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Synonyms: 3-Thienylacetic acid
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CAS No. : | 6964-21-2 |
Formula : | C6H6O2S |
M.W : | 142.18 |
SMILES Code : | C1=CSC=C1CC(O)=O |
Synonyms : |
3-Thienylacetic acid
|
MDL No. : | MFCD00005473 |
InChI Key : | RCNOGGGBSSVMAS-UHFFFAOYSA-N |
Pubchem ID : | 23404 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With acetyl chloride; at 0 - 20℃; | Acetyl chloride (7.50 ml, 106 mmol) was added dropwise to a solution of <strong>[6964-21-2]3-thiopheneacetic acid</strong> (5.00 g, 35.3 mmol) in dry MeOH (150 ml) at 0 C. The mixture was left to slowly reach room temperature and stirred overnight. Solvents were evaporated and residue filtered through a short plug of silica gel (DCM) to give a quantitative yield of the title compound as an oil. 1H NMR (400 MHz, CDCl3): δ 3.64 (s, 2H), 3.70 (s, 3H), 7.03-7.05 (m, 1H), 7.14-7.15 (m, 1H), 7.27-7.29 (m, 1H). |
100% | With acetyl chloride; at 0 - 20℃; | Acteyl chloride (7.50 ml, 106 mmol) was added dropwise to a solution of <strong>[6964-21-2]3-thiopheneacetic acid</strong> (5.00 g, 35.3 mmol) in dry MeOH (150 ml) at 0 C. The mixture was left to slowly reach room temperature and stirred overnight. Solvents were evaporated and residue filtered through a short plug of silica gel (DCM) to give a quantitative yield of the title compound an oil. 1H MR (400 MHz, CDC13): 3.64 (s, 2H), 3.70 (s, 3H), 7.03-7.05 (m, 1H), 7.14 7.15 (m, 1H), 7.27-7.29 (m, 1H). |
80% | With sulfuric acid; at 0℃; for 14h;Reflux; | To a stirred solution of 2-(thiophen3-yflacetic acid (5 g, 35.2 mmoi) in methanol (60 ml) at 0 cc was added drop wise solution of H2S04 (6.92 ml, 130 mmofl, The reaction mixture was refluxed for 1 4h, After completion of reaction, methanol was evaporated and residue was further diluted with dichioromethane, An organic layer was washed with saturated sodium bicarbonate solution and evaporated under reduced pressure to afford methyl 2-(thiophen-3-yl)acetate (4.4 g, 80%) as oil. |
With sulfuric acid; for 24h;Reflux; | [00165] Methyl thiophene-3-acetate LXXXIV (M3) was synthesized following the method reported by Kim, L. Chen, Gong, Y. Osada, Macromolecules 1999, 32, 3964- 3969, the disclosure of which is incorporated herein by reference in its entirety. Briefly, 3-Thiopheneacetic acid (8.52 g, 60 mmol) was dissolved in 50 mL of methanol with 2 drops of concentrated H2504. The mixture was heated in an oil bath and refluxed for 24 hours. After the removal of methanol, the crude product was redissolved in diethylether, washed with DI water and dried with anhydrous magnesium sulfate. Pure product was obtained after filtration and evaporation of solvent. The structure was analyzed and confirmed with ‘H NMR spectroscopy. | |
With thionyl chloride; at 0 - 68℃; for 12h; | To a solution of 2-(3-thienyl)acetic acid (12.1, 5.40 g, 37.9 mmol, 1 equivalent) in MeOH (50 mL) was added thionyl chloride (6.78 g, 56.9 mmol, 4.13 mL, 1.5 equivalent) at 0 C. The mixture was heated to 68 C. for 12 hours. After this time, the reaction solution was evaporated and to this residue was added saturated sodium bicarbonate solution (80 mL). The suspension was extracted with ethyl acetate (35 mL*3), then dried over sodium sulfate and the solvent was removed to afford methyl 2-(thiophen-3-yl)acetate (12.2, 5.8 g, yield=93%) as a yellow oil without further purification. | |
With thionyl chloride; at 0 - 25℃; for 1h; | To a solution of 2-(thiophen-3-yl)acetic (500 mg, 3.52 mmol) in MeOH (5 ml) at 0 C was added SOCl2 (1.02 ml, 14.07 mmol) and stirred at 25 C for 1 h. The RM was concentrated in vacuo to give methyl 2-(thiophen-3-yl)acetate as a yellow oil.1H NMR (400 MHz, MeOD) d 7.35 (dd, J = 5, 3 Hz, 1H), 7.21 (dd, J = 3, 1 Hz, 1H), 7.03 (dd, J = 5, 1 Hz, 1H), 3.69 (s, 3H), 3.63 (s, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With oxalyl dichloride;N,N-dimethyl-formamide; In tetrahydrofuran; | The procedure described above for the synthesis of 1-chloro-3-[2-(3-methylbenzo[b]thiophen-2-yl)propan-2-one was followed, reacting thiophene-3-acetic acid (5.32 g, 37.4 mmol) with oxalyl chloride (3.6 mL, 5.2 g, 41 mmol, then ethereal diazomethane, then dry HCl gas. Work-up gave pure product, a brown oil which solidified upon refrigeration to a golden-brown, waxy solid (6.52 g, 100% yield): 1H NMR (400 MHz, CDCl3) δ 3.94 (s, 2H) 4.13 (s, 2H) 6.99 (d, J=5.1 Hz, 1H) 7.16 (dd, J=1.5, 0.8 Hz, 1H) 7.33 (dd, J=4.9, 2.9 Hz, 1H). | |
With oxalyl dichloride;N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 3h; | General method 2: preparation of ethyl-5-substituted-1 ,2,4-oxadiazole-3carboxylateStep I A mixture of a 2-aryl acetic acid (3.78 mmol; 1 equivalent) and oxalyl chloride (4.16 mmol,1.1 equivalents) in dichloromethane (12 ml_) with few drops of DMF was stirred at room temperature for 3 h.Step IlThe resulting solution from step I was added to a mixture of ethyl 2-amino-2- (hydroxyimino)acetate (3.78 mmol 1 equivalent) and N1N diisopropylethylamine (6.06 mmol, 1.60 equivalents) in dichloromethane (6 ml.) at -15C. The reaction mixture was then stirred at room temperature for 12 to 36 h and poured into a mixture of ice and water. The formed precipitate was filtered off. When a precipitate was not formed, the organic layer was separated, dried over magnesium sulphate, filtered and evaporated to dryness. Step III The precipitate or the residue from step Il was refluxed in a sealed tube with pyridine (18 ml.) for 20 h and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica to yield the desired compound.; INTERMEDIATE 105 - PREPARATION OF ethyl 5-(thiophen-3-ylmethyl)-1 ,2,4- oxadiazole-3-carboxylate; This compound was prepared according to general method 2 with (step I) 2-(thiophen-3- yl)acetic acid (0.568 g; 3.78 mmol), oxalyl chloride (0.352 ml 4.16 mmol) in dichloromethane (12 ml.) with few drops of DMF; (step II) ethyl 2-amino-2- (hydroxyimino)acetate (0.5 g; 3.78 mmol); N, N diisopropylethylamine (1.05 ml 6.06 mmol) in dichloromethane (6 mL) and (step III) pyridine (18 ml_).The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.343 g (38%) of ethyl 5-(thiophen-3-ylmethyl)-1 ,2,4-oxadiazole-3-carboxylate as a yellow solid. ESI/APCI(+): 239(M+H). | |
