* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With sodium hydroxide; water In tetrahydrofuran; methanol for 2 h;
To a solution of 2-methoxycarbonyl-5-phenylthiophene (437 mg) in methanol (5 ml) and tetrahydrofuran (5 ml) was added an aqueous solution of sodium hydroxide (IN, 3 ml) followed by stirring for 2 hours.. To the mixture was added hydrochloric acid (IN, 5 ml).. The precipitate was collected by filtration and dried to give 5-phenylthiophene-2-carboxylic acid (397 mg, 97.1percent).NMR (DMSO-d6, δ): 7.3-7.5 (3H, m), 7.58 1(1H, d, J=3.9 Hz), 7.6-7.8 (3H, m), 13.15 (1H, broad s) ESI-Mass m/z: 203 (M-1).
91.7%
With sodium hydroxide In methanol at 20℃; for 4 h;
General procedure: Sodium hydroxide (2N) was added to a solution of intermediate 2a-i (1 equiv.) in methanol at ambient temperature. The reaction mixture was stirred for 4h and the methanol was removed by rotary evaporation. The resultant mixture was adjusted to pH=5–6 with 1N HCl solution. The precipitated white solid was collected by filtration and dried to give the carboxylic acid intermediate (1a-i).
Reference：
[1] Patent: US6770667, 2004, B1, . Location in patent: Page column 11
[2] ChemMedChem, 2011, vol. 6, # 2, p. 362 - 377
[3] European Journal of Medicinal Chemistry, 2017, vol. 137, p. 96 - 107
[4] Journal of Medicinal Chemistry, 2010, vol. 53, # 15, p. 5536 - 5548
2
[ 7311-63-9 ]
[ 98-80-6 ]
[ 19163-24-7 ]
Reference：
[1] Journal of the American Chemical Society, 2009, vol. 131, # 45, p. 16346 - 16347
[2] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 19, p. 4915 - 4918
[3] Patent: US6399656, 2002, B1,
[4] Patent: WO2006/57922, 2006, A2, . Location in patent: Page/Page column 54-55
3
[ 825-55-8 ]
[ 124-38-9 ]
[ 19163-24-7 ]
Reference：
[1] Organic Letters, 2016, vol. 18, # 11, p. 2576 - 2579
[2] Bulletin of the Chemical Society of Japan, 2012, vol. 85, # 3, p. 369 - 371
[3] Molecules, 2018, vol. 23, # 4,
4
[ 825-55-8 ]
[ 19163-24-7 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 4450,4452
[2] Patent: US4024156, 1977, A,
5
[ 649569-52-8 ]
[ 19163-24-7 ]
Reference：
[1] Bioorganic and Medicinal Chemistry, 2003, vol. 11, # 22, p. 4729 - 4742
6
[ 19163-21-4 ]
[ 19163-24-7 ]
[ 500604-89-7 ]
Yield
Reaction Conditions
Operation in experiment
51%
With sodium hydroxide; potassium dihydrogenphosphate; NaClO2 In tetrahydrofuran; water; <i>tert</i>-butyl alcohol
5-Phenylthiophene-2-carboxaldehyde (750 mg, 4 mmol) is dissolved in a mixture of THF, tBuOH, and water (2:1:1, 60 mL). KH2PO4 (1.36 g, 10 mmol) is added followed by NaClO2 (900 mg, 10 mmol). The mixture is stirred at rt for 5 days. Aqueous NaOH (2M, 10 mL) is added and a majority of the organic solvents are removed in vacuo yielding an aqueous suspension. This suspension is diluted with water and washed with three times with CH2Cl2. The aqueous layer is acidified to pH<2 with 25percent H2SO4 and the product is extracted three times with CH2Cl2. The combined organic washes are dried over Na2SO4, filtered and concentrated in vacuo to yield 417 mg (51percent) of 5-phenylthiophene-2-carboxylic acid. MS for C11H8O2S, (ES) m/z: 203 (M-H)-.
Reference：
[1] Patent: US2003/69290, 2003, A1,
7
[ 1383628-95-2 ]
[ 19163-24-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 2012, vol. 55, # 12, p. 5982 - 5986
8
[ 98-80-6 ]
[ 19163-24-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 11, p. 1585 - 1599
[2] Heterocycles, 2014, vol. 89, # 2, p. 453 - 464
[3] European Journal of Medicinal Chemistry, 2017, vol. 137, p. 96 - 107
9
[ 19163-21-4 ]
[ 19163-24-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 11, p. 1585 - 1599
[2] Heterocycles, 2014, vol. 89, # 2, p. 453 - 464
10
[ 4701-17-1 ]
[ 19163-24-7 ]
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 11, p. 1585 - 1599
[2] Heterocycles, 2014, vol. 89, # 2, p. 453 - 464
11
[ 10341-87-4 ]
[ 19163-24-7 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 4450,4452
12
[ 76576-48-2 ]
[ 19163-24-7 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 4450,4452
13
[ 824-90-8 ]
[ 19163-24-7 ]
Reference：
[1] Journal of the American Chemical Society, 1954, vol. 76, p. 4450,4452
With n-butyllithium; In tetrahydrofuran; hexane; water;
EXAMPLE 2 Acylation - Method B Another method for preparing 2-acylthiophenes is exemplified by the following preparation of 2-acetyl-5-phenyl-thiophene: A solution of 2- phenylthiophene (16.0 g, 0.1 mole) in 100 ml anhydrous tetrahydrofuran (THF) is treated dropwise with a solution of n-butyl lithium (0.11 mole) in hexane (2M solution). Thereafter the mixture is stirred for 1 hr. The resulting black solution is poured onto 50 g of solid CO2 covered with ether. When all the CO2 is evaporated, the mixture is treated with 200 ml of water, acidified with 10percent HCI and extracted with ether. The extract is washed with 5percent NaOH. The latter washings are cooled and rendered acidic with 20percent HCI. The resulting precipitate is collected and recrystallized from 1000 ml CCI4 to give 5-phenyl 2-thiophenecarboxylic acid, mp 180° C, gammamax CHCI 1665 cm-1, as yellow green crystals.
