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CAS No. : | 1799610-97-1 | MDL No. : | MFCD31558277 |
Formula : | C10H3BrClFN2OS | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OEBAPNYAYMNZBF-UHFFFAOYSA-N |
M.W : | 333.56 | Pubchem ID : | 118157043 |
Synonyms : |
|
Num. heavy atoms : | 17 |
Num. arom. heavy atoms : | 14 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 67.78 |
TPSA : | 67.16 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | Yes |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.21 cm/s |
Log Po/w (iLOGP) : | 2.71 |
Log Po/w (XLOGP3) : | 4.4 |
Log Po/w (WLOGP) : | 4.93 |
Log Po/w (MLOGP) : | 2.5 |
Log Po/w (SILICOS-IT) : | 5.26 |
Consensus Log Po/w : | 3.96 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -5.22 |
Solubility : | 0.00199 mg/ml ; 0.00000598 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.53 |
Solubility : | 0.00099 mg/ml ; 0.00000297 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -6.05 |
Solubility : | 0.000299 mg/ml ; 0.000000897 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.08 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
45% | With palladium diacetate; caesium carbonate; tert-butyl XPhos In tetrahydrofuran at 70℃; for 3h; Inert atmosphere; Darkness; | |
With palladium diacetate; caesium carbonate; tert-butyl XPhos In tetrahydrofuran; water at 70℃; Inert atmosphere; | 2b 5-Bromo-4-chloro-6-(5-fluoro-2-fnryl)thieno f 2,3-ti] pyrimidine 112.6 g (300 inmol) 5-bromo-4-chloro-6-iodo-thicno[2,3-d]pyrimidinc (Preparation la),254.4 g (1200 mmol) 2-(5-fluoro-2-furyl)-4,4,5,5 -tetramethyl- 1,3 ,2-dioxaborolane, 195.5 g(600 mmol) cesium carbonate, 3.36 g (15 mmol) Pd(OAc)2, 12.74 g (30 mmol) ‘BuX-Phoswere placed in a 2 L flask. 1000 mL THE and 400 mL water were added, and then stirredovernight at 70°C under argon atmosphere. THE was evaporated, and then the product was collected by filtration. Crude product was dissolved in THE, and then celite was added and the volatilcs were evaporated under reduced pressure. The solid residue was purified by flash chromatography on silica gel using hcptanc / EtOAc as clucnts. ‘H NMR (400 MHz, DMSO-d6): 8.95 (s, 1H), 7.55 (t, 111), 6.23 (dd, 11*1). | |
With palladium diacetate; caesium carbonate; tert-butyl XPhos In tetrahydrofuran; water at 7℃; for 20h; | 16.B B. Compound 44 (3.75 g, 10.0 mmol), reagent 45 (8.48 g, 40 mmol), CsCO3 (6.52 g, 20.0 mmol), Pd(OAc) 2 (112 mg, 0.5 mmol),tBuX-Phos (477 mg, 1 mmol) was added to THF (33 mL) and water(13mL). The reaction mixture was stirred at 70 ° C for 20 h. The THF was distilled off.The crude solid product was collected by filtration and purified by silica gel column chromatography(0-80% EtOAc/hexane)Purification afforded compound 46. |
With palladium diacetate; caesium carbonate; tert-butyl XPhos In tetrahydrofuran; water at 70℃; for 20h; | 16.B Compound 44 (3.75 g, 10.0 mmol), reagent 45 (8.48 g, 40 mmol), CsCO3 (6.52 g, 20.0 mmol), Pd(OAc)2 (112 mg, 0.5 mmol), tBuX-Phos (477 Mg, 1 mmol) was added to THF (33 mL) and distilled water (13 mL). The reaction mixture was stirred at 70° C. for 20 h. Then THF was evaporated, and the crude solid was collected by filtration. Finally, the residue was purified (0-80% EtOAc/hexane) by silica gel column chromatography to obtain Compound 46. ES/MS: m/z: 332 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol / 2 h / 60 °C 5: potassium carbonate / N,N-dimethyl-formamide / 7 h / 20 °C / Inert atmosphere 6: lithium hydroxide monohydrate / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 6: tetrakis(triphenylphosphine) palladium(0); copper(I) thiophene-2-carboxylate / tetrahydrofuran / 70 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol 5: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene; phenol / 50 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol 5: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol / 2 h / 60 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol / 2 h / 60 °C 5: potassium carbonate / N,N-dimethyl-formamide / 7 h / 20 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 6: lithium hydroxide monohydrate / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol 5: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 6: lithium hydroxide monohydrate / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 7 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 6: tetrakis(triphenylphosphine) palladium(0); copper(I) thiophene-2-carboxylate / tetrahydrofuran / 70 °C / Inert atmosphere 7: sodium hydroxide / methanol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene; phenol / 50 °C / Inert atmosphere 6: lithium hydroxide monohydrate / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 70 °C / Inert atmosphere 2: caesium carbonate; bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) / tetrahydrofuran / 60 °C / Inert atmosphere 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere 4: hydrogenchloride / ethanol 5: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere 6: lithium hydroxide monohydrate / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With caesium carbonate In <i>tert</i>-butyl alcohol at 35℃; for 4h; Inert atmosphere; Darkness; | |
With caesium carbonate In <i>tert</i>-butyl alcohol at 70℃; Inert atmosphere; | 4c Ethyl (2R)-2- [5-bromo-6-(5-fluoro-2-furyl)thieno j2,3-d]pyrimidin-4-oxy-3-(2-tetrahydropyran-2-yloxyphenyl)propanoate 50.03 g 5-bromo-4-chloro-6-(5-fluoro-2-furyl)thieno[2,3 -d]pyrimidine (Preparation 2b)(150 mmol), 44.15 g ethyl (2R)-2-hydroxy-3 -(2-tetrahydropyran-2-yloxyphenyl)propanoate (Preparation 3ab4R)) (150 nimol) and 146.6 g Cs2CO3 (450 mmol) wereplaced in a 2 L flask. 1,5 L ter/-butanol was added and the mixture was stirred at 70°Cunder N2 until no further conversion was observed. Approximately 1 L solvent wasevaporated, then it was diluted with DCM and water, the pH was set to 8 with 2 M HC1, and then it was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and EtOAc as eluents to obtain Preparation 4e asa mixture of diastereoisomers.‘H NMR (500 MHz, DMSO-d6): 8.63/8,62 (s, lET), 7.44 (dm, lfl), 7.42 (m, IH), 7.19 (tm, IH), 7.07 (d, 1H), 6.90 (t, lH), 6.17 (m, 1H), 5.80/5.68 (dd, IH), 5.61/5.55 (t, IH), 4.14 (m, 2H), 3.78-3.40 (m, 2H), 3.51 (m, 111), 3.18 (m, lI-I), 2.00 (m, IH), 1,82 (m, 2H), 1.68- 1.37 (m, 2H), 1.66 (rn, IH), 1.14/1.11 (t, 3T-T).HRMS calculated for C26H24BrFN2O6S: 590.0522, found: 591.0599 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: trichlorophosphate; <i>N</i>,<i>N</i>-dimethyl-aniline / 1 h / 105 °C / Reflux 2: N-Bromosuccinimide; tetrafluoroboric acid diethyl ether complex / acetonitrile / 17 h / 0 - 20 °C 3: caesium carbonate; palladium diacetate; tert-butyl XPhos / water; tetrahydrofuran / 70 °C / Inert atmosphere | ||
Multi-step reaction with 3 steps 1: calcium chloride; trichlorophosphate / <i>N</i>,<i>N</i>-dimethyl-aniline / 1 h / 105 °C 2: N-Bromosuccinimide; tetrafluoroboric acid diethyl ether / acetonitrile / 16 h / 20 °C 3: caesium carbonate; palladium diacetate; tert-butyl XPhos / tetrahydrofuran / 3 h / 70 °C / Inert atmosphere; Darkness |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: iodine; sulfuric acid; periodic acid / water / 1 h / 60 °C / Reflux 2: trichlorophosphate; <i>N</i>,<i>N</i>-dimethyl-aniline / 1 h / 105 °C / Reflux 3: N-Bromosuccinimide; tetrafluoroboric acid diethyl ether complex / acetonitrile / 17 h / 0 - 20 °C 4: caesium carbonate; palladium diacetate; tert-butyl XPhos / water; tetrahydrofuran / 70 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: sulfuric acid; periodic acid; iodine / acetic acid / 1 h / 60 °C 2: calcium chloride; trichlorophosphate / <i>N</i>,<i>N</i>-dimethyl-aniline / 1 h / 105 °C 3: N-Bromosuccinimide; tetrafluoroboric acid diethyl ether / acetonitrile / 16 h / 20 °C 4: caesium carbonate; palladium diacetate; tert-butyl XPhos / tetrahydrofuran / 3 h / 70 °C / Inert atmosphere; Darkness |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: N-Bromosuccinimide; tetrafluoroboric acid diethyl ether complex / acetonitrile / 17 h / 0 - 20 °C 2: caesium carbonate; palladium diacetate; tert-butyl XPhos / water; tetrahydrofuran / 70 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: N-Bromosuccinimide; tetrafluoroboric acid diethyl ether / acetonitrile / 16 h / 20 °C 2: caesium carbonate; palladium diacetate; tert-butyl