N,N-dimethyl-3-oxobutanamide

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: 0.03 mole of 2-methyl-6-phenylimidazo[2,1-b]-1,3,4-thiadiazol-5-carbaldehyde, 0.1 mole (13.0 g) of acetoacetic acid dimethylamide and 0.6 ml of piperidine were heated to 120° C. for 4 hours. The mixture was then cooled and the precipitate formed was recrystallised from 30 ml of ethyl acetate. After drying, α-acetyl-β-(2-methyl-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazol-5-yl)-propenoic acid dimethylamide of melting point 185° to 187° C. was obtained. The mixture was then cooled the precipitate formed was recrystallised from 30 ml of ethyl acetate After drying

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

Procedure: tert-Butyl 2-(3-methoxycarbonyladamant-1-ylcarbonylamino)pent-4-ynoate (0.44 g) was dissolved in 0.8 mL of dry benzene under nitrogen. To this solution was added a catalytic amount of CuSO4 and the reaction mixture was brought to reflux. N,N-Dimethyl acetoacetamide was added dropwise in excess. Evolution of nitrogen was observed. The addition was complete after 30 min. The reaction was then heated for another 30 min. After cooling the reaction mixture, the solvent was evaporated under reduced pressure and the crude product was purified on a prep plate (silica gel; EtOAc/hexanes, 2:3) to afford the title compound as an oil. to reflux The addition The reaction was then heated for another 30 min After cooling the reaction mixture the solvent was evaporated under reduced pressure the crude product was purified on a prep plate (silica gel; EtOAc/hexanes, 2:3)

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

Procedure: N,N-Dimethyl acetoacetamide (46.8 g; 0.363 mole) was converted to its dianion by treatment with 80% sodium hydride (11.8 g; 0.393 mole) in dry tetrahydrofuran (350 ml) under nitrogen, at 20° C. The resulting suspension was diluted with dry ether (1 L) and stirred mechanically for 15 minutes at 0° C. before a solution of n-butyl lithium in hexane (227 ml; 1.6 M; 0.363 mole) was added dropwise. To the now clear mixture was then added 3-chloromethyl thiophene (38 g; 0.287 mole) in dry tetrahydrofuran (50 ml), again dropwise, and the reaction allowed to warm up to room temperature. After the solution had stood at room temperature overnight the solvents were removed on a rotary evaporator and the residue acidified with dilute HCl in the presence of ethyl acetate (200 ml). The organic layer was separated off and the aqueous layer extracted once again with ethyl acetate (200 ml). The combined organic layers were dried (anhydrous MgSO4), and evaporated to give an oil which was purified on a short silica gel column using chloroform as eluant affording the product as a red-brown oil (48.5 g; 75%). was added dropwise the solvents were removed on a rotary evaporator The organic layer was separated off the aqueous layer extracted once again with ethyl acetate (200 ml) The combined organic layers were dried (anhydrous MgSO4) evaporated to give an oil which was purified on a short silica gel column

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

Procedure: In 40 ml of a mixture of chloroform and ethyl alcohol (1:1) were suspended 1.49 g (10 mmoles) of D-penicillamine and 1.89 g (15 mmoles) of N,N-dimethylacetoacetamide. The suspension was heated at 80°-90° C. with stirring under a stream of argon to concentrate to a half its volume. 20 ml of a mixture of chloroform and ethyl alcohol (1:1) was added. The concentration and addition of the solvent were repeated until the reaction mixture turned completely clear and a small amount of insolubles was removed by filtration. The solvent was distilled off, and the resulting residue was treated according to the same procedure as in Example 1 to give 1.98 g of 4-carboxy-2,5,5-trimethylthiazolidine-2-N,N-dimethylacetamide as colorless prisms. The suspension was heated at 80°-90° C. to concentrate to a half its volume 20 ml of a mixture of chloroform and ethyl alcohol (1:1) was added The concentration and addition of the solvent a small amount of insolubles was removed by filtration The solvent was distilled off the resulting residue was treated

