* 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 caesium carbonate In tetrahydrofuran at 60℃; Inert atmosphere
3,5-Dibromoisonicotinaldehyde (80 g, 303 mmol), followed by cesium carbonate (98 g, 302 mmol) was added to a 2 L round bottom flask containing THF (1.3 L) under N2. Methyl mercaptoacetate (32 g, 302 mmol) was added and the mixture was heated at 60 °C overnight. After cooling to rt, ethyl acetate was added and the organic layer was washed with water, aqueous saturated NaHCO3, solution, and brine, then dried over and filtered to give a white solid The crude product was purified by recrystallization from ethyl acetate to give the desired product (60 g, 73percent).
73%
With caesium carbonate In tetrahydrofuran at 60℃; Inert atmosphere
3,5-Dibromoisonicotinaldehyde (80 g, 303 mmol), followed by cesium carbonate (98 g, 302 mmol) was added to a 2 L round bottom flask containing THF (1.3 L) under Ni. Methyl mercaptoacetate (32 g, 302 mmol) was added and the mixture was heated at 60 °C overnight. After cooling to rt, ethyl acetate was added and the organic layer was washed with water, aqueous saturated NaHOO:, solution, and brine, then dried over and filtered to give a white solid The crude product was purified by recrystallization from ethyl acetate to give the desired product (60 g, 73percent).
73%
With caesium carbonate In tetrahydrofuran at 60℃; Inert atmosphere
3,5-Dibromoisonicotinaldehyde (80 g, 303 mmol), followed by cesium carbonate (98 g, 302 mmol) was added to a 2 L round bottom flask containing THF (1.3 L) under N2. Methyl mercaptoacetate (32 g, 302 mmol) was added and the mixture was heated at 60 °C overnight. After cooling to rt, ethyl acetate was added and the organic layer was washed with water, aqueous saturated NaHCO3, solution, and brine, then dried over and filtered to give a white solid The crude product was purified by recrystallization from ethyl acetate to give the desired product (60 g, 73percent).
73%
With caesium carbonate In tetrahydrofuran at 60℃; Inert atmosphere
[0188] Step 2: Methyl 4-bromothieno [2,3-cl pyridine-2-carboxylate. 3,5- Dibromoisonicotinaldehyde (80 g, 303 mmol), followed by cesium carbonate (98 g, 302 mmol) was added to a 2 L round bottom flask containing THF (1.3 L) under N2. Methyl mercaptoacetate (32 g, 302 mmol) was added and the mixture was heated at 60 °C overnight. After cooling to rt, ethyl acetate was added and the organic layer was washed with water, aqueous saturated NaHCO3 solution, and brine, then dried over Na2504 and filtered to give a white solid. The crude product was purified by recrystallization from ethyl acetate to give the desired product (60 g, 73percent).
With caesium carbonate In tetrahydrofuran at 60℃; Inert atmosphere
0196] Step 2: Methyl 4-bromothienor2,3-c]pyridine-2-carboxylate. 3,5- Dibromoisonicotinaldehyde (80 g, 303 mmol), followed by cesium carbonate (98 g, 302 mmol) was added to a 2 L round bottom flask containing THF (1.3 L) under N2. Methyl mercaptoacetate (32 g, 302 mmol) was added and the mixture was heated at 60 °C overnight. After cooling to rt, ethyl acetate was added and the organic layer was washed with water, aqueous saturated NaHC03 solution, and brine, then dried over Na2S04 and filtered to give a white solid. The crude product was purified by recrystallization from ethyl acetate to give the desired product (60 g, 73percent).
With caesium carbonate; In tetrahydrofuran; at 60℃; for 2h;Microwave irradiation; Inert atmosphere;
The title compound was prepared according to published literature.223 To as suspension of 3,5-dibromopyridine-4-carboxaldehyde (1.00 g, 3.59 mmol) andanhydrous C52C03 (1.29 g, 3.94 mmol) in anhydrous THF (17 mL) in a 20 mL microwave vial under argon was added methyl thioglycolate (0.34 mL, 3.59 mmol). The capped reaction was heated to 60 C for 2 h. The reaction mixture was cooled to rt and concentrated in vacuo. The crude product was diluted in EtOAc, mixed with water and extracted with EtOAc (3x). The combined organicphase was washed with water (lx) and brine (2x), dried over Na2SO4, filtered and concentrated in vacuo to give a white solid (0.75 g, 77%) that was used for the next reaction without further purification. ?H NMR (400 MHz, CDCI3) O 9.08 (5, 1H), 8.65 (5, 1H), 8.16 (d, J = 0.8 Hz, 1H), 4.01 (5, 3H); ?3C NMR (101 MHz, CDCI3) O 162.3, 145.0, 144.1, 139.7, 138.4, 129.2, 116.3, 53.3; ESI-HRMS calcdfor C9H7BrNO2S (M + H) 271.9375, found 271.9377; HPLC tR = 11.57 mm.
