* 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.
Step 1 : Methyl 3-methylthiophene-2-carboxylate: To a solution of 3-Methylthiophene-2- carboxylic acid (15 g, 105 mmol, 1.0 eq) in methanol (150 mL) was added cone sulfuric acid (7.5 mL) drop wise and refluxed for 12 h. The solvent was evaporated under vacuum and the residue was taken into ethyl acetate (200 mL), washed with water (2x50 mL), saturated aqueous sodium bicarbonate solution (2x50 mL), brine (50 mL), dried (Na2S04) and filtered. The filtrate was evaporated under vacuum to afford 20 g (97percent) of the desired product as a oil. 'HNMR (400 MHz, CDC13) 6 7.38 (d, J = 5.0 Hz, 1H), 6.91 (d, J = 5.0 Hz, 1H), 3.85 (s, 3H), 2.55 (s, 3H); ESI- MS [(m/z) 157 (MH)+]
82%
at 0 - 20℃; Cooling with ice
In a 1 L round-bottomed flask, 3-methylthiophene-2-carboxylic acid (15 g, 106 mmol) was combined with methanol (211 mL) to give an off-white suspension. This mixture was cooled to 0 °C in an ice- water bath. Concentrated sulfuric acid (6 ml, 113 mmol) was added dropwise to the cold suspension. The reaction mixture was stirred with gradual warming to room temperature. The reaction mixture was stirred at room temperature over three days. After this time, TLC showed complete conversion of the starting material to a less polar product. The reaction mixture was concentrated to remove methanol. The remaining light brown oil was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried over Na2S04, filtered, and concentrated to afford a brown oil which contained a mixture of the desired methyl ester (84percent) and the starting material (16percent) based on 1H NMR integration. The crude product was re-dissolved in ethyl acetate and the solution was washed with 1 M aqueous NaOH. The organic phase was dried over MgS04, filtered, and concentrated down to provide 3-methyl-thiophene-2-carboxylic acid methyl ester (13.6 g, 82percent) as a light brown oil. 1H NMR (300 MHz, CHLOROFORM- ) δ ppm 7.39 (d, J=5.09 Hz, 1 H), 6.92 (d, J=5.20 Hz, 1 H), 3.87 (s, 3 H), 2.57 (s, 3 H).
82%
at 0 - 20℃; for 72 h;
A suspension of 3-methylthiophene-2-carboxylic acid (available from Aldrich; 15 g, 106 mmol) in MeOH (211 mL) was cooled to 0 °C. Concentrated sulfuric acid (6 ml, 113 mmol) was added drop wise and the mixture was stirred at room temperature for 3 days. The reaction mixture as concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHC03 solution. The organic phase was dried (Na2S04), filtered, and concentrated to afford a brown oil which contained a mixture of the desired methyl ester (84percent) and the starting material (16percent) by NMR. The crude product was dissolved in EtOAc and the solution was washed with 1 M aqueous NaOH. The organic phase was dried (MgS04), filtered, and evaporated to give 3- methyl-thiophene-2-carboxylic acid methyl ester (13.6 g, 82percent) as a light brown oil. 1H NMR (300 MHz, CDCls) δ ppm 7.39 (d, J=5.09 Hz, 1 H), 6.92 (d, J=5.20 Hz, 1 H), 3.87 (s, 3 H), 2.57 (s, 3 H).
Reference：
[1] Patent: WO2012/56478, 2012, A1, . Location in patent: Page/Page column 75-76
[2] Patent: WO2007/124546, 2007, A1, . Location in patent: Page/Page column 58
[3] Patent: WO2014/64131, 2014, A2, . Location in patent: Page/Page column 114; 115
[4] Patent: WO2014/76104, 2014, A1, . Location in patent: Page/Page column 79-80
[5] Journal of Medicinal Chemistry, 1995, vol. 38, # 24, p. 4806 - 4820
[6] Bioorganic and Medicinal Chemistry Letters, 1997, vol. 7, # 15, p. 1969 - 1972
[7] Journal of Medicinal Chemistry, 2007, vol. 50, # 7, p. 1558 - 1570
2
[ 23806-24-8 ]
[ 77-78-1 ]
[ 81452-54-2 ]
Yield
Reaction Conditions
Operation in experiment
95.6%
With potassium carbonate In acetone at 25 - 30℃; for 4 h;
To a stirred solution of 100 g (0.7023 mol) of 3-methyl-2-thiophene carboxylic acid in 1000 ml of acetone was added 122.0 g (0.8827 mol) of potassium carbonate in 500 ml of acetone and was added drop wise of 89.0 g (0.7056 mol) of dimethyl sulfate, whilemaintaining the temperature of the reaction mixture at 25-30°C. When the addition was complete, the solution was stirred at 25-30°C for 4 hr. The acetone was removed by distillation under vacuum and the reaction mixture was diluted with 3000 ml of water while maintaining at 25-30°C by cooling and extracted with three 1000 ml portions of ethyl acetate. The ethyl aceiate extracts were combined, washed two times with 1000 mlportions of water, and dried over anhydrous sodium sulfate. The ethyl acetate was removed by distillation under vacuum at 60°C to give 105.2 g (95.6 percent) as a light yellow oily mass with 99.8 percent purity by HPLC.