With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 20℃; for 18h;Inert atmosphere; | General procedure: Carboxylic acid (0.735 mmol, 1.0 eq.) was added to a flame dried microwave vial under Argon. DCM (3 mL) was added, followed by oxalyl chloride (0.075mL, 0.885 mmol, 1.2 eq) and DMF (1 drop). The reaction mixture was stirred at room temperature under Argon for 18 hours. The solvent was removed under reduced pressure to afford the crude product. The resulting crude material was used directly for the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With sulfuric acid; for 24h;Reflux; | Step 1: Preparation of ethyl 2-(thiophen-3-yl)acetate 10.75 g (74.1 mmol) of 2-(thiophen-3-yl)acetic acid were solubilized in 100 ml of ethanol, 6 ml (72 mmol) of sulfuric acid were added to this solution. The mixture was heated with magnetic stirring with reflux for 24 h. After returning to r.t., the mixture was concentrated in vacuo, the crude residue was treated with 100 ml of a mixture consisting of water and ice. The aqueous phase was extracted with 2*100 ml of ethyl acetate. The combined organic phases were washed with 100 ml of water, 100 ml of a saturated NaHCO3 aqueous solution and 100 ml of a saturated NaCl aqueous solution and then dried on MgSO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo in order to obtain 12.27 g (yield=97%) of ethyl 2-(thiophen-3-yl)acetate as a colorless oil. LC-MS: m/z=non-ionized. 1H NMR (300 MHz, CDCl3) δ 7.24 (dd, J=6.0, 3.0 Hz, 1H), 7.16-7.07 (m, 1H), 7.02 (dd, J=4.9, 1.1 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.23 (t, J=7.1 Hz, 3H). |
97% | With sulfuric acid; for 24h;Reflux; | 10.75 g (74.1 mmol) of 2-(thiophen-3-yl)acetic acid were solubilized in 100 ml of ethanol, 6 ml (72 mmol) of sulfuric acid were added to this solution. The mixture was heated with magnetic stirring with reflux for 24 h. After returning to r.t., the mixture was concentrated in vacuo, the crude residue was treated with 100 ml of a mixture consisting of water and ice. The aqueous phase was extracted with 2*100 ml of ethyl acetate. The combined organic phases were washed with 100 ml of water, 100 ml of a saturated NaHCO3 aqueous solution and 100 ml of a saturated NaCl aqueous solution and then dried on MgSO4 which was then removed by filtration. The obtained filtrate was concentrated in vacuo in order to obtain 12.27 g (yield=97%) of ethyl 2-(thiophen-3-yl)acetate as a colorless oil. LC-MS: m/z=non-ionized. 1H NMR (300 MHz, CDCl3) δ 7.24 (dd, J=6.0, 3.0 Hz, 1H), 7.16-7.07 (m, 1H), 7.02 (dd, J=4.9, 1.1 Hz, 1H), 4.13 (q, J=7.1 Hz, 2H), 3.62 (s, 2H), 1.23 (t, J=7.1 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; | Take a 100mL round bottom flask,DCC (1.0320g, 5mmol)And DMAP (0.1222 g, 1 mmol) was added to 10 mL of dry dichloromethane.Stir until all dissolved.3-Thiopheneacetic acid (0.7109 g, 5 mmol) was dissolved in 20 mL of dry dichloromethane, and then slowly added dropwise to the above solution using a constant pressure dropping funnel.Stir for 24-72h.It was dried to dryness and then subjected to column chromatography (eluent: ethyl acetate: petroleum ether: = 1:5) to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 2 This Example illustrates the preparation of (E)-methyl 3-methoxy-2-(3-thienyl)propenoate (compound number 1 of Table II). Methyl 3-thienylacetate was prepared by heating 3-thienylacetic acid in acidic methanol. It is an oil, 1H nmr: delta 3.71 (2H,s), 3.76 (3H,s) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-chloro-succinimide; In acetic acid; at 20℃; for 12h; | A solution of 3-thiophene acetic acid (1.42 g, 10.0 mmol) in acetic acid (10 mL) was treated with N-chlorosuccinimide (3. 1 g, 23 mmol, 2.3 equivalents), and the solution was stirred for 12 h at room temperature then concentrated in vacuo. The residue was diluted with water and stirred for 1 h whereupon the resulting solid was collected by filtration. The solid was dried in a vacuum oven at room temperature for 10 hours providing 1.51 g (72%) of (2, 5-dichlorothien-3-vl) acetic acid as a brown solid, which was used as such in the next step. MS (ESI) m/z 209/211/213 ( [M-H]-). |
72% | With N-chloro-succinimide; In acetic acid; at 20℃; for 12h; | A solution of 3-thiophene acetic acid (1.42 g, 10.0 mmol} in acetic acid (10 mL) was treated with N-chlorosuccinimide (3. 1g, 23 mmol, 2.3 equivalents), and the solution was stirred for 12 h at room temperature then concentrated in vacuo. The residue was diluted with water and stirred for 1 h whereupon the resulting solid was collected by filtration. The solid was dried in a vacuum oven at room temperature for 10 hours providing 1.51 g (72%) of (2. 5-dichlorothien-3-yl) acetic acid as a brown solid, which was used as such in the next step. MS (ESI) m/z 209/211/213 ( [M-H]-). |