73%
With caesium carbonate; In tetrahydrofuran; at 60℃;Inert atmosphere;
3,5-Dibromoisonicotinaldehyde (80 g, 303 mmol), followed by cesium carbonate (98 g, 302 mmol) was added to a 2 L round bottom flask containing THF (1.3 L) under N2. Methyl mercaptoacetate (32 g, 302 mmol) was added and the mixture was heated at 60 C overnight. After cooling to rt, ethyl acetate was added and the organic layer was washed with water, aqueous saturated NaHCO3, solution, and brine, then dried over and filtered to give a white solid The crude product was purified by recrystallization from ethyl acetate to give the desired product (60 g, 73%).
73%
With caesium carbonate; In tetrahydrofuran; at 60℃;Inert atmosphere;
3,5-Dibromoisonicotinaldehyde (80 g, 303 mmol), followed by cesium carbonate (98 g, 302 mmol) was added to a 2 L round bottom flask containing THF (1.3 L) under Ni. Methyl mercaptoacetate (32 g, 302 mmol) was added and the mixture was heated at 60 C overnight. After cooling to rt, ethyl acetate was added and the organic layer was washed with water, aqueous saturated NaHOO:, solution, and brine, then dried over and filtered to give a white solid The crude product was purified by recrystallization from ethyl acetate to give the desired product (60 g, 73%).
73%
With caesium carbonate; In tetrahydrofuran; at 60℃;Inert atmosphere;
3,5-Dibromoisonicotinaldehyde (80 g, 303 mmol), followed by cesium carbonate (98 g, 302 mmol) was added to a 2 L round bottom flask containing THF (1.3 L) under N2. Methyl mercaptoacetate (32 g, 302 mmol) was added and the mixture was heated at 60 C overnight. After cooling to rt, ethyl acetate was added and the organic layer was washed with water, aqueous saturated NaHCO3, solution, and brine, then dried over and filtered to give a white solid The crude product was purified by recrystallization from ethyl acetate to give the desired product (60 g, 73%).
73%
With caesium carbonate; In tetrahydrofuran; at 60℃;Inert atmosphere;
[0188] Step 2: Methyl 4-bromothieno [2,3-cl pyridine-2-carboxylate. 3,5- Dibromoisonicotinaldehyde (80 g, 303 mmol), followed by cesium carbonate (98 g, 302 mmol) was added to a 2 L round bottom flask containing THF (1.3 L) under N2. Methyl mercaptoacetate (32 g, 302 mmol) was added and the mixture was heated at 60 C overnight. After cooling to rt, ethyl acetate was added and the organic layer was washed with water, aqueous saturated NaHCO3 solution, and brine, then dried over Na2504 and filtered to give a white solid. The crude product was purified by recrystallization from ethyl acetate to give the desired product (60 g, 73%).
With caesium carbonate; In tetrahydrofuran; at 60℃; for 2h;
To 3,5-dibromo-pyridine-4-carbaldehyde (prepared using general procedure A) (2.00 g, 7.54 mmol) in THF (75 mL) was added cesium carbonate (2.71 g, 8.29 mmol) and methylthioglycolate (0.800 g, 7.54 mmol). The resulting mixture was heated at about 60 C for about 2 hours. The reaction mixture was cooled to ambient temperature, poured into ice water, extracted with DCM (2 x 75 mL), washed with brine (75 mL), dried over magnesium sulfate, filtered, and concentrated to yield 4-bromo-thieno[2,3-cJpyridine-2-carboxylic acid methyl ester as a light yellow solid (1.56 g, 5.73 mmol) ; ¹H NMR (DMSO-d6, 400 MHz) No. 9.38 (s, 1H), 8.73 (s, 1H), 8.03 (s, 1H), 4.0 (s, 3H) ; RP-HPLC (Table 1, Method i), Rt 2.90 min; m/z: (M + H)+ 272, 274.