Methyl 3-Methylthiophene-2-carboxylate 101a3-Methylthiophene-2-carbonyl chloride (1) (10 mL, 18mmol) in 30 mL of meth-nol was heated to boiling under reflux for 18 hours, then concentrated in vacuo. The residue was partitioned between diethyl ether and water. The organic layer was dried with Na2S04 and concentrated to afford 101a (12.12 g, 100percent) as a clear oil, which was used without further purification.
100%
for 18 h; Reflux
Example 102Methyl 3-Methylthiophene-2-carboxylate 102aCGIPHARM60WO3-Methylthiophene-2-carbonyl chloride (1) (10 mL, 18mmol) in 30 mL of methanol was heated to boiling under reflux for 18 hours, then concentrated in vaculo. The residue was partitioned between diethyl ether and water. The organic layer was dried with Na2S04 and concentrated to afford 102a (12.12 g, 100percent) as a clear oil, which was used without further purification.
Reference：
[1] Patent: WO2012/30990, 2012, A1, . Location in patent: Page/Page column 52
[2] Patent: WO2012/31004, 2012, A1, . Location in patent: Page/Page column 61
[3] Archiv der Pharmazie, 1998, vol. 331, # 12, p. 405 - 411
4
[ 1184731-51-8 ]
[ 81452-54-2 ]
Reference：
[1] Chemical Communications, 2009, # 27, p. 4046 - 4048
Reference：
[1] European Journal of Organic Chemistry, 2009, # 8, p. 1144 - 1147
7
[ 26137-08-6 ]
[ 80-48-8 ]
[ 81452-54-2 ]
Reference：
[1] Chemical Communications, 2017, vol. 53, # 73, p. 10180 - 10183
8
[ 181226-89-1 ]
[ 80-48-8 ]
[ 81452-54-2 ]
Reference：
[1] Chemical Communications, 2017, vol. 53, # 73, p. 10180 - 10183
9
[ 14282-76-9 ]
[ 144-55-8 ]
[ 616-38-6 ]
[ 81452-54-2 ]
Yield
Reaction Conditions
Operation in experiment
84%
With hydrogenchloride; magnesium In tetrahydrofuran
EXAMPLE 6 Methyl 3-methyl-thiophenecarboxylate via Gringnard reaction of 2-bromo-3-methylthiophene 2-Bromo-3-methylthiophene (10.0 g, 0.0565 mol) was slowly added dropwise over a 60 minute period to a slurry of magnesium turnings (1.72 g, 0.0706) in THF. During the course of the addition, the exotherm was controlled to <40° C. by external cooling with a water bath. After the addition was completed, the resulting mixture was stirred at ambient temperature for 60 minutes. Dimethylcarbonate (7.63 g, 0.0847 mol) was then added dropwise over a 5-minute period, and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was quenched by the addition of 6 M HCl (50 mL), and extracted with ethylacetate (100 mL). The organic phase was washed with water (25 mL), followed by saturated aqueous NaHCO3. Concentration of the organic phase then gave 7.38 g (84percent) of methyl 3-methyl-2-thiophenecarboxylate as a light yellow oil.