72% | With N-chloro-succinimide; In acetic acid; at 20℃; for 12h; | Step 1: A solution of 3-thiophene acetic acid (1.42 g, 10.0 mmol) in acetic acid (10 mL) was treated with N-chlorosuccinimide (3. 1g, 23 mmol, 2.3 equivalents), and the solution was stirred for 12 h at room temperature then concentrated in vacuo. The residue was diluted with water and stirred for 1 h whereupon the resulting solid was collected by filtration. The solid was dried in a vacuum oven at room temperature for 10 hours providing 1.51 g (72%) of (2, 5-dichlorothien-3-yl) acetic acid as a brown solid, which was used as such in the next step. MS (ESI) m/z 209/211/213 ( [M-H]-). |
72% | With N-chloro-succinimide; In acetic acid; at 20℃; for 12h; | Example 141: 1-(2, 5-dichlorothien-3-vl)-2-piperazine-1-ylethyllcyclohexanol dihvdrochloride [0391] Step 1: A solution of 3-thiophene acetic acid (1.42 g, 10.0 mmol) in acetic acid (10 mL) was treated with N-chlorosuccinimide (3. 1g, 23 mmol, 2.3 equivalents), and the solution was stirred for 12 h at room temperature then concentrated in vacuo. The residue was diluted with water and stirred for 1 h whereupon the resulting solid was collected by filtration. The solid was dried in a vacuum oven at room temperature for 10 hours providing 1.51 g (72%) of (2. 5-dichlorothien-3-yl) acetic acid as a brown solid, which was used as such in the next step. MS (ESI) m/z 209/211/213 ( [M-H]-). |
72% | With N-chloro-succinimide; In acetic acid; at 20℃; for 12h; | A solution of 3-thiophene acetic acid (1.42 g, 10.0 mmol) in acetic acid (10 mL) was treated with N-chlorosuccinimide (3. 1g, 23 mmol, 2.3 equivalents), and the solution was stirred for 12 h at room temperature then concentrated in vacuo. The residue was diluted with water and stirred for 1 h whereupon the resulting solid was collected by filtration. The solid was dried in a vacuum oven at room temperature for 10 hours providing 1.51 g (72%) of (2. 5-dichlorothien-3-yl) acetic acid as a brown solid, which was used as such in the next step. MS (ESI) m/z 209/211/213 ( [M-H]-). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example B60 Synthesis of N-[(3-thienyl)acetyl]alanine Iso-butyl Ester Following General Procedure BI above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H). | ||
Example B60 Synthesis of N-[(3-Thienyl)acetyl]alanine iso-Butyl Ester Following General Procedure BI above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. | ||
Example 60 Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester Following General Procedure I above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1 H-nmr (CDCl3): δ=7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H). |
EXAMPLE A60 Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester Following General Procedure I' above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H). | ||
EXAMPLE A60 Synthesis of N-[(3-thienyl)acetyl]alanine Iso-butyl Ester Following General Procedure I' above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H). | ||
Example A60 Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester Following General Procedure I' above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H). | ||
With 1-(3-(1-pyrrolidinyl)-propyl)-3-ethylcarbodiimide; In chloroform; at 23℃; for 96h; | Example 60 Synthesis of N-[(3-thienyl)acetyl]alanine iso-butyl ester Following General Procedure I above, and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and alanine iso-butyl ester (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ = 7.33 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.09 (m, 1H), 4.58 (m, 1H), 3.88 (m, 2H), 3.60 (s, 2H), 1.91 (m, 1H), 1.37 (d, 3H) 0.92 (d, 6H). Optical Rotation: [α]23-52 (c 1 MeOH) ã 589 nm. C13H19NO3S (MW = 269, Mass Spectroscopy (MH+ 269)). GENERAL PROCEDURE IP-EPC coupling P-EPC coupling employs an amino acid ester and a substituted acetic acid compound. The acetic acid derivative is well known in the art and is typically commercially available. The amino acid ester is prepared by conventional methods from the known and typically commercially available N-BOC amino acid as described in GENERAL PROCEDURE J below. Specifically, the appropriate amino ester free base (0.0346 mmols) and substituted phenylacetic acid (0.069 mmols) were dissolved in 2.0 mL CHCl3 (EtOH free), treated with 150 mg of P-EPC (0.87 meq./g) and the reaction was mixed for 4 days at 23C. The reaction was filtered through a plug of cotton, rinsed with 2.0 mL of CHCl3 and the filtrate evaporated under a stream of nitrogen. The purity of each sample was determined by 1H NMR and ranged from 50% to >95%. Between 8.0 and 15.0 mg of final product was obtained from each reaction and was tested without additional purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example B18 Synthesis of 2-[(thien-3-yl)acetamido]butyric Acid Iso-butyl Ester Following General Procedure BI above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H). | ||
Example B18 Synthesis of 2-[(Thien-3-yl)acetamido]butyric Acid iso-Butyl Ester Following General Procedure BI above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H). | ||
Example 18 Synthesis of 2-[(thien-3-yl)acetamido]butyric acid iso-butyl ester Following General Procedure I above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1 H-nmr (CDCl3): δ=7.37 (m, 1H), 7.16 (m, 1i), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H). |