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; for 1h;
To a suspension of 5-phenylthiophene-2-carboxylic acid (102 mg) and oxalyl chloride (0.2 ml) in dichloromethane (2 ml) was added N,N-dimethylformamide (0.01 ml), and the mixture was stirred for an hour.. The resultant solution was evaporated under reduced pressure to give a crude acid chloride.. To a suspension of 3-(1,2-dimethylimidazol-5-yl)aniline (94 mg) and pyridine (0.12 ml) in dichloromethane (2 ml) was dropwise added a solution of the acid chloride obtained above in dichloromethane (2 ml) followed by stirring for 12 hours.. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine.. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure.. The residue was purified by a silica gel column chromatography eluding with 3percent methanol in dichloromethane to give N-[3-(2,3-dimethyl-3H-imidazol4-yl)-phenyl]-5-phenyl-thiophene-2-carboxamide (155 mg, 82.9percent).NMR DMSO-d>6, delta): 2.36 (3H,s), 3.57 (3H, s), 6.89 (1H, s), 7.17 (1H, d, J=7.8 HZ), 7.4-7.6 (4H, m), 7.64 (1H, d, J=4.0 Hz), 7.7-7.9 14H, m), 8.04 (1H, d, J=4.0 Hz), 10.34 (1H, s) APCI-Mass m/z: 374 (M+1).
Step 3b The product of Step 3a (750 mg, 4 mmol) is dissolved in a mixture of THF, t-BuOH, and water (2:1:1, 60 mL). KH2PO4 (1.36 g, 10 mmol) is added followed by NaClO2 (900 mg, 10 mmol). The mixture is stirred at rt for 5 days. Aqueous NaOH (2M, 10 mL) is added, and a majority of the organic solvents are removed in vacuo yielding an aqueous suspension. This suspension is diluted with water and washed three times with CH2Cl2. The aqueous layer is acidified to pH<6 with 25percent H2SO4 and the product is extracted three times with CH2Cl2. The combined organic washes are dried over Na2SO4, filtered and concentrated in vacuo to yield 5-phenylthiophene-2-carboxylic acid (417 mg, 51percent). MS for C11H8O2S (ESI) (M-H)- m/z 203.
Preparation 7 Preparation of 5-phenyl-2-thiophenecarboxylic Acid Following the procedure of Preparation 1(a), except substituting phenylboronic acid for 4-carboxybenzeneboronic acid and 5-bromo-2-thiophenecarboxylic acid for 3-bromopyridine, afforded the title compound.
EXAMPLE 53; A sealed tube was charged with phenylboronic acid (0.695g, 5.7 mmol), 2-bromo- thiophene-5-carboxylic acid (Ig, 4.8 mmol), Pd(PPh3)4 (277 mg, 0.05 quiv)), sodium carnonate (1.53g, 3 quiv.) in 20 mL dioxane was heated at 100 0C overnight. The mixture was partitioned between EtOAc and IN NaOH, the aqueous phase was washed with EtOAc, then acidified to pH 3. The precipitate was collected by filtration and dried to obtain the acid. A solution of this acid intermediate (0.886g, 4.3mmol) EPO <DP n="56"/>in 40 mL THF was treated with LiAlH4 (0.326g, 8.6 mmol) at O 0C and stirred for 1.5h. The reaction was quenched by saturated solution of potassium tartrate. The mixture was extracted with EtOAc, and organic phase was washed with brine and dried over Na2SO4. Evaporation of the solvent gave the alcohol. To the solution of this alcohol (0.446g, 2.3mmol) in CH2Cl2 (20 mLO, at O0C, was added pyridiniumchlorochromate (0.99g, 4.6 mmol) in one portion. The mixture was stirred at 23 0C overnight. After evaporation of the solvent, the residue was purified on silica gel chromatography using 5percent EtOAc/Hexane to obtain the aldehyde. To a solution of trimethylphosphonoacetate (0.297 mL, 1.8 mmol) in 15 mL THF, at 0 0C, was added n-butyllithium (l,28mL, 1.6M in hexane, 2.04 mmol) dropwisely. After stirred at O0C for 0.5h, a solution of the above aldehyde intermediate (0.326g, 1.7 mmol) in THF (20 mL) was added to the above solution dropwise, and the resulting solution was stirred for 2h at r.t. After evaporation of the solvent, the residue was purified on silica gel chromatography using 5percent EtOAc/hexane to obtain the enoate. A solution of this enoate intermediate (80 mg, 0.327 mmol) and p- toluenesulfonylhydrazide (0.6 Ig, 3.27 mmol) in methanol (60 mL) was refluxed for 3 days. The compound was purified on silica gel chromatography using 4percent EtOAc as eluting solvent to obtain the methyl ester. Following methods described in the above examples, this intermediate was elaborated into Example 53; 1H NMR (DMSO-d6, 500 MHz) delta 11.14(lH,s), 8.47(lH,d), 7.97(1H, d), 7.59(3H, m), 7.38(2H, t), 7.30 (IH, d), 7.25(1H, t), 7.15(1H, t), 6.9O(1H, d), 3.16(2H, t), 2.80(2H, t); LCMS m/z 352.31 (M++.), 350.40 (M+-I).
