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The synthesis of the cyano analogue of UCL 1963 was achieved in a one step dehydration reaction of the amide, UCL 1883. This method of amide dehydration, which occurs under mild conditions, was first reported by Campagna et The procedure involves addition of trifluoroacetic anhydride to a solution of the amide in dioxane containing 2 molar equivalents of pyridine at about 5°C. Using this procedure, yields of the product nitriles in the range of 85-99% were reported. For example, the dehydration of benzamide was reported to give the corresponding nitrile in 99% yield. The dehydration reaction is thought to occur via the formation of the enol form of the amide:

Compound Synthesis and Characterisation

R - c ( °

R - c f ^ ---

^

9;

The mass spectrum of the product isolated from the dehydration reaction of the amide

UCL 1883 indicated that a mixture of the un reacted amide and the nitrile product was present. The product was purified by flash chromatography using 5% methanol in ether as the eluant, resulting in the isolation of a pale tan hygroscopic residue having a low Rf value and which was not soluble in dichloromethane or ether, but was readily soluble in water. These observations suggest that the product was formed as the trifluoroacetate salt. Subsequent treatment with dilute sodium bicarbonate gave the free base as a pale yellow oil. The FAB mass spectrum of the free base showed an MH+ peak at 297 corresponding to the nitrile compound and no peak corresponding to the amide was observed. However, an impurity having a mass of 329 was found in the sample. This impurity was not found in the original crude product isolated from the reaction mixture. ^H NMR analysis of the oil showed the presence of a singlet at 5 3.97 ppm which did not correspond to the nitrile product. This singlet was not present in the ^H NMR spectrum of the crude product prior to chromatography. HPLC analysis of the oil revealed two main peaks of 79% and 19%, with the major peak corresponding to the nitrile compound.

The analytical evidence suggests that the impurity was formed after the column chromatography procedure since it was not present in the crude product. The ^H NMR and mass spectra indicated that the impurity corresponds to the methyl ester (i.e. compound 118). The formation of this ester may be attributed to the presence of trifluoroacetic acid in the crude product, catalysing the reaction of the nitrile with methanol from the eluant mixture. Attempts to purify the product by recrystallisation of the oxalate salt were met with little success. Finally, the compound was treated with sodium bicarbonate to liberate the free base, which was subsequently purified successfully by preparative HPLC (eluant 80% methanol + 2 0% HgO + 0.1% triethylamine), followed by careful removal of the solvent under reduced pressure without the application of heat, to avoid potential hydrolysis. The nitrile was treated with oxalic acid in ethanol and recrystallised to give the oxalate salt as a white powder (Table 3.9). The infrared spectrum of the nitrile compound, UCL 1971

Compound Synthesis and Characterisation

OC H2C H2NEtBu

Compound X Yield

(free base) Melting point

UCL 1970 COOH 6 6% 178-180°C (oxalate salt) UCL 1883 CONH2 45% 134-135 °C (free base) UCL 1971 ON 57% 160-161 °C (oxalate salt) Table 3.9

3.4.7 Formation of 7-Carboxymethyl-Propranolol

The synthesis of the 7-carboxymethyl analogue of propranolol was achieved in two steps, starting from the appropriate naphthol. The initial step involves condensation of the substituted naphthol with epichlorohydrin. Initially a test reaction was carried out with 1-naphthol 121 using a procedure similar to that previously described by Stephenson,^®® in which the naphthol was heated with an excess of epichlorohydrin containing a catalytic quantity of 1-methylpiperazine, for 30-45 minutes. Under these conditions, a mixture of two products, 122 and 124, was formed.

Initially 1-methylpiperazine abstracts the acidic aromatic hydroxyl proton. Due to the inherent ring strain of the 3-membered epoxide ring, nucleophilic attack of the epoxide is more likely than Sn2 attack of the alkylchloride function. Nucleophilic attack occurs at the least hindered carbon of the epoxide leading to ring opening to form the secondary alkoxide anion. The incoming nucleophile may attack on either face of the epoxide molecule, resulting in the formation of a racemic mixture:

Compound Synthesis and Characterisation

O H

HN NMe

121 X = H 111 X = COgMe

The alkoxide anion will preferentially undergo an intramolecular Williamson alkylation to form the epoxide 1 2 2 which was observed as the major product in this reaction:

^ 0“

122 X = H 123 X = COgMe

However, since the alkoxide anion is strongly basic, it may also abstract another hydroxyl proton from the naphthol molecule to form the chlorohydrin 124. The reaction therefore requires only a catalytic quantity of base to form the initial aryl alkoxide; further quantities are generated during the reaction by the intermediate secondary alkoxide.

O "

OH

124 X = H 125 X = COglVIe

Compound Synthesis and Characterisation

Similarly, the reaction of epichlorohydrin with 7-carboxymethyl-1-naphthol 111 generated a mixture of the epoxide 123 and the chlorohydrin 125, as confirmed by the mass spectrum. The mass spectra of the products from the reactions also revealed the presence of a third impurity

126, which is formed by the attack of chloride ion on epichlorohydrin.

O H

126

Since the epoxide and chlorohydrin react with the amine in the next step to give the same product, no attempts were made to separate the mixtures.

Reaction of the mixture of 122 and 124 with isopropylamine in ethanol gave the crude product as a yellow oil. Treatment of the crude product with excess oxalic acid in ethanol followed by recrystalllsation gave the oxalate salt as a white crystalline solid (UCL 1961, propranolol). Following the same procedure for the 7-carboxymethyl analogue, using methanol as the reaction solvent, the crude product was isolated as an off-white solid which was recrystallised to give 7- carboxymethyl propranolol UCL 1962 as white needles (Table 3.10).

0' ' '^ Y '" ^ N H ' P r 1 O H _