Tetrahydrofuran reaction with, phosgene

To this acid was then added 1 g of 4-ethyl-2,3-dioxo-1-piperazinocarbonyl chloride (from the reaction of N-ethylethylenediamine and diethyl oxalate to give 2,3-dioxo-4-ethyl-piperazine which Is then reacted with phosgene) and the resulting mixture was reacted at 15°C to 20°C for 2 hours. After the reaction, a deposited triethylamine hydrochloride was separated by filtration, and the filtrate was incorporated with 0.4 g of n-butanol to deposit crystals. The deposited crystals were collected by filtration to obtain 1.25 g of white crystals of 6-[ D(—l-Ct-(4-ethyl-2,3-dioxo-1 -piperazinocarbonylaminolphenylacetamido] penicillanic acid. Into a solution of these crystals in 30 ml of tetrahydrofuran was dropped a solution of 0.38 g of a sodium salt of 2-ethyl-hexanoic acid in 10 ml of tetrahydrofuran, upon which white crystals were deposited. The deposited crystals were collected by filtration, sufficiently washed with tetrahydrofuran and then dried to obtain 1.25 g of sodium salt of 6-[D(—)-a-(4-ethyl-2,3-di-0X0-1-piperazinocarbonylaminolphenylacetamido] penicillanic acid, melting point 183°C to 185°C (decomposition), yield 90%. 

Therefore, our first idea was to 0-acylate simple enolates with phosgene. In a first course of attempts, we investigated the reaction of phosgene with alkaline metals enolates. For example we prepared lithium enolate of acetaldehyde through cleavage of tetrahydrofuran by n- butylllthium (Ref. 116) and reacted with phosgene under various conditions. Unfortunately, no trace of vinyl chloroformate was found in all experiments performed [Scheme 90]. 

Fig. 44. The modified metering flask of a piogram-controlled peptide synthesizer for the direct preparation of N-protected amino acid anhydrides with phosgene. (A) Solutions of N-protected amino acid salts in dichloromethane or tetrahydrofurane (B) Solution of phosgene in tetrahydrofurane (C) Dry air inlet for stirring (D) Vacuum jacket (E) Drain valve (V) Vent line. Photo sensor levels to meter (2) The solution of N-protected amino add salts (1) The addition of the phosgene solution (3) The draining of the reaction flask...

A V -Carbonyldiimidazole (CDI) is prepared in a convenient and safe procedure from phosgene and imidazole as a non-toxic crystalline compound (m.p. 116-118 °C).[5],[6] It reacts almost quantitatively at room temperature or by short and moderate heating with an equimolar quantity of a carboxylic acid in tetrahydrofuran, chloroform, or similar inert solvents within a few minutes to give the corresponding carboxylic acid imidazolide, which is formed under release of carbon dioxide, together with one equivalent of readily separable and recyclable imidazole.Thus, this reaction leads under very mild conditions to the activation of a carboxylic acid appropriate for transacylation onto a nucleophile with an alcohol to an ester, with an amino compound to an amide or peptide, etc. 

By the aid of a modified peptide synthesizer solutions of two moles of Boc- or Ddz-amino acid salts (sodium- or triethylammonium form) in tetrahydrofuran or dichloro-methane at —40 °C are mixed for 5 minutes with one mole of phosgene in the same solvent at —40 °C, controlled by the punched tape program of the synthesizer (Fig. 44). The solution of the symmetric anhydride is added at —40 C to the gel polymer, which is contained in the centrifugal reactor (see p. 75) and is allowed to warm up to the cooling water temperature level (9—13 C) of the reactor during the peptide synthesis period of 30 minutes. Since the mode of action of the centrifugal reactor renders it possible to perfuse an external IR flow cell with the reaction solution, we are in a position to monitor directly the quality of the symmetric anhydride and its consumption, watching the characteristic absorptions on 1,830 and 1,760 cm [71]. In several cases the symmetric anhydrides were isolated in crystalline or solid form for characterization (Table 6). 

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