5-phenyl-thiophene-2-carboxylic acid (tetrahydro-pyran-2-yloxy)-amide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 7h;
To a solution of <strong>[19163-24-7]5-phenyl-thiophene-2-carboxylic acid</strong> (72mg, 0.35mmol) in N, [N-DIMETHYLFORMAMIDE] (3ml) at [0C] was added [O- (TETRAHYDRO-2H-PYRAN-2-] yl) hydroxylamine (45mg, 0.39mmol), diisopropylethylamine [(153UL,] 0.88mmol), and [O-] [(7-AZABENZOTRIAZOL-1-YL)-N,V, 1VAPOS;, NAPOS;-TETRAMETHYLURONIUM] hexafluorophosphate (148mg, 0. 39mmol). The mixture was allowed to equilibrate to room temperature over 7 hours. The volatiles were evaporated and the residue was partitioned between ethyl acetate and water. The two phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined extracts were washed with water, then with 10percent citric acid solution, then with saturated sodium bicarbonate solution, then with brine, then dried over magnesium sulfate and then evaporated. The residual yellow gum was subjected to column chromatography on silica eluting with ethyl acetate/pentane [(1] : 3 v/v) to yield [5-PHENYL-] thiophene-2-carboxylic acid [(TETRAHYDRO-PYRAN-2-YLOXY)-AMIDE] (87mg, [81percent)] as a white gum, which crystallised on standing. LCMS (Method A): RT = 8.48 minutes; 304 (M+H) +.
1,4-diazabicyclo[3.2.2]nonane dihydrochloride[ No CAS ]
[ 661462-24-4 ]
Yield
Reaction Conditions
Operation in experiment
78%
With benzotriazol-1-ol; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 20h;
<strong>[19163-24-7]5-Phenylthiophene-2-carboxylic acid</strong> (103 mg, 0.50 mmol), [1,4-diaza-bicyclo[3.2.2]nonane dihydrochloride (100 mg, 0.50 mmol), 1-hydroxybenzotriazole hydrate (68 mg, 0.50 mmol), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (161 mg, 0.50 mL) and diisopropylethylamine (0.35 mL, 250 mg, 2.0 mmol) in dry N,N-dimethylformamide (2 mL) were stirred at ambient temperature for 20 h. The reaction mixture was poured into 1N sodium hydroxide solution and extracted with ethyl acetate (2x). The ethyl acetate layers were combined and washed with water (2x). The solvent was blown off with a stream of nitrogen to yield (1,4-diazabicyclo[3.2.2]non-4-yl)(5-phenylthiophene-2- yl)methanone (122 mg, 78percent) as a tan oil. MS (APCI+) 313 [M+1]+; 1H-NMR (300 MHz, CDCl3): delta 7.74-7.66 (2H, m), 7.53-7.32 (5H, m), 4.53-4.39 (1H, m), 3.89-3.72 (2H, m), 3.01- 2.83 (6H, m), 2.06-1.85 (2H, m), 1.82-1.64 (2H, m).
With sodium hydroxide; water; In tetrahydrofuran; methanol; for 2h;
To a solution of 2-methoxycarbonyl-5-phenylthiophene (437 mg) in methanol (5 ml) and tetrahydrofuran (5 ml) was added an aqueous solution of sodium hydroxide (IN, 3 ml) followed by stirring for 2 hours.. To the mixture was added hydrochloric acid (IN, 5 ml).. The precipitate was collected by filtration and dried to give 5-phenylthiophene-2-carboxylic acid (397 mg, 97.1percent).NMR (DMSO-d6, delta): 7.3-7.5 (3H, m), 7.58 1(1H, d, J=3.9 Hz), 7.6-7.8 (3H, m), 13.15 (1H, broad s) ESI-Mass m/z: 203 (M-1).
91.7%
With sodium hydroxide; In methanol; at 20℃; for 4h;
General procedure: Sodium hydroxide (2N) was added to a solution of intermediate 2a-i (1 equiv.) in methanol at ambient temperature. The reaction mixture was stirred for 4h and the methanol was removed by rotary evaporation. The resultant mixture was adjusted to pH=5?6 with 1N HCl solution. The precipitated white solid was collected by filtration and dried to give the carboxylic acid intermediate (1a-i).
