Methods for preparing 2-alkynyladenosine derivatives

Abstract

Disclosed are methods for preparing 2-alkynyladenosine derivatives of formula A: or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate or isomorphic crystalline form thereof, the method comprising the step of: contacting 2-iodoadenosine-5′-N-ethyluronamide with a compound of formula B: wherein Z is —C(═O)OR or —CH2OC(═O)R, where R is a C1 to C5 alkyl, preferably methyl. The methods are useful for preparing 2-alkynyladenosine derivatives that are, in certain embodiments, adenosine receptor agonists.

Description

FIELD OF THE INVENTION This invention relates to improved methods for preparing 2-alkynyladenosine derivatives, more specifically, to improved methods for preparing 2-alkynyladenosine derivatives that are, in certain embodiments, adenosine receptor agonists and, even more specifically, to improved methods for preparing 2-alkynyladenosine derivatives that are, in certain embodiments, A2 adenosine receptor agonists. BACKGROUND OF THE INVENTION Adenosine is known to modulate a number of physiological functions. At the cardiovascular system level, adenosine is a strong vasodilator and a cardiac depressor. In the central nervous system, adenosine induces sedative, anxiolytic and antiepileptic effects. At the kidney level, it exerts a diphasic action, inducing vasoconstriction at low concentrations and vasodilation at high doses. Adenosine acts as a lipolysis inhibitor on fat cells and as an anti-aggregant on platelets (Stone T. W., Purine Receptors and their Pharmacological Roles, Adva...

AI Technical Summary

Benefits of technology

In Step A3, the acid (3) is converted to the N-ethylamide (4), preferably in a one pot reaction. Conventional activation methods use acid chloride. In certain embodiments, the acid may be activated as a succinimide derivative using a carbodiimide, such as N-ethyl-dimethylaminopropylcarbodiimide (EDC). The activated acid may then be treated with an excess of ethylamine to afford the amide in good yield and reasonable purity. In a preferred embodiment, Step A3 may be carried out by activating the acid using 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), for example, by mixing at about 35° C. for about 3 hours and then cooling to about 5 to 10° C. The reaction solution may then be directly treated with ethanol and saturated with ethylamine, to afford the N-ethylamide product (4) in high purity and yield after recrystallization. The recrystallization may be carried out, for example, by first distilling the crude product (4) to a minimum volume, dissolving the residue in dichloromethane, washing with acid and base, exchanging the dichloromethane with ethanol, cooling to 0° C. for 2 to 5 hours, filtering the product and drying at about 40° C. under vacuum for 12 to 24 hours. Typical yields are in the range of 65 to 70%. Preferably, the ethylamine is added as a 4 to 8 M solution in ethanol to the reaction mixture and stirred, for example, for about 16 hours. Alternatively, the reaction mixture may be saturated with gaseous ethylamine.

It has been reported that the acetylide substitution on the tosylate is problematic, requiring a large excess of reagent with long reaction times, or the use of a protected intermediate with heating (Rieger, J. M., Brown, M. L., Sullivan, G. W., Linden, J., and MacDonald, T. L., J. Med. Chem., 2000, 44, 531-539). Steps B1-3 and B2-3 of the invention using lithium acetylide-ethylene diamine complex and dimethylsulfoxide (DMSO) are rapid, producing high yields (90%), requiring no steps of heating, further purification or deprotection to generate the product alcohol (9).

For cyclohexane-containing acetylene compound where Z is —C(═O)OR (where R is C1-C5 alkyl) (Scheme B2), compound 9 is oxidized in step B2-4 using standard Jones oxidation conditions. Oxidation of the hydroxyl of hydroxyl acetylene species using standard Jones oxidation conditions has been reported to afford 70-75% yields (Rieger, J. M., Brown, M. L., Sullivan, G. W., Linden, J., and MacDonald, T. L., J. Med. Chem., 2000, 44, 531-539; WO 00 / 44763). Use of the TEMPO / bis-acetoxyiodobenzene (BAIB) in step B2-4 provides mild conditions for carrying out this transformation quickly (about 3 hours) and cleanly, in high isolated yields (95%).