XPhos / tetrahydrofuran / 3 h / 70 °C / Inert atmosphere; Darkness |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 24 h / 70 °C 2: caesium carbonate; palladium diacetate; tert-butyl XPhos / tetrahydrofuran / 20 h / 70 °C 3: lithium hydroxide; water / 1,4-dioxane / 24 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 24 h / 70 °C 2: caesium carbonate; palladium diacetate; tert-butyl XPhos / tetrahydrofuran / 20 h / 70 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In <i>tert</i>-butyl alcohol at 70℃; for 24h; | 17 Example 17. Preparation of Compound 47: Compound 46 (331 mg, 1 mmol), compound 17 (411, mg, 1.1 mmol) and CsCO3 (579 mg, 3 mmol)Stir at t-BuOH (10 mL) at 70 ° C for 24 h. The solvent was evaporated, water (10 mL) was added and the mixture was adjusted to 8 with 1N HCl. Extracted with CH2Cl2 Take, the organic phase is dried with Na2SO4, and the solvent is evaporated.The residue was purified by silica gel column chromatography(2S)-47 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate In <i>tert</i>-butyl alcohol at 70℃; for 24h; | 17 Example 17 Preparation of Compound 47 Compound 46 (331 mg, 1 mmol), compound 17 (411, mg, 1.1 mmol) and CsCO3 (579 mg, 3 mmol) was added to t-BuOH (10 mL) and stirred at 70° C. for 24 h. Then the solvent was evaporated and distilled water (10 mL) was added. After the pH of the solution was adjusted to 8 with 1N HCl, CH2Cl2 was used to extract organics that was then dried over Na2SO4. Subsequently, the organic solvent was evaporated, and the residue was purified by silica gel column chromatography to obtain Compound (2S)-47. ES/MS: m/z: 669 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | With caesium carbonate In <i>tert</i>-butyl alcohol at 40℃; for 16h; | 2.1 first step; (R)-2-((5-Bromo-6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidin-4-yl)oxy)-3-(5-((2-(2-methoxyphenyl)pyrimidin-4-yl)methoxy)-3-methyl-1H-pyrazol-1-yl)propionic acidMethyl ester 2b 1e (360 mg, 0.90 mmol), 5-bromo-4-chloro-6-(5-fluorofuran-2-yl)thieno[2,3-d]pyrimidine 2a(350mg, 1.05mmol, prepared by the method disclosed in the patent application "EP2886545A1")And cesium carbonate (450mg, 1.38mmol) were dissolved in a 50mL round bottom flask,10 mL of tert-butanol was added, and the reaction solution was heated to 40° C. and stirred for 16 hours.The reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated under reduced pressure to remove the solvent,The resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 2b (220 mg), yield: 30%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness 6: lithium hydroxide / water; 1,4-dioxane / 2 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 4 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere; Darkness 6: lithium hydroxide / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness 6: lithium hydroxide / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness 6: lithium hydroxide / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness 6: lithium hydroxide / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness 6: lithium hydroxide / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: potassium carbonate / N,N-dimethyl-formamide / 20 °C / Inert atmosphere; Darkness |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness 6: lithium hydroxide / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness 6: lithium hydroxide / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness 6: lithium hydroxide / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 6 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness 6: lithium hydroxide / water; 1,4-dioxane / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 5 steps 1: caesium carbonate / <i>tert</i>-butyl alcohol / 4 h / 35 °C / Inert atmosphere; Darkness 2: caesium carbonate / tetrahydrofuran / 1.5 h / 80 °C / Inert atmosphere; Darkness 3: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 1 h / 50 °C / Inert atmosphere; Darkness 4: hydrogenchloride / ethanol / 2 h / 20 °C / Darkness 5: triphenylphosphine; di-tert-butyl-diazodicarboxylate / toluene / 50 °C / Inert atmosphere; Darkness |
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