Example 3: (N- (R)-l-Azabicyclor2. 2. 21oct-3-vl)-3-fluoro-5-phenylthiophene-2-carboxylic acid amide To a solution of 5-phenylthiophene-2-carboxylic acid (250 mg, 1.22 mmol) in dry THF (10 mL) cooled to-78 °C and stirred under N2, was added n-BuLi (2.5 M solution in hexane; 1.08 mL, 2.69 mmol, 2.2 eq). The resulting mixture was stirred at-78 °C for 30 min. N-fluorobenzenesulfonimide (577 mg, 1.83 mmol, 1.5 eq. ) was then added as a solution in dry THF (7 mL). The reaction mixture was stirred for 5 h at-78 °C, then at room temperature overnight. The reaction mixture was cooled to 0 °C and quenched by the addition of 6 N HCl (2 mL) then diluted with Et20 (10 mL). The layers were separated and the aqueous layer was extracted with 20 mL Et20. The organic extracts were combined and dried over MgS04. After filtration, the solvent was removed in vacuo to yield a product, a mixture of desired 3-fluoro- 5-phenylthiophene-2-carboxylic acid and starting 5-phenylthiophene-2-carboxylic acid, which was carried on without further purification. The mixture (155 mg,-0. 70 mmol), R- (+)- 3-aminoquinuclidine dihydrochloride (140 mg, 0.70 mmol), 1-hydroxybenzotriazole hydrate (95 mg, 0.70 mmol), 0- (benzotriazol-1-yl)-N, N, N', N'-tetramethyluronium tetrafluoroborate (225 mg, 0.70 mL) and diisopropylethylamine (0.37 mL, 2.1 mmol) in dry N, N- dimethylformamide (3 mL) were stirred at ambient temperature overnight. The reaction mixture was poured into 5percent NaHC03 solution and extracted with ethyl acetate. The ethyl acetate layer was washed with 0.5 N NaOH (lx), water (lx), 5percent LiCl, and dried over MgS04. After filtration, the solvent was removed in vacuo. The residue was purified successively by silica gel chromatography [ (NH3/EtOAc)- (NH3/MeOH/EtOAc)] and preparative HPLC [C8, reverse phase, (5percent CH3CN/95percent H20/0. 1percent TFA)- (95percent CH3CN/5percent H20/0. 1percent TFA) ] to give an aqueous residue, which was treated with aq. K2CO3, and extracted with EtOAc (2x), and dried over MgS04. After filtration, the solvent was removed in vacuo to yield (N- (R)-1- azabicyclo [2.2. 2] oct-3-yl)-3-fluoro-5-phenylthiophene-2-carboxylic acid amide (25 mg, 11percent, two steps) as a white solid. MS (APCI+) 331 [M+I] +.'H-NMR (300 MHz, CDC13) : 8 7.62- 7.55 (2H, m), 7.46-7. 36 (3H, m), 7.05 (1H, s), 6.55-6. 44 (1H, m), 4.23-4. 10 (1H, m), 3.52- 3.38 (1H, m), 2.99-2. 79 (4H, m), 2.69-2. 56 (1H, m), 2.09-1. 99 (1H, m), 1. 84-1. 47 (4H, m).
EXAMPLE 53; A sealed tube was charged with phenylboronic acid (0.695g, 5.7 mmol), 2-bromo- thiophene-5-carboxylic acid (Ig, 4.8 mmol), Pd(PPh3)4 (277 mg, 0.05 quiv)), sodium carnonate (1.53g, 3 quiv.) in 20 mL dioxane was heated at 100 0C overnight. The mixture was partitioned between EtOAc and IN NaOH, the aqueous phase was washed with EtOAc, then acidified to pH 3. The precipitate was collected by filtration and dried to obtain the acid. A solution of this acid intermediate (0.886g, 4.3mmol) EPO <DP n="56"/>in 40 mL THF was treated with LiAlH4 (0.326g, 8.6 mmol) at O 0C and stirred for 1.5h. The reaction was quenched by saturated solution of potassium tartrate. The mixture was extracted with EtOAc, and organic phase was washed with brine and dried over Na2SO4. Evaporation of the solvent gave the alcohol. To the solution of this alcohol (0.446g, 2.3mmol) in CH2Cl2 (20 mLO, at O0C, was added pyridiniumchlorochromate (0.99g, 4.6 mmol) in one portion. The mixture was stirred at 23 0C overnight. After evaporation of the solvent, the residue was purified on silica gel chromatography using 5percent EtOAc/Hexane to obtain the aldehyde. To a solution of trimethylphosphonoacetate (0.297 mL, 1.8 mmol) in 15 mL THF, at 0 0C, was added n-butyllithium (l,28mL, 1.6M in hexane, 2.04 mmol) dropwisely. After stirred at O0C for 0.5h, a solution of the above aldehyde intermediate (0.326g, 1.7 mmol) in THF (20 mL) was added to the above solution dropwise, and the resulting solution was stirred for 2h at r.t. After evaporation of the solvent, the residue was purified on silica gel chromatography using 5percent EtOAc/hexane to obtain the enoate. A solution of this enoate intermediate (80 mg, 0.327 mmol) and p- toluenesulfonylhydrazide (0.6 Ig, 3.27 mmol) in methanol (60 mL) was refluxed for 3 days. The compound was purified on silica gel chromatography using 4percent EtOAc as eluting solvent to obtain the methyl ester. Following methods described in the above examples, this intermediate was elaborated into Example 53; 1H NMR (DMSO-d6, 500 MHz) delta 11.14(lH,s), 8.47(lH,d), 7.97(1H, d), 7.59(3H, m), 7.38(2H, t), 7.30 (IH, d), 7.25(1H, t), 7.15(1H, t), 6.9O(1H, d), 3.16(2H, t), 2.80(2H, t); LCMS m/z 352.31 (M++.), 350.40 (M+-I).
