* 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.
Reference：
[1] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 1, p. 17 - 28
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 8, p. 2265 - 2279
[3] Journal of Medicinal Chemistry, 2012, vol. 55, # 12, p. 5982 - 5986
[4] Patent: WO2017/31176, 2017, A1, . Location in patent: Page/Page column 85
2
[ 67808-64-4 ]
[ 50340-79-9 ]
Reference：
[1] Patent: US5047554, 1991, A,
3
[ 67808-64-4 ]
[ 4565-31-5 ]
Yield
Reaction Conditions
Operation in experiment
59%
With potassium hydroxide; water In tetrahydrofuran
The compound 25 (2 g, 12.8 mmol) was dissolved in 200 ml of mixture solvent (THF: H20=1 : 1) and HYDROLYZATION was conducted by adding KOH (1.1 g, 19.2 MMOL). After the completion of the reaction, THF was removed under reduced pressure. The water layer was titrated with 1N HC1 solution in pH 1-2 and then extracted with ethyl acetate (200 ml X 5) to obtain the desirable compound 25 (1.2 g, yield 59percent). 1H NMR (300MHZ, CDC13) 10.00 (s, 1H), 7.93-7. 92 (d, J=3.92Hz, 1H), 7.78-7. 77 (d, J=3.9Hz, 1H). I3C NMR (300MHZ, CDC13) 182. 2, 163. 70, 141. 57, 139. 70, 133. 79, 132. 79.
With sodium carbonate In N,N-dimethyl-formamide at 25℃; for 20 h;
Step 1. Methyl 5-formyl-2-thiophenecarboxylateA mixture of 5-formyl-2-thiophene carboxylic acid (2.34 g, 15 mmol) and sodium carbonate (5.57 g, 52.5 mmol) in DMF (25 ml) at 25 0C was treated with iodomethane (1.15 ml, 18 mmol) and the mixture was stirred for 20 h before being quenched with the addition of water and saturated aqueous NH4Cl. The resulting solid precipitate was collected by filtration to give methyl 5-formyl-2- thiophenecarboxylate as a solid. The filtrate was extracted with EtOAc (3 x 30 ml) and the combined organic extracts were washed with water and brine, dried (Na2SO4), concentrated under reduced pressure, and subjected to flash chromatography to give solid material that was combined with the solid collected by precipitation to give methyl 5-formyl-2-thiophenecarboxylate as a white solid (1.60 g, 62percent): ESI-MS (m/z): 171.2 (M+H+).
Reference：
[1] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 1, p. 17 - 28
[2] Journal of Medicinal Chemistry, 2012, vol. 55, # 12, p. 5982 - 5986
[3] Patent: WO2008/124582, 2008, A1, . Location in patent: Page/Page column 130
[4] Patent: US5047554, 1991, A,
[5] Patent: US2006/293343, 2006, A1, . Location in patent: Page/Page column 89
[6] Journal of Medicinal Chemistry, 2009, vol. 52, # 8, p. 2265 - 2279
[7] Patent: WO2005/79791, 2005, A1, . Location in patent: Page/Page column 125-126
[8] Patent: WO2006/123639, 2006, A1, . Location in patent: Page/Page column 135-136
5
[ 108499-32-7 ]
[ 67808-64-4 ]
Yield
Reaction Conditions
Operation in experiment
70%
With 4-methylmorpholine N-oxide In acetonitrile at 25℃; for 12 h; Molecular sieve
To a solution of 4-methylmorpholine N-oxide (0.449 g, 3.83 mmol) in MeCN (5 mL) at 0 °C, in presence of molecular sieves 3Å, compound 13 in MeCN (0.300 g, 1.28 mmol) was added. Reaction mixture was kept stirring at 25 °C for 12 h and then filtered and purified by column chromatography on silica gel (EtOAc/n-hexane 1:20) to obtain the title compound (yield 70percent);
Reference：
[1] European Journal of Medicinal Chemistry, 2018, vol. 157, p. 127 - 138
6
[ 530145-16-5 ]
[ 67808-64-4 ]
Yield
Reaction Conditions
Operation in experiment
75%
With manganese(IV) oxide In acetone for 48 h;
The compound 24 (3 g, 17.4 mmol) was dissolved in acetone and an excess of MN02 was added thereto. After 2days of the reaction time, the reaction solution was filtered under reduced pressure with Celite545 and then an exraction process was conducted with acetone sufficiently. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 2: 1) to obtain the compound 25 (2.2 g, yield 75percent) 1H NMR (300MHZ, CDC13) 9.98 (s, 1H), 7.85-7. 84 (d, J=3.9Hz, 1H), 7.76-7. 75 (d, J=3.9Hz, 1H). 13C NMR (300MHZ, CDC13) 183.02, 160.99, 139.75, 136.36, 135.09, 132.28, 51.96.