To the solution of 3,5-dibromoisonicotinaldehyde (15 g, 56.63 mmol) in THF (80 mL) was added methyl 2-mercaptoacetate (6.4 g, 60.3 mmol) at 0 C. The mixture was stirred at 0 C. for 1 h. Then the mixture was warmed to 25 C. and stirred for another 1 h and Cs2CO3 (18.45 g, 56.63 mmol) was added to the mixture. Then the mixture was stirred at rt for 16 h. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to give the crude product as a yellow solid. The crude product was purified by FCC (petroleum ether/ethyl acetate=100:0 to 80:20). The solvents were concentrated to get the crude products as a pale yellow solid (15 g, 97.3%).
4-vinyl-thieno[2,3-c]pyridine-2-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50%
(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 150℃; for 3h;
4-Bromo-thieno [2,3-c]pyridine-2-carboxylic acid methyl ester (272 mg, 1.0 mmol) was combined with Tributyl-vinyl-stannane (317 mg, 1.0 mmol) and Pd C12 dppf (40.8 mg, 0.05 mmol) in p-Dioxane (5.0 ml). The mixture is degassed and heated in a sealed vessel at 150C for 3 hours and then cooled. The reaction is filtered through silica gel, chasing with EtOAc and then the organic solvents are removed under reduced pressure. The residue was be further purified by preparative reversed phase chromatography (method k) to yield 4- Vinyl- thieno(2,3-c Jpyridiiie-2-carboxylic acid methyl ester (109 mg, 50%) as an off-white solid; RP-HPLC (Table 1, Method M, Rt 1.96 min; m/z: (M + H) + 220.
(4-bromo-thieno[2,3-c]pyridin-2-yl)-methanol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
4-Bromo-thieno[2,3-c]pyridine-2-carboxylic acid methyl (prepared using general procedures A and B) (1.09 g, 4.00 mmol) was suspended in ethanol (20.0 mL) and treated with CaCl2 (888 mg, 8.00 mmol). Tetrahydrofuran (10 ml) was added to aid solubility and the mixture was stirred for 1 hour at room temperature. The reaction mixture was cooled to 0 C and Sodium cyanoborohydride (608 mg, 16.0 mmol)) was added in portions. The mixture is stirred for 1 hour at 0 C and then allowed to warm to room temperature with stirring overnight. The mixture is treated with water (25 ml) and extracted with CH2CL2 (40 ml). The extract was washed with brine (25 ml), dried (MgS04), filtered and concentrated to yield 705 mg (72 %) of (4-Bromo-t7aieno(2,3-cjpyridin-2-yl)-n2etlaanol as a white solid; RP-HPLC (Table 1, Method M, Rt 1.27 min; m/z: (M + H)+ 244/246.
4-(biphenyl-4-ylamino)-thieno[2,3-c]pyridine-2-carboxylic acid methyl ester[ No CAS ]
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 1,4-dioxane; at 100℃; for 16h;
A mixture of 4-bromo-thieno [2,3-c]pyridine-2-carboxylic methyl ester (5.0 g, 0.0184 mol), 4-aminobiphenyl (3.41 g, 0.0202 mol), cesium carbonate (14.47 g, 0.0441 mol), 4,5-bis9diphenylphosphino0-9,9-dimethyl-xanthene (0.638 g, 0.0011 mol) and tris9dibenzylideneacetone) dipalladium (0) in 1,4-dioxane was degassed and then heated at 100C under continuous nitrogen flow for 16 hours. The solvent was removed under reduced pressure; the residue was triturated in water and the precipitate was collected by filtration. It was washed with ice-cold water (2x50 mL) and acetonitrile (2x40 mL) and dried to yield 4- (biphenyl-4-ylamino)-thieno[2,3-c]pyridine-2-carboxylic methyl ester (5.9 g, 0.0164 mol) as a yellow solid. m/z: (M + H)+ 361.
EXAMPLE 93B methyl 4-bromothieno[2,3-c]pyridine-2-carboxylate Example 93A was processed as in Example 17C except at 0-25 C. to provide the title compound. MS (DCI/NH3) m/z 274 (M+H)+; 1H NMR (500 MHz, DMSO-d6) delta 3.95 (s, 3H), 7.99 (s, 1H), 8.67 (s, 1H), 9.31 (s, 1H).
