* 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.
Stage #1: Reflux Stage #2: With sodium hydrogencarbonate In water at 20℃;
Example 7A Ethyl 4-bromothiophene-2-carboxylate 663 mg (3.20 mmol) of the compound from Example 6A are provided in 25 ml of ethanol, 0.1 ml of concentrated sulfuric acid is added and the mixture is heated under reflux overnight. After cooling to room temperature, a saturated aqueous sodium bicarbonate solution is added and the mixture is diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. 700 mg (89percent of theory) of the title compound are obtained. 1H-NMR (400 MHz, DMSO-d6): δ=8.07 (d, 1H), 7.78 (d, 1H), 4.30 (q, 2H), 1.30 (t, 3H). GC-MS (Method 11): Rt=4.69 min; MS (EIpos): m/z=234 [M]+.
Reference：
[1] Nippon Kagaku Zasshi, 1959, vol. 80, p. 1021,1023[2] Chem.Abstr., 1961, p. 5467
[3] Patent: US2010/184649, 2010, A1,
3
[ 16694-18-1 ]
[ 62224-16-2 ]
Yield
Reaction Conditions
Operation in experiment
98%
With sulfuric acid In methanol at 65℃; for 17 h;
A few drops of concentrated sulphuric acid are added to a solution of 5.0 g of the compound obtained during Stage 1 of Preparation 1 in 25 ml of methanol. The reaction medium is stirred at 65° C. for 17 hours and is then concentrated under reduced pressure. The oily residue obtained is dissolved in ethyl acetate (200 ml), washed with water (3.x.100 ml), dried over sodium sulphate and then concentrated under reduced pressure in order to produce 5.24 g of the desired product. Yield: 98percent 1H NMR (CDCl3) δ (ppm): 3.90 (s, 3H), 7.45 (s, 1H), 7.70 (s, 1H)
95%
With thionyl chloride In methanol; dichloromethane
b) Methyl 4-bromothiophene-2-carboxylate
To a cooled (-20° C.) solution of 6.02 g (29.1 mmol) of 4-bromothiophene-2-carboxylic acid (as prepared in the previous step) in 100 mL of anhyd MeOH under nitrogen was added 2.55 mL (34.9 mmol) of thionyl chloride dropwise at a rate to keep the temperature below -5° C. (ca. 8-10 min). After stirring for 1 h at room temperature, the mixture was refluxed for 8 h, cooled, and concentrated in vacuo. The resulting 6.7 g of pale amber oil was passed through a 150 g pad of silica gel with ca. 600 mL of CH2Cl2 (discarding the first 120 mL which contained a minor impurity) to afford, after concentration in vacuo, the title compound as a colorless oil (6.11 g, 95percent). 1H-NMR (300 MHz, CDCl3) δ7.69 (d, 1 H, J=1.5 Hz), 7.45 (d, 1 H, J=1.5 Hz), and 3.90 (s, 3 H).
95%
With thionyl chloride In methanol; dichloromethane
b) Methyl 4-bromothiophene-2-carboxylate
To a cooled (-20° C.) solution of 6.02 g (29.1 mmol) of 4-bromothiophene-2-carboxylic acid (as prepared in the previous step) in 100 mL of anhyd MeOH under nitrogen was added 2.55 mL (34.9 mmol) of thionyl chloride dropwise at a rate to keep the temperature below -5° C. (ca. 8-10 min). After stirring for 1 h at room temperature, the mixture was refluxed for 8 h, cooled, and concentrated in vacuo. The resulting 6.7 g of pale amber oil was passed through a 150 g pad of silica gel with ca. 600 mL of CH2Cl2 (discarding the first 120 mL which contained a minor impurity) to afford, after concentration in vacuo the title compound as a colorless oil (6.11 g, 95percent). 1H-NMR (300 MHz, CDCl3) δ 7.69 (d, 1H, J=1.5 Hz), 7.45 (d, 1H, J=1.5 Hz), and 3.90 (s, 3H).
95%
With thionyl chloride In methanol; dichloromethane
b 4-Bromothiophene-2-carboxylic acid Methyl Ester To a dry flask under N2 with a stirbar was added 6 g (29.1 mmol) of 4-bromothiophene-2-carboxylic acid (as prepared in the previous step) and dry methanol (100 mL). The solution was cooled in an ice-salt bath for 15 min and 2.55 mL (34.9 mmol) of thionyl chloride was added over 15 min, keeping the temperature <-5° C. The reaction mixture was stirred on the ice-salt bath for an additional 15 min, then for 1 h at rt, and finally refluxed for 8 h under N2. The resulting solution was cooled and concentrated to 6.7 g of pale amber oil. This oil was passed through 150 g of silica with ~600 mL CH2Cl2 (discarded the first 120 mL which contained minor impurities and no ester). The solvent was removed in vacuo to afford 6.11 g (95percent yield) of the title compound as a colorless solid, which was used in the next step without further purification.