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In chloroform at 5 - 20℃; for 1 h;
In a reaction vessel,5-formylthiophene-2-carboxylic acid (0.50 g),4-dimethylaminopyridine (0.11 g), methanol (0.87 g) and chloroform (12 mL) were added,It was cooled to 5 ° C.To this was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.74 g).After stirring at room temperature for 1 hour,3 mol / L hydrochloric acid (8 mL) was added.The reaction solution was extracted with chloroform,The organic layer was washed with saturated brine.The organic phase was dried over anhydrous sodium sulfate,The solvent was distilled off to obtain a crude product.This was purified with a silica gel column (chloroform)To give a yellow product (5-formylthiophene-2-carboxylic acid methyl ester, 0.45 g).
Reference：
[1] Patent: JP2015/86268, 2015, A, . Location in patent: Paragraph 0125-0127
With pyridine; hydroxylamine hydrochloride; In ethanol; for 3h;Reflux;
Hydroxylamine hydrochloride (420 mg, 6.1 mmol) and pyridine (0.5 mL) were added to a solution of <strong>[67808-64-4]methyl 5-formylthiophene-2-carboxylate</strong> (690 mg, 4.1 mmol) in EtOH (25 mL). The reaction mixture was refluxed for 3 h, cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in diethyl ether, the organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get product methyl 5-((hydroxyimino)methyl)thiophene-2-carboxylate (440 mg, yield 60percent), which was carried through without any further purification. 1H NMR (400 MHz, DMSO-d6) delta 12.5 (s, 1 H), 7.98 (s, 1 H), 7.78 (d, J = 4.1 Hz, 1H), 7.51 (d, J = 4.1 Hz, 1 H), 3.82 (s, 3H). MS (ESI) m/z: Calculated for C7H7NO3S: 185.01; found: 186.0 (M+H)+.
In ethanol;
EXAMPLE 19 Methyl 5-formyl-2-thiophenecarboxylate oxime A solution of <strong>[67808-64-4]methyl 5-formyl-2-thiophenecarboxylate</strong>, prepared according to Example 10, (6.26 g, 36.78 mmoles), hydroxylamine hydrochloride (3.07 g, 44.14 mmoles) and pyridine (3.49 g, 44.14 mmoles) in 200 ml of ethanol was refluxed for 2 hours. The ethanol was removed in vacuo, the residue dissolved in ether and washed with water. The organic layer was dried (magnesium sulfate) and evaporated to a yellow solid. Trituration with a small amount of ether furnished the title compound as a white solid (4.93 g, 72percent), m.p. 164°-7° C. Oxime Z:E ratio:(82:18). Analysis: Calculated for C7 H7 NO3 S: C, 45.39; H, 3.81; N, 7.56percent. Found: C, 45.41; H, 3.69; N,7.48percent. EIMS (m/z): 185 (M+, 97percent), 154 (M+ --CH3 O, base); 1 H-NMR (DMSO-d6) delta, Z isomer:12.52 (1H, br s), 7.99 (1H, s), 7.77 (1H, d, J=4.0 Hz), 7.50 (1H, d, J=4.0 Hz), 3.83 (3H, s); E isomer:11.66 (1H, br s), 8.38 (1H, s), 7.74 (1H, d, J=4.0 Hz), 7.34 (1H, d, J=4.0 Hz), 3.82 (3H, s); ir (potassium bromide): 3400, 1649, 918 cm-1.