EXAMPLE A18 Synthesis of 2-[(thien-3-yl)acetamido]butyric acid iso-butyl ester Following General Procedure I' above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H). | ||
Example A18 Synthesis of 2-[(thien-3-yl)acetamido]butyric Acid Iso-butyl Ester Following General Procedure I' above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tIc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, H), 0.91 (d, 61), 0.86 (t, 3H). | ||
EXAMPLE A18 Synthesis of 2-[(thien-3-yl)acetamido]butyric Acid Iso-butyl Ester Following General Procedure I' above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J' above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ=7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H). | ||
With 1-(3-(1-pyrrolidinyl)-propyl)-3-ethylcarbodiimide; In chloroform; at 23℃; for 96h; | Example 18 Synthesis of 2-[(thien-3-yl)acetamido]butyric acid iso-butyl ester Following General Procedure I above and using <strong>[6964-21-2]3-thiopheneacetic acid</strong> (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure J above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure. NMR data was as follows: 1H-nmr (CDCl3): δ = 7.37 (m, 1H), 7.16 (m, 1H), 7.04 (m, 1H), 6.05 (bd, 1H), 4.57 (m, 1H), 3.66 (s, 2H), 1.93 (m, 2H), 1.67 (m, 1H), 0.91 (d, 6H), 0.86 (t, 3H). GENERAL PROCEDURE IP-EPC coupling P-EPC coupling employs an amino acid ester and a substituted acetic acid compound. The acetic acid derivative is well known in the art and is typically commercially available. The amino acid ester is prepared by conventional methods from the known and typically commercially available N-BOC amino acid as described in GENERAL PROCEDURE J below.Specifically, the appropriate amino ester free base (0.0346 mmols) and substituted phenylacetic acid (0.069 mmols) were dissolved in 2.0 mL CHCl3 (EtOH free), treated with 150 mg of P-EPC (0.87 meq./g) and the reaction was mixed for 4 days at 23C. The reaction was filtered through a plug of cotton, rinsed with 2.0 mL of CHCl3 and the filtrate evaporated under a stream of nitrogen. The purity of each sample was determined by 1H NMR and ranged from 50% to >95%. Between 8.0 and 15.0 mg of final product was obtained from each reaction and was tested without additional purification |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | EXAMPLE 13; 3-[4-(5-Methoxy-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-yl)-phenyl]-2-[3-methyl-2-(2-thiophen-3-yl-acetylamino)-butyrylamino]-propionic acid, Cpd 107; A solution of Compound 12a (17 mg, 0.027 mmol), Compound 13a (4 mg, 0.03 mmol), EDC (8 mg, 0.04 mmol), HOBt (7 mg, 0.054 mmol), and DIEA (16 μL, 0.09 mmol) in 5 mL of CH2Cl2 was allowed to stir at rt overnight. The mixture was washed with 10% citric acid (aq) followed by saturated NaHCO3 (aq) solution. The organic layer was dried (MgSO4), filtered, and concentrated to yield Compound 13b (12 mg). |
Yield | Reaction Conditions | Operation in experiment |
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72% | In acetic acid; at 20℃; for 12h; | A solution of 3-thiophene acetic acid (1.42 g, 10.0 mmol) in acetic acid (10 mL) was treated with N-chlorosuccinimide (3.1 g, 23 mmol, 2.3 equivalents), and the solution was stirred for 12 h at room temperature then concentrated in vacuo. The residue was diluted with water and stirred for 1 h whereupon the resulting solid was collected by filtration. The solid was dried in a vacuum oven at room temperature for 10 hours providing 1.51 g (72%) of (2,5-dichlorothien-3-yl)acetic acid as a brown solid, which was used as such in the next step. MS (ESI) m/z 209/211/213 ([M-H]-). |
Yield | Reaction Conditions | Operation in experiment |
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With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 20℃; for 16h; | A stirred solution of 711 mg (5.0 mmol) of 3-thienylacetic acid, 720 mg (5.0 mmol) of Meldrum's acid, and 610 mg (5. 0 mmol) of 4-dimethylaminopyridine in 10 mL of DCM was treated with a solution of 1. 03 g (5.0 mmol) of DCC in 10 mL of DCM. The resulting solution was stirred at room temperature for 16 h, during which time a white precipitate appeared in the reaction mixture. The reaction mixture was filtered through a pad of Celite to remove the precipitated dicyclohexylurea and the filtrate was washed successively with 1 N HCl (1 x 15 mL), H2O (1 x 15 mL), brine (1 x 15 mL). The filtrate was dried (MgS04) and solvents were removed in vacuo. The resulting crude oil was dissolved in 8 mL of absolute ethanol and heated to 80 C for 4 h. The reaction mixture was cooled to room temperature and ethanol was removed in vacuo. Purification of the resulting oil by silica gel flash column chromatography eluting with hexanes/EtOAc 2: 1 afforded 1.02 g (97%) of the title compound as a yellow oil :'H NMR (CDC13, 400 MHz) 8 7.27 (m, 1 H), 7.06 (s, 1 H), 6.92 (m, 1 H), 4.09 (q, 2 H, J= 6. 8), 3.83 (s, 2 H), 3.41 (s, 2 H), 1.22 (t, 3 H, J= 6. 8). |
Yield | Reaction Conditions | Operation in experiment |
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68% | With selenium(IV) oxide; acetic acid; In tetrahydrofuran; 1,4-dioxane; water; ethyl acetate; | (1) A mixture of thiophen-3-acetic acid (56.9 g), selenium dioxide (66.6 g), dioxane (500 ml), acetic acid (35 ml) and water (10 ml) is refluxed with stirring for 24 hours and filtered. The filtrate is concentrated and to the residue is added ethyl acetate (700 ml). The insoluble materials are filtered off and the filtrate is dried and then the solvent is distilled off. The residue is dissolved in tetrahydrofuran (1 l) and thereto is added diphenyldiazomethane (103 g) under ice cooling over a period of 30 minutes. The mixture is stirred at room temperature for 1 hour and then filtered. The filtrate is concentrated and purified by silica gel column chromatography (solvent: hexane/ethyl acetate) to give (3-thienyl)glyoxylic acid diphenylmethyl ester (88.1 g). Yield: 68 % M.p.: 63 - 64C |
