 1H NMR: (CDCl3) delta: 11.0 (br, s, 1H), 8.57 (d, 1H), 8.04 (d, 1H), 7.61 (dd, 1H), 6.95 (d, 1H), 6.37 (d, 1H), 4.04 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | a) (4-Chloro-phenyl)-propynoic acid ethyl ester (Va) Under argon atmosphere, a four neck flask was charged with 1-chloro-4-iodo-benzene (130.0 g, 0.55 mol), bis(triphenylphosphine) palladium(II) chloride (7.57 g, 10.8 mmol, 2 mol %), copper(I) iodide (4.19 g, 22.0 mmol, 4 mol %) and dry THF (1.4 l). At r.t., cesium carbonate (355.3 g, 1.09 mol, 2 eq.) was added over 5 min. Afterwards propynoic acid ethyl ester (111.3 ml, 1.09 mol, 2 eq.) was added, and the reaction mixture was stirred overnight at 35 C. An additional portion of propynoic acid ethyl ester (11.1 ml, 0.11 mol, 0.2 eq.) was added, and the reaction was stirred for another 3 h at 35 C. The reaction mixture was evaporated to dryness, and the residue was taken up in toluene (0.5 l) and heptane (1 l). The resulting suspension was stirred at 40 C. for 1 h and filtered over celite. The filtrate was concentrated, and the product purified by silica gel filtration (toluene/heptane 1:2) to yield 72.6 g (61%) of Va as a light yellow solid. | |
With copper(l) iodide; caesium carbonate;bis-triphenylphosphine-palladium(II) chloride; In tetrahydrofuran; at 35℃; for 41h;Inert atmosphere; | A mixture of 1-chloro-4-iodobenzene (120.4 g, 0.50 mol) and cesium carbonate (352.8 g, 1.0 mol) in tetrahydrofuran (1.275 L) was evaporated and flushed with argon. Then cuprous iodide (3.81 g, 20.0 mmol) and bis(triphenylphosphine)palladium(II) chloride (7.02 g, 10.0 mmol) were added and then ethyl propiolate (100 g, 1.01 mol) was added dropwise over a period of 20 min. The resulting dark brown suspension was stirred for 41 h at 35 C., then filtrated over Hyflo and washed with THF (5 L). The solution was concentrated and treated with toluene /heptane 1:2 (1.5 L) and stirred for 1 h at 45 C. under reduced pressure (250 mbar). The resulting suspension was filtered and the residue was washed with further toluene /heptane 1:2 (1.5 L). The solid was dried affording 181.64 g (MS m/e: 209.0/211.2 [M+H]+) of a dark brown oil as crude product which was used without further purification. | |
With caesium carbonate;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; In tetrahydrofuran; at 35℃; for 41.3333h;Inert atmosphere; | a) (4-Chloro-phenyl)-propynoic acid ethyl esterA mixture of l-chloro-4-iodobenzene (120.4 g, 0.50 mol) and cesium carbonate (352.8 g, 1.0 mol) in tetrahydrofuran (1.275 L) was evaporated and flushed with argon. Then cuprous iodide (3.81 g, 20.0 mmol) and bis(triphenylphosphine)palladium(II) chloride (7.02 g, 10.0 mmol) were added and then ethyl propiolate (100 g, 1.01 mol) was added dropwise over a period of 20 min. The resulting dark brown suspension was stirred for 41 h at 35 C, then filtrated over Hyflo and washed with THF (5 L). The solution was concentrated and treated with toluene/heptane 1 :2 (1.5 L) and stirred for 1 h at 45 C under reduced pressure (250 mbar). The resulting suspension was filtered and the residue was washed with further toluene/heptane 1 :2 (1.5 L). The solid was dried affording 181.64 g (MS m/e: 209.0/211.2 [M+H]+) of a dark brown oil as crude product which was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | General procedure: A mixture of Pd2dba3·CHCl3 (6.2 mg, 2 mol%), Xantphos (14.0 mg,8 mol%), and ethyl 4-iodobenzoate (50.5 muL, 0.3 mmol) in THF (0.5mL) was stirred for 10 min at r.t. This mixture was added to a 0.105M solution of lithium tetrakis(ethoxycarbonylethynyl)indate in anhydrousTHF (3; 0.105 mmol) under a N2 atmosphere. The reactionmixture was heated at reflux for 3 h. After cooling to r.t., the reactionmixture was quenched with sat. aq NH4Cl (20 mL). The aqueouslayer was extracted with CH2Cl2 (3 × 20 mL), and the combinedorganic phases were sequentially washed with brine (3 × 20 mL),dried (MgSO4), filtered, and concentrated under reduced pressure.The residue was purified by column chromatography (silica gel,EtOAc-hexane, 1:20) to give 5a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