To a solution of 4-bromo-2-thiophenecarboxylic acid (4g, 19 mmol) in MeOH (100 ml.) was added H2SO4 (5 ml.) dropwise at 25 0C. The solution was stirred for 12 h at 50 0C and was poured into ice-H2O and the pH was adjusted to ~1 1 with aqueous NaOH. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and used directly (4.27g, quant.): LCMS (ES) m/z 222 (M+H)+.
100%
at 50℃;
Example 1; Preparation of Λ/-{(1 S)-2-amino-1-[(3,4-difluorophenyl)methyl1ethyl}-4-(1 /-/-pyrazol-4-yl)-2- thiophenecarboxamide; a) methyl 4-bromo-2-thiophenecarboxylate; To a solution of 4-bromo-2-thiophenecarboxylic acid (7 g, 34 mmol) in MeOH (170 ml.) was added cone. H2SO4 (17 ml_). After heating to 50 0C for 12 h, the reaction solution was cooled to room temperature and diluted with CHCI3 (100 ml_). The CHCI3 solution was washed with cold aqueous NaHCO3, then 5N NaOH and dried over Na2SO4. Concentration under vacuum gave the title compound as a yellow oil (7.2 g, quant.): LCMS (ES) m/z 222 (M+H)+.
95%
Stage #1: at -5℃; for 0.75 h; Stage #2: at 20℃; for 1 h; Stage #3: for 8 h; Heating / reflux
To a dry flask under N2 with a stirbar was added 6 g (29.1 mmol) of 4- bromothiophene-2-carboxylic acid (as prepared in the previous step) and dry methanol (100 mL). The solution was cooled in an ice-salt bath for 15 min and 2.55 mL (34.9 mmol) of thionyl chloride was added over 15 min, keeping the temperature <-5o C. The reaction mixture was stirred on the ice-salt bath for an additional 15 min, then for 1 h at rt, and finally refluxed for 8 h under N2. The resulting solution was cooled and concentrated to 6.7 g of pale amber oil. This oil was passed through 150 g of silica WITH ~600 mL CH2C12 (discarded the first 120 mL which contained minor impurities and no ester). The solvent was removed in vacuo to afford 6.11 g (95percent yield) of the title compound as a colorless solid, which was used in the next step without further purification.
91.4%
for 6 h; Reflux
In 100ml single neck flask was added 4-bromo-2-thiophenecarboxylic acid 2.07g (10mmol), thionyl chloride 1.19g (10mmol) and absolute ethanol 25ml, refluxed, 6h After TLC showed the starting material is no longer remaining. The solvent was distilled off under reduced pressure, ice water was added, adjusting the pH with saturated sodium carbonate solution to 9 to 10, and extracted with ethyl acetate (40ml × 3), the combined organic phase was washed twice with saturated brine, dried over anhydrous MgSO 4, pale yellow oily liquid 2.02g, yield 91.4percent.
90%
for 10 h; Heating / reflux
Example 1 : Methyl 4-{6-[4-(2-piperidin-l-ylethoxy)phenyllpyrazolo[l,5-alpyrimdin-3-vUthiophene- 2-carboxylate; Step 1 : methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate; 4-Bromothiophene-2-carboxylic acid (0.418 g, 2 mmol) was dissolved in methanol (1 mL), and concentrated sulfuric acid (0.039 g, 0.4 mmol) was added. The mixture was refluxed for 1O h, poured into water, and subjected to 3-fold extraction with ethyl acetate. The organic layer was washed with K2CO3- solution, concentrated, dried over MgSO4, filtered and evaporated to give methyl 4-bromothiophene-2- carboxylate, weight 0.4 g (90percent yield).A flask containing PdCl2(dppf) (0.32 g, 0.43 mmol), dppf (0.24 g, 0.43 mmol), KOAc (4.23 g, 0.043 mol), and pinacolediborone (5.5 g, 0.021 mol) was flushed with argon, then a solution of the ester from the foregoing step (3.2 g, 0.014 mol) in dioxane (60 mL) was added. The mixture was stirred at 850C under argon atmosphere for 40 h. Water (5-fold excess) was added, and the mixture was subjected to 3-fold extraction with ethyl acetate. The organic layer was washed with brine, concentrated, dried over MgSO4, filtered, and evaporated to give the crude methyl 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)thiophene- 2-carboxylate (5.1 g, purity 85percent according to 1H NMR data). This crude boronate was used without further purification.