Yield | Reaction Conditions | Operation in experiment |
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55% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; N,N-dimethyl-formamide; at 70℃; | A solution of 3,4-dihydro-2H-1,4-benzoxazine (0.52 g, 3.8 mmol) and thiophene-3-acetic acid (0.82 g, 5.7 mmol) in 1:1 CH2Cl2:DMF (20 mL) was treated with DIPEA (2.6 ml, 15 mmol), HOBt (1.29 g, 9.5 mmol), and EDCI (1.83 g, 9.5 mmol) and stirred at 70 C. overnight. The reaction was then diluted with CH2Cl2, washed with saturated aqueous NaHCO3, dried over Na2SO4, and concentrated. Chromatography (0-10% 1 N NH3-MeOH/EtOAc) provided 2A as a red solid (0.54 g, 55%) |
Yield | Reaction Conditions | Operation in experiment |
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Reference Production Example 9 [Show Image] To a mixture of 3.08 g of 2-bromo-4'-chloropropiophenone, 1.79 g of <strong>[6964-21-2]3-thiopheneacetic acid</strong>, acetonitrile and 10 ml of DMF was added 1.53 g of triethylamine, and the mixture was stirred for 2 hours at room temperature. The resultant mixture was cooled to 0C, and 4.60 g of 1,8-diazabicyclo[5.4.0]undec-7-ene was added dropwise into this, and the mixture was stirred for 3 hours at room temperature. Then, the reaction mixture was stirred for 11 hours at room temperature while blowing air into the reaction mixture. To the reaction mixture was added 200 ml of 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and saturated brine sequentially, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure to obtain 3.98 g of 4-(4-chlorophenyl)-5-hydroxy-5-methyl-3-(3-thienyl)-2(5H)-fu ranone. |
Yield | Reaction Conditions | Operation in experiment |
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69% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 20h; | Step A: N-{3-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(3-thienyl)acetamide To solution of {3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}amine (125 mg, 0.4 mmol) (see Example 2, step A) in THF (5 mL) were added 3-thienylacetic acid (67 mg, 0.47 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.47 mmol), N-hydroxybenzotriazole (63 mg, 0.47 mmol), and diisopropylethylamine (200 μL, 1.2 mmol). After 20 h at rt, the reaction mixture was diluted with DCM, washed with water, dried over Na2SO4, filtered, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 69% yield. ES-LC/MS m/z=446 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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47% | Step C. Preparation of N-{3-[3-(2-[3-(1,3-oxazol-5-yl)phenyl]amino}-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2-(3-thienyl)acetamide (title compound) To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[3-(1,3-oxazol-5-yl)phenyl]-2-pyrimidinamine (50 mg, 0.112 mmol) in 5:1 THF:DMA (2 mL) was added HOBT (46 mg, 0.34 mmol), 0.28 g polystyrene-bound carbodiimide resin (280 mg, 0.34 mmol), and 3-thienylacetic acid (48 mg, 0.34 mmol). After stirring at rt for 48 h, excess Dowex 550A OH anion-exchange resin was added and the resulting mixture was allowed to stir overnight. The solids were then removed by vacuum filtration and rinsed with THF (25 mL) and MeOH (25 mL). The filtrate was concentrated under reduced pressure and purified by mass-guided prep LC (C18, 15% H20 (with 0.1% formic acid)/CH3OH to 100% CH3OH gradient) to afford the title compound (30 mg, 47%). 1H NMR (400 MHz, DMSO-d6) δ 3.65 (s, 2H), 6.51 (d, 1H, J=5.37 Hz), 7.07-7.12 (m, 2H), 7.23-7.48 (m, 7H), 7.55 (s, 1H), 7.68-7.76 (m, 2H), 7.89 (s, 1H), 8.20 (s, 1H), 8.27 (d, 1H, J=5.37 Hz), 8.38 (s, 1H), 8.50-8.51 (m, 1H), 8.81 (d, 1H, J=6.84 Hz), 9.73 (s, 1H), 10.28 (s, 1H). ES-LC/MS m/z=570 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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50% | Step B. N-(3-{3-[2-({3-[(Dimethylamino)methyl]phenyl}amino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)-2-(3-thienyl)acetamide (title compound)To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-{3-[(dimethylamino)methyl]phenyl}-2-pyrimidinamine (50 mg, 0.115 mmol) in 5:1 THF:DMA (2 mL) was added HOBT (46 mg, 0.34 mmol), 0.28 g polystyrene-bound carbodiimide resin (280 mg, 0.34 mmol), and 3-thienylacetic acid (48 mg, 0.34 mmol). After stirring at rt for 48 h, excess Dowex 550A OH anion-exchange resin was added and the resulting mixture was allowed to stir overnight. The solids were then removed by vacuum filtration and rinsed with THF (25 mL) and MeOH (25 mL). The filtrate was concentrated under reduced pressure and purified by column chromatography (0-100% 9:1:0.1 DCM:MeOH: NH4OH) to afford the title compound (32 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 2.27 (s, 6H), 3.46 (s, 2H), 3.78 (s, 2H), 6.54 (d, 1H, J=5.31 Hz), 6.90 (dd, 1H, J=1.47, 6.96 Hz), 6.99-7.00 (m, 1H), 7.06 (dd, 1H, J=1.28, 4.94 Hz), 7.22-7.38 (m, 8H), 7.53-7.56 (m, 2H), 7.61-7.63 (m, 1H), 7.77-7.80 (m, 1H), 8.16 (d, 1H, J=5.31 Hz), 8.32-8.35 (m, 1H), 8.46-8.48 (m, 1H). ES-LC/MS m/z=560 