With phthalic anhydride; hydroxylamine hydrochloride; triethylamine; In acetonitrile; at 20 - 90℃; for 48h;
Reference Example 8 methyl 5-cyanothiophene-2-carboxylate Hydroxyamine hydrochloride (1.44 g, manufactured by Wako Pure Chemical Co.) was suspended in acetonitrile (80 mL), and triethylamine (2.88 mL, manufactured by Wako Pure Chemical Co.), an acetonitrile solution (100 mL) of the compound (2.93 g) obtained in Reference Example 7 and phthalic anhydride (2.82 g, manufactured by Aldrich Co.) were sequentially added at room temperature, and the solution was stirred at 90° C. for 48 hours in nitrogen atmosphere. After concentrating the reaction solution, ethyl acetate was added to the residue obtained, and the ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate solution followed by concentration after drying over anhydrous magnesium sulfate. The residue obtained was purified by column chromatography (hexane/ethyl acetate=6/1) to obtain the titled compound (2.48 g)
N-(5-methoxycarbonyl-2-thenyl)-3-(piperidinomethyl)aniline[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75%
With sodium tris(acetoxy)borohydride; In tetrahydrofuran; acetic acid;
Compound AA (0.19 g, 75percent) was obtained as pale yellow crystals using 1-(3-aminobenzyl)piperidine (0.16 g) obtained by the known process (WO99/32100), <strong>[67808-64-4]methyl 5-formyl-2-thiophenecarboxylate</strong> (0.12 g) obtained by the known method (J. Heterocycl. Chem., 28: 17-28 (1991)), sodium triacetoxyborohydride (0.89 g), acetic acid (0.25 mL) and tetrahydrofuran (5.0 mL) as described in Reference Example 6. [0592] 1H NMR (270 MHz, CDCl3) delta7.63 (1H, d), 7.09 (1H, t), 6.96 (1H, brd), 6.72-6.63 (2H, m), 6.52 (1H, m), 4.49 (2H, brs), 4.37 (1H, brs), 3.82 (3H, s), 3.41 (2H, brs), 2.38 (4H, m), 1.57 (4H, m), 1.42 (2H, m).
The compound 24 (3 g, 17.4 mmol) was dissolved in acetone and an excess of MN02 was added thereto. After 2days of the reaction time, the reaction solution was filtered under reduced pressure with Celite545 and then an exraction process was conducted with acetone sufficiently. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate= 2: 1) to obtain the compound 25 (2.2 g, yield 75percent) 1H NMR (300MHZ, CDC13) 9.98 (s, 1H), 7.85-7. 84 (d, J=3.9Hz, 1H), 7.76-7. 75 (d, J=3.9Hz, 1H). 13C NMR (300MHZ, CDC13) 183.02, 160.99, 139.75, 136.36, 135.09, 132.28, 51.96.
Further examples of compounds of Formula 3 are:...3-carboxy-thiophene-5-carboxaldehyde;3-methoxycarbonyl-thiophene-5-carboxaldehyde;3-ethoxycarbonyl-thiophene-5-carboxaldehyde;2-carboxy-thiophene-5-carboxaldehyde;2-methoxycarbonyl-thiophene-5-carboxaldehyde;2-ethoxycarbonyl-thiophene-5-carboxaldehyde;3-carboxy-furan-5-carboxaldehyde;3-methoxycarbonyl-furan-5-carboxaldehyde;...
46
[ 31108-35-7 ]
[ 67808-64-4 ]
[ 656227-58-6 ]
Yield
Reaction Conditions
Operation in experiment
With ammonium acetate; In acetonitrile; at 150℃; for 0.0833333h;
A mixture of <strong>[67808-64-4]5-formyl-thiophene-2-carboxylic acid methyl ester</strong> [3.37g, 19.8mmol, Reference Example 37 [(A)],] 2,3-dioxo-butyric acid tert-butyl ester (3.4g, 19. [8MMOL),] ammonium acetate (15.25g, [198MMOL)] and acetonitrile [(38ML)] was subjected to microwave irradiation, heating to [150C] for 5 minutes. The reaction mixture was concentrated and the residue was partitioned between 2M sodium carbonate solution and ethyl acetate. The organic layer was separated, dried [(MGS04)] and concentrated to give an orange residue, which was subjected to flash column chromatography on silica using a mixture of pentane and ethyl acetate (gradient, 4: 1 to 1 : [1,] v/v) as eluent, to provide 2-(5-methoxycarbonyl- [THIOPHEN-2-YL)-5-METHYL-1H-IMIDAZOLE-4-CARBOXYLIC] acid tert-butyl ester [(1.] [OG)] as a yellow powder.