21 g | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 48.0h; | To a magnetically stirred white suspension of 1 -amino-3 -bromo-5 -methoxypyridin- 1 -ium 2,4,6-trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion- wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 mm and then vacuum filtered. Solids collected were rinsed with water and airdried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by ?H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in ?H NMR (CDC13) 3.98 (6-Br isomer) vs. 3.83 (4-Br isomer). |
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 48.0h; | To a magnetically stirred white suspension of 1 -amino-3 -bromo-5 -methoxypyridin- 1 -ium 2,4,6- trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by dropwise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion- wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 mm and then vacuum filtered. Solids collected were rinsed with water and air- dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by ?H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in ?H NMR (CDC13) 3.98 (6-Br isomer) vs. 3.83 (4-Br isomer). | |
21 g | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 48.0h; | Preparation of Ethyl 6-bromo-4-methoxypyrazolo|"l,5-a"|pyridine-3- carboxylate and Ethyl 4-bromo-6-methoxypyrazolo|"l,5-a"|pyridine-3-carboxylate. To a magnetically stirred white suspension of l-amino-3-bromo-5-methoxypyridin-l-ium 2,4,6- trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion-wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 min and then vacuum filtered. Solids collected were rinsed with water and air-dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4: 1 (by MR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in 1H MR (CDCh) delta 3.98 (6-Br isomer) vs. 3.83 (4-Br isomer). |
21 g | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 48.0h; | To a magnetically stirred white suspension of1 -amino-3-bromo-5-methoxypyridin-1 -ium 2,4,6-trimethyl- benzenesulfonate (2a) (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). Afier vigorous stirring for 2 d, the reaction was slowly quenched via portion-wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 mm and then vacuum filtered. Solids collected were rinsed with water and air-dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by ?H NMR) with compound 3a as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in the next step without further purification. MS (apci) mlz=298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in ?H NMR (CDC13) oe 3.98 (3a) vs. 3.83 (4a). |
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 48.0h; | To a magnetically stirred white suspension of 1-amino-3-bromo-5-methoxypyridin-1-ium-2,4,6-trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by dropwise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion-wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 min and then vacuum filtered. Solids collected were rinsed with water and air-dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by 1H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in 1H NMR (CDCl3) delta 3.98 (6-Br isomer) vs.3.83 (4-Br isomer). | |
