* 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.
With aluminum (III) chloride; bromine In chloroform at 25℃; for 6 h;
To a 1 L round bottom flask was added aluminum chloride (1 1.32 g, 85 mmol) and methyl δ-chloro^-thiophenecarboxylate (10 g, 56.6 mmol) dissolved in CHCI3 (250 ml_). Br2 (4.08 ml, 79 mmol) was added dropwise over 10 minutes. After stirring for 6 h at 25 0C, the light orange reaction solution was washed with sat NaHCO3. The organic layer was dried Na2SO4, filtered and concentrated. The residue was purified on silica gel [hexanes/EtOAc, 9:1 ] to give the product [12 g, 80percent] as a white solid. LCMS (ES) m/z 256 (M+H)+ .
Reference：
[1] Patent: WO2008/98104, 2008, A1, . Location in patent: Page/Page column 188
[2] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
2
[ 24065-33-6 ]
[ 1047630-72-7 ]
Reference：
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
3
[ 1047630-72-7 ]
[ 1047644-62-1 ]
Reference：
[1] Drugs of the Future, 2014, vol. 39, # 8, p. 541 - 546
With aluminum (III) chloride; bromine; In chloroform; at 25℃; for 6h;
To a 1 L round bottom flask was added aluminum chloride (1 1.32 g, 85 mmol) and methyl delta-chloro^-thiophenecarboxylate (10 g, 56.6 mmol) dissolved in CHCI3 (250 ml_). Br2 (4.08 ml, 79 mmol) was added dropwise over 10 minutes. After stirring for 6 h at 25 0C, the light orange reaction solution was washed with sat NaHCO3. The organic layer was dried Na2SO4, filtered and concentrated. The residue was purified on silica gel [hexanes/EtOAc, 9:1 ] to give the product [12 g, 80%] as a white solid. LCMS (ES) m/z 256 (M+H)+ .
With potassium carbonate;bis(tri-t-butylphosphine)palladium(0); In 1,4-dioxane; water; at 75℃; for 1.5h;
To a 300 mL sealed flask was added 1 -methyl-5-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole (8.14 g, 39.1 mmol). potassium carbonate (12.98 g, 94 mmol), methyl 4-bromo-5-chloro-2-thiophenecarboxylate (8 g, 31.3 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.40 g, 0.78 mmol) in 1 ,4-dioxane (50 ml) and H2O (6 ml). After stirring for 90 min at 75 0C, the reaction solution was diluted with DCM (100 mL) and washed with H2O. The organic layer was dried Na2SO4, filtered <n="190"/>and concentrated. The reaction residue was purified on silica gel [hexanes/EtOAc, 2:1 ] to give the product [5.7 g, 70percent] as a tan solid: LCMS (ES) m/z 258 (M+H)+ .
methyl 4-benzyl-5-chlorothiophene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74 mg
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; caesium carbonate; In tetrahydrofuran; water; at 75℃; for 16h;Microwave irradiation; Inert atmosphere; Sealed tube;
1: Methyl 4-benzyl-5-chlorothiophene-2-carboxylate. [00408] A microwave vial was charged with a stirbar, methyl 4-bromo-5-chlorothiophene-2- carboxylate (0.10 g, 0.39 mmol), Benzyltrifluoroborate potassium salt (94.0 mg, 0.47 mmol), Cs2C03 (0.39 g, 1.18 mmol) and [ l,r-bis(diphenylphosphino)feiTocene]palladium(II)dichloride (64.4 mg, 78.3 umol). The mixture was sealed under an atmosphere of argon. THF (4.7 mL) and water (0.47 mL, 26 mmol) were then added and the resulting solution stirred at 75 C for 16 h. The reaction was concentrated. The crude pdt was purified on ISCO column chromatography (0% - 5% EtOAC/hexanes as eluent) to give the title compound (yield = 74 mg). LCMS (FA): m/z = 267.0 (M+ l )
6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridine-3-carbaldehyde[ No CAS ]
methyl 4-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)(hydroxy)methyl]-5-chlorothiophene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
To a solution of <strong>[1047630-72-7]methyl 4-bromo-5-chlorothiophene-2-carboxylate</strong> (900 mg) in THF (20 mL) is added dropwise at -20 C. isopropylmagnesuim chloride-lithium chloride complex (iPrMgClxLiCl, 2.7 mL of a 1.3 M solution in THF). The mixture is stirred for 30 min and is then treated dropwise with a solution of 6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridine-3-carbaldehyde (712 mg) in THF (20 mL). After stirring for 30 min at -20 C. and for 15 min at room temperature the reaction is quenched by addition of 1 M aqueous HCl. The aqueous phase is extracted with DCM. The organic phase is dried (MgSO4) and concentrated in vacuo to give the title compound. LC (Method 1): tR=0.79 min; Mass spectrum (ESI+): m/z=379/381 (Cl) [M+H]+.
Methyl 4,4-dibromo-2-carboxylate (2 g) is dissolved in THF (25 mL) cooled to -25 C. and treated slowly with isopropylmagnesuim (iPrMgCl, 3.3 mL of a 2 M solution in THF). The mixture is stirred for 30 min, cooled to -60 C. and treated with N-chlorosuccinimide (0.89 g). Then the mixture is stirred for 30 min while warming to room temperature. The mixture is partitioned between 10% aqueous NH4Cl and EtOAC. The phases are separated and the aqueous phase is extracted twice with EtOAC. The combined organic phases are dried (MgSO4) and concentrated in vacuo. The residue is triturated with MeOH. The title compound is collected by filtration. LC (Method 1): tR=1.16 min.
4-[(6-{3-azabicyclo[3.1.0]hexan-3-yl}-2-methylpyridin-3-yl)methyl]-5-cyano-N-[(6R)-3-methyl-1H,4H,5H,6H-cyclopenta[c]pyrazol-6-yl]thiophene-2-carboxamide[ No CAS ]
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