(2S)-2-(ethoxycarbonylamino)propanoic acid

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

Procedure: Production of 3-(methyl ONN azoxy)-2,2-propylene dioxy-butane [Compound (IV):R3 =H, R4 =-CH2CH2CH2 -]: (a) In 700 ml of water were dissolved 40 g of L-alanine and 127 g of sodium carbonate. Then 64 ml of ethyl chloroformate was added dropwise to the mixture under ice-cooling and its stirring was conducted at room temperature for 30 minutes. A 35% hydrochloric acid was added to the reaction liquid to make this acidic and the reaction liquid was adsorbed on the column (6.5×60 cm) of diaion HP-20. After washing with water this was eluted with 70% methanol. The eluate was condensed under vacuum thereby to obtain 69 g (yield of 96%) of N-ethoxycarbonyl alanine as an oily substance. cooling the reaction liquid After washing with water this was eluted with 70% methanol condensed under vacuum

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

Procedure: Production of 3-(methyl ONN azoxy)-2,2-propylene dioxy-butane [Compound (IV):R3 =H, R4 =-CH2CH2CH2 -]: (a) In 700 ml of water were dissolved 40 g of L-alanine and 127 g of sodium carbonate. Then 64 ml of ethyl chloroformate was added dropwise to the mixture under ice-cooling and its stirring was conducted at room temperature for 30 minutes. A 35% hydrochloric acid was added to the reaction liquid to make this acidic and the reaction liquid was adsorbed on the column (6.5×60 cm) of diaion HP-20. After washing with water this was eluted with 70% methanol. The eluate was condensed under vacuum thereby to obtain 69 g (yield of 96%) of N-ethoxycarbonyl alanine as an oily substance. cooling the reaction liquid After washing with water this was eluted with 70% methanol condensed under vacuum

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

Procedure: Production of 3-(methyl ONN azoxy)-2,2-propylene dioxy-butane [Compound (IV):R3 =H, R4 =-CH2CH2CH2 -]: (a) In 700 ml of water were dissolved 40 g of L-alanine and 127 g of sodium carbonate. Then 64 ml of ethyl chloroformate was added dropwise to the mixture under ice-cooling and its stirring was conducted at room temperature for 30 minutes. A 35% hydrochloric acid was added to the reaction liquid to make this acidic and the reaction liquid was adsorbed on the column (6.5×60 cm) of diaion HP-20. After washing with water this was eluted with 70% methanol. The eluate was condensed under vacuum thereby to obtain 69 g (yield of 96%) of N-ethoxycarbonyl alanine as an oily substance. cooling the reaction liquid After washing with water this was eluted with 70% methanol condensed under vacuum

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

Procedure: The techniques which resulted in successful amido acylation of benzene using phenyllithium were next applied to the Grignard reaction. N-ethoxycarbonylalanine was treated with 300 mol percent of phenylmagnesium bromide at -78° C. and allowed to warm to room temperature. The desired ketone was not observed. Several hours of refluxing in ether and tetrahydrofuran yielded biphenyl and starting material which was optically intact. were next applied to the Grignard reaction

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

Procedure: The techniques which resulted in successful amido acylation of benzene using phenyllithium were next applied to the Grignard reaction. N-ethoxycarbonylalanine was treated with 300 mol percent of phenylmagnesium bromide at -78° C. and allowed to warm to room temperature. The desired ketone was not observed. Several hours of refluxing in ether and tetrahydrofuran yielded biphenyl and starting material which was optically intact. were next applied to the Grignard reaction

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

Procedure: The techniques which resulted in successful amido acylation of benzene using phenyllithium were next applied to the Grignard reaction. N-ethoxycarbonylalanine was treated with 300 mol percent of phenylmagnesium bromide at -78° C. and allowed to warm to room temperature. The desired ketone was not observed. Several hours of refluxing in ether and tetrahydrofuran yielded biphenyl and starting material which was optically intact. were next applied to the Grignard reaction

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

Procedure: N-(Ethoxycarbonyl)alanine* (1.35 eq) and HATU (1.35 eq) in DMF (0.1 M) were stirred at RT for 20 min and then N2 (Example 14, step 2) (1 eq) and DMAP (1.35 eq) were added. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM and washed with 1N HCl solution and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The resulting crude was dissolved in DMF (0.1 M) and DMAP (1 eq) was added. The mixture was heated in a microwave oven at 180° C. for 50 min. The product was isolated by purification at prep RP-HPLC using H2O (+0.1% TFA) and MeCN (+0.1% TFA) as eluents. The desired fractions were lyophilized to afford the desired compound. 1H NMR (400 MHz, DMSO-d6) δ: 10.91 (1H, d, J=5.6 Hz), 8.51 (1H, s), 7.37-7.23 (3H, m), 7.15 (1H, s), 6.54 (1H, d, J=5.6 Hz), 4.38 (2H, s), 4.35-4.24 (1H, m), 1.41-1.30 (3H, m). MS (ES) C18H13Cl2FN4O3 requires: 422/424, found: 423/425 (M+H)+. washed with 1N HCl solution and brine The organic phase was dried (Na2SO4) filtered concentrated The resulting crude was dissolved in DMF (0.1 M) The mixture was heated in a microwave oven at 180° C. for 50 min The product was isolated by purification at prep RP-HPLC

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

Procedure: Production of 3-(methyl ONN azoxy)-2,2-propylene dioxy-butane [Compound (IV):R3 =H, R4 =-CH2CH2CH2 -]: (a) In 700 ml of water were dissolved 40 g of L-alanine and 127 g of sodium carbonate. Then 64 ml of ethyl chloroformate was added dropwise to the mixture under ice-cooling and its stirring was conducted at room temperature for 30 minutes. A 35% hydrochloric acid was added to the reaction liquid to make this acidic and the reaction liquid was adsorbed on the column (6.5×60 cm) of diaion HP-20. After washing with water this was eluted with 70% methanol. The eluate was condensed under vacuum thereby to obtain 69 g (yield of 96%) of N-ethoxycarbonyl alanine as an oily substance. cooling the reaction liquid After washing with water this was eluted with 70% methanol condensed under vacuum