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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72% | With triethylamine; HATU; In tetrahydrofuran; at 20℃; | Step C: N-[3-(3-{2-[(3-[2-(dimethylamino)ethyl]oxy}phenyl)amino]-4-pyrimidinyl}pyrazolo[1,5-a]pyridin-2-yl)phenyl]-2-(3-thienyl)acetamide (title compound) To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-[2-(dimethylamino)ethyl]oxy}phenyl)-2-pyrimidinamine (140 mg, 0.3 mmol) in THF were added 3-thienylacetic acid (51 mg, 0.36 mmol), TEA (125 μL, 0.9 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (136 mg, 0.36 mmol). The reaction was stirred overnight at rt, after which the reaction mixture was diluted with DCM, washed with 5% aqueous Na2CO3, dried over Na2SO4, and adsorbed onto silica gel. The crude product was purified by column chromatography and lyophilized to generate the title compound in 72% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.27 (s, 1H), 9.55 (s, 1H), 8.83 (d, J=6.7 Hz, 1H), 8.51 (d, J=8.8 Hz, 1H), 8.26 (d, J=5.1 Hz, 1H), 7.89 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.40-7.53 (m, 4H), 7.26-7.31 (m, 3H), 7.08-7.18 (m, 3H), 6.53 (d, J=8.2 Hz, 1H), 6.48 (d, J=5.3 Hz, 1H), 3.99 (t, J=5.7 Hz, 2H), 3.66 (s, 2H), 2.58 (t, J=5.9 Hz, 2H), 2.18 (s, 6H). ES-LC/MS m/z=588 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
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27% | A solution of 3-thienylacetic acid (2.544 g, 17.89 mmol) in dry tetrahydrofuran (100 mL) was cooled with an ICE/SALT bath TO-10 C and the solution of lithium HEXAMETHYLSILAZANE (40 ML, 1M, in THF) was added drop-wise, over a period of 30 minutes. After additional stirring at cold for 30 minutes, the neat 2, 2-DIMETHOXY-1-BROMOETHANE was added via syringe. The cooling bath was removed and the stirring at room temperature was continued for another 3 hrs. The reaction mixture was poured onto water (100 mL), the non-acidic components were extracted with diethyl ether (2 x 50 mL). The pH of the aqueous solution was set to 3, (HCI, 2 N) and the crude acid was extracted into diethyl ether (3 x 50 mL). The combined organic extracts were dried with anhydrous sodium sulfate, and the solvent was evaporated to dryness to leave 1.12 g (27 %) of the crude acid, used in the next step without additional purification. This racemic acid could be resolved into its respective enantiomers using (R)-AND/OR (S) -a- PHENYLETHYLAMINE salts via crystallization from ethyl acetate. The acid, which ultimately led to the more active enantiomer of the racemate shown under Example 30, was obtained by crystallizations using the salts derived form the (S)-AMINE |
Yield | Reaction Conditions | Operation in experiment |
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Example 41 Preparation of methyl 2-(thiophen-3-yl)acetate (E41) To 2-(thiophen-3-yl)acetic acid in MeOH at 0 C. was added TMS-CH2N2. The solution was stirred for 3 hours then quenched with a few drops of AcOH. The solvents were evaporated. Column chromatography (SiO2, 3-15% EtOAc/Hex) gave pure methyl 2-(thiophen-3-yl)acetate (E41). | ||
In methanol; at 0℃; for 3h; | To 2-(thiophen-3-yl)acetic acid in MeOH at 0C was added TMS-CH2N2. The solution was stirred for 3 hours then quenched with a few drops of AcOH. The solvents were evaporated. Column chromatography (Si02, 3-15% EtO Ac/Hex) gave pure methyl 2- (thiophen-3-yl)acetate (E41). |
Yield | Reaction Conditions | Operation in experiment |
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4% | 5. 3,3-Dimethyl-6-(3-thienylmethyl)-2,3,4,7-tetrahydro-1 H-indolo[2,3-c]quinolin-1 -one3-Hydroxy-2-(1 H-indol-3-yl)-5,5-dinnethylcyclohex-2-en-1-one (example A1 ) (1.0 g) is dissolved in dry dichloroethane (15 ml) and the solution is cooled to O0C (ice bath). Zinc chloride (1 M in diethyl ether, 8.2 ml) is added drop by drop and the mixture is stirred at O0C for 30 min. In parallel, 3- thiopheneacetic acid (1.17 g) is dissolved in trifluoroacetic acid anhydride (1.17 ml) and the mixture is stirred for 20 min at room temperature. The formed mixed anhydride is diluted with dichloroethane (5 ml) and added to the zinc chloride mixture, prepared above, within 5 min at O0C. The mixture is stirred for 5 h at room temperature. After that, ammonia (7M in methanol, 5.6 ml) and ammonium acetate (3.02 g) are added and the mixture is refluxed for 18 h. After cooling, 2M am- monia solution (30 ml) is added and the aqueous phase is extracted with dichloromethane (2 x 30 ml). The combined organic extracts are washed with 2M ammonia solution (2 x 50 ml), dried (MgSO4) and concentrated in vacuo. The crude product is purified by column chromatography (silica gel, eluting with gradient dichloromethane / ethyl acetate 98:2 to 90:10 (v/v)) to yield 57 mg (4%) of the title compound. 1H-NMR (300 MHz, d6-DMSO + CD3OD); δ = 1.10 (s, 6H), 2.68 (s, 2H), 3.16 (s, 2H), 4.52 (s, 2H), 7.10 (dd, J = 1.5 Hz, 4.9 Hz, 1 H), 7.23 (ddd, J = 1.5 Hz, 6.4 Hz, 8.1 Hz, 1 H), 7.26-7.29 (m, 1 H), 7.39-7.44 (m, 1 H), 7.55-7.66 (m, 1 H), 9.24 (d, J = 8.1 Hz, 1 H). MS (MH+ found) = 361.3 |
Yield | Reaction Conditions | Operation in experiment |
