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• Synthesis Method

  The convergent synthesis of edoxiban tosilate (XI) involves the union of three key structural subunits, diamino cyclohexane intermediate 127, pyridyl amino oxoacetate 128, and thiazole acid 129 (Scheme 1) and the discovery synthesis and related compounds were disclosed in several publications. Several patents on the improved synthesis of the diamino and thiazole intermediates have been disclosed, including an improved synthesis of edoxaban. Because the synthesis described in the latest patents do not involve any chromatographic purification, this is the most likely processscale route, and will be highlighted (Scheme 1–3).
  
  The preparation of the tetrahydropyridyl thiazolo acid 129 is shown in Scheme 2. N-Methyl piperidone (130) is treated with catalytic pyrrolidine, cyanamide, and sulfur in warm isopropanol to yield aminothiazole 131. Diazotization of thiazole amine 131 in the presence of 48% HBr with sodium nitrite at 30°C gave the thiazole bromide, which was directly converted to tosylate salt 132 in 78% yield from piperidone 130. After free-basing the salt with sodium hydroxide, the resulting bromide was treated with n-BuLi followed by bubbling carbon dioxide gas to give lithium carboxylate salt 133. Acidification of this salt in ethanolic HCl gave the desired thiazole acid hydrochloride salt (129) in 90% yield over two steps.
  
  The synthesis of edoxaban tosilate is shown in Scheme 3. Commercially available epoxide ester 134 was reacted with sodium azide to afford the corresponding hydroxyazide intermediate regiospecifically and in quantitative yield. This intermediate was immediately subjected to catalytic hydrogenation in the presence of Boc2O to provide alcohol 135 in 68% yield. Alcohol 135 was converted to the corresponding mesylate, followed by the treatment with sodium azide to give primarily cis-azide 136 in 32% yield over two steps after separation of diastereomers. Reduction of the azide followed by a Cbz protection provided carbamate 137 in 67% yield over two steps. The ester group of 137 was hydrolyzed with lithium hydroxide and reacted with dimethylamine to furnish N,N-dimethylamide 138 in 76% yield over the two step sequence. The Cbz group of 138 was then removed by catalytic hydrogenation and the resulting amine was immediately converted to oxalate salt 127.
  
  Amine 127 was then condensed with the key pyridylamino oxoacetate 128, prepared in 96% yield by reacting 5-chloropyridin-2-amine (140) with ethyl 2-chloro-2-oxoacetate in warm acetonitrile, to provide amide 139 in 86% yield. Finally, removal of the Boc group of 139 with methanesulfonic acid and EDCI-mediated coupling with tetrahydropyridyl thiazolo acid 129 gave edoxaban in 93% yield. Treatment with TsOH led to isolation of edoxaban tosilate (XI).;

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