Stage #1: at 60 - 85℃; for 6 h; Stage #2: With zinc In acetic acid at 85℃; for 1 h;
Step 2: Methyl 4-bromo-3-methylthiophene-2-carboxylate: A solution of methyl 3- methylthiophene-2-carboxylate (20 g, 103 mmol, 1.0 eq) and sodium hydroxide (12.3 g, 307 mmol, 3 eq) in acetic acid (75 mL) was heated to 60 °C. Bromine (46.9 g, 294 mmol, 2.85 eq) was added drop wise at such a rate so as to maintain the temperature of the reaction mixture at <85 °C. The resulting mixture was stirred at 85 °C for 6 h. The solution was then allowed to cool to 50 °C and zinc dust (15.4 g, 236 mmol, 2.3 eq) was added in 3 gram portions to the reaction such that the exotherm was controlled to remain below 85 °C. The resulting mixture was stirred at 85 °C for 1 h, and then filtered hot through a small bed of celite. Water (300 mL) was added and the mixture was extracted with hexane (300 mL). The organic phase was washed with water, then concentrated to dryness to give 27 g (89percent) an off white oil which slowly crystallized upon standing at room temperature. 'HNMR (400 MHz, CDC13) δ 7.43 (s, 1H), 3.87 (s, 3H), 2.56 (s, 3H)
80%
Stage #1: at 60 - 85℃; for 12 h; Stage #2: at 85℃; for 1 h;
To a stirred solution of methyl 3-methylthiophene-2-carboxylate (10 g, 0.064 mol) and NaOH (6.15 g, 0.15 mol) in AcOH glacial (38 mL) was heated to 60° C. Bromine (7.5 mL, 0.15 mol) was added dropwise and stirred at 85° C. for 12 h. The solution was allowed to cool to 50° C. and zinc (7.7 g, 0.12 mol) was added in portions, then the mixture was stirred at 85° C. for 1 h. After 1 h, the reaction was cooled to RT and filtered, then water and EA were added. The organic layer was washed with water and concentrated to dryness to give methyl 4-bromo-3-methylthiophene-2-carboxylate (12 g, 80percent) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.42 (s, 1H), 3.85 (s, 3H), 2.54 (s, 3H).
78%
Stage #1: at 60 - 85℃; for 6 h; Stage #2: at 50 - 85℃; for 1 h;
Synthesis of methyl 4-bromo-3 -methylthiophene-2-carb oxylate (76): Methyl 3- methylthiophene-2-carboxylate (75; 6.46 g, 41.4 mmol) was dissolved in 25 mL of acetic acid. NaOH (4.97 g, 124.2 mmol) was added. The mixture was heated to 60 °C. Bromine (18.6 g, 118 mmol) was added drop wise. The resulting mixture was stirred at 85 °C for 6 h. After cooling down to 50 °C, zinc dust (6.2 g, 95 mmol) was added in 3 portions. The mixture was then reheated at 85 °C for 1 h, and cooled. The mixture was filtered; the filtrate was poured into water, extracted with hexanes (50 mL X 2). The organic phases were washed with water, dried over anhydrous Na2 SO4, concentrated to give 8.5 g of methyl 4-bromo-3- methylthiophene-2-carboxylate 76 as white solid, which was used directly to next step (78percent yield). LCMS: m/z 234.9 [M+H], , tR=2.O6 min
46%
With bromine; acetic acid In dichloromethane at 20℃; for 20 h;
To a solution of 3-methylthiophene-2-carboxylic acid methyl ester (2.0 g, 12.8 mmol) in CH2Cl2 (10 mL) and acetic acid (10 mL) was added Br2 (0.79 mL, 15.3 mmol). The mixture was stirred at room temperature for 20 h and then partitioned between CH2Cl2 and H2O. The aqueous layer was extracted with CH2Cl2. The combined organic phases were washed with saturated sodium thiosulfate solution, dried (Na2SO4), concentrated and purified by column chromatography to give 1.4 g (46percent) of 01 as a white solid: 1H NMR (300 MHz, CD3OD) δ 7.41 (s, 1H), 3.88 (s, 3H), 2.52 (s, 3H).
Reference：
[1] Patent: WO2012/56478, 2012, A1, . Location in patent: Page/Page column 76
[2] Patent: US2018/170948, 2018, A1, . Location in patent: Paragraph 0469
[3] Patent: WO2017/31213, 2017, A1, . Location in patent: Paragraph 00385
[4] Patent: US2007/244094, 2007, A1, . Location in patent: Page/Page column 40
[5] Justus Liebigs Annalen der Chemie, 1938, vol. 536, p. 135,142
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 70℃; for 3h;Inert atmosphere; Reflux;
Example 116c Methyl 3-(Bromomethyl)thiophene-2-carboxylate 116c2fA 1-L single-neck round-bottomed flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was purged with nitrogen and charged with 116b (5.00 g, 32.0 mmol), N-bromosuccinimide (5.70 g, 32.0 mmol) and carbon tetra-chloride (300 mL). The solution was heated to 70 C (oil bath temperature), and 2,2' -azobisisobutyronitrile (526 mg, 3.20 mmol) was added. The resulting mixture was refluxed for 3 h. After that time, the mixture was cooled to room temperature and filtered. The filter cake was washed with carbon tetrachloride (2 x 50 mL). The filtrate was diluted with ethyl acetate (300 mL) and washed with water (40 mL), saturated aqueous sodium bicarbonate (40 mL) and brine (40 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford a quantitative yield (7.50 g) of 116c as a colorless oil: ]H NMR (300 MHz, CDC13) delta 7.39 (d, 1H, / = 5.0 Hz), 7.11 (d, 1H, / = 5.1 Hz), 4.85 (s, 2H), 3.83 (s, 3H).