With potassium carbonate; In methanol; for 0.5h;Heating / reflux;
A mixture of 4.5 g (29 mmol) of 5-formyl-2-thiophene carboxylic acid and 12.6 g (102 mmol, 3.5 eqiv. ) of Na2C03 in 50 mL of DMF was treated with 2.2 mL of iodomethane (35 mmol, 1.2 eqiv. ) at room temperature for 20 h. The mixture was quenched with H20 with some addition of sat. NH4Cl sol. 5-Formyl-thiophene-2-carboxylic acid methyl ester formed as a precipitate and was collected by filtration (quantitative yield), used directly for next step. A mixture of 170 mg (1 mmol) of <strong>[67808-64-4]5-formyl-thiophene-2-carboxylic acid methyl ester</strong>, 197 mg (lmmol) of tosylmethyl isocyanide and 138 mg (lmmol) of K2CO3 in MeOH was refluxed for 0.5 hr. The solvent was evaporated under reduced pressure. The resulting residue was poured into ice-water, and extracted with EtOAc. The extract was washed with saturated aquaous NH4Cl, water, brine and dried over MgS04. The organic solvent was evaporated under reduced pressure and the residue was purified by combiflash to yield 170 mg of 5-oxazol-5-yl-thiophene-2-carboxylic acid methyl ester. Yield 81percent. The above ester (170 mg) was dissolved in 9 mL of THF, 3 mL of MeOH and 3 mL of IN OH solution and stirred overnight. The organic solvent was removed. Acetic acid was added to pH-4-5 and a light yellow precipitate formed. The suspension was diluted with water and the precipitate collected by filtration to yield 105 mg of the title compound. Yield 66percent.
Methyl 5-formylthiophene-2-carboxylate (7) To a solution of 6 (500 mg, 2.5 mmol) in 10 mL of dry methanol was added 2 mL of SOCl2 at 0° C. The reaction mixture was stirred for 18 h at room temperature, monitoring the reaction by TLC. After the starting material was consumed, 5 mL of dist. H2 O was added to the mixture and let stir for 3 to 4 h at room temperature. The reaction mixture was concentrated at 50° C. using a rotary evaporator and extracted with CH2 Cl2. The CH2 Cl2 layer was dried over Na2 SO4 and filtered through a silica gel column. Removal of the solvent gave cream crystals of 7. Yield 400 mg (95percent) mp 79° C.; MS m/z, 171 (MH+); calcd for (C7 H6 O3 S), 170. Anal. C,H,S. NMR (CDCl3) delta7.89 (c,2H, thiophene 2H, thiophene 3-H) 4.05 (s,3H COOCH3).
methyl 5-(difluoromethyl)thiophene-2-carboxylate[ No CAS ]
diethylaminosulfur trifluoride [DAST][ No CAS ]
[ 144-55-8 ]
[ 67808-64-4 ]
5-(difluoromethyl)thiophene-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
With sodium hydroxide; In methanol; dichloromethane; water;
Reference Example 125 5-Difluoromethyl-2-thiophenecarboxylic Acid <strong>[67808-64-4]5-Formyl-2-thiophenecarboxylic acid methyl ester</strong> (1.7 g) (synthesised in accordance with the method described in J. Heterocyclic Chem., 28, 17 (1991)) in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.6 g) in methylene chloride (20 ml). The mixture was stirred at room temperature for 2 hours, and then diethylaminosulfur trifluoride (DAST) (0.5 g) was further added. The resulting mixture was stirred at room temperature for 1 hour, and water (10 ml) and saturated aqueous sodium bicarbonate (10 ml) were added. The resulting mixture was allowed to stand overnight. The organic layer was collected, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-difluoromethyl-2-thiophenecarboxylic acid methyl ester (0.81 g). 5-Difluoromethyl-2-thiophenecarboxylic acid methyl ester (2.58 g) synthesised in this manner was dissolved in methanol (50 ml), and 1N sodium hydroxide (30 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-difluoromethyl-2-thiophenecarboxylic acid (2.13 g) as crystals. mp 111°-112° C.