Reference：
[1] Patent: WO2008/98104, 2008, A1, . Location in patent: Page/Page column 134
[2] Patent: WO2010/93885, 2010, A1, . Location in patent: Page/Page column 37-38
[3] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 3, p. 491 - 495
[4] Patent: WO2003/99805, 2003, A1, . Location in patent: Page 151
[5] Patent: CN103408540, 2016, B, . Location in patent: Paragraph 0100; 0164; 0165
[6] Patent: WO2007/85873, 2007, A1, . Location in patent: Page/Page column 18
[7] Journal of Medicinal Chemistry, 1992, vol. 35, # 6, p. 1109 - 1116
[8] Journal of Chemical Research, Miniprint, 1981, # 5, p. 1801 - 1824
[9] Patent: WO2005/40161, 2005, A1, . Location in patent: Page/Page column 78
[10] Patent: CN108341774, 2018, A, . Location in patent: Paragraph 0531-0534
5
[ 16694-18-1 ]
[ 18107-18-1 ]
[ 62224-16-2 ]
Reference：
[1] Journal of Medicinal Chemistry, 2016, vol. 59, # 23, p. 10435 - 10450
6
[ 16694-18-1 ]
[ 60729-37-5 ]
Yield
Reaction Conditions
Operation in experiment
79%
With N-chloro-succinimide In N,N-dimethyl-formamide at 50℃; for 10 h;
To a solution of 4-bromo-2-thiophenecarboxylic acid (2.07 g, 10 mmol) in DMF (5 ml.) was added NCS (2.7 g, 15 mmol) in one portion. The reaction mixture was stirred at 50 0C for 10 h, and then cooled to room temperature. The desired product precipitated after water (5 ml.) was added. The white solid was filtered and dried under high vacuum to give 1.9 g (79percent). LC-MS (ES) m/z =242 (M+H)+,
Stage #1: With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 2 h; Stage #2: With ammonia In water; N,N-dimethyl-formamide at 0 - 20℃; for 5 h;
A solution of 4 bromo-thiophene-2-carbo xylic acid (2.Og, 9.66mmol), l-ethyl-3-(3'- dimethylaminopropyl)carbodiimide hydrochloride (2.04g, 10.63mmol) and 1 -hydroxybenzotriazole hydrate (1.44g, 10.63mmol) in DMF (2OmL) is stirred at room temperature for 2 hours. The reaction mixture is then cooled to O0C and aq. NH3 (ImL, 17.3mmol) is added. The mixture is stirred at room temperature for an additional 5 hours, then water is added to the reaction mixture and the resultant precipitate is collected by filtration and washed with IM NaOH, H2O and petroleum ether. The title compound is isolated as a white solid (1.56g, 78percent).
8 g
With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile
A) 4-bromothiophene-2-carboxamide [0504] To a solution of 4-bromothiophene-2-carboxylic acid (15 g), HOBt ammonium salt (16.5 g) and triethylamine (20.08 mL) in acetonitrile (250 mL) was added EDCI hydrochloride (16.87 g), and the mixture was stirred overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.0 g). 1H NMR (300 MHz, CDCl3) δ 5.87 (2H, brs), 7.43 (2H, q, J = 1.4 Hz)
With diphenyl phosphoryl azide; triethylamine In <i>tert</i>-butyl alcohol at 100℃; for 5 h;
To the solution of 4-bromothiophene-2-carboxylic acid (3.0 g, 14.5 mmol) in 36 mL of anhydrous t-BuOH were added DPPA (4.06 mL, 18.8 mmol) and Et3N (4.04 mL, 29.0 mmol). The reaction was stirred at 100°C for 5h. Upon completion (monitored by HPLC), the solvent was removed and the crude product was purified by Combiflash silica gel chromatography (0-5percent of EtOAc in hexane), which provided 3.10 g (77percent) of the title compound 51 as a white solid. 1H NMR (400 MHz, CDCl3) δ= 7.04 (br. s., 1H), 6.73 (dd, J = 1.8 Hz, 0.4 Hz, 1H), 6.44 (d, J=1.8 Hz, 1H), 1.52 (s, 9H).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2018, vol. 28, # 19, p. 3210 - 3215
9
[ 16694-18-1 ]
[ 75-65-0 ]
[ 868387-45-5 ]
Yield
Reaction Conditions
Operation in experiment
60%
at 85℃; for 15 h;
To a mixture of 5-bromothiophenecarboxylic acid (24.2 mmoles, 5.0 g) in t- BuOH (20 ml_) was added DPPA (31.4 mmoles, 6.8 mL) and triethyl amine (72.6 mmole, 10.1 mL). The mixture was heated to 85 °C for 15 h under an atmosphere of N2. After cooling to RT, the reaction was concentrated in vacuo. Flash chromatography (silica gel, hexanes/EtOAc, 4:1 )) gave the title compound (4.0 g, 60percent) as a tan foam. LCMS (ES) m/z 278 (M+H)+.
55%
for 5 h; Heating / reflux
tert-Butyl4-bromothiophen-2-ylcarbamate:; 4-Bromothiophene-2-carboxylic acid (1.75 g, 8.5 mmol) was dissolved in 40 mL of t- BuOH. To this solution diphenylphosphoryl azide (2.8 g, 10.2 mmol) and triethylamine (1.4 mL, 10.1 mmol) were added. The reaction mixture was heated to reflux for 5 hours, cooled room temperature, and diluted with EtOAc. The organic layer was washed with 10percent citric acid, saturated sodium bicarbonate and brine, and concentrated to an oil, which was purified by column chromatography on silica (0 to 25percent EtOAc/hexanes) to give the product, 1.3 g, 4.7 mmol, 55percent. 1H NMR 500 MHz (CDC13) 6.96 (lH, br s), 6.83 (lH, s), 6.43 (1H, s), 1.54 (9H, s).