97%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 18h;
Methyl 3-methylthiophene-2-carboxylate (1.5 g, 9.60 mmol) was dissolved in CCl4 (45 mL). NBS (1.7 g, 9.55 mmol) was added followed by AIBN (0.5 mL, 12% in acetone). The mixture was heated at 80 C. for 18 h, followed by workup to provide methyl 3-(bromomethyl)thiophene-2-carboxylate (2.15 g, 97%). MS (M+Na) 258.1
80%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 16h;Inert atmosphere;
Methyl 3-(bromomethyl)thiophene-2-carboxylate In a 250-mL round bottom flask purged and maintained with an inert atmosphere of nitrogen, <strong>[81452-54-2]methyl 3-methylthiophene-2-carboxylate</strong> (10 g, 64.02 mmol, 1.00 equiv) was dissolved in CCl4 (120 mL), to which were added NBS (17.09 g, 96.03 mmol, 1.50 equiv) and AIBN (2.103 g, 12.81 mmol, 0.20 equiv) at room temperature. The resulting solution was then stirred for 16 h at 80 C. When the reaction was done, it was quenched by 50 mL water and the mixture was extracted with ethyl acetate (3*100 mL). The organic layers were combined, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified in a silica gel column eluting with ethyl acetate in petroleum ether (5% to 30% gradient) to afford methyl 3-(bromomethyl)thiophene-2-carboxylate (12 g, 80%) as yellow solid. MS: m/z=235.1 [M+H]+.
69%
With N-Bromosuccinimide;2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 1.5h;Reflux; Inert atmosphere; Microwave irradiation;
Bromosuccinimide (13.2 mmol) and a catalytic amount of azobis-isobutyronitrile in carbon tetrachloride were heated at reflux under nitrogen. The reaction mixture was irradiated with a 500 W UV lamp for 1.5 hours, cooled down to room temperature and then filtered under autocup 0.45 mum, followed by the evaporation of the filtrate. The residue was purified by chromatography on silica gel (eluent: stepwise gradient of 3-5% diethyl ether in petroleum ether) to give 2.13 g of Intermediate IV.1 (69%), which was characterized by 1H NMR (CDCl3, 400 MHz) delta (ppm) 3.90 (s, 3H), 4.92 (s, 2H), 7.18 (d, J= 5.3 Hz, IH), 7.47 (d, J = 5.3 Hz, IH).
63%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 90℃;Reflux;
To a solution of <strong>[81452-54-2]methyl 3-methylthiophene-2-carboxylate</strong> (10.0 g, 64.0 mmol) in CCl4 (100 mL) was added AIBN (180 mg, 1.1 mmol) and N-bromosuccinimide (11.4 g, 64.0 mmol). The reaction mixture was refluxed for 10 min, and then an additional portion of AIBN (460 mg, 2.8 mmol) was added. This reaction was heated overnight at 90 C. under a reflux condenser. At completion, the reaction was filtered over a short plug of silica gel (100% DCM eluent). The filtrate was concentrated and purified by flash chromatography over silica gel (2% EtOAc/hexane eluent) to afford methyl 3-(bromomethyl)thiophene-2-carboxylate (9.5 g, 63% yield) as a white solid. 1H NMR (400 MHz, METHANOL-d4) delta ppm 7.66 (d, J=5.0 Hz, 1H), 7.23 (d, J=5.0 Hz, 1H), 4.95 (s, 2H), 3.89 (s, 3H); MS (EI) m/z=236.1 [M+1]+.
63.0%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; at 75 - 80℃; for 4h;
To a stirred solution of 200 g (1.2805 mol) of <strong>[81452-54-2]methyl 3-methylthiophene-2-carboxylate</strong> in1220 ml of carbon tetrachloride was added 228.0 g (1.2805 mol) of N-bromosuccinimide and 12.40 g (0.0512 rnol) of benzoyl peroxide was added while maintaining the temperature of the reaction mixture at 25-30C. When the addition was complete, the reaction mixture was heated to 75-80C and was stirred for 4 hr. The reaction mixturewas filtered and washed with 100 ml of carbon tetrachloride. The filtrate mass was withed twol66O-ml portions of 5% sodium carbonate and two times with 1660- ml portions of water, and dried over anhydrous sodium sulfate. The carbon tetrachioride was removed by distillation under vacuum at 65C to give crude product. Then crude product was triturated. with hexane (.540 ml) to give 190.0 g (63.0 %) as a- solid with 97.4 % purity by HPLC.
