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General Properties.
Tautomerism in the Allopurinol Series. (with UV and NMR spectra)
Anion Formation in Allopurinols.
Cation Formation in Allopurinols.
Theoretical Calculations. (with Energy and Dipole Moment)
13C NMR Shifts and Fine Spilitting Pattern



            Allopurinol (C5H4N4O) is used to treat hyperuricaemia associated with a variety of conditions including chronic gout. Common adverse effects include skin rashes and hypersensitivity reactions; acute attacks of gout may initially be precipitated.


             General PropertiesA white or off-white, almost odourless powderThe melting point is above 350C.  The molecular weight is 136.11.  C 44.12%, H 2.96%, N 41.16%, O111.75%.   It is a tautomeric mixture of 1H-pyrazolo[3,4-d] pyrimidin-4-ol and 1,5-dihydro-4H-pyrazolo[3,4-d] pyrimidin-4-one. Very slightly soluble in water and alcohol; practically insoluble in chloroform and in ether; dissolves in dilute solutions of alkali hydroxides.  Other proprietary names are Adenock; Aloral; Alositol; Allo-Puren; Allozym; Allural; Anoprolin; Anzief; Apulonga; Apurol; Apurin; Bleminol; Bloxanth; Caplenal; Cellidrin; Cosuric; Dabroson; Embarin; Epidropal; Foligan; Geapur; Gichtex; Hamarin; Hexanurat; Ketanrift; Ketobun-A; Ledopur; Lopurin; Lysuron; Miniplanor; Monarch; Nektrohan; Remid; Riball; Sigapurol; Suspendol; Takanarumin; Urbol; Uricemil; Uripurinol; Urobenyl; Urosin; Urtias; Xanturat; Zyloprim; Zyloric.

              Incompatibility. Allopurinol sodium as a 3 mg per ml solution in 0.9% sodium chloride was visually incompatible with a number of drugs including amikacin sulphate, amplotericin, carmustine, cefotaxime sodium, chloropromazine hydrochloride, cimetidine hydrochloride, clindamycin phosphate, cytarabine, dacarbazine, daunorubicin hydrochloride, diphenhydramine hydrochloride, doxorubicin hydrochloride, doxycycline hydrochloride, droperidol, floxuridine, gentamicin sulphate, haloperidol latate, hydroxyzine hydrochloride, idarubicin hydrochloride, imipenem with cilastatin sodium, methylprednisolone sodium succinate, metoclopramide hydrochloride, minocycline hydrochloride, mustine hydrochloride, nalbuphine hydrochloride, metilmicin sulphate, ondansetron hydrochloride, pethidine hydrochloride, prochlorperazine edisylate, promethazine hydrochloride, sodium bicarbonate, streptozocin, tobramycin sulphate, and vinorelbine tartrate.


  Scheme 1

              Tautomerism in the Allopurinol Series.  The lmax of (1) is identical with the value for the 5-methyl (4) and the 1,5-dimethyl (6) derivatives.  The UV absorption spectra of allopurinols is shown in Table 1 below:


              Letter a,n and c refer respectively to the neutral molecule, the anion, and the cation. Thus it might be supposed that in aqueous solution (1) is present in its 1,5-di-NH form.  However, introduction of an NMe group generally shift lmax by a few nm to longer wavelengths, as in the pair (1)/(6) and (3)/(7).  Therefore (1) should absorb at a shorter wavelength than e.g. (2).  In fact its absorption maximum is found between those of (2) and (3), indicating that (1) is a mixture of the 1,5- and 2,5-di-NH tautomers.  By similar reasoning, 5-methylallopurinol (4) is present in aqueous solution as a mixture of 1- and 2-NH tautomers.  The 13C n.m.r. spectrum of allopurinol supports the presence of both tautomers in solution.  The NMR spectra of allopurinols are shown in Table 2 below:

              The X-ray interferogram of (1) shows a hydrogen bridge between the 1-NH group and 7-N of another molecule, while 2-N is bound to the hydrogen of a 5-NH group, suggesting that in the crystal allopurinol is present as the 1,5-di-NH tautomer.

