Process for manufacture of amantadine nitrate derivatives

A process for manufacture of amantadine nitrate derivatives, comprising following steps:

• (1) synthesis of adamantanol from adamantane;
• (2) carboxylation of adamantanol;
• (3) acetylation of adamantanoic acid;
• (4) reduction;
• (5) hydrolysis of amido adamantanol and Boc protection of amino group;
• (6) crystallization of Boc protected amantadinol;
• (7) nitrate esterification of Boc protected amantadinol;
• (8) refining of the product of nitrate esterification;
• (9) Boc deprotection and salt formation;
• and (10) refining of amantadine nitrate hydrochloride:
• wherein, the adamantane has the structure of:
• wherein, R1 and R2 are each independently hydrogen, straight-chain or branched-chain alkyl, substituted or unsubstituted aryl or heteroaryl;
• wherein, the steps further comprise:
• (1) synthesis of adamantanol:
• treating a substituted or unsubstituted adamantane to be brominated with liquid bromine and hydrolyzed with sodium oxalate to form an adamantanol;
• (2) carboxylation of adamantanol:
• treating the adamantanol via Koch-Haff reaction, and condensation with formic acid to obtain an adamantanoic acid;
• (3) acetylation of adamantanoic acid:
• treating the damantanoic acid via condensation with acetonitrile via Ritter reaction to obtain an amido adamantanic acid;
• (4) reduction:
• treating the amido adamantanic acid via reduction with sodium borohydride to obtain an amido adamantanol;
• (5) hydrolysis of amido adamantanol and Boc protection of amino group:
• treating the amido adamantanol, after an acyl group thereof being removed with strong alkali hydrolysis, via condensation with Boc anhydride;
• (6) crystallization of Boc protected amantadinol:
• treating the product of Boc condensation via crystallization with mashing in n-hexane;
• (7) nitrate esterification of Boc protected amantadinol:
• reacting the Boc protected amantadinol with a nitrating agent at low temperature to obtain a product of nitrate esterification, wherein the nitrating agent is a reagent with a mixture of fuming nitric acid and acetic anhydride;
• (8) refining of the product of nitrate esterification:
• dissolving the product of nitrate esterification in alcohol, and adding water for crystallization with mashing;
• (9) Boc deprotection and salt formation:
• removing Boc protecting group of the product obtained in step (8) via hydrolysis with HCl to obtain amantadine nitrate hydrochloride;
• and
• (10) refining of amantadine nitrate hydrochloride:
• dissolving the amantadine nitrate hydrochloride in ethanol, resulting solution being filtered, concentrated and evaporated to remove partially the ethanol, adding ethyl acetate for crystallization with mashing, to obtain, after centrifugation, an amantadine nitrate hydrochloride;
• wherein, in step (5), reaction solution for hydrolysis is polyethylene glycol;
• and in step (7), molar ratio of reaction feed is raw material:acetic anhydride:fuming nitric acid=1:1.08-1.8:1.68-2.8;
• and in step (9), molar ratio of reaction feed is raw material:HCl=1:
• 5-10.