54%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 70℃; for 3h;
A mixture of <strong>[81452-54-2]methyl 3-methylthiophene-2-carboxylate</strong> (ID) (5.00 g, 32.0 mmol), 2,2'-azobisisobutyronitrile (526 mg, 3.20 mmol) and N-bromosuccinimide (5.70 g, 32.0 mmol) in CCl4 (300 mL) was heated to 70 C. After 3 hr, the mixture was allowed to cool to room temperature and was filtered. The resulting filter cake was washed with carbon tetrachloride (2 x 50 mL). The filtrate was diluted with ethyl acetate (300 mL) and washed with water (40 mL), saturated aqueous sodium bicarbonate (40 mL) and saturated brine (40 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (1% - 2% EtOAc in PE) to afford compound IE (4.0 g, 54%) as a colorless oil. ESI m/z 234.9 [M+H] +.
54%
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 70℃; for 3h;
A mixture of <strong>[81452-54-2]methyl 3-methylthiophene-2-carboxylate</strong> (5.00 g, 32.0 mmol), 2,2'- azobisisobutyronitrile (526 mg, 3.20 mmol) and N-bromosuccinimide (5.70 g, 32.0 mmol) in CCl4 (300 mL) was heated to 70 C. After 3 hr, the mixture was allowed to cool to room temperature and was filtered. The resulting filter cake was washed with carbon tetrachloride (2 x 50 mL). The filtrate was diluted with ethyl acetate (300 mL) and washed with water (40 mL), saturated aqueous sodium bicarbonate (40 mL) and saturated brine (40 mL). The organic layer was dried over anhydrous Na2S04, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (1% - 2% EtOAc in PE) to afford compound 39B (4.0 g, 54% yield) as a colorless oil. ESI m/z 234.9 [M+H] +.
27%
With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 6h;Heating / reflux;
Step 1 3-Bromomethyl-thiotaophene-2-carboxyhc acid methyl ester[00376] 3-Methyl-thiophene-2-carboxylic acid methyl ester (Ig, 6 4mmol) is dissolved in CCLt(15mL), and NBS (1 19g, 6 7mmol) and benzoyl peroxide (15mg) are added The reaction mixture is refluxed for 6 hours, then water is added and the mixture is extracted with EtOAc (3x) The organic layers are dried over MgStheta4, filtered and concentrated The crude product is purified by silica gel column chromatography elutmg with 98 2 petroleum ether-EtOAc to give the title compound (1 34g, 27%)
With N-Bromosuccinimide; dibenzoyl peroxide; In chloroform; at 70℃;Inert atmosphere;
The <strong>[81452-54-2]3-methyl-thiophene-2-carboxylic acid methyl ester</strong> (10g, 64mmol) dissolved in 150 ml dry chloroform, and adding NBS (10.83g, 60 . 82mmol) and a catalytic amount of benzoyl peroxide, nitrogen protection, heating to 70 C stirring reaction sleepovers, cooling to room temperature, aqueous washing with full and sodium bicarbonate, water washing, washing of salt water, after drying by anhydrous sodium sulfate, the filtrate turns on lathe does light brown oily crude product to 15g, without the need of separation and purification, used directly in the next reaction.
With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In acetonitrile; at 85℃; for 15h;Inert atmosphere;
Under N2, to a solution of <strong>[81452-54-2]methyl 3-methylthiophene-2-carboxylate</strong> (2.99 g, 19.2 mmol) in acetonitrile (38 mL) was added NBS (3.98 g, 22.4 mmol) and AIBN (1.01 g, 6.20 mmol),The mixture was stirred at 85 C for 15 h.The reaction system was cooled to room temperature and concentrated under reduced pressure.The residue was added with water (50 mL) and extracted with EtOAc (100 mL).The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain crude methyl 3- (bromomethyl) thiophene-2-carboxylate (5.57 g), which was used in the next step without purification.