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Method B 1-{4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}-2-(thiophen-3-yl)ethanone (I-63) Thiophen-3-ylacetic acid (156 mg) and Hünig base (323 mg) are dissolved in dichloromethane (10 ml) and stirred for 30 min. 4-[4-(2-Phenylethyl)-1,3-thiazol-2-yl]piperidine hydrochloride (II-1, 309 mg), prepared according to Process 1.2, is added, and the mixture is stirred for a further 5 min before bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (599 mg) is added. The reaction mixture is stirred at room temperature overnight. After removal of the solvent under reduced pressure, the residue is purified chromatographically. This gives 1-{4-[4-(2-phenylethyl)-1,3-thiazol-2-yl]piperidin-1-yl}-2-(thiophen-3-yl)ethanone (99 mg). 1H NMR (DMSO-d6): δ 7.44-7.43 (m, 1H), 7.28-7.12 (m, 6H), 7.05 (s, 1H), 6.99 (d, 1H), 4.38 (bs, 1H), 3.99 (bs, 1H), 3.72 (s, 2H), 3.22-3.15 (m, 2H), 2.96 (s, 4H), 2.81 (bs, 1H), 2.00 (d, 2H), 1.52 (m, 2H) ppm MS (ESI): 397 ([M+H]+) |
Yield | Reaction Conditions | Operation in experiment |
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100% | With N-chloro-succinimide; acetic acid; In benzene; at 80℃; for 1h;Inert atmosphere; | 2-(thiophen-3-yl)acetic acid (150 mg, 1.06 mmol) was dissolved in acetic acid/benzene (1:1, 2 mL) and stirred under nitrogene atmosphere. N-chlorosuccinimide (141.0 mg, 1.06 mmol, 1 eq) was added and the reaction mixture was heated to 80C. After 1 h the solution was poured into ice water and extracted with DCM (3x20 mL). The combined organic layers were dried (MgSO4), the solvent evaporated in vacuo and purified by column chromatography (1% MeOH, 1% acetic acid in DCM) to yield 188 mg (1.06 mmol, quant.) of the title compound. TLC: Rf (1 % MeOH, 1 % AcOH in DCM): 0.25 |
Yield | Reaction Conditions | Operation in experiment |
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80% | 5.169 N-[2-(2,6-DIOXO-PIPERIDIN-3-YL)-1,3-DIOXO-2,3-DIHYDRO-1H-ISOINDOL-4-YLMETHYL]-2-THIOPHEN-3-YL-ACETAMIDE To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in acetonitrile (60 mL), was added 1,8-diazabicyclo[5,4,0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzotriazole (0.4 g, 2.6 mmol) and <strong>[6964-21-2]3-thiopheneacetic acid</strong> (0.3 g, 2.4 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.2 mmol). The mixture was stirred at room temperature overnight then was concentrated in vacuo. The residue was dissolved in CH2Cl2 (80 mL) and washed with water (3×40 mL) and brine (40 mL), and dried over MgSO4. Solvent was removed in vacuo, and the residue was purified by ISCO silica gel flash chromatography (Eluent: EtOAc:CH2Cl2 3:7) to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-2-thiophen-3-yl-acetamide (0.7 g, 80%) as a white solid: mp 163-165 C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=2.39 min. (99%); 1H NMR (DMSO-d6) δ 2.02-2.09 (m, 1H), 2.52-2.63 (m, 2H), 2.84-2.96 (m, 1H), 3.55 (s, 2H), 4.71 (d, J=5.9 Hz, 2H), 5.12-5.18 (dd, J=5.3 and 12.7 Hz, 1H), 7.04-7.06 (m, 1H), 7.28-7.29 (m, 1H), 7.45-7.48 (m, 1H), 7.61-7.67 (m, 1H), 7.76-7.83 (m, 2H), 8.60 (t, J=5.9 Hz, 1H), 11.13 (s, 1H); 13C NMR (DMSO-d6) δ 21.95, 30.90, 36.88, 37.83, 48.83, 121.87, 122.35, 125.76, 127.11, 128.67, 131.51, 133.18, 134.67, 135.82. 139.17, 166.91, 167.44, 169.78, 170.23, 172.73; Anal. Calcd. for C20H17N3O5S: C, 58.39; H, 4.16; N, 10.21; S, 7.79. Found: C, 58.37; H, 3.98; N, 10.05; S, 7.83. ; |
Yield | Reaction Conditions | Operation in experiment |
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With dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 110℃; | General procedure: A solution of ortho-hydroxybenzaldehyde (1-4, 8 mmol), substituted acetic acid (a-c, 10 mmol) and DCC (12 mmol) in dimethylsulfoxide (DMSO, 10 mL), was heated (oil bath) at 110 C for 24-48 h. On completion of the reaction, cold water (100 mL) and acetic acid (15 mL) were added. The reaction mixture was stirred at room temperature for 4 h and extracted with diethyl ether (4 × 100 mL). The precipitated dicyclohexylurea was filtered off. The filtrate was extracted with 5% aqueous NaHCO3 (200 mL). The organic phase was stirred for 1 h with 5% aqueous sodium metabisulfite in order to remove the unreacted hydroxybenzaldehyde. The organic phase was washed with water, dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography (Hexane/EtOAc, 9:1). |
Yield | Reaction Conditions | Operation in experiment |
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With dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 110℃; | General procedure: A solution of ortho-hydroxybenzaldehyde (1-4, 8 mmol), substituted acetic acid (a-c, 10 mmol) and DCC (12 mmol) in dimethylsulfoxide (DMSO, 10 mL), was heated (oil bath) at 110 C for 24-48 h. On completion of the reaction, cold water (100 mL) and acetic acid (15 mL) were added. The reaction mixture was stirred at room temperature for 4 h and extracted with diethyl ether (4 × 100 mL). The precipitated dicyclohexylurea was filtered off. The filtrate was extracted with 5% aqueous NaHCO3 (200 mL). The organic phase was stirred for 1 h with 5% aqueous sodium metabisulfite in order to remove the unreacted hydroxybenzaldehyde. The organic phase was washed with water, dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography (Hexane/EtOAc, 9:1). |
Yield | Reaction Conditions | Operation in experiment |
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With dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 110℃; | General procedure: A solution of ortho-hydroxybenzaldehyde (1-4, 8 mmol), substituted acetic acid (a-c, 10 mmol) and DCC (12 mmol) in dimethylsulfoxide (DMSO, 10 mL), was heated (oil bath) at 110 C for 24-48 h. On completion of the reaction, cold water (100 mL) and acetic acid (15 mL) were added. The reaction mixture was stirred at room temperature for 4 h and extracted with diethyl ether (4 × 100 mL). The precipitated dicyclohexylurea was filtered off. The filtrate was extracted with 5% aqueous NaHCO3 (200 mL). The organic phase was stirred for 1 h with 5% aqueous sodium metabisulfite in order to remove the unreacted hydroxybenzaldehyde. The organic phase was washed with water, dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography (Hexane/EtOAc, 9:1). |
