Triethylamine reaction with, phosgene

Initially, 50 was converted into the benzoxazinone 51 by reaction with phosgene in the presence of triethylamine and 51 was isolated in 95% yield upon crystallization from methanol. Deprotection of the pMB group from 51 was accomplished with ceric ammonium nitrate (CAN) in aqueous acetonitrile. Efavirenz was isolated in 76% yield after crystallization from EtOAc-heptane (5 95), as shown in Scheme 1.19. There were two issues identified in this route. First, lequiv of ani-saldehyde was generated in this reaction, which could not be cleanly rejected from product 1 by simple crystallization to an acceptable level under the ICH guideline. Anisaldehyde was removed from the organic extract as a bisulfite adduct by washing with aqueous Na2S205 twice, prior to the crystallization of 1. Secondly,... 

Addition of DBU to a solution of 149 in THF induced an elimination reaction accompanied by loss of a molecule of CO2 and provided the unstable amine 150, which was converted in situ into isocyanate 151 by reaction with phosgene and triethylamine. After filtration to remove hydrochloride salts, the solution of 151 was treated with samarium (II) iodide in the presence of lithium chloride. These conditions, which had been previously determined to be optimal for spirooxindole generation on a model system, provided compound 152 as an inseparable 7 1 mixture of diastereoisomers [43]. The major component of this mixture was determined by NOE analysis to have the required configuration, which is consistent with bond formation from the less hindered, convex face of 151 (Scheme 35). 

With the two molecular systems in hand, we then set out to separate and identify each of the three atropisomers of 47 and 48. After extensive attempts, we found that by using semipreparative thin layer chromatography plates (0.25 mm thick silica, 20 x 20 cm), the rotamers could be separated in excellent yield, although it was necessary to use cold solvents to avoid thermal interconversion of individual atropisomers during the isolation process. The conformations of individual atropisomers were initially tentatively assigned by use of 1- and 2-D low temperature 1H NMR spectroscopy. The initial assignments were then confirmed by reaction with phosgene and triethylamine as discussed below. 

SYNTHESIS The synthesis is similar to that of poly(7-benzyl-L-glutamate). (See also the entry on Poly(j-benzyl-L-glutamate) in this handbook.) It involves the conversion of the amino acid to the N-carboxyanhydride (NCA) monomer by reaction with phosgene gas followed by polymerization of the NCA with an appropriate initiator (e.g., triethylamine). Typical comonomers include other amino add NCAs. 

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%. 

Anhydrides, preparation with phosgene and triethylamine, 47, 91 Aniline, reaction with e-nitrobenzalde-hyde, 48,113... 

The diazepine 85 (tetramethyleneurea) has been prepared by a variety of routes. Among these are the treatment of tetramethylene diisocyanate with water,70-72 the rearrangement of the oxime (86) in polyphosphoric acid,73,74 and the reaction of 1,4-diaminobutane with sulfur, methanol, and carbon monoxide at high pressure.75 A novel preparation of 85 involves the reaction of 1,4-diaminobutane with 87 to give the silylated diamine (88). Reaction of 88 with phosgene and triethylamine yielded the bistrimethylsilyldiazepine (89) which was then hydrolyzed in aqueous ethanol to give 85.76... 

Preparation. This a-chloro enamine (1) is prepared in about 80% yield by the reaction of phosgene with N,N-dimcthylisobutyramide followed by elimination of hydrogen chloride with triethylamine. ... 

The reaction of phosgene with CH-acid imines followed by dehydrochloridation in the presence of triethylamine affords N-substituted vinyl carbamoyl chlorides in good yields. For example, N-methyl-N-vinyl carbamoyl chloride was prepared in 67% distilled yield through phosgenation of ethy-lidene methyl amine as depicted in scheme 128 (Ref. 181). 

In general, these two reactions are definitely not suitable for the preparation of appreciable quantities of pure isonitriles indeed, they have been largely replaced by the more widely applicable dehydration method [lc,d,fj. This was first discovered by Hagedorn in 1956 and entails transformation of primary amines into for-mamides, followed by dehydration either with phosgene (or its precursors) and triethylamine, or phosphorus oxychloride and di-wo-propylamine [If]. 

Phosphonothioformic esters. Consecutive reaction of phosgene with a thiol (in the presence of triethylamine) at low temperature and trialkyl phosphite furnishes... 

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