An improved synthesis of ( S )-1-[[4-(dimethylamino)-3- methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1 H - imidazo[4,5-c ]pyridine-6-carboxylic acid ditrifluoroacetate dihydrate (PD123319)

The following report describes several improvements to the earlier synthesis of the non-peptide Angiotensin II antagonist ( S )-1-[[4-(dimethylamino)-3-methylphenyl]-methyl]-5-(diphenyl-acetyl)-4,5,6,7-tetrahydro-1 H -imidazo[4,5-c ]pyridine-6-carboxylic acid ditrifluoroacetate dihydrate ( 1 ) (PD123319).


Introduction
The peptide hormone Angiotensin II (Ang II) is responsible for a variety of physiological functions. 1,2Progress in the study of Ang II receptor subtypes and their functional diversity has been facilitated by the discovery of a class of non-peptide antagonists.One of these compounds PD123319 (1) has been used to demonstrate the existence of non-vascular Ang II binding sites in a narrow range of tissue types 3 and has been examined as a potential antihypertensive agent.
To augment evaluation studies, we required gram quantities of 1.A survey of the literature yielded only one report describing the synthesis. 4In our hands, however, the procedures described therein were problematic and not amenable to scale-up.The present report details a modified synthesis protocol capable of delivering gram quantities of 1, and provides a more comprehensive spectroscopic examination of the intermediates and final product than was previously available.

Results and Discussion
The procedure employed for the synthesis of 1 is presented in Scheme 1.The preparation of the di-t-butoxycarbonyloxy derivative 3 of L-histidine methyl ester dihydrochloride was carried out according to the method reported by Hodges. 5With the careful exclusion of moisture this procedure yielded 3 in 82% yield.In order to alkylate the unsubstituted imidazole nitrogen atom, following Blankley's details, the triflate (4) of 3-methyl-4-nitrobenzyl alcohol was prepared in situ and reacted with 3 at −70 o C to afford the coupled product 5 in a 61% yield after a buffered quench.
Ester hydrolysis and deprotection of the amino functionality in 5 was achieved using 6N hydrochloric acid thereby furnishing the amino acid bis-hydrochloride salt (6) as an amorphous foam in 80% yield.This was in contrast to the quantitative yield of a gum-like material reported by Blankley et al. 4 Conversion of 6 to the imidazopyridine 7 was not possible using the procedure of Blankley et al. 4 despite numerous attempts.Accordingly, an alternative procedure based on the same publication of Blankley 4 was employed without incident.In this alternative method the annulation was carried out in 12 N hydrochloric acid and subsequently 7 was available in 71% yield.
The published procedure 4 for the conversion of 7 tothe corresponding methyl ester (8) by treatment with trimethyl orthoformatein the presence of acid was used without modification and provided thedesired product in 85% yield.In our hands, however, the N-acylationof 8 through treatment with dicyclo-hexylcarbodiimide (DCC) / 1-hydroxybenzotriazole(BtOH) in the presence of diphenylacetic acid proved capricious.Alternatively,we found that reaction of 8 with diphenylacetyl chloride and triethylamine resulted in a rapid conversion to the acetamide (9) in good yield.
Blankley's protocol for the synthesis of 9 − 10 suggested that the reduction of the aromatic nitro group of 9 could be effected by either stannous chloride or Raney nickel.Our experience however, was that the use of Raney nickel consistently led to products contaminated with starting material and an uncharacterised polymeric by-product.On the other hand the stannous chloride mediated procedure routinely provided the aniline (10) in 85% yield.The final two transformations (reductive methylation and saponification) were reportedly 4 carried out without isolation of the intermediate N,N-dimethyl ester, and the final product was purified by reverse phase chromatography.In our hands this one pot method proved unsatisfactory for gram scale batches.We examined a stepwise approach and investigated a number of reagents for reductive methylation, including sulfuric acid mediated sodium borohydride / formaldehyde, 7 sodium cyanoborohydride formaldehyde in glacial acetic acid, 8 and direct treatment with dimethyl sulfate. 9From this we determined that the combination of sodium cyanoborohydride / formaldehyde in methanol and 1 N hydrochloric acid was the most satisfactory method.Using this modification the dimethylaniline (11) could be purified by flash column chromatography in gram quantities.The hydrolysis of the methyl ester and subsequent salt formation with trifluoroacetic acid was accomplished without isolation of the free dimethylamino carboxylic acid.This procedure provided material which required only a rapid pass through a plug of reverse phase silica to obtain 1 in 79% yield.The overall yield of 1 by this current procedure is 9%.In conclusion, the authors of this present report have developed an improved method for the gram scale preparation of PD123319 (1).This method circumvents the limitations associated with of the preparation of 1 as outlined by Blankley. 4

N-1-Bis[t-butoxycarbonyl]-L-histidine methyl ester (3).
Triethylamine (82.8 mL, 0.594 mol) was slowly added over a 15 min period to a mixture of L-histidine methyl ester dihydrochloride (72.0 g, 0.297 mol) in methanol (660 mL) and the resulting solution was stirred at room temperature for 30 min A mixture of di-t-butyl dicarbonate (130 g, 0.596 mol) in methanol (330 mL) was then added dropwise over 30 min and stirring was continued for 48 h at room temperature.The solvent was then evaporated to dryness under vacuum and the residue partitioned between water (0.5 L) and CH2Cl2 (1 L).The organic fraction was washed with 10% citric acid (2 x 500 mL), dried (MgSO4) and solvent removed under vacuum yielding a light yellow oil which was dissolved in petroleum ether (200 mL).Evaporation of the solvent and redissolution with petroleum ether (200 mL) followed by agitation with a glass rod liberated a white crystalline precipitate.Upon cooling overnight and filtration, the title compound 3 was isolated as a fine white solid (90.4 g, 82% yield): mp 86−88 o C (lit. 5