Step 1 : Methyl 3-methylthiophene-2-carboxylate: To a solution of 3-Methylthiophene-2- carboxylic acid (15 g, 105 mmol, 1.0 eq) in methanol (150 mL) was added cone sulfuric acid (7.5 mL) drop wise and refluxed for 12 h. The solvent was evaporated under vacuum and the residue was taken into ethyl acetate (200 mL), washed with water (2x50 mL), saturated aqueous sodium bicarbonate solution (2x50 mL), brine (50 mL), dried (Na2S04) and filtered. The filtrate was evaporated under vacuum to afford 20 g (97%) of the desired product as a oil. 'HNMR (400 MHz, CDC13) 6 7.38 (d, J = 5.0 Hz, 1H), 6.91 (d, J = 5.0 Hz, 1H), 3.85 (s, 3H), 2.55 (s, 3H); ESI- MS [(m/z) 157 (MH)+]
82%
With sulfuric acid; at 0 - 20℃;Cooling with ice;
In a 1 L round-bottomed flask, <strong>[23806-24-8]3-methylthiophene-2-carboxylic acid</strong> (15 g, 106 mmol) was combined with methanol (211 mL) to give an off-white suspension. This mixture was cooled to 0 C in an ice- water bath. Concentrated sulfuric acid (6 ml, 113 mmol) was added dropwise to the cold suspension. The reaction mixture was stirred with gradual warming to room temperature. The reaction mixture was stirred at room temperature over three days. After this time, TLC showed complete conversion of the starting material to a less polar product. The reaction mixture was concentrated to remove methanol. The remaining light brown oil was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried over Na2S04, filtered, and concentrated to afford a brown oil which contained a mixture of the desired methyl ester (84%) and the starting material (16%) based on 1H NMR integration. The crude product was re-dissolved in ethyl acetate and the solution was washed with 1 M aqueous NaOH. The organic phase was dried over MgS04, filtered, and concentrated down to provide 3-methyl-thiophene-2-carboxylic acid methyl ester (13.6 g, 82%) as a light brown oil. 1H NMR (300 MHz, CHLOROFORM- ) delta ppm 7.39 (d, J=5.09 Hz, 1 H), 6.92 (d, J=5.20 Hz, 1 H), 3.87 (s, 3 H), 2.57 (s, 3 H).
82%
With sulfuric acid; at 0 - 20℃; for 72h;
A suspension of <strong>[23806-24-8]3-methylthiophene-2-carboxylic acid</strong> (available from Aldrich; 15 g, 106 mmol) in MeOH (211 mL) was cooled to 0 C. Concentrated sulfuric acid (6 ml, 113 mmol) was added drop wise and the mixture was stirred at room temperature for 3 days. The reaction mixture as concentrated and the residue was partitioned between EtOAc and saturated aqueous NaHC03 solution. The organic phase was dried (Na2S04), filtered, and concentrated to afford a brown oil which contained a mixture of the desired methyl ester (84%) and the starting material (16%) by NMR. The crude product was dissolved in EtOAc and the solution was washed with 1 M aqueous NaOH. The organic phase was dried (MgS04), filtered, and evaporated to give 3- methyl-thiophene-2-carboxylic acid methyl ester (13.6 g, 82%) as a light brown oil. 1H NMR (300 MHz, CDCls) delta ppm 7.39 (d, J=5.09 Hz, 1 H), 6.92 (d, J=5.20 Hz, 1 H), 3.87 (s, 3 H), 2.57 (s, 3 H).
Example 19 Synthesis of 5-nitro-3-[3-cyano-furan-3-yl-6-(4-morpholin-4-yl-phenyl)- pyridin-2-yl-oxymethyl]-thiophene-2-carboxylic acid and 4-nitro-3-[3-cyano-furan-3-yl-6- (4-morpholin-4-yl-phenyl)-pyridin-2-yl-oxymethyl]-thiophene-2"carboxyIic acid .; The nitration reaction of <strong>[81452-54-2]3-methyl-thiophene-2-carboxylic acid methyl ester</strong> gave two isomers which were separated by flash chromatography to give 3 (7.8 g, 70 % yield) and 4 (1.9 g, 17 % yield). Each of them was converted to the bromomethyl compound by NBS/BPO giving 1.0 g of compound 5 and 0.8 g of compound 6 respectively. The side chains 5 and 6 were coupled to the cores by adapting the method as described in example 11 and hydrolysed to the acid by adapting the method in example 16 to give respectively 5-nitro-3-[3-cyano-furan-3-yl-6-(4- morpholin-4-yl-phenyl)-pyridin-2-yl-oxymethyl]-thiophene-2-carboxylic acid (ES-MS 532, M-H+) and its sodium salts (Rt 13.5min, method 2) and 4-nitro-3-[3-cyano-furan-3-yl-6-(4- morpholin-4-yl-phenyl)-pyridin-2-yl-oxymethyl]-thiophene-2-carboxylic acid.