Example 6A 4-Bromothiophene-2-carboxylic acid Under argon, 1.00 g (4.13 mmol) of 2,4-dibromothiophene is provided in 15 ml of diethyl ether, and the mixture is cooled to -78 C. 2.6 ml (4.13 mmol) of a 1.6N solution of n-butyllithium in hexane are added, and the reaction mixture is stirred for 5 minutes. The reaction mixture is added to a mixture of dry ice and 15 ml of diethyl ether and stirred for 10 minutes. The mixture is subsequently diluted with water, and the phases are separated. The aqueous phase is acidified and extracted with ethyl acetate, and the organic phase is dried over sodium sulfate, filtered and concentrated. 0.66 g (74% of theory) of the title compound are obtained. 1H-NMR (400 MHz, DMSO-d6): delta=13.5 (s, 1H), 8.02 (d, 1H), 7.69 (d, 1H). LC-MS (Method 1): Rt=1.88 min; MS (ESIpos): m/z=207 [M+H]+.
Reflux 4-bromo-2-fhiophenecarboxylic acid (960 mg, 4.63 mmol) in SOCl2 (5 mL) for Ih. Evaporate excess SOCl2. Add THF (5 mL) to the residue. Slowly drop the resulting solution to cone NH4OH (15 mL) in ice bath. Stir the mixture overnight. Concentrate the mixture, followed by addition of EtOAc, wash with brine; and dry over MgSO4; filter and concentrate in vacuo. Add NaCl (307 mg, 5.26 mmol) and dichloromethane (10 mL) to the residue and reflux for 30 min. After the addition OfPOCl3 (3.36 g, 21.9 mmol), reflux the mixture for 1 h. Dilute the mixture with dichloromethane and wash with aqueous NaHCO3 solution, brine and dry over MgSO4; filter and concentrate in vacuo to provide 753 mg of the desired product.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 2h;
To a solution of 2.06 g of [4-BROMOTHIOPHENE-2-CARBOXYLIC] acid in 60 ml of dichloromethane were added a few drops of dimethylformamide followed by the addition of 9.94 [ML] (2 equivalents) of oxalyl chloride. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure to afford 2.24 g of yellow oil, which was used crude in the next step.
With Dichloromethyl methyl ether; for 5h;Heating / reflux;
B. A suspension of <strong>[16694-18-1]4-bromothiophene-2-carboxylic acid</strong> (47.0 mmol crude, from previous step) in a, A-DICHLOROMETHYL METHYL ether (13.0 mL, 150 MMOL) was slowly heated to reflux. As the reaction mixture was heated a pale brown solution formed, and gas evolution was evident. After stirring at a gentle reflux for 5 hours, the reaction solution was allowed to cool and was then concentrated under reduced pressure to afford 4-bromothiophene-2-carbonyl chloride as a brown liquid. This liquid was dissolved in CH2CI2 (150 ML) and the reaction flask was cooled in an ice bath. The cold reaction solution was treated with a small amount of 4-(N, N- dimethylamino) pyridine, N, O-dimethylhydroxylamine hydrochloride (5.5 g, 56 MMOL), and finally N, N-DIISOPROPYLETHYLAMINE (14 mL, 80 MMOL). After stirring for 10 minutes, the ice bath was removed and the reaction mixture was allowed to warm to ambient temperature. After stirring for 16 hours, the pale brown reaction solution was quenched by the addition of ice-cold H2O, and diluted with CH2CI2 (500 mL). The layers were separated, and the organic layer was washed with 1 N HCI (100 mL), H20 (50 mL), and saturated aqueous NAHCO3 (50 mL). The organic layer was dried over NA2SO4, filtered and concentrated under reduced pressure to afford a brown liquid. The crude product was purified by silica gel column chromatography eluting with a gradient from 0% to 30% ethyl acetate/hexane on silica. The product peak was collected to afford <strong>[16694-18-1]4-bromothiophene-2-carboxylic acid</strong> methoxymethylamide as a yellow oil. (9.9 g, 83% yield over three STEPS). 1H-NMR (400 MHz, CDCI3) : 8 7.83 (1 H, d, J = 1. 5 HZ), 7.45 (1H, d, J = 1. 5 HZ), 3.78 (3H, s), 3.37 (3H, s).
With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 110℃; for 4h;
General procedure: A solution of bromo heteroaryl carboxylic acid (2mmol), thionyl chloride (4mmol) and DMF (5 drops) in toluene (10mL) was refluxed at 110C for 4h. The reaction mixture was cooled to room temperature and the solvent and the excess of thionyl chloride removed under reduced pressure. To the residue was added at 0C the corresponding N-methyl amine (2mmol) and Et3N (2mmol) in CH2Cl2 (10mL) under N2 atmosphere. After 30min at 0C, the ice bath was removed and the solution was warmed up and stirred at room temperature overnight. The reaction mixture was extracted twice with CH2Cl2 (2×15mL) and the organic layer dried over MgSO4, filtered and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using hexanes and EtOAc as eluant or by trituration in a mixture of diethyl ether/petroleum ether to afford the desired compound.