6
[ 104-81-4 ]
[ 145325-40-2 ]
[ 106-93-4 ]
methyl 4-[(4-methylphenyl)methyl]thieno[2,3-c]pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With chloro-trimethyl-silane; lithium chloride;CuCN; In tetrahydrofuran; ethyl acetate;
EXAMPLE 121A methyl 4-[(4-methylphenyl)methyl]thieno[2,3-c]pyridine-2-carboxylate Example 121A is processed as in J. Org. Chem, 1988, 53, pp. 2392-2394. For example, a suspension of Zn dust (92 mg, 1.4 mM) in THF (2 ml) containing 1,2-dibromoethane (0.05 ml, 0.054 mmol) is heated at 65 C. for 2 minutes, cooled to 25 C., treated with trimethylsilyl chloride (0.009 ml, 0.043 mM), stirred at room temperature for 25 minutes, cooled to 0 C., slowly treated with a solution of 4-methylbenzyl bromide (0.248 mL, 1.0 mmol) in THF (5 mL), warmed to 40 C. for 3 hours, cooled to -10 C., treated with CuCN (106 mg, 1.18 mM) and LiCl (100 mg, 2.35 mM) in THF (10 mL), stirred at 0 C. for 30 minutes, treated slowly with a solution of Example 93B (272 mg, 1 mmol) in THF (5 mL), stirred at 0 C. for 3 hours, warmed to 25 C. over 18 hours, treated with ethyl acetate, washed sequentially with saturated NH4Cl and brine, dried (MgSO4), filtered and concentrated. The residue is purified by flash chromatography on silica gel to provide the title compound.
With 3-chloro-benzenecarboperoxoic acid; In dichloromethane; at 0 - 20℃;
At 0 C, to a solution of <strong>[145325-40-2]methyl 4-bromothieno[2,3-c]pyridine-2-carboxylate</strong> (Compound 106; 1.9 g, 7.0 mmol) in CH2C12 (50 mL) was added meta-chloroperoxybenzoic acid (1.7g, 8.4 mmol), and the mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with CH2C12 (100 mL), the organic layer was washed with 1 N NaOH solution, brine and water, dried over anhydrous Na2504, filtered and concentrated to obtain crude 4-bromo-2-(methoxycarbonyl)thieno [2,3 -c]pyridine 6-oxide as a solid which was used without further purification (Compound 107; 2.8 g, assumed quantitative). MS (ESI) calcd for C9H6BrNO3: 286.93.
4-Methylene-piperidine-1-carboxylic acid benzyl ester (250 mg, 1.08 mmol) is dissolved in a 0.5 M solution of 9-Bora-bicyclo[3.3.1]nonane in THF (2.16 ml, 1.08 mmol) and heated at 67C for 1.5 hour. The mixture was cooled and Pd C12 dppf (40.8 mg, 0.05 mmol), Cs2CO3 (0.98 g, 3.00 mmol) and a solution 4-Bromo-thieno[2,3-c]pyridine-2- carboxylic acid methyl ester (272 mg, 1.00 mmol) in p=Dioxane (3.0 ml) were added. The mixture was de-gassed and heated at 90C for 3 hours. The mixture was cooled and filtered through silica gel, chasing with EtOAc. The organic layer was concentrated and the residue was further purified by flash chromatography on silica gel using 4 : 1/ CH2CL2 : EtOAc , then 1 : 1/ CH2CL2 : EtOAc as eluant. Product fractions were combined and concentrated to yield 128 mg (30%) of 4-(1-Benzyloxycarbonyl piperidin-4-ylmethyl)-thieno@2,3-cJpyridine- 2-carboxylic acid methyl ester as a yellow solid; RP-HPLC (Table 1, Method M), Rt 2.40 min; m/z: (M + H) + 425.
methyl thieno[2,3-c]pyridine-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
80%
With palladium 10% on activated carbon; hydrogen; triethylamine; In tetrahydrofuran; methanol; under 2327.23 Torr; for 72h;Inert atmosphere;
Methyl 4-bromothieno[2,3-c]pyridine-2-carboxylate (115 g, 423 mmol), TEA (42,7 g, 423 mmol), THF (1.5 L), and MeOH (500 mL) were mixed and degassed. Under nitrogen, palladium on carbon (10%, 14.7 g, 139 mmol) was added The mixture was hydrogenated with a Parr apparatus at 45 psi H2 for 3 days. The catalyst was filtered off and the filtrate was concentrated to give the desired compound as a white solid (65g, 80%).
80%
With palladium 10% on activated carbon; hydrogen; triethylamine; In tetrahydrofuran; methanol; under 2327.23 Torr; for 72h;Inert atmosphere;
Methyl 4- bromothieno[2,3-c]pyridine-2-carboxylate (115 g, 423 mmol), TEA (42,7 g, 423 mmol), THF (1.5 L), and MeOH (500 mL) were mixed and degassed. Under nitrogen, palladium on carbon (10/o, 14.7 g, 139 mmol) was added The mixture was hydrogenated with a Parr apparatus at 45 psi H2 for 3 days. The catalyst was filtered off and the filtrate was concentrated to give the desired compound as a white solid (65g, 80%).