With hydrogenchloride; magnesium; In tetrahydrofuran;
EXAMPLE 6 Methyl 3-methyl-thiophenecarboxylate via Gringnard reaction of 2-bromo-3-methylthiophene 2-Bromo-3-methylthiophene (10.0 g, 0.0565 mol) was slowly added dropwise over a 60 minute period to a slurry of magnesium turnings (1.72 g, 0.0706) in THF. During the course of the addition, the exotherm was controlled to <40 C. by external cooling with a water bath. After the addition was completed, the resulting mixture was stirred at ambient temperature for 60 minutes. Dimethylcarbonate (7.63 g, 0.0847 mol) was then added dropwise over a 5-minute period, and the reaction mixture was stirred at ambient temperature for 4 hours. The reaction mixture was quenched by the addition of 6 M HCl (50 mL), and extracted with ethylacetate (100 mL). The organic phase was washed with water (25 mL), followed by saturated aqueous NaHCO3. Concentration of the organic phase then gave 7.38 g (84%) of methyl 3-methyl-2-thiophenecarboxylate as a light yellow oil.
With potassium acetate;palladium diacetate; In ISOPROPYLAMIDE; at 150℃; for 1h;Inert atmosphere; Sealed vessel;
At room temperature, a solution of 4-iodobenzene (9.6 mmol) and methyl 3- methylthiophene-2-carboxylate (19.2 mmol) in dimethylacetamide (20 ml) were degassed with nitrogen for 15 minutes. Potassium acetate (0.87 mmol) and palladium acetate (0.02 mmol) were added, the reaction vessel was sealed and heated at 150 0C for 1 hour. Then, the reaction mixture was cooled down to room temperature and poured into water, extracted with dichloromethane, washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by chromatography on silica gel (eluent: gradient of 3% diethyl ether in petroleum ether) to give 100 mg of Intermediate V.I (22%) as a yellow solid, which was characterized by the following spectroscopic data: 1H NMR (CDCI3, 400 MHz) delta (ppm) 2.57 (s, 3H), 3.88 (s, 3H), 7.13 (s, IH), 7.32-7.34 (m, 3H), 7.59-7.64 (m, 2H); and MS (ESI, EI+) m/z = 233 (MH+).
AICI3 (15.60 g, 117 mMol) was suspended in CH2C12 (18 mL) and the mixture was cooled to -78 C. A solution of 12.28 g (78 mMol) of 101a in CH2C12 (9 mL) was added dropwise over 5 min. The mixture was stirred for 5 min. A solution of 8.9 mL (82 mMol) 2- chloro-2-methylpropane in CH2C12 (9 mL) was then added over 45 min, and the resulting mixture was stirred at -78 C for lh. The reaction mixture was gradually warmed to room temperature and stirred for 24h. The reaction mixture was then poured onto ice and extracted with CH2C12. The organic layer was dried with Na2S04, and concentrated to an oil, which was purified on silica eluting with a gradient of CH2C12 in Hexane (0 to 10%) to afford 9.94 g(60%) of 101b.
60%
thyl 5-ieri-Butyl-3-methylthiophene-2-carboxylate 102bAICI3 (15.60 g, 117 mMol) was suspended in CH2CI2 (18 mL) and the mixture was cooled to -78 C. A solution of 12.28 g (78 mMol) of 102a in CH2C12 (9 mL) was added dropwise over 5 min. The mixture was stirred for 5 min. A solution of 8.9 mL (82 mMol) 2- chloro-2-methylpropane in CH2CI2 (9 mL) was then added over 45 min, and the resulting mixture was stirred at -78 C for lh. The reaction mixture was gradually warmed to room temperature and stirred for 24h. The reaction mixture was then poured onto ice and extracted with CH2CI2. The organic layer was dried with Na2S04, and concentrated to an oil, which was purified on silica eluting with a gradient of CH2CI2 in Hexane (0 to 10%) to afford 9.94 g (60%) of 102b.