In step B2-5, the carboxylic acid (11) may be converted to the desired ester (12) by a simple Fisher esterification reaction using a suitable alcohol (methanol for compound (12) or ethanol or 1-propanol), and catalyst, such as concentrated sulfuric acid, hydrochloric acid, anhydrous hydrogen chloride, p-toluenesulfonic acid and acid form of an ion exchange resin, followed by distillation, to produce the product (12) in good yield and purity without the use of expensive reagents like trimethylsilydiazomethane. This improved synthesis affords the desired ester-alkyne in four steps in 40% overall yield with no chromatographic purifications. This contrasts to the prior art syntheses that proceeded in four steps with a 22% yield after three column chromatography steps (Rieger, J. M., Brown, M. L., Sullivan, G. W., Linden, J., and MacDonald, T. L., J. Med. Chem., 2000, 44, 531-539) or in six steps with a 28% overall yield with four chromatographic purifications (WO 00 / 44763).

In connection with the preparation of adenosine derivatives, the methods of the present invention may offer improved yields, purity, ease of preparation and / or isolation of intermediates and final product, and more industrially useful reaction conditions and workability over prior art methods of preparation. The present methods are particularly useful for the preparation of adenosine derivatives on a large scale, including commercial scale, for example, from multi-kilogram to ton quantities or more of adenosine derivative. Specifically, isolation and / or purification steps of intermediates to the adenosine derivatives may be advantageously substantially or completely avoided using the methods of the present invention. The present methods may be particularly advantageous in that the adenosine derivatives may be obtained in substantially pure form. The term “substantially pure form”, as used herein, means that the adenosine derivative prepared using the present processes may preferably be substantially devoid of organic impurities. The term “organic impurities”, as used herein, refers to organic materials, compounds, etc., other than the desired product, including, for example, the cis-isomer of compound of formula A, that may be typically associated with synthetic organic chemical transformations including, for example, unreacted starting reagents, unreacted intermediate compounds, and the like. In preferred form, the present processes may provide adenosine compounds that are at least about 75% pure, as measured by standard analytical techniques such as, for example, HPLC. Preferably, the adenosine derivatives prepared using the present methods may be at least about 80% pure, with a purity of at least about 85% being more preferred. Even more preferably, the adenosine derivatives prepared using the present methods may be at least about 90% pure, with a purity of at least about 95% being more preferred. In particularly preferred embodiments,. the adenosine derivatives prepared using the present methods may be more than about 95% pure, with a purity of about 99.8% being even more preferred, and with a purity of about 100% being especially preferred.

Compounds described herein throughout, can be used or prepared in alternate forms. For example, many amino-containing compounds can be used or prepared as an acid addition salt. Often such salts improve isolation and handling properties of the compound. For example, depending on the reagents, reaction conditions and the like, compounds as described herein can be used or prepared, for example, as their hydrochloride or tosylate salts. Isomorphic crystalline forms, all chiral and racemic forms, hydrates, solvates, and acid salt hydrates, are also contemplated to be within the scope of the present invention.

Problems solved by technology

Unfortunately, NECA is also active on the A1 receptor and thus lacks specificity for the A2 receptors alone.

These above-described synthetic methods for producing 2-alkynyladenosine derivatives, including DWH-146e, provide lower yields than desired, require prolonged reaction times and require extensive chromatographic purification.

Furthermore, the oxidation procedure (second step of Scheme III above) requires prolonged reaction times and has been noted to be troublesome due to competing oxidation at the 2-iodo position.

Furthermore, the cross-coupling reaction between the cyclohexane-containing acetylene and 2-iodoNECA proceeds with poor yield after chromatography.

Images