With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 48.0h; | To a magnetically stirred white suspension of 1-amino-3-bromo-5-methoxypyridin-1-ium 2,4,6- trimethylbenzenesulfonate (33.24 g, 82.42 mmol) in DMF (82 mL) at ambient temperature was added TEA (22.98 mL, 164.8 mmol), followed by drop-wise addition of ethyl propiolate (16.71 mL, 164.8 mmol). After vigorous stirring for 2 d, the reaction was slowly quenched via portion- wise addition to rapidly stirring ice water (820 mL). The mixture was stirred at ambient temperature for 10 min and then vacuum filtered. Solids collected were rinsed with water and air- dried, yielding the title compounds as an orange solid in an isomeric ratio of about 4:1 (by 1H NMR) with the 6-Br isomer as the major isomer (21 g). The wet solid isomeric mixture (about 75% w/w) was directly used in Step 3 without further purification. MS (apci) m/z = 298.9, 300.9 (M+H). Regioisomeric ratio was determined by MeO chemical shift in 1H NMR (CDCl3) delta 3.98 (6-Br isomer) vs.3.83 (4-Br isomer). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; potassium carbonate; In 1,2-dimethoxyethane; at 40℃; for 22h;Inert atmosphere; Schlenk technique; Sealed tube; | General procedure: Bis(triphenylphosphane)palladium(II)dichloride (14.2 mg,20.0 mmol, 2.00 mol%) and copper(I) iodide (7.62 mg, 40.0 mmol,4.00 mol%) were placed in a flame-dried 10 mL Schlenk tube with amagnetic stir bar under a nitrogen atmosphere and the Schlenktube was evacuated and flushed with nitrogen two more times.DME (3.0 mL) was added and the resulting yellow solution wasstirred for several minutes at rt. Aryl iodide 1 (1.00 mmol, 1.00equiv) and potassium carbonate (276 mg, 2.00 mmol, 2.00 equiv)were added and the vessel was closed and heated to 40 C. Ethylpropiolate (2) (198 mg, 2.00 mmol, 2.00 equiv) was dissolved inDME (0.95 mL) and added slowly over 21 h (1.0 mL syringe,0.50 mm/min feed rate). After complete addition, the syringe wasrinsed in the reaction mixture and stirring was continued for 1 h at40 C. Celite was added to the dark brown mixture and the solventwas removed under reduced pressure. For purification, chromatographyon silica gel was performed using manual flash techniqueor a Biotage SP4 flash purification system with eluents consisting ofn-hexane and EtOAc or acetone. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11% | With triethylamine; at 20℃; for 0.25h;Flow reactor; | The reaction was performed using general flow procedure reacting 3-bromopyridine 2a with ethylpropiolate 4b. The outlet solution (195 mL, collected over 51 mins) was stirred at room temperature whiletriethylamine (17.5 mL, 126 mmol) was added followed by ethyl propiolate (9.30 mL, 98.4 mmol). The bright redmixture was stirred at room temperature for 15 minutes was concentrated in vacuo to remove the MeCN and thendiluted with EtOAc (250 mL) and brine (100 mL). The organic layer was separated and the aqueous phase washedtwice more with EtOAc (2 x 200 mL). The combined organic layers were dried over anhydrous sodium sulfate andconcentrated in vacuo to give a dark red oil.The crude material was purified by column chromatography on a 100 g silica column using the Biotage machine anda gradient from 7 to 60 % EtOAc/heptane. 5c eluted first from the column. Pale red solid (1.94 g, 51 min collectiontime, 11 %). 1H NMR (400 MHz, d6-DMSO) (3H, t, J = 4 Hz, CH2CH3), 4.31 (2H, q, J = 4 Hz, CH2CH3), 7.743 SYNLETT: LETTERTemplate for SYNLETT and SYNTHESIS Thieme Stuttgart · New York 2017-04-25 page 3 of 4(1H, d, J = 8 Hz, ArH), 8.01 (1H, d, J = 4 Hz, ArH), 8.47 (1H, s, ArH), 9.31 (1H, s, ArH) ppm. 13C NMR (101 MHz,d6-DMSO) 14.3, 59.8, 103.6, 108.1, 118.9, 130.3, 131.3, 138.6, 144.7, 162.2 ppm. HRMS (FAB) calcd forC10H10O2N2Br 268.99202, found 268.99194/270.98981 |
Tags: 623-47-2 synthesis path| 623-47-2 SDS| 623-47-2 COA| 623-47-2 purity| 623-47-2 application| 623-47-2 NMR| 623-47-2 COA| 623-47-2 structure
A958456 [762-21-0]
Diethyl acetylenedicarboxylate
Similarity: 0.88
A958456 [762-21-0]
Diethyl acetylenedicarboxylate
Similarity: 0.88
A958456 [762-21-0]
Diethyl acetylenedicarboxylate
Similarity: 0.88
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