A solution of 4 bromo-thiophene-2-carbo xylic acid (2.Og, 9.66mmol), l-ethyl-3-(3'- dimethylaminopropyl)carbodiimide hydrochloride (2.04g, 10.63mmol) and 1 -hydroxybenzotriazole hydrate (1.44g, 10.63mmol) in DMF (2OmL) is stirred at room temperature for 2 hours. The reaction mixture is then cooled to O0C and aq. NH3 (ImL, 17.3mmol) is added. The mixture is stirred at room temperature for an additional 5 hours, then water is added to the reaction mixture and the resultant precipitate is collected by filtration and washed with IM NaOH, H2O and petroleum ether. The title compound is isolated as a white solid (1.56g, 78%).
8 g
With N-hydroxybenzotriazole ammonium salt; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In acetonitrile;
A) 4-bromothiophene-2-carboxamide [0504] To a solution of <strong>[16694-18-1]4-bromothiophene-2-carboxylic acid</strong> (15 g), HOBt ammonium salt (16.5 g) and triethylamine (20.08 mL) in acetonitrile (250 mL) was added EDCI hydrochloride (16.87 g), and the mixture was stirred overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8.0 g). 1H NMR (300 MHz, CDCl3) delta 5.87 (2H, brs), 7.43 (2H, q, J = 1.4 Hz)
69.7 ml (3 equivalents) of oxalyl chloride are added dropwise to a solution of 9.62 g of the compound obtained in Stage 1 in 150 ml of anhydrous dichloromethane to which a few drops of dimethylformamide have been added. After reacting for 1 hour at ambient temperature and under nitrogen, the reaction medium is concentrated under reduced pressure, making it possible to obtain yellow oil, which is immediately dissolved in 150 ml of anhydrous dichloromethane. The reaction medium is cooled to 0 C. and then 6.4 ml of 2-morpholin-4-ylethanamine (1.05 equivalents) are added dropwise. The reaction medium is stirred at 0 C. for 1 hour and then 7.1 ml of triethylamine are added. The reaction medium is subsequently diluted with 500 ml of dichloromethane, washed with water (3×250 ml), dried over sodium sulphate, filtered and then concentrated under reduced pressure. Chromatography of the residue on silica gel (dichloromethane/methanol: 96/4) makes it possible to isolate 14.52 g of the expected product. Yield: 98% 1H NMR (CDCl3) delta (ppm): 2.50 (m, 4H), 2.60 (m, 2H), 3.55 (m, 2H), 3.75 (m, 4H), 6.60 (bs, 1H), 7.35 (s, 1H), 7.40 (s, 1H) MS: MH+ 320
With diphenyl phosphoryl azide; triethylamine; at 85℃; for 15h;
To a mixture of 5-bromothiophenecarboxylic acid (24.2 mmoles, 5.0 g) in t- BuOH (20 ml_) was added DPPA (31.4 mmoles, 6.8 mL) and triethyl amine (72.6 mmole, 10.1 mL). The mixture was heated to 85 C for 15 h under an atmosphere of N2. After cooling to RT, the reaction was concentrated in vacuo. Flash chromatography (silica gel, hexanes/EtOAc, 4:1 )) gave the title compound (4.0 g, 60%) as a tan foam. LCMS (ES) m/z 278 (M+H)+.
55%
With diphenyl phosphoryl azide; triethylamine; for 5h;Heating / reflux;
tert-Butyl4-bromothiophen-2-ylcarbamate:; <strong>[16694-18-1]4-Bromothiophene-2-carboxylic acid</strong> (1.75 g, 8.5 mmol) was dissolved in 40 mL of t- BuOH. To this solution diphenylphosphoryl azide (2.8 g, 10.2 mmol) and triethylamine (1.4 mL, 10.1 mmol) were added. The reaction mixture was heated to reflux for 5 hours, cooled room temperature, and diluted with EtOAc. The organic layer was washed with 10% citric acid, saturated sodium bicarbonate and brine, and concentrated to an oil, which was purified by column chromatography on silica (0 to 25% EtOAc/hexanes) to give the product, 1.3 g, 4.7 mmol, 55%. ¹H NMR 500 MHz (CDC13) 6.96 (lH, br s), 6.83 (lH, s), 6.43 (1H, s), 1.54 (9H, s).
With diphenyl phosphoryl azide; triethylamine; at 100℃; for 5h;
Example 2; Preparation of Compound 62; As shown in Scheme 5, a mixture of <strong>[16694-18-1]4-bromothiophene-2-carboxylic acid</strong> (53 g, 255 mmol), diphenylphosphoryl azide (70 mL, 323 mmol), and triethylamine (45 mmol) in tertiary butanol (675 mL) was heated at 100 C. for 5 hours. After cooling to room temperature, the volatiles were removed in vacuo to give a brown gum, which was dissolved in ethyl acetate (500 mL). The organics were washed with saturated NaHCO3 and water, followed by drying over Na2SO3 and concentration in vacuo. The residue was dissolved in a minimum amount of CH2Cl2 and purified by chromatography on silica gel (10-15% EtOAc/hexanes) to produce tert-butyl 4-bromothiophen-2-ylcarbamate as a white solid (compound 1010, 47 g, ESMS: M+H+=2781).