               Anion Formation in Allopurinols.  Dissociation of the 5-NH group in the pyrimidine moiety of (2) and  (3) leads to a marked bathochromic shift of lmax of 232 nm (from Table 1).  In contrast, ionisation of an NH-group in the pyrazole moiety of (4) and  (5) causes a very small bathochromic or a marked hypsochromic displacement of lmax.  Allopurinol itself occupies an intermediate position, i.e. monoanion fromation is accompanied by a moderate bathochromic shift of 9 nm, indicating the presence of the tautomeric forms (1a)-(1c).  Di-anion formation shifts the absorption maximum of (1) by a further 17 nm, i.e. somewhat less than the displacement of lmax characteristic for anion formation in the pyrimidine ring of (2) and (3).  It is concluded that (1a) makes the larger contribution to the tautomeric mixture of the monoanion of (1), i.e. the main ionisation sequence of (1) is from 1(2) to 5.  This conclusion is supported by th esimilar chemical shifts of the anions of (1) and (4) illustrated in Table 2.

             Cation Formation in Allopurinols.  The allopurinols are divided into two classes (as in Table 1).  All 7-methyl derivatives have pK values above +3, which all others show pK values between +0.4 and 1.8.  Attachment of a proton to the pyrazole ring causes only small downfield shifts of the 3-H signals (see Table 2, compounds (1),(2) and (6).)

               Moreover, the physical properties of 4-mehtylthiopyrazolo[3,4-d]pyrimidines and related compounds are shown in Table 4 below:

               Theoretical Calculations.  Energies and dipole moments are shown in Table 6 below:


               The possible tautomers of each compound are arranged in order of decreasing stability.  It can be observed that

(a)    The most stable form of allopurinol is the 1,5-di-NH tautomer and the least stable one the 1,2-di-Nh tautomer.  Likewise in compounds (2) and (3) and all the dimethyl derivatives, the 1,2-disubstituted form is always the least stable, and 1,2-dimethylallopurinol is still unknown.  Furthermore, the spectral data for 2-NH and 2-NMe derivatives indicate that whenever protonation occurs at position 1, the 7-Nh tautomer is also formed.  Alkylation of 2,5-dimethylallopurinol (7) takes place at N-7 and not at N-1, to yield compound (11).

(b)   The 2-NH form of 5-methylallopurinol (4) is more stable than the 1-NH tautomer.  However, the anion of (4) is attacked by methylating agents to about the same degree at N-1 and N-2 (see scheme 1)

(c)    For 7-methylallopurinol (5), the 2-NH tautomer is considerably more stable than 1-NH form, in accordance with the spectral and chemical properties of this compound.

(d)   The calculated dipole moments roughly follow the order of energies, the least stable form having the highest dipole moment4.

             Below are the 13C NMR Shifts in 1H-Decoupled NMR Spectra of Pyrazolo[3,4-d]-and Pyrazolo[1,5-a]pyrimidines and also Fine Spilitting Pattern (refer to the molecule pattern above the Tables):


Structural proof was provided by 13C and 1H NMR spectra (Table I).  The monomethyl isomers 5 and 6 are stable in alkaline medium, which is contrast to the N-1 / N-5 or the N-2 / N-5 dimethylated allopurinol which suffer ring opening of the pyrimidine moiety.  These findings can be explained by the fact that - in contrast to the dimethylated allopurinols - 5 and 6 can form inert anions in alkaline medium.

For an unequivocal structural proof, the proton-coupled 13C NMR spectrum of 7b was measured (Table II).  A positive indicator of N-1 alkylation is the fine splitting of the C-7a signal.  This carbon shows three 3J(CH) couplings: 1,3J(C-7a / H-6) =12.4 Hz; 2,3J(C-7a / H-3) = 3.7 Hz; 3,3J(C-7a / CH2N) = 1.6 Hz.  the complex pattern of the C-7a signal appears as a double pseudoquintet since two signals coinincide because of the incomplete resolution (0.5 Hz).  Furthermore, the coupling pattern of C-3, C-3a and C-6 (Table II) reveal N-1 alkylation5.

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