With sodium hydroxide; potassium dihydrogenphosphate; NaClO2; In tetrahydrofuran; water; tert-butyl alcohol;
5-Phenylthiophene-2-carboxaldehyde (750 mg, 4 mmol) is dissolved in a mixture of THF, tBuOH, and water (2:1:1, 60 mL). KH2PO4 (1.36 g, 10 mmol) is added followed by NaClO2 (900 mg, 10 mmol). The mixture is stirred at rt for 5 days. Aqueous NaOH (2M, 10 mL) is added and a majority of the organic solvents are removed in vacuo yielding an aqueous suspension. This suspension is diluted with water and washed with three times with CH2Cl2. The aqueous layer is acidified to pH<2 with 25percent H2SO4 and the product is extracted three times with CH2Cl2. The combined organic washes are dried over Na2SO4, filtered and concentrated in vacuo to yield 417 mg (51percent) of 5-phenylthiophene-2-carboxylic acid. MS for C11H8O2S, (ES) m/z: 203 (M-H)-.
EXAMPLE 63 1-(5-Phenylthiophen-2-ylmethyl)-4-(3-chlorophenyl)piperazine 5-Phenyl-2-thiophenecarboxylic acid was reacted as in Example 44 to the amide which was then reduced to the title compound as in Example 53. m.p. 115° C.
General procedure: 2-Methylfuran was obtained from commercial supplies. 2-Phenylthiophene was prepared according to a previously described method [48]. Under an N2 atmosphere, 2-([1,10-biphenyl]-4-yl) thiophene, 2-(4-phenoxyphenyl)thiophene, or 2-methylfuran (1.0 equiv.) was placed in a three-necked flask with distilled THF or Et2O. The flask was cooled at 0 °C, and n-butyllithium (1.1 equiv.) was added dropwise over a period of 15 min. The mixture was then stirred for 30 min at room temperature. After the mixture was cooled at -78 °C with a dry ice/acetone bath, CO2 gas was introduced under vigorous stirring and cooling. After stirring for 2 h, the mixture was warmed to room temperature and quenched with water. The ether layer was separated and washed with water. The combined solution was acidified with a 3 N HCl solution at 0 °C, and then extracted with EtOAc. The organic layer was washed with brine, dried with MgSO4, and concentrated under reduced pressure. The desired products were obtained without further purification.
With benzotriazol-1-ol; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; for 15h;
General procedure: A mixture of compound 10 (135 mg, 0.49 mmol) and 4-(thiophen-3-yl)benzoic acid (99.4 mg, 0.49 mmol) in dichloromethane (10 mL) was stirred at 0 °C (ice-water bath). Dicyclohexylcarbodiimide(DCC) (121 mg, 0.59 mmol) and hydroxybenzotriazole(HOBt) (80 mg, 0.59 mmol) were added to the above solution.The ice bath was removed, and the reaction mixture was stirred at ambient temperature for 15 h. Dichloromethane (20 mL) was added into the reaction mixture, and the solution was washed with saturated aqueous NaHCO3 solution (3*10 mL). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography using dichloromethane?methanol (20:1) as the mobile phase to give 11a as a white solid (194 mg, 86percent). TLC Rf 0.20 (dichloromethane?methanol 20:1); mp 125.5?126.6 °C. 1H NMR(300 MHz, CDCl3) delta 7.75 (d, J = 8.7 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H),7.43 (s, 1H), 7.33 (s, 2H), 7.19 (s, 1H), 6.81?6.94 (m, 4H), 3.85 (s,3H), 3.44 (q, J = 5.1 Hz, 2H), 3.25?3.20 (m, 4H), 2.83?2.76 (m,4H), 2.57 (t, J = 5.2 Hz, 2H), 1.93 (t, J = 4.2 Hz, 2H), 1.61?1.69 (m,4H). 13C NMR (CDCl3, 300 MHz): 167.4, 151.4, 142.1, 141.2,138.8, 133.4, 127.5, 126.6, 126.3, 126.1, 121.3, 121.0, 120.7,117.9, 111.6, 57.1, 56.1, 55.3, 54.3, 52.5, 51.8, 39.4, 27.7, 27.3,25.5. HRMS (ESI) Calcd for C27H33N3O2S (M+H)+: 464.2372. Found:464.2379. Anal. (C27H33N3O2S 1.5H2C2O4) C, H, N.
