2-methylpropanedioic acid

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

Procedure: 630 ml of pyridine was added to 76 g of 4-nitrobenzaldehyde (m.p. 105°-106.5° C.), 118 g of methylmalonic acid (prepared by hydrolysis of diethyl methylmalonate) and 85 g of piperidine. The mixture was heated with stirring over a steam bath for 24 hours. After being allowed to cool, the reaction mixture was then added to a mixture of 1,250 ml of concentrated hydrochloric acid and 2.5 kg of ice. The resulting oil content was then extracted with diethyl ether. The oil content was further extracted with a 5% aqueous solution of sodium hydroxide. The aqueous solution was then slightly acidified. The resulting crystal composition was then filtered off and dried. (Yield: 86 g (83%)) The mixture was heated to cool The resulting oil content was then extracted with diethyl ether The oil content was further extracted with a 5% aqueous solution of sodium hydroxide The resulting crystal composition was then filtered off dried

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

Procedure: 630 ml of pyridine was added to 76 g of 4-nitrobenzaldehyde (m.p. 105°-106.5° C.), 118 g of methylmalonic acid (prepared by hydrolysis of diethyl methylmalonate) and 85 g of piperidine. The mixture was heated with stirring over a steam bath for 24 hours. After being allowed to cool, the reaction mixture was then added to a mixture of 1,250 ml of concentrated hydrochloric acid and 2.5 kg of ice. The resulting oil content was then extracted with diethyl ether. The oil content was further extracted with a 5% aqueous solution of sodium hydroxide. The aqueous solution was then slightly acidified. The resulting crystal composition was then filtered off and dried. (Yield: 86 g (83%)) The mixture was heated to cool The resulting oil content was then extracted with diethyl ether The oil content was further extracted with a 5% aqueous solution of sodium hydroxide The resulting crystal composition was then filtered off dried

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

Procedure: Phosphorus and Bromine is added into dry 2-methylmalonic acid according to the procedure of Braun, in Berichte 42, p. 839 (1909) to form 2-Bromo-2-methyl malonic acid.

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

Procedure: Phosphorus and Bromine is added into dry 2-methylmalonic acid according to the procedure of Braun, in Berichte 42, p. 839 (1909) to form 2-Bromo-2-methyl malonic acid.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 1.0 ml of water was dissolved 1.5 g of methylmalonic acid, after which 1.26 g of a 50% aqueous dimethylamine solution and 0.96 ml of a 37% aqueous formaldehyde solution were added with stirring at 0° C., and the resulting mixture was stirred at 0° to 5° C. for 3 hours and then at 80° C. for 30 minutes. the resulting mixture was stirred at 0° to 5° C. for 3 hours

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In 1.0 ml of water was dissolved 1.5 g of methylmalonic acid, after which 1.26 g of a 50% aqueous dimethylamine solution and 0.96 ml of a 37% aqueous formaldehyde solution were added with stirring at 0° C., and the resulting mixture was stirred at 0° to 5° C. for 3 hours and then at 80° C. for 30 minutes. the resulting mixture was stirred at 0° to 5° C. for 3 hours

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 75 g (0.85 mol) of 1,3-dimethylurea and 102 g (0.86 mol) of methyl malonic acid were dissolved in 300 ml of glacial acetic acid at 65° C. To the solution was added 330 ml of acetic anhydride, the temperature was gradually raised and the mixture was refluxed by heating at 90° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and benzene was added to the residue. The crystals thus-deposited were collected by filtration and recrystallized from benzene to obtain 60 g of 1,3,5-trimethylbarbituric acid. Yield: 42%, Melting Point: 83° to 85° C. the temperature was gradually raised the mixture was refluxed The reaction solution was concentrated under reduced pressure, and benzene was added to the residue The crystals thus-deposited were collected by filtration recrystallized from benzene

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 75 g (0.85 mol) of 1,3-dimethylurea and 102 g (0.86 mol) of methyl malonic acid were dissolved in 300 ml of glacial acetic acid at 65° C. To the solution was added 330 ml of acetic anhydride, the temperature was gradually raised and the mixture was refluxed by heating at 90° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and benzene was added to the residue. The crystals thus-deposited were collected by filtration and recrystallized from benzene to obtain 60 g of 1,3,5-trimethylbarbituric acid. Yield: 42%, Melting Point: 83° to 85° C. the temperature was gradually raised the mixture was refluxed The reaction solution was concentrated under reduced pressure, and benzene was added to the residue The crystals thus-deposited were collected by filtration recrystallized from benzene

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

Procedure: The compound [(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (173 mg, 0.46 mmol, prepared as described in WO PCT 0250019) was dissolved in 5 mL of 1:1 CH2Cl2/DMF. The resultant solution was charged sequentially with 2-methyl-malonic acid (54 mg, 0.46 mmol), meta-trifluoromethylaniline (0.06 mL, 0.46 mmol), N,N-diisopropylethylamine (0.8 mL, 4.6 mmol) and HATU (434 mg, 1.1 mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo, and partitioned between EtOAc and sat. NH4Cl. The aqueous phase was extracted with EtOAc (1×). The combined organic extracts were washed with sat. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to provide {(2S,3S)-3-hydroxy-2-[2-(3-trifluoromethyl-phenylcarbamoyl)-propionylamino]-hex-4-ynyl}-carbamic acid benzyl ester (40 mg, 17% yield). MS found: (M+Na)+=528.4. (25b) A solution of {(2S,3S)-3-hydroxy-2-[2-(3-trifluoromethyl-phenylcarbamoyl)-propionylamino]-hex-4-ynyl}-carbamic acid benzyl ester (40 mg, 0.08 mmol) in MeOH (2 mL) was charged with 5% Pd/C, Degussa style (8 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (2 mL). The resultant solution was charged sequentially with 2,4-dimethylbenzaldehyde (0.009 mL, 0.06 mmol) and sodium cyanoborohydride (5 mg, 0.08 mmol), stirred for 12 h at RT, quenched with sat. NaHCO3, and extracted twice with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=494.4. concentrated in vacuo partitioned between EtOAc and sat. NH4Cl The aqueous phase was extracted with EtOAc (1×) The combined organic extracts were washed with sat. NaHCO3 and brine dried (Na2SO4) filtered concentrated in vacuo The residue was purified by flash chromatography

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

Procedure: Phosphorus and Bromine is added into dry 2-methylmalonic acid according to the procedure of Braun, in Berichte 42, p. 839 (1909) to form 2-Bromo-2-methyl malonic acid.

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

Procedure: Phosphorus and Bromine is added into dry 2-methylmalonic acid according to the procedure of Braun, in Berichte 42, p. 839 (1909) to form 2-Bromo-2-methyl malonic acid.

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

Procedure: Phosphorus and Bromine is added into dry 2-methylmalonic acid according to the procedure of Braun, in Berichte 42, p. 839 (1909) to form 2-Bromo-2-methyl malonic acid.