80%
With palladium 10% on activated carbon; hydrogen; triethylamine; In tetrahydrofuran; methanol; under 2327.23 Torr; for 72h;Inert atmosphere;
Methyl 4-bromothieno[2,3-c]pyridine-2-carboxylate (115 g, 423 mmol), TEA (42,7 g, 423 mmol), THF (1.5 L), and MeOH (500 mL) were mixed and degassed. Under nitrogen, palladium on carbon (10%, 14.7 g, 139 mmol) was added The mixture was hydrogenated with a Parr apparatus at 45 psi H2 for 3 days. The catalyst was filtered off and the filtrate was concentrated to give the desired compound as a white solid (65g, 80%).
80%
With palladium 10% on activated carbon; hydrogen; triethylamine; In tetrahydrofuran; methanol; under 2327.23 Torr; for 72h;Inert atmosphere;
[0189] Step 3. Methyl thieno [2,3-cl pyridine-2-carboxylate. Methyl 4-bromothieno [2,3- c]pyridine-2-carboxylate (115 g, 423 mmol), TEA (42.7 g, 423 mmol), THF (1.5 L), and MeOH (500 mL) were mixed and degassed. Under nitrogen, palladium on carbon (10%, 14.7 g, 13.9 mmol) was added. The mixture was hydrogenated with a Parr apparatus at 45 psi H2 for 3 days. The catalyst was filtered off and the filtrate was concentrated to give the desired compound as a white solid (65 g, 80%).
80%
With palladium 10% on activated carbon; hydrogen; triethylamine; In tetrahydrofuran; methanol; under 2327.23 Torr; for 72h;Inert atmosphere;
Step 3. Methyl thienor2,3-c]pyridine-2-carboxylate. Methyl 4-bromothieno[2,3- c]pyridine-2-carboxylate (115 g, 423 mmol), triethylamine (42.7 g, 423 mmol), THF (1.5 L), and MeOH (500 mL) were mixed and degassed. Under nitrogen, palladium on carbon (10%, 14.7 g, 13.9 mmol) was added. The mixture was hydrogenated with a Parr apparatus at 45 psi H2 for 3 days. The catalyst was filtered off and the filtrate was concentrated to give the desired compound as a white solid (65 g, 80%).
With caesium carbonate; In tetrahydrofuran; at 60℃;Inert atmosphere;
0196] Step 2: Methyl 4-bromothienor2,3-c]pyridine-2-carboxylate. 3,5- Dibromoisonicotinaldehyde (80 g, 303 mmol), followed by cesium carbonate (98 g, 302 mmol) was added to a 2 L round bottom flask containing THF (1.3 L) under N2. Methyl mercaptoacetate (32 g, 302 mmol) was added and the mixture was heated at 60 C overnight. After cooling to rt, ethyl acetate was added and the organic layer was washed with water, aqueous saturated NaHC03 solution, and brine, then dried over Na2S04 and filtered to give a white solid. The crude product was purified by recrystallization from ethyl acetate to give the desired product (60 g, 73%).
With water; lithium hydroxide; In tetrahydrofuran; at 20℃; for 4h;
B. 4-bromothieno[2,3-c]pyridine-2-carboxylic acid, 364b Lithium hydroxide (2.640 g, 110.246 mmol) was added to a solution of <strong>[145325-40-2]methyl 4-bromothieno[2,3-c]pyridine-2-carboxylate</strong> (15 g, 55.123 mmol) in THF/H2O=1:1 (20 mL). The mixture was reacted at room temperature for 4 h. The solvent was concentrated under reduced pressure and 30 mL H2O was added to the mixture. The mixture was acidized by 1M hydrochloric to pH=5 and the solid was filtered, washed with H2O (30 mL*2). The solid was dried under reduced pressure to afford product as a white solid (12 g, 84.3%).
ethyl 3-[2-[(4-bromothieno[2,3-c]pyridine-2-carbonyl)amino]ethyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 2 steps
1.1: water
2.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.25 h / 20 °C
2.2: 20 °C
methyl 3-[[(4-bromothieno[2,3-c]pyridine-2-carbonyl)amino]methyl]benzoate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
Multi-step reaction with 2 steps
1.1: water
2.1: N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate / N,N-dimethyl-formamide / 0.25 h / 20 °C
2.2: 20 °C
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