(B) (R)-N-(1-Azabicyclo[2.2.2]oct-3-yl)(4-bromothiophene-2-carboxamide) Prepared by a method analogous to that described for the preparation of Intermediate 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and <strong>[16694-18-1]4-bromothiophene-2-carboxylic acid</strong>. The residue from evaporation of the reaction mixture was partitioned between aqueous hydrochloric acid and chloroform. The aqueous layer was then basified with aqueous sodium hydroxide and extracted with chloroform. The organic extracts were dried (MgSO4), filtered, and evaporated and resulting solid was recrystallized from ethyl acetate/hexane to give the title compound as a colourless solid; MS (ES+) 315, 317 (MH+).
With hydrogenchloride; dihydrogen peroxide; In water; acetonitrile;
a 4-Bromothiophene-2-carboxylic acid To a flask equipped with a mechanical stirrer was added 25 g (130 mmol) 4-bromothiophene-2-carbaldehyde (Aldrich Chemical Company), acetonitrile (200 mL), and 4.5 g (37.5 mmol) of sodium dihydrogen phosphate dissolved in 35 mL of water. After cooling this mixture on an ice-salt bath, 15 mL (169 mmol) of 35% hydrogen peroxide and 15.3 g (169 mmol) of sodium chlorite were added, and the mixture was stirred for 1 h. The reaction mixture was then stirred at room temperature for 3 h. The solvent was removed in vacuo, and the solid was suspended in a mixture of water (175 mL) and I N hydrochloric acid (4 mL) and stirred for 10 min at rt. The solid was collected on a Buechner funnel and washed with water (2*150 mL) to afford 26 g (97%) of 4-bromothiophene-2-carboxylic acid, which was used in the next step without further purification.
With N-chloro-succinimide; In N,N-dimethyl-formamide; at 50℃; for 10h;
To a solution of <strong>[16694-18-1]4-bromo-2-thiophenecarboxylic acid</strong> (2.07 g, 10 mmol) in DMF (5 ml.) was added NCS (2.7 g, 15 mmol) in one portion. The reaction mixture was stirred at 50 0C for 10 h, and then cooled to room temperature. The desired product precipitated after water (5 ml.) was added. The white solid was filtered and dried under high vacuum to give 1.9 g (79%). LC-MS (ES) m/z =242 (M+H)+,
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; for 2h;
To a solution of <strong>[16694-18-1]4-bromo-2-thiophenecarboxylic acid</strong> (1.0 g, 4.83 mmol) in DCM (10 ml.) was added PyBrop (3.4 g, 7.24 mmol) and Hunig's base (2 mL, 12.6 mmol). After 15 min, 1 ,1-dimethylethyl [2-(hydroxyamino)-3-phenylpropyl]carbamate (641 mg, 2.41 mmol) was added to the reaction mixture in DCM (2 mL) and stirred for 2h at RT. The reaction solution was concentrated to give crude 1 ,1-dimethylethyl [2-([(4-bromo-2-thienyl)carbonyl][(4-bromo-2-thienyl)carbonyl]oxy}amino)-3- phenylpropyl]carbamate. LC-MS (ES) m/z = 645 (M+H)+.To a solution of 1 ,1-dimethylethyl [2-([(4-bromo-2-thienyl)carbonyl][(4- bromo-2-thienyl)carbonyl]oxy}amino)-3-phenylpropyl]carbamate in MeOH (5 mL) was added K2CO3 (1.0 g, 7.3 mmol). The mixture was stirred at RT for 2h. The mixture was concentrated under vacuum and purified on silica gel (EtOAc/Hexane, 30%) to give the the title compound (410 mg, 37 % for two steps) as an off white solid: LC-MS (ES) m/z = 456 (M+H)+.
Ta a solution of <strong>[16694-18-1]4-bromo-2-thiophenecarboxylic acid</strong> (80 mg, 0.39 mmol) in DCM (2 ml.) at 25 0C was added bromo-tris-pyrrolidino phosphoniumhexafluorophosphate (PyBrOP) (218 mg, 0.47 mmol) in one portion, followed by addition of DIPEA (0.2 ml_, 1.14 mmol). After stirring for 10 min, diamine 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1 /-/-isoindole-1 , 3(2 H)- dione (165mg, 0.43 mmol) was added to above solution. After 2h, the solution was concentrated and purified via column chromatography (silica, 10% MeOH in CH3CI) affording the title compound (206 mg, 99%) as a white solid: LC-MS (ES) m/z 538 (M+H)+.