N-[5-amino-2-(trifluoromethoxy)phenyl]-2-(morpholin-4-yl)acetamide[ No CAS ]
N-{3-[(morpholin-4-ylacetyl)amino]-4-(trifluoromethoxy)phenyl}-5-phenylthiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
33%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;
To a solution of N-[5-amino-2-(trifluoromethoxy)phenyl]-2-(morpholin-4-yl)acetamide (prepared in a manner analogous to that described in intermediate 32, 0.075 g, 0.24 mmol) and 5-phenylthiophene- 2-carboxylic acid (0.097 g, 0.57 mmol, 1.0 equiv) in DMF (2.5 mL) was added (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, 0.18 g, 0.35 mmol, 1.5 equiv) followed by diisopropylethylamine (0.16 mL, 0.94 mmol, 4.0 equiv). The resulting mixture was stirred at room temperature for 24 h, was then concentrated under reduced pressure. The residue was treated with water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL). The organic phase was dried (Na2S04 anh), and concentrated under reduced pressure. The residue (0.25 g) was purified using HPLC (method 2) to give N-{3-[(morpholin-4-ylacetyl)amino]-4- (trifluoromethoxy)phenyl}-5-phenylthiophene-2-carboxamide (0.041 g, 33percent). 1H-NM (400 MHz, DMSO-d6): delta [ppm] = 2.51-2.56 (m, 4H), 3.18 (s, 2H), 3.59-3.64 (m, 4H), 7.32-7.47 (m, 4H), 7.59 (d, J=4.0 Hz, 1H), 7.66-7.74 (m, 3H), 8.04 (d, J=4.0 Hz, 1H), 8.61 (d, J=2.6 Hz, 1H), 9.76 (s, 1H), 10.46 (s, 1H). LC-MS (Method 3): Rt = 1.40 min; MS (ESIpos): m/z = 506 ([M+H]+, 100percent); MS (ESIneg): m/z = 504 ([M-H]-, 100percent).
N-{4-tert-butyl-3-[(morpholin-4-ylacetyl)amino]phenyl}-5-phenylthiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
18%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20℃; for 24h;
To a solution of N-(5-amino-2-tert-butylphenyl)-2-(morpholin-4-yl)acetamide (prepared in a manner analogous to that described in intermediate 33, 0.090 g, 0.31 mmol) and 5-phenylthiophene-2- carboxylic acid (0.078 g, 0.39 mmol, 1.25 equiv) in DMF (2.4 mL) was added propanephosphonic acid cyclic anhydride solution (50percent in ethyl acetate, 0.23 mL, 0.39 mmol, 1.25 equiv) followed by diisopropylethylamine (0.16 mL, 0.93 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 24 h, was then concentrated under reduced pressure. The residue was then treated with water (50 mL). The resulting mixture was extracted with ethyl acetate (50 mL). The organic phase was dried (Na2S04 anh), and concentrated under reduced pressure. The residue was purified by HPLC (method 2) to give N-{4-tert-butyl-3-[(morpholin-4-ylacetyl)amino]phenyl}-5- phenylthiophene-2-carboxamide (28 mg, 18percent). 1H-NMR (400 MHz, DMSO-d6): delta [ppm] = 1.36 (s, 9H), 2.55-2.60 (m, 4H), 3.14 (s, 2H), 3.60-3.65 (m, 4H), 7.29-7.38 (m, 2H), 7.43 (t, J=7.3 Hz, 2H), 7.54-7.59 (m, 2H), 7.71 (d, J=7.2 Hz, 2H), 8.00-8.03 (m, 2H), 9.38 (s, 1H), 10.23 (s, 1H). LC-MS (Method 3): Rt = 1.40 min; MS (ESIpos): m/z = 478 ([M+H]+, 100percent), 955 ([2M+H]+, 30percent); MS (ESIneg): m/z = 476 ([M-H]", 100percent).
N-(5-amino-2-chlorophenyl)-2-(morpholin-4-yl)acetamide[ No CAS ]
N-{4-chloro-3-[(morpholin-4-ylacetyl)amino]phenyl}-5-phenylthiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;
To a solution of N-(5-amino-2-chlorophenyl)-2-(morpholin-4-yl)acetamide (prepared in a manner analogous to that described in intermediate 34, 0.13 g, 0.48 mmol) and 5-phenylthiophene-2- carboxylic acid (0.15 g, 0.72 mmol, 1.5 equiv) in DMF (5 mL) was added (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, 0.38 g, 0.723 mmol, 1.5 equiv) followed by diisopropylethylamine (0.34 mL, 1.93 mmol, 4.0 equiv). The resulting mixture was stirred at room temperature for 24 h, was then concentrated under reduced pressure. The residue was treated with water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL). The organic phase was dried (Na2S04 anh), and concentrated under reduced pressure. The residue (3.5 g) was purified by HPLC (method 2) to give N-{4-chloro-3-[(morpholin-4-ylacetyl)amino]phenyl}-5- phenylthiophene-2-carboxamide (37 mg, 16percent). 1H-NM (400 MHz, DMSO-d6): delta [ppm] = 2.53-2.58 (m, 4H), 3.18 (s, 2H), 3.62-3.67 (m, 4H), 7.31-7.48 (m, 4H), 7.59 (d, J=4.0 Hz, 1H), 7.65 (dd, J=2.6, 8.7 Hz, 1H), 7.72 (d, J=7.0 Hz, 2H), 8.03 (d, J=4.1 Hz, 1H), 8.61 (d, J=2.5 Hz, 1H), 9.89 (s, 1H), 10.41 (s, 1H). LC-MS (Method 3): Rt = 1.34 min; MS (ESIpos): m/z = 456 ([M+H]+, 100percent), 911 ([2M+H]+, 20percent); (ESIneg): m/z = 454 ([M-H]", 50percent).
