4-methylmorpholine-2,6-dione

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 15 ml of dimethylformamide (DMF), 2 g of thyroxine methyl ester hydrochloride was dissolved and 500 μl of triethylamine was added to the resulting solution. After 10 minutes passed, a solution of 0.55 g of N-methyliminodiacetic acid anhydride in 5 ml of tetrahydrofuran (THF) was added to the mixture. After completion of the reacton, the reaction mixture was condensed using a rotary evaporator and the residue was dissolved in 50 ml of THF. Further, 150 ml of ethyl acetate was added to the solution. After stirring the mixture by shaking, the ethyl acetate layer was taken out and washed three times with distilled water and then once with a saturated aqueous sodium chloride solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the supernatant was condensed using a rotary evaporator. To the residue, 20 ml of THF was added and then a small quantity of n-hexane was added to form precipitates. The precipitates were subjected to suction filtration to obtain white crystals. The crystals were dried in a dessicator under reduced pressure to obtain 2.3 g of white crystals. The yield was 69%. condensed a rotary evaporator the residue was dissolved in 50 ml of THF Further, 150 ml of ethyl acetate was added to the solution by shaking washed three times with distilled water After the ethyl acetate layer was dried over anhydrous sodium sulfate condensed a rotary evaporator To the residue, 20 ml of THF was added a small quantity of n-hexane was added to form precipitates The precipitates were subjected to suction filtration to obtain white crystals The crystals were dried in a dessicator under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 15 ml of dimethylformamide (DMF), 2 g of thyroxine methyl ester hydrochloride was dissolved and 500 μl of triethylamine was added to the resulting solution. After 10 minutes passed, a solution of 0.55 g of N-methyliminodiacetic acid anhydride in 5 ml of tetrahydrofuran (THF) was added to the mixture. After completion of the reacton, the reaction mixture was condensed using a rotary evaporator and the residue was dissolved in 50 ml of THF. Further, 150 ml of ethyl acetate was added to the solution. After stirring the mixture by shaking, the ethyl acetate layer was taken out and washed three times with distilled water and then once with a saturated aqueous sodium chloride solution. After the ethyl acetate layer was dried over anhydrous sodium sulfate, the supernatant was condensed using a rotary evaporator. To the residue, 20 ml of THF was added and then a small quantity of n-hexane was added to form precipitates. The precipitates were subjected to suction filtration to obtain white crystals. The crystals were dried in a dessicator under reduced pressure to obtain 2.3 g of white crystals. The yield was 69%. condensed a rotary evaporator the residue was dissolved in 50 ml of THF Further, 150 ml of ethyl acetate was added to the solution by shaking washed three times with distilled water After the ethyl acetate layer was dried over anhydrous sodium sulfate condensed a rotary evaporator To the residue, 20 ml of THF was added a small quantity of n-hexane was added to form precipitates The precipitates were subjected to suction filtration to obtain white crystals The crystals were dried in a dessicator under reduced pressure

Conditions: temp:165.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,2′-(methylazanediyl)diacetic acid (500 mg, 3.40 mmol) and acetic anhydride (5 mL) was stirred at 165° C. for 30 min. The reaction mixture was concentrated under reduced pressure to give 4-methylmorpholine-2,6-dione as a crude product. The obtained crude product was dissolved in THF (10 mL), and p-aminobenzonitrile (401 mg, 3.40 mmol) was added thereto. The mixture was heated with reflux for 22 hr, and concentrated under reduced pressure to give 2-((2-((4-cyanophenyl)amino)-2-oxoethyl)(methyl)amino)acetic acid (467 mg, 56%) as a pale-brown powder. The reaction mixture was concentrated under reduced pressure

Conditions: temp:165.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,2′-(methylazanediyl)diacetic acid (500 mg, 3.40 mmol) and acetic anhydride (5 mL) was stirred at 165° C. for 30 min. The reaction mixture was concentrated under reduced pressure to give 4-methylmorpholine-2,6-dione as a crude product. The obtained crude product was dissolved in THF (10 mL), and p-aminobenzonitrile (401 mg, 3.40 mmol) was added thereto. The mixture was heated with reflux for 22 hr, and concentrated under reduced pressure to give 2-((2-((4-cyanophenyl)amino)-2-oxoethyl)(methyl)amino)acetic acid (467 mg, 56%) as a pale-brown powder. The reaction mixture was concentrated under reduced pressure

Conditions: temp:165.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 2,2′-(methylazanediyl)diacetic acid (500 mg, 3.40 mmol) and acetic anhydride (5 mL) was stirred at 165° C. for 30 min. The reaction mixture was concentrated under reduced pressure to give 4-methylmorpholine-2,6-dione as a crude product. The obtained crude product was dissolved in THF (10 mL), and p-aminobenzonitrile (401 mg, 3.40 mmol) was added thereto. The mixture was heated with reflux for 22 hr, and concentrated under reduced pressure to give 2-((2-((4-cyanophenyl)amino)-2-oxoethyl)(methyl)amino)acetic acid (467 mg, 56%) as a pale-brown powder. The reaction mixture was concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-methylmorpholine-2,6-dione (1 eq) (see for Ref. WO 03/093261) in toluene (0.06 M) was added N2 (Example 14, step 2). The reaction mixture was refluxed for 2 h and then allowed to stand at RT overnight. The solvent was removed under reduced pressure. The resulting crude was dissolved in DMF (0.2 M) and to the resulting solution were added sequentially TBTU (1.3 eq), DIPEA (2.2 eq) and DMAP (0.3 eq). The mixture was stirred at RT for 2 h and then the product was isolated by purification at prep RP-HPLC using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents (C18 column). The desired fractions were lyophilized to afford the desired compound as a white powder. 1H NMR (400 MHz, DMSO-d6+TFA) δ: 7.41-7.27 (2H, m), 7.14 (1H, s), 7.08 (1H, d, J=6.8 Hz), 6.59 (1H, br. s), 4.38 (2H, s), 4.25 (4H, m), 2.85 (3H, s). MS (ES) C19H15Cl2FN4O3 requires: 436/438, found: 437/439 (M+H)+. The reaction mixture was refluxed for 2 h The solvent was removed under reduced pressure The resulting crude was dissolved in DMF (0.2 M) and to the resulting solution the product was isolated by purification at prep RP-HPLC