To a solution of sodium acetate (1.2g, 13. [9MMOL)] in water (15ml) was added [1,] [1-DIBROMO-] 3,3, 3-trifluoroacetone (0. [80ML,] 5.37mmol) and the resulting mixture was heated to [80C] for 45 minutes. The solution was cooled to [0C] and [5-FORMYL-TLIIOPHENE-2-CARBOXYLIC] acid methyl ester (0.84g, 4. [92MMOL)] in methanol [(20ML)] was added followed by conc. ammonium hydroxide solution [(25ML)] and the solution was allowed to warm to room temperature overnight. The reaction mixture was concentrated and the aqueous residue was extracted three times with ethyl acetate. The combined organic phase was evaporated and the crude product was purified by column chromatography on silica eluting with 10percent [V/V] ethyl acetate in dichloromethane to yield [5-(4-TRIFLUOROMETHYL-LH-IMIDAZOL-2-YL !-] [THIOPHENE-2-CARBOXYLIC] acid methyl ester (0.22g, 16percent) as a pale yellow powder. LCMS (Method A): RT = 7.55 minutes; 277 (M+H) +.
To a cooled [(-78C)] solution of [2- (5-BROMO-THIOPHEN-2-YL)- [1,] 3] dioxolane [(5.] 0g, [21. 3MMOL)] in tetrahydrofuran [(150ML)] was added n-butyl lithium (8. [52ML,] 21.3mmol, 2. 5M in hexanes) whilst keeping the temperature below [70C.] After 45 minutes [METHYLCHLOROFORMATE] (1. [65ML,] 21. [3MMOL)] in tetrahydrofuran [(5ML)] was added, and the reaction mixture was stirred for a further 4 hours. [1M] hydrochloric acid [(500ML)] was added and the resultant mixture was extracted with diethyl ether (2x [250ML).] The organic layers were combined, dried [(MGS04)] and concentrated to give an oil which was subjected to flash column chromatography on silica using a mixture of cyclohexane and ethyl acetate (4: 1, v/v) as eluent. The resulting fractions were concentrated and dissolved in 1,2- dimethoxyethane and water, to which concentrated sulphuric acid was added. After 1 hour the mixture was concentrated, to provide [5-FORMYL-THIOPHENE-2-CARBOXVLIC] acid methyl ester as a black solid, which was used in the next reaction without further purification.
Methyl 5-formylthiophene-2-carboxylate (1.0 g, 5.87 mmol, 1.0 eq.) was dissolved in 50 mL MeOH cooled to 0 °C in an ice bath. To this solution was added NaBH4 (0.445 g, 11.75 mmol, 2.0 eq.) slowly in portions and the reaction was monitored by TLC (Si02, 9:1 n- hexanes:EtOAc). Upon full conversion of the aldehyde, the reaction was quenched by slow addition of ice cooled water (10 mL). The mixture was then transferred into a separation funnel, diluted with 50 mL H20 end extracted with diethyl ether (3 times 100 mL). The combined organics were washed with brine (50 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The product was obtained pure (0.935 g, 5.4 mmol, 92percent) and used for the next step without further purification. NMR (300 MHz, CDC13) delta 7.67 (d, J= 3.8 Hz, 1H), 6.98 (dt, J= 3.8, 0.8 Hz, 1H), 4.85 (d, J= 0.7 Hz, 2H), 3.87 (s, 3H), 1.95 (s (br), 1H).
Preparation 24 A solution of <strong>[67808-64-4]methyl 5-formylthiophene-2-carboxylate</strong> (486 mg) in MeOH (20 mL) was cooled to 0°C, and was added sodium borohydride (108 mg) slowly. The reaction mixture was stirred at 0°C for 30 minutes. To the reaction mixture was added saturated NH4Cl aqueous solution (20 mL) and stirred. The mixture was concentrated to approximately 25 mL under reduced pressure and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated in vacuo to afford methyl 5-(hydroxymethyl)thiophene-2-carboxylate (472 mg) as a colorless oil.
