Daraprim Synthesis

Following unsuccessful intial and subsequent attempts to produce 2-(4-chlorophenyl)-3-methoxypent-2-enenitrile by the alkylation of 2-(4-chlorophenyl)-3-oxopentanenitrile (SGS 10-2-3), alkoxylation reactions using a mixture of trimethylorthoformate, methanol and concentrated sulfuric acid were attempted.

2- (4-chlorophenyl)-3-oxopentanenitrile (SGS 10-2-3) 0.25g was dissolved in a mixture of trimethyl orthoformate (1mL) and methanol (1mL). 3 drops of 18M sulfuric acid were added and the mixture was placed in a 60 degree centigrade water bath.  After 3 hours, TLC indicated that two less polar products were cleanly forming, apart from some highly polar material on the baseline.  Unreacted starting material was also present.

The reaction mix was worked up by pouring into a solution of saturated sodium hydrogen carbonate and extracted with dichloromethane, which was then dried with anhydrous sodium sulfate.

The dichloromethane solvent was removed to provide 0.20g of red oil. This oil was provided to the University of Sydney for NMR analysis to determine whether the two new products are the E and Z isomers of the methyl enol ether SGS 11-2.

The TLC of the reaction mixture in dichloromethane (below) indicated that three compounds were present.  The most polar spot was consistant with the starting material SGS 10-2-3. The two more polar spots are presumably the E and Z isomers. The H nmr of the sample shows three different types of methyene groups from three diffent ethyl groups. The CH₂ protons of the starting material (SGS 10-2-3) is evident at 4.65 whilst the spikes at 4.00 and 3.88 are presumably the methoxy groups of the vinyl ethers, the more intense peak at 3.88 being that for the methoxy group of theless polat product. 

A series of other reactions were undertaken in an effort to increase the yield of the reaction. The quantities of trimethylorthoformate, methanol and sulfuric acid utilised were varied.  The reaction to the methoxy enol ether never went to completion and most of the methanol and trimethylorthoformate were lost from the reaction, even though the reaction temperature was only 60 degrees C. It is presumed that the methanol and trimethylorthoformate reacted somwhat faster with each other than with the desired compound.

It was noted that TLC of the reaction mixes indicated that reactions with greater loadings of sulfuric acid formed larger amounts of the upper, less polar enol ether and less of the lower, more polar ether.  Presumably the less polar product is the more thermodynamically stable under acidic conditions.  Crystals were seen to be forming in the crude reaction mix.  Isolation of a few of these crystals and subsequent TLC of them indicated that they were comprised of the less polar product.

Column chromatography of the product in dichloromethane yielded a number of fractions, most of which contained the E and Z products along with starting keto nitrile (SGS 10-2-3).  The first fraction, which did not contain much starting material, was called SGS 11-2-1 and was submitted for IR analysis. The strong absorption band at 2206cm^-1 indicated that the nitrile functionality had survived the strongly acid reaction conditions.

A sample of SGS 11-2, free of staring material, was prepared by combining the reaction mix of previous reactions to yield about 1.8g of crude starting material (SGS 11). Dissolution of the crude oil in dichloromethane was followed by the addition of 1mL of triethylamine to the mix in order to convert the unwanted starting material into the much more polar SGS 14-1.  

Stirring the reaction mix with column chromatography silica gel removed the more polar baseline products. Subsequent washing of the reaction mix with 1M HCL removed the triethylamine from the solution.  The solution was reduced and a sample was prepared for high resolution NMR analysis (SGS 11-2-3).  As before, it was noted that some of the material crystalised.  The crystals were harvested and also submitted for nmr analysis (SGS 11-2-4), as a different ratio of E and Z isomers were present and might aid identification of the individual isomers.