N-(5-amino-2-methylphenyl)-2-(morpholin-4-yl)acetamide[ No CAS ]
N-{4-methyl-3-[(morpholin-4-ylacetyl)amino]phenyl}-5-phenylthiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
23%
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine; In ethyl acetate; N,N-dimethyl-formamide; at 20℃; for 24h;
To a solution of N-(5-amino-2-methylphenyl)-2-(morpholin-4-yl)acetamide (prepared in a manner analogous to that described in intermediate 35, 0.085 g, 0.34 mmol) and 5-phenyl-thiophene-2- carboxylic acid (0.084 g, 0.41 mmol, 1.22 equiv) in DMF (2.7 mL) was added propanephosphonic acid cyclic anhydride solution (50percent in ethyl acetate, 0.24 mL, 0.41 mmol, 1.20 equiv) followed by diisopropylethylamine (0.18 mL, 1.02 mmol, 3.0 equiv). The resulting mixture was stirred at room temperature for 24 h, was then concentrated under reduced pressure. The residue was then treated with water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL). The organic phase was dried (Na2S04 anh), and concentrated under reduced pressure. The residue was purified by HPLC (method 2) to give N-{4-methyl-3-[(morpholin-4-ylacetyl)amino]phenyl}-5-phenylthiophene- 2-carboxamide (34 mg, 23percent). XH-NMR (400 MHz, DMSO-d6): delta [ppm] = 2.18 (s, 3H), 2.53-2.56 (m, 4H), 3.12 (s, 2H), 3.61-3.66 (m, 4H), 7.16 (d, J=8.3 Hz, 1H), 7.35 (t, J=7.2 Hz, 1H), 7.43 (t, J=7.5, 2H), 7.50 (dd, J=2.0, 8.3, 1H), 7.57 (d, 4.0 Hz, 1H), 7.71 (d, J=7.3 Hz, 2H), 8.01 (d, J=4.0 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H), 9.38 (s, 1H), 10.21 (s, 1H). LC-MS (Method 3): Rt = 1.23 min; MS (ESIpos): m/z = 436 ([M+H]+, 100percent), 871 ([2M+H]+, 70percent); MS (ESIneg): m/z = 434 ([M-H]", 100percent), 869 ([2M-H]", 10percent).
N-(5-amino-2-methoxyphenyl)-2-(morpholin-4-yl)acetamide[ No CAS ]
N-{4-methoxy-3-[(morpholin-4-ylacetyl)amino]phenyl}-5-phenylthiophene-2-carboxamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
49%
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 24h;
To a solution of N-(5-amino-2-methoxyphenyl)-2-(morpholin-4-yl)acetamide (prepared in a manner analogous to that described in intermediate 36, 0.075 g, 0.28 mmol) and 5-phenylthiophene-2- carboxylic acid (0.072 g, 0.35 mmol, 1.25 equiv) in DMF (3 mL) was added (benzotriazol-1- yloxy)tripyrrolidinophosphonium hexafluorophosphate (PYBOP, 0.18 g, 0.35 mmol, 1.25 equiv) followed by diisopropylethylamine (0.19 mL, 1.13 mmol, 4.0 equiv). The resulting mixture was stirred at room temperature for 24 h, was then concentrated under reduced pressure. The residue was treated with water (10 mL). The resulting mixture was extracted with ethyl acetate (10 mL). The organic phase was dried (Na2S04 anh), and concentrated under reduced pressure. The residue (0.3 g) was purified by HPLC (method 2) to give N-{4-methoxy-3-[(morpholin-4-ylacetyl)amino]phenyl}-5- phenylthiophene-2-carboxamide (62 mg, 49percent). XH-NMR (400 MHz, DMSO-d6): delta [ppm] = 2.49-2.57 (m, 4H), 3.12 (br s, 2H), 3.61-3.68 (m, 4H), 3.85 (s, 3H). 7.02 (d, J=9.0 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.43 (t, J=7.3 Hz, 2H), 7.52 (br d, J=8.5 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.71 (d, J=7.0 Hz, 2H), 8.00 (d, J=4.0 Hz, 1H), 8.47 (br s, 1H), 9.73 (br s, 1H), 10.19 (s, 1H). LC-MS (Method 3): t = 1.23 min; MS (ESIpos): m/z = 452 ([M+H]+, 100percent), 903 ([2M+H]+, 30percent); MS (ESIneg): m/z = 450 ([M-H]", 100percent), 901 ([2M-H]", 10percent).
General procedure: EDCI (1.1 equiv.) and HOBt (1.1 equiv) were added to a solution of the intermediate acid compound 1a-j (1 equiv.) in anhydrous DMF. The reaction mixture was stirred for 1h at ambient temperature, and the L-serine ester (1.1 equiv.) and DIEA (3 equiv.) were added. The solution was heated to 70°C for 6h and then cooled to room temperature. The reaction mixture was poured into ice water, and the resulting solid was filtered and dried to give the desired compound.
General procedure: EDCI (1.1 equiv.) and HOBt (1.1 equiv) were added to a solution of the intermediate acid compound 1a-j (1 equiv.) in anhydrous DMF. The reaction mixture was stirred for 1h at ambient temperature, and the L-serine ester (1.1 equiv.) and DIEA (3 equiv.) were added. The solution was heated to 70°C for 6h and then cooled to room temperature. The reaction mixture was poured into ice water, and the resulting solid was filtered and dried to give the desired compound.