303 mg
With sodium tetrahydroborate; ammonium chloride; In methanol; water; for 2.16667h;Cooling with ice;
Methyl 5-formylthiophene-2-carboxylate (311 mg,1.82 mmol) was dissolved in MeOH (4 mE), cooled in an ice bath and NaI3H4 (68 mg, 1.82 mmol) added portion wise over ten minutes. The reaction was stirred for 2 h after which time sat. aq. ammonium chloride (10 mE) was added. The aqueous phase was extracted with DCM (2x1 5 mE), passed through a phase separator and concentrated in vacuo to yield the sub-title compound (303 mg) as a colourless oil.1H NMR (400 MHz, CDC13) oe 7.61 (d. 1H), 6.92 (dt, 1H), 4.86-4.69 (m, 2H), 3.81 (s, 3H).
Example 805-[[1-[[3-(1,1-dimethylethyl)-phenyl]sulfonyl]-3-methyl-5-trifluoromethyl-1H-indol-2-yl]-hydroxymethyl]-thiophene-2-carboxylic acid methyl esterUnder an argon atmosphere, 240 mg (4.5 mM) of a solution of n-butyllithium (c=1.6 M in hexane) was added slowly to a solution of 1.12 g (3 mM) of 1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-3-methyl-5-trifluoromethyl-1H-indole (preparation XXXIII) in 12 mL of tetrahydrofuran cooled to 0° C. The reaction mixture was stirred for 15 min at 0° C., then added dropwise at -78° C. to a solution of 433 mg (2.62 mM) of <strong>[67808-64-4]5-formyl-thiophene-2-carboxylic acid methyl ester</strong> in 12 mL of tetrahydrofuran. The mixture was stirred for 30 minutes at -70° C., then diluted with a saturated aqueous solution of NH4Cl and extracted three times with dichloromethane. The combined organic fractions was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography, eluting with a cyclohexane/ethyl acetate mixture (95/5; v/v), then cyclohexane/ethyl acetate (90/10, v/v). The fractions containing the expected product were combined and concentrated to dryness under reduced pressure to give 1020 mg of 5-[[1-[[3-(1,1-dimethylethyl)phenyl]sulfonyl]-3-methyl-5-trifluoromethyl-1H-indol-2-yl]-hydroxymethyl]-thiophene-2-carboxylic acid methyl ester as an orange oil (yield=62percent).1H NMR (300 MHz, DMSOd6) delta=8.34 (d, 1H), 7.69 (m, 5H), 7.6 (d, 1H), 7.46 (t, 1H), 6.95 (m, 2H), 6.78 (d, 1H), 3.78 (s, 3H), 2.22 (s, 3H), 1.14 (s, 9H).
Preparation XXXVIII5-(1-hydroxy-prop-2-ynyl)-thiophene-2-carboxylic acid methyl ester40 mL of ethynylmagnesium bromide was added dropwise to a solution of 1.7 g (10 mM) of methyl ester of 5-formyl-thiophene-2-carboxylic acid in 17 mL of tetrahydrofuran cooled to 0° C., then the mixture was stirred for 30 minutes at 0° C. The solution was poured into 100 mL of a saturated aqueous solution of NH4Cl and extracted three times with ethyl acetate. The combined organic layers were dried over magnesium sulfate, and evaporated under reduced pressure to give 2 g of 5-(1-hydroxy-prop-2-ynyl)-thiophene-2-carboxylic acid methyl ester as a brown solid (quantitative yield). M.p.=67° C.
M-12 (2.08 g, 7.8 mmol) was dissolved in tetrahydrofuran (30 mL), 60percent sodium hydride (0.37 g, 9.25 mmol) was added at 0°C, and the mixture was stirred for 30 min.To the reaction mixture was added a solution of 5-formyl-2-thiophenecarboxylic acid methyl ester (1.02 g, 6.0 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature overnight.The solvent was evaporated, and the residue was partitioned between ethyl acetate and 1N hydrochloric acid, and washed successively with water and saturated brine.After drying over anhydrous magnesium sulfate, the residue was purified by silica gel column chromatography to give the title compound (1.18 g).1H-NMR(300MHz, CDCl3) delta 7.75(1H, d, J=4.2Hz), 7.69(1H, s), 7.19(1H, d, J=4.2Hz), 3.90(3H, s), 2.19(3H, s), 1.54(9H, s).