With N-ethyl-N,N-diisopropylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; for 0.5h;
A solution of <strong>[16694-18-1]4-bromo-2-thiophenecarboxylic acid</strong> (1.29 g, 6.22 mmol), 2- [(2S)-2-amino-3-(2,4-dichlorophenyl)propyl]-1 H-isoindole-1 ,3(2H)-dione (2.0 g, 5.19 mmol), PyBrop (3.62 g, 7.78 mmol) and Hunig's Base (3.62 ml, 20.74 mmol) in DCM (50 ml) was stirred at RT for 30 min. The reaction mixture was washed with H2O, 1 N HCI, NaHCOs (sat. aq.) and brine. The solvent was removed and the residue was dissolved in MeOH, hydrazine monohydrate (1.3 g, 26 mmol) was added. The reaction was stirred at rt overnight. The white solid formed, and was filtered and rinsed with DCM. To the filtrates were added (Boc)2O (1.7g, 7.78 mmol) and NaHCOs (sat. aq., 3 ml). The reaction mixture was stirred at RT for 2 hours and was washed with NaHCO3 (sat. aq.) and brine. The solvent was removed and the residue was purified by biotage (50% H/E) to give the product (2.Og, 76%). LC- MS (ES) m/z = 531.0 (M+Na)+.
With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 80℃; for 14h;
To a solution of <strong>[16694-18-1]4-bromo-2-thiophenecarboxylic acid</strong> (1 g, 4.83 mmol) in dioxane/H2O (5:1 , 16 ml.) was added K2CO3 (2.7 g, 19 mmol), tetrakistriphenylphosphine Pd(O) (279 mg, 0.241 mmol) and 5-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-1 -methyl-1 H-pyrazole (1.2 g, 6.27 mmol). The reaction mixture was heated to 80 C in a sealed tube for 2h and additional tetrakistriphenylphosphine Pd(O) (279 mg, 0.241 mmol) and 5-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-1 -methyl-1 H-pyrazole (1.2 g, 6.27 mmol) were added. After 12h, the reaction was partitioned between 6N NaOH and DCM. The pH of the aqueous <n="119"/>phase was adjusted to -3 with 3M HCI and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (-1 g, quant.): LCMS (ES) m/z = 209 (M+H)+.
A mixture of <strong>[16694-18-1]4-bromo-2-thiophenecarboxylic acid</strong> (1 eq) and BOP (1.2 eq) in DMF (10 mL) was stirred over a period of 15 min. Diisopropylethylamine (3 eq) and the corresponding amine 2,2,2-trifluoro-l-pyridin-2-ylethanamine (1.2 eq) were added. The mixture was stirred overnight at room temperature. The DMF was distilled off. The residue was subjected to coevaporation with xylene, washed with water, 5% NaHCO3, brine, and dried. 4-Bromo-7V-(2,2,2-trifluoro-l- pyridin-2-ylethyl)thiophene-2-carboxamide was obtained by column chromatography (dichloromethane-hexane, 10:1).
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; diisopropyl-carbodiimide; In dichloromethane; at 25℃; under 760.051 Torr;Inert atmosphere;
11. Coupling step C [00250] To a stirred solution of acid RiCOOH (1 equivalent), HOBt (2.1 equivalents), and amine 1-1 (1 equivalent) in 9: 1 CH2C12:DIEA at 25C was added DIC (2 equivalents) and the mixture was stirred overnight. After quenching with water, the reaction was added to a separatory funnel and washed 3x with CH2Cl2. The organic layers were combined, and washed with saturated aqueous brine solution. The organic layer was dried over MgStheta4, and concentrated in vacuo. The crude material was then subjected to flash chromatography to give pure IH-I as a white solid (93 % yield). 4-BROMO-N-(3-BROMO-4-METHOXYPHENETHYL)THIOPHENE-2-CARBOXAMIDE [00251] 1H NMR (400 MHz, DMSO-d6) delta 7.41 (d, J= 2.0 Hz, IH), 7.37 (s, IH), 7.27 (s, IH), 7.12 (dd, J= 2.0, 8.4 Hz, IH), 6.86 (d, J= 8.0 Hz, IH), 5.93 (m, IH), 3.89 (s, 3H), 3.63 -->(q, J= 6.8 Hz, 2H), 2.84 (t, J= 7.2 Hz, 2H), 2.17 (s, IH). 13C NMR (100 MHz, DMSOd6) delta 159.8, 153.8, 141.1, 133.0, 132.9, 129.7, 129.1, 128.5, 112.5, 110.3, 108.6, 56.1, 40.7, 33.5. HRMS (Q-TOF): m/z calc for Ci4Hi3Br2NO2S [M + H]: 417.9112; found 417.9120. 79 % yield.
bis(triphenylphosphine)palladium(II) dichloride[ No CAS ]
[ 380427-38-3 ]
[ 497-19-8 ]
[ 1233389-74-6 ]
Yield
Reaction Conditions
Operation in experiment
In acetonitrile;
Example 12 Preparation of 4-(4-(isopropylthio)phenyl)thiophene-2-carboxylic acid (73) A mixture of commercially available 4-(isopropylthio)phenylboronic acid (735 mg, 3.75 mmol), <strong>[16694-18-1]4-bromothiophene-2-carboxylic acid</strong> (776 mg, 3.75 mmol), Bis(triphenylphosphine)palladium (II) chloride (131 mg, 0.188 mmol), acetonitrile (7.5 mL) and aqueous sodium carbonate (1M, 7.5 mL) was heated to 150 C. by microwave irradiation (Biotage Intiator Sixty, 0-300 W, pre-stirring 2 minutes) for 5 minutes under an argon atmosphere. The reaction mixture was cooled to ambient temperature, diluted with water (75 mL), and extracted with EtOAc (2*50 mL). The aqueous layer obtained was then acidified with aqueous HCl (3.0M) to pH 2 and extracted with EtOAc (2*50 mL). The combined organic layers were dried over sodium sulfate, filtrated and concentrated to afford compound 73 (990 mg) which was used in next step without further purification.