38%
In a 500 mL round-bottom flask, aluminum trichloride (17.3 g, 130 mmol) was combined with DCM (20 mL) to give an off-white suspension. This mixture was back-filled with argon and then cooled to -78 C in a dry ice/acetone bath. A solution of methyl 3-methylthiophene-2- carboxylate (13.5 g, 86.4 mmol) in 10 mL DCM was added dropwise over 5 minutes. The reaction mixture was stirred at -78 C for 5 minutes. A solution of 2-chloro-2-methylpropane (9.87 mL, 90.7 mmol) in 10 mL DCM was added dropwise to the cold reaction mixture over 30 minutes. The reaction mixture was stirred over the weekend under a reflux condenser with the dry ice/acetone bath gradually melting and allowing the reaction flask to warm to room temperature. The reaction mixture was poured into ice water. After the ice melted, the organic phase was separated and then dried over Na2S04. The organic phase was filtered thenconcentrated to afford a brown oil. This oil was loaded directly onto a 330 gram silica gel column. Flash chromatography (0-5% EtOAc-hexanes) was used to isolate 5-tert-butyl-3- methyl-thiophene-2-carboxylic acid methyl ester (7.05 g, 38%) as a yellow oil. 1H NMR (300 MHz, CHLOROFORM- ) delta ppm 6.68 (s, 1 H), 3.84 (s, 3 H), 2.50 (s, 3 H), 1.38 (s, 9 H).
38%
With aluminum (III) chloride; In dichloromethane; at -78 - 20℃;Inert atmosphere;
A mixture of AICI3 (17.3 g, 130 mmol) and CH2CI2 (20 mL) under argon was cooled to -78 C. A solution of <strong>[81452-54-2]methyl 3-methylthiophene-2-carboxylate</strong> (13.5 g, 86.4 mmol) in CH2CI2 (10 mL) was added dropwise over 5 minutes. The reaction mixture was stirred at -78 C for 5 minutes. A solution of 2-chloro-2-methylpropane (available from Aldrich; 9.9 mL, 90.7 mmol) in CH2CI2 (10 mL) was added dropwise to the cold reaction mixture over 30 min. The reaction mixture was allowed to warm to room temperature and stir over the weekend. The reaction mixture was then poured into ice-water. The organic phase was separated, dried (Na2S04), filtered, and concentrated. The residue was purified by chromatography (silica gel, 0-5%> EtOAc/hexanes) to give 5-tert-butyl-<strong>[81452-54-2]3-methyl-thiophene-2-carboxylic acid methyl ester</strong> (7.05 g, 38%) as a yellow oil. 1H NMR (300 MHz, CDC13) delta ppm 6.68 (s, 1 H), 3.84 (s, 3 H), 2.50 (s, 3 H), 1.38 (s, 9 H).
4.74 g
Under nitrogen atmosphere, aluminum chloride (6.4 g, 48.0 mmol) was dissolved in DCM (7.3 mL). To this solution, <strong>[81452-54-2]methyl 3-methylthiophene-2-carboxylate</strong> (5.0 g, 32.0 mmol) in DCM solution (3.6 mL) was added dropwise during a period of 5 min at -80 C then stirred for 5 min. To this reaction mixture, 2-chloro-2-methylpropane (3.55 g, 38.4 mmol) in DCM solution (3.6 mL) was added dropwise during a period of 5 min. The reaction mixture was allowed to warm gradually to ambient temperature and stirred for 14 h. The reaction mixture was poured into ice then extracted with DCM (3x300 mL). The combined organic layer was washed with water, saturated sodium hydrogen carbonate solution and brine, dried over sodium sulfate, filtered and concentrated. The crude material was purified by chromatography on silica gel, eluted with hexane/ethyl acetate to afford methyl 5-(tert-butyl)-3-methylthiophene-2-carboxylate (4.74 g). 1H NMR (400 MHz, CDCl3) delta6.67 (s, 1H), 3.83 (s, 3H), 2.49 (s, 3H), 1.37 (s, 9H) ; LCMS (m/z): 213.0 [M+H]+.
With potassium carbonate; In acetone; at 25 - 30℃; for 4h;
To a stirred solution of 100 g (0.7023 mol) of <strong>[23806-24-8]3-methyl-2-thiophene carboxylic acid</strong> in 1000 ml of acetone was added 122.0 g (0.8827 mol) of potassium carbonate in 500 ml of acetone and was added drop wise of 89.0 g (0.7056 mol) of dimethyl sulfate, whilemaintaining the temperature of the reaction mixture at 25-30C. When the addition was complete, the solution was stirred at 25-30C for 4 hr. The acetone was removed by distillation under vacuum and the reaction mixture was diluted with 3000 ml of water while maintaining at 25-30C by cooling and extracted with three 1000 ml portions of ethyl acetate. The ethyl aceiate extracts were combined, washed two times with 1000 mlportions of water, and dried over anhydrous sodium sulfate. The ethyl acetate was removed by distillation under vacuum at 60C to give 105.2 g (95.6 %) as a light yellow oily mass with 99.8 % purity by HPLC.
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