Step 2. Methyl 5-[(methylamino)methyl]-2-thiophenecarboxylate A solution of <strong>[67808-64-4]methyl 5-formyl-2-thiophenecarboxylate</strong> (1.58 g, 9.3 mmol), methyl amine (5.6 ml, 2N, 11.2 mmol) and glacial acetic acid (3.0 ml) in THF (30 ml) at 25 0C was treated with sodium triacetoxyborohydride (11.83 g, 55.8 mmol) and the mixture was stirred for 18h. Aqueous 2N NaOH was added until the solution reached pH 5. The resulting mixture was extracted with Et2O (3 x 50 ml), and the combined organic extracts were washed with brine, dried (Na2SO4), concentrated under reduced pressure, and subjected to flash chromatography to give methyl 5- [(methylamino)methyl]-2-thiophenecarboxylate as a white solid (650 mg, 41percent): ESI- MS (m/z): 186.0 (M+H+).
With sodium tris(acetoxy)borohydride; triethylamine; In dichloromethane; at 30℃; for 16h;
To a mixture of intermediate (200 mg), selected aldehyde (1 .2 eq) and TEA (100 muIota) in DCM (4 ml) was added NaBH(OAc)3 (1 .5 eq). The reaction mixture was stirred at 30°C for 16 hrs and concentrated to dryness. Then the crude product was dissolved in DCM / TFA= 7:1 (4 ml). The reaction mixture was stirred at 30°C for 16 hrs, concentrated and the crude product was purified by prep HPLC to give the expected compound.
With sodium tris(acetoxy)borohydride; triethylamine; In dichloromethane; at 30℃; for 16h;
General procedure: To a mixture of intermediate (200 mg), selected aldehyde (1.2 eq) and TEA (100 mul) in DCM (4 ml) was added NaBH(OAc)3 (1.5 eq). The reaction mixture was stirred at 30° C. for 16 hrs and concentrated to dryness. Then the crude product was dissolved in DCM/TFA=7:1 (4 ml). The reaction mixture was stirred at 30° C. for 16 hrs, concentrated and the crude product was purified by prep HPLC to give the expected compound.
methyl 5-(difluoromethyl)thiophene-2-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.23 g
With diethylamino-sulfur trifluoride; In toluene; at 0 - 20℃;
Example 178 1- (2-Cyclopropyl-3-methylimidazo [1, 2-a] pyridin-6-yl) -4- ( (5- (difluoromethyl) -2-thienyl) methoxy) pyridin-2 ( 1H) -one A) Methyl 5- (difluoromethyl ) thiophene-2-carboxylate To a solution of <strong>[67808-64-4]methyl 5-formylthiophene-2-carboxylate</strong> (4.15 g) in toluene (100 ml) was added dropwise DAST (4.83 ml) at 0°C, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated NaHCC>3 solution and extracted with EtOAc. The extract was washed with brine, dried over MgS04, concentrated and purified by silica gel column chromatography (hexane/EtOAc) to give the title compound (2.23 g) as a pale yellow solid. XH NMR (400 MHz, CDC13) : delta 3.91 (3H, s) , 6.83 (1H, t, J = 55.8 Hz), 7.27 (1H, brs), 7.69-7.77 (1H, m) .
2.23 g
With diethylamino-sulfur trifluoride; In toluene; at 0 - 35℃;
To a solution of <strong>[67808-64-4]methyl 5-formylthiophene-2-carboxylate</strong> (4.15 g) in toluene (100 ml) was added dropwise N,N- diethylaminosulfur trifluoride (4.83 ml) at 0°C, and the mixture was stirred at room temperature overnight. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.23 g) . 1H NMR (400 MHz, CDCl3) delta 3.91 (3H, s) , 6.83 (1H, t, J = 55.8 Hz), 7.27 (1H, brs), 7.69-7.77 (1H, m)
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