Method CN'-(4-bronnothiophene-2-carbonyl)pyndine-3-carbohvdrazide (Intermediate compound)4-Bromo-2-thiophenecarboxylic acid (2.5 g, 12.1 mmol) was solved in dichloromethane (25 ml) and triethylamine (3.5 ml, 25.3 mmol). 1 - Propanphosphonic acid cyclic anhydride (8.07 g, 25.3 mmol) was added dropwise to the stirred mixture followed by stirring for 30 minutes. Nicotinic hydrazide (1 .82 g, 13.3 mmol) was added followed by stirring overnight. The mixture was evaporated, water was added and the mixture was stirred and filtered and washed with water. The solid product was stirred in dichloromethane followed by filtration. Yield 2.0 g (51 %).
Example 7A Ethyl 4-bromothiophene-2-carboxylate 663 mg (3.20 mmol) of the compound from Example 6A are provided in 25 ml of ethanol, 0.1 ml of concentrated sulfuric acid is added and the mixture is heated under reflux overnight. After cooling to room temperature, a saturated aqueous sodium bicarbonate solution is added and the mixture is diluted with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated. 700 mg (89% of theory) of the title compound are obtained. 1H-NMR (400 MHz, DMSO-d6): delta=8.07 (d, 1H), 7.78 (d, 1H), 4.30 (q, 2H), 1.30 (t, 3H). GC-MS (Method 11): Rt=4.69 min; MS (EIpos): m/z=234 [M]+.
Example 19: (Z)-4-{2-hydroxy-3-[N'-(1-indan-5-yl-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene)-hydrazino]-phenyl}-thiophene-2-carboxylic acid bis-(ethanolamine); Step 1; 4-(3-Nitro-2-methoxy-phenyl)-thiophene-2-carboxylic acid; 2-(2-Methoxy-3-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 4d (0.81 g, 2.9 mmol), <strong>[16694-18-1]4-bromo-thiophene-2-carboxylic acid</strong> (0.3 g, 1.45 mmol), tetrakis (triphenylphosphine)palladium (80 mg, 0.073 mmol) and sodium carbonate (0.31 g, 2.9 mmol) were dissolved in a solvent mixture of 20 mL of 1,4-dioxane and 10 mL of water. The reaction was heated to reflux for 0.5 hours. The mixture was adjusted to pH 3 with 1 N hydrochloric acid and extracted with ethyl acetate (20 mLx3). The combined organic extracts were concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound 4-(3-nitro-2-methoxyphenyl)-thiophene-2-carboxylic acid 19a (0.54 g) as a brown oil, which was directly used in the next step. MS m/z (ESI): 277.6 [M-1]
0.54 g
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; for 0.5h;Reflux;
2-(2-methoxy-3-nitrophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan 4d (0.81g, 2.9 mmol), <strong>[16694-18-1]4-bromothiophene-2-carboxylic acid</strong> (0.3g, 1.45mmol), tetrakis(triphenylphosphine)palladium (80mg, 0.073mmol), and sodium carbonate (0.31g, 2.9mmol) dissolved in a mixed solvent 20mL 1,4-dioxane and 10mL of water was heated at reflux for 0.5 hours. The reaction solution was adjusted with 1M hydrochloric acid to pH = 3 and was extracted with ethyl acetate (20mL × 3). The combined organic phases was concentrated under reduced pressure column chromatography to give 4-(3-nitro-2-methoxyphenyl)thiophene-2-carboxylic acid 19a (0.54g, brown oil), directly to the next step reaction.
At rt, a solution of tert-butyl 2,2,2-trichloroacetimidate (27.7 mL, 155 mmol) in CH2CI2 (50 mL) was added dropwise to a soln of <strong>[16694-18-1]4-bromothiophene-2-carboxylic acid</strong> (94; 16.0 g, 77.3 mmol) in CH2CI2 (150 mL). The mixture was stirred for 16 h. A precipitate was formed, which was removed by filtration. The filtrate was concentrated. FC (hexane/EtOAc 99:1 to 97:3) yielded 95 (18.7 g, 92%).
92%
In dichloromethane; at 20℃; for 16h;
At rt, a solution of tert-butyl 2,2,2-trichloroacetimi- date (27.7 mE, 155 mmol) in CH2C12 (50 mE) was added dropwise to a soln of <strong>[16694-18-1]4-bromothiophene-2-carboxylic acid</strong> (94; 16.0 g, 77.3 mmol) in CH2C12 (150 mE). The mixture was stirred for 16 h. A precipitate was formed, which was removed by filtration. The filtrate was concentrated. FC (hexane/EtOAc 99:1 to 97:3) yielded 95 (18.7 g, 92%).
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