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

Procedure: A suspension of 2.00 g (13.4 mmoles) of D-penicillamine and 1.73 g (13.4 mmoles) of N,N-dimethylacetoacetamide in 15 ml of dry benzene, and 0.6 g of anhydrous magnesium sulfate was refluxed for 3.5 hours under a stream of argon. The reaction mixture became clear and then the solvent was distilled off. The resulting residue was dissolved in hot methyl alcohol. Insolubles were removed by filtration and the solvent was again distilled off. The residue was crystallized from chloroform and further recrystallized from ethyl alcohol-ether to give 2.3 g of 4-carboxy-2,5,5-trimethylthiazolidine-2-N,N-dimethylacetamide as colorless prisms. was refluxed for 3.5 hours under a stream of argon the solvent was distilled off The resulting residue was dissolved in hot methyl alcohol Insolubles were removed by filtration the solvent was again distilled off The residue was crystallized from chloroform further recrystallized from ethyl alcohol-ether

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

Procedure: A suspension of 2.00 g (13.4 mmoles) of D-penicillamine and 1.73 g (13.4 mmoles) of N,N-dimethylacetoacetamide in 15 ml of dry benzene, and 0.6 g of anhydrous magnesium sulfate was refluxed for 3.5 hours under a stream of argon. The reaction mixture became clear and then the solvent was distilled off. The resulting residue was dissolved in hot methyl alcohol. Insolubles were removed by filtration and the solvent was again distilled off. The residue was crystallized from chloroform and further recrystallized from ethyl alcohol-ether to give 2.3 g of 4-carboxy-2,5,5-trimethylthiazolidine-2-N,N-dimethylacetamide as colorless prisms. was refluxed for 3.5 hours under a stream of argon the solvent was distilled off The resulting residue was dissolved in hot methyl alcohol Insolubles were removed by filtration the solvent was again distilled off The residue was crystallized from chloroform further recrystallized from ethyl alcohol-ether

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

Procedure: 0.03 mole of 2-methyl-6-phenylimidazo[2,1-b]-1,3,4-thiadiazol-5-carbaldehyde, 0.1 mole (13.0 g) of acetoacetic acid dimethylamide and 0.6 ml of piperidine were heated to 120° C. for 4 hours. The mixture was then cooled and the precipitate formed was recrystallised from 30 ml of ethyl acetate. After drying, α-acetyl-β-(2-methyl-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazol-5-yl)-propenoic acid dimethylamide of melting point 185° to 187° C. was obtained. The mixture was then cooled the precipitate formed was recrystallised from 30 ml of ethyl acetate After drying

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

Procedure: 0.03 mole of 2-methyl-6-phenylimidazo[2,1-b]-1,3,4-thiadiazol-5-carbaldehyde, 0.1 mole (13.0 g) of acetoacetic acid dimethylamide and 0.6 ml of piperidine were heated to 120° C. for 4 hours. The mixture was then cooled and the precipitate formed was recrystallised from 30 ml of ethyl acetate. After drying, α-acetyl-β-(2-methyl-6-phenyl-imidazo[2,1-b]-1,3,4-thiadiazol-5-yl)-propenoic acid dimethylamide of melting point 185° to 187° C. was obtained. The mixture was then cooled the precipitate formed was recrystallised from 30 ml of ethyl acetate After drying

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

Procedure: 4.5 g (0.035 mol) of N,N-dimethyl-3-oxobutyramide, a solution of 4.9 g (0.122 mol) of NaOH in 45 ml of water and 0.037 mol of phenyldiazonium chloride were treated as described in preparation 8. The crude reaction mixture was purified by chromatography on silica gel (hexane/Et2O 0%→100%) obtaining 3.5 g of the title compound which was used as such in the subsequent step. M.p.=131°-133° C. as described in preparation 8 The crude reaction mixture was purified by chromatography on silica gel (hexane/Et2O 0%→100%)

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

Procedure: A solution of 9 ml (0.05 mmol) of diketene-acetone adduct in 20 ml of toluene was treated with gaseous dimethylamine at room temperature until the reaction was complete. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (EtOAc/MeOH 0%→10%) yielding 7.0 g of the title compound. The solvent was removed in vacuo the residue was purified by chromatography on silica gel (EtOAc/MeOH 0%→10%)