(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxabor-ol-2-yl]butan-1-amine hydrochloride[ No CAS ]
(R)-(1-(5-phenylthiophene-2-carboxamido)-3-methylbutyl)boronic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
26%
Under nitrogen protection conditions, 5 mL of anhydrous dichloromethane was added5-phenylthiophene-2-carboxylic acid (22 mg, 0.11 mmol) was added, stirred at room temperature,HOBt (18 mg, 0.13 mmol) was added,After stirring for 10 minutes, EDC · HCl (25 mg, 0.13 mmol) was added,Compound 10-8-a (50 mg, 0.17 mmol) and DIPEA (0.04 mL, 0.22 mmol) were added to Example 6,TLC after 12 hours showed complete reaction,The reaction solution was washed with 5percent NaHCO3 solution, 10percent citric acid solution, 5percent NaHCO3 solution and saturated brine, respectively,Adding to the organic phase anhydrous sodium sulfate drying, drying and filtering,The solvent was removed using a rotary evaporator and the product was added directly to 5 mL of methanol,After stirring at room temperature, 2-methylpropylboronic acid (22 mg, 0.22 mmol) was added5 mL of n-hexane, followed by the addition of 1 M HCl solution (0.33 mL, 0.33 mmol)After 5 hours, the TLC assay showed complete reaction, the reaction solution was allowed to stand,The lower layer was washed with n-hexane, dried over anhydrous sodium sulfate,Drying after filtration, the use of rotary evaporator in addition to solvent,Column chromatography (dichloromethane: methanol = 50: 1) gave 9 mg of a pale yellow solid,Yield 26percent.
(S)-methyl (5-phenylthiophene-2-carbonyl)tryptophanate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
41%
General procedure: Furan-2-carboxylic acid, thiophene-2-carboxylic acid, 5-methylthiophene-2-carboxylic acid, benzofuran-2-carboxylic acid, benzothiophene-2-carboxylic acid, and amino acid ester hydrochlorides were obtained from commercial supplies and were used without further purification. To a two?necked flask, an amino acid ester hydrochloride (1.1 mmol), 1?ethyl?3?dimethylaminopropylcarbodiimide hydrochloride (EDC, 0.29 g, 1.5 mmol), HOBt (0.20 g, 1.5 mmol), Et3N (0.42 mL, 3.0 mmol), and CHCl3 or DMF (2.2 mL) were added, and the mixture was stirred at 0 °C for 10 min. Furan-2-carboxylic acid or thiophene-2-carboxylic acid dissolved in DMF (2.2 mL) was added, and then stirred for 17 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 20 mL). The organic phase was then washed with 3 N HCl aq. (3 x 20 mL), saturated NaHCO3 aq. (3 x 20 mL), and brine (20 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 1/1) to obtain the product. The purity of the product was confirmed by 1H-NMR. Stereochemistry of the final product was measured by high-performance liquid chromatography (HPLC) with a chiral column (Compound 16). The chart is shown in the supporting information.
(S)-methyl (5-phenylthiophene-2-carbonyl)phenylalaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
61%
General procedure: Furan-2-carboxylic acid, thiophene-2-carboxylic acid, 5-methylthiophene-2-carboxylic acid, benzofuran-2-carboxylic acid, benzothiophene-2-carboxylic acid, and amino acid ester hydrochlorides were obtained from commercial supplies and were used without further purification. To a two?necked flask, an amino acid ester hydrochloride (1.1 mmol), 1?ethyl?3?dimethylaminopropylcarbodiimide hydrochloride (EDC, 0.29 g, 1.5 mmol), HOBt (0.20 g, 1.5 mmol), Et3N (0.42 mL, 3.0 mmol), and CHCl3 or DMF (2.2 mL) were added, and the mixture was stirred at 0 °C for 10 min. Furan-2-carboxylic acid or thiophene-2-carboxylic acid dissolved in DMF (2.2 mL) was added, and then stirred for 17 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 20 mL). The organic phase was then washed with 3 N HCl aq. (3 x 20 mL), saturated NaHCO3 aq. (3 x 20 mL), and brine (20 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 1/1) to obtain the product. The purity of the product was confirmed by 1H-NMR. Stereochemistry of the final product was measured by high-performance liquid chromatography (HPLC) with a chiral column (Compound 16). The chart is shown in the supporting information.
(S)-ethyl (5-phenylthiophene-2-carbonyl)alaninate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
53%
General procedure: Furan-2-carboxylic acid, thiophene-2-carboxylic acid, 5-methylthiophene-2-carboxylic acid, benzofuran-2-carboxylic acid, benzothiophene-2-carboxylic acid, and amino acid ester hydrochlorides were obtained from commercial supplies and were used without further purification. To a two?necked flask, an amino acid ester hydrochloride (1.1 mmol), 1?ethyl?3?dimethylaminopropylcarbodiimide hydrochloride (EDC, 0.29 g, 1.5 mmol), HOBt (0.20 g, 1.5 mmol), Et3N (0.42 mL, 3.0 mmol), and CHCl3 or DMF (2.2 mL) were added, and the mixture was stirred at 0 °C for 10 min. Furan-2-carboxylic acid or thiophene-2-carboxylic acid dissolved in DMF (2.2 mL) was added, and then stirred for 17 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x 20 mL). The organic phase was then washed with 3 N HCl aq. (3 x 20 mL), saturated NaHCO3 aq. (3 x 20 mL), and brine (20 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/EtOAc = 1/1) to obtain the product. The purity of the product was confirmed by 1H-NMR. Stereochemistry of the final product was measured by high-performance liquid chromatography (HPLC) with a chiral column (Compound 16). The chart is shown in the supporting information.
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