Yield | Reaction Conditions | Operation in experiment |
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With dicyclohexyl-carbodiimide; In dimethyl sulfoxide; at 110℃; | General procedure: A solution of ortho-hydroxybenzaldehyde (1-4, 8 mmol), substituted acetic acid (a-c, 10 mmol) and DCC (12 mmol) in dimethylsulfoxide (DMSO, 10 mL), was heated (oil bath) at 110 C for 24-48 h. On completion of the reaction, cold water (100 mL) and acetic acid (15 mL) were added. The reaction mixture was stirred at room temperature for 4 h and extracted with diethyl ether (4 × 100 mL). The precipitated dicyclohexylurea was filtered off. The filtrate was extracted with 5% aqueous NaHCO3 (200 mL). The organic phase was stirred for 1 h with 5% aqueous sodium metabisulfite in order to remove the unreacted hydroxybenzaldehyde. The organic phase was washed with water, dried (Na2SO4) and the solvent removed under reduced pressure. The residue was purified by column chromatography (Hexane/EtOAc, 9:1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19.2% | General procedure: The appropriate acetic acid (15 mmol) was refluxed for 30 min with triphosgene [bis(trichloromethyl) carbonate] (5 mmol) in dry CH2Cl2 (50 mL). A solution of the appropriately substituted imine (10 mmol) in dry CH2Cl2 (10 mL) was added dropwise to the refluxing solution. Triethylamine (30 mmol) was added. The reaction mixture was heated at reflux for 5 h and stirred at room temperature overnight. The mixture was washed firstly with distilled water (twice) (50 mL) and then with saturated aqueous sodium bicarbonate solution (50 mL). The organic layer was dried over anhydrous sodium sulphate. The pure product was isolated by flash column chromatography over silica gel (hexane/ethyl acetate gradient). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | With pyridine; HATU; at 80℃; for 12h; | Example 20Production of N-(5-{4-fluoro-3-[(thiophen-3-ylacetyl)amino]phenoxy}[1,3]thiazolo[5,4-b]pyridin-2-yl)cyclopropanecarboxamide N-[5-(3-Amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]cyclopropanecarboxamide (55 mg, 0.16 mmol) produced in Example 16(vi) was dissolved in pyridine (2.0 mL), thiophen-3-ylacetic acid (45 mg, 0.32 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (120 mg, 0.32 mmol) were added, and the mixture was stirred at 80 C. for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), and washed successively with 5% aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The obtained residue was washed with ethyl acetate/heptane to give the title compound (51 mg, 68%) as a colorless powder.1H-NMR (DMSO-d6, 300 MHz) δ 0.88-1.04 (4H, m), 1.92-2.08 (1H, m), 3.75 (2H, s), 6.80-7.02 (1H, m), 7.03-7.19 (2H, m), 7.24-7.41 (2H, m), 7.47 (1H, dd, J=4.9, 3.0 Hz), 7.82 (1H, dd, J=6.6, 2.8 Hz), 8.15 (1H, d, J=8.7 Hz), 10.04 (1H, s), 12.69 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium acetate; In toluene; at 210 - 245℃;Inert atmosphere; | General procedure: 2.2 mmol of phthalic anhydride, 2.7 mmol of the corresponding phenylacetic acid and 0.26 mmol of sodium acetate with 5 mL of toluene were adapted in a round bottom flask to a Dean-Stark apparatus. The mixtures were maintained under Nitrogen at 210-245 C, with magnetic stirring, for 9-33 h. After cooling the reaction mixture was treated with ethyl acetate and washed with (sat.) Na2CO3, brine and water, dried over Na2SO4 and concentrated under reduced pressure to give the crude products. Solid products were purified by crystallization and oils by flash chromatography on silica gel. All phthalides were obtained as Z-isomers, configuration confirmed through NOE or ROESY experiments, and yields ranged 40-95%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With dicyclohexyl-carbodiimide; In dichloromethane; at 50℃; for 24h; | General procedure: 2-F-alkylethyl 4-hydroxythiobenzoate was synthesized in three steps following a synthesis procedure previously reported [20], [21] and [22]. Dicyclohexylcarbodiimide (DCC) (1.07 g, 5.2 mmol) was added to a solution of <strong>[6964-21-2]3-thiopheneacetic acid</strong> (0.74 g, 5.2 mmol) in dichloromethane. After stirring during 30 min at 50 C, 2-F-alkylethyl 4-hydroxythiobenzoate (5.2 mmol) was added. After a day, the solvent was removed and the crude was purified by column chromatography (silica gel; eluent: dichloromethane) to yield the products as white solids. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With dicyclohexyl-carbodiimide; In dichloromethane; at 50℃; for 24h; | General procedure: 2-F-alkylethyl 4-hydroxythiobenzoate was synthesized in three steps following a synthesis procedure previously reported [20], [21] and [22]. Dicyclohexylcarbodiimide (DCC) (1.07 g, 5.2 mmol) was added to a solution of <strong>[6964-21-2]3-thiopheneacetic acid</strong> (0.74 g, 5.2 mmol) in dichloromethane. After stirring during 30 min at 50 C, 2-F-alkylethyl 4-hydroxythiobenzoate (5.2 mmol) was added. After a day, the solvent was removed and the crude was purified by column chromatography (silica gel; eluent: dichloromethane) to yield the products as white solids. |