Chapter One

Recent Progress in Pyrimido[5,4-d]pyrimidine Chemistry

Gunther Fischer     Geibelstraße 15, D-04129 Leipzig, Germany
E-mail: gunther_fischer@yahoo.de

Abstract

The review deals with the pharmaceutically important group of pyrimido[5,4-d]pyrimidines (PPs) and covers the relevant literature published from about 1986 through 2014. A synthetic section describes the formation of PPs from pyrimidines both by cyclization to give a second pyrimidine ring and by transformation of another fused heterocyclic ring. In the structure-related section, properties such as the spectroscopic and electrochemical behavior are stressed. The reactivity of PPs is dominated by the nucleophilic substitution of chloro compounds and the formation of derivatives and analogs of Dipyridamole. This useful drug is also the main focus of the application section.

Keywords

Bicyclic heterocycles; Dipyridamole; Heterocycles; Nitrogen heterocycles; Nucleophilic substitution; Organic chemistry; Pharmaceutical use; Pyrimidines; Pyrimido[5,4-d]pyrimidines

1. Introduction

1.1. General Survey

The chemistry of pyrimido[5,4-d]pyrimidine (PP, 1, Scheme 1) and its derivatives has quickly developed after they had been investigated as purine mimetics and derivative Dipyridamole (Dipy, 2) had proven to be an important drug (cf. 84CHEC(3)329). Results have been summarized, in a wider context, in Katritzky's Comprehensive Heterocyclic Chemistry (see above and 96CHEC2(7)737, 08CHEC3(10)977), by Delia in Weissberger's Chemistry of Heterocyclic Compounds (92HC(24/4)149), by Ishikawa in Science of Synthesis (04SOS(16)1337), by Wang et al. (11YCH1773), and by Abdel-Rahman and El-Mahdy (12H(85)2391).
Scheme 1

1.2. Scope and Limitation

The present review is based on Delia's compilation cited above and covers the literature in the area of PPs from about 1986 through 2014. The presentation is confined to PPs showing maximum unsaturation of the bicyclic parent ring system and to corresponding tautomers, such as tris-lactam 3 and tetrakis-lactam 4. Examples extracted from the extensive patent literature are taken into account provided they reveal additional information on synthesis or application.

1.3. Nomenclature

In this review, for consistency, PPs are generally drawn and numbered as shown in Formula 1. Numbering 1, 2, 3, 4 and 5, 6, 7, 8 may in many cases be exchanged. Among tautomerizable derivatives, hydroxy compounds have been confirmed to exist largely in the oxo forms (e.g., 3 and 4) that, therefore, will be used in this chapter. For other hydroxy as well as mercapto and amino PPs, when the exact position of tautomeric equilibria is uncertain, the most probable or the respective authors' form will be depicted. An alternative name of PPs is that of 1,3,5,7-tetraazanaphthalenes (e.g., 06JCC1980). Initially the compounds had been denominated homopurines (51LA(572)217, 02GEP10115921). It should be noted, however, that the modern term homopurine is related to certain DNA sequences (cf. 96MI1).

2. Synthesis

2.1. Survey

PPs are nearly exclusively formed (cf. 92HC(24/4)149, p. 163 ff) (a) from monocyclic pyrimidine derivatives (especially 5-aminopyrimidine-4-carboxylic acids) by cyclization forming a second pyrimidine ring and (b) from fused pyrimidines (pyrimidooxazinones or purines) by ring transformation.

2.2. Synthesis from Unsubstituted 5-Aminopyrimidine

A new direct synthesis of the PP parent substance (1) by a one-pot three-component heterocyclization using a Vilsmeier reagent (Scheme 2) has been reported (12JOC8492). The reaction is supposed to involve twofold attack of the reagent (amidination and imination to give intermediates 5 and 6, respectively) and cyclization.
Scheme 2
Scheme 3

2.3. Synthesis from 2-Substituted 5-Aminopyrimidine-4-carboxylic Acids

This synthesis requires the reaction of free carboxylic acids (such as 7 or 9) with C1N1 units or of carboxamides (e.g., 11) or nitriles (e.g., 13, see below) with C1 units to close another pyrimidine ring. Scheme 3 shows the formation of 4-oxo derivatives 8 (97WOP32880), 10 (60TH1), and 12 (97JME1820). The use of reagents formamidine (to give 8) or diethoxymethyl acetate (to give 12) is more advantageous than that of formamide or triethyl orthoformiate, respectively, is. Suitable sulfur-containing reagents lead to mercapto PP 10.
Scheme 4 Amino and imino derivatives, for example, 15 and 17 (Scheme 4 1 ) are obtained from nitrile 13 by reacting intermediate formamidate 14 with ammonia, anilines, benzyl- or alkylamines (05JCR530).

2.4. Synthesis from Aminoorotic Acid or Derivatives

Continued efforts have been made to improve the fundamental synthesis of tetraoxo compound 4 from 5-aminouracil-4-carboxylic acid (aminoorotic acid, 19, Scheme 5) as earlier described (84CHEC(3)329, p. 364; 92HC(24/4)149, p. 163 ff). Hence, path A describes an example of modified technical procedures (89DDP263891), and path B is a new preparative method (02JCS(P1)108). The product is easily obtained as disodium salt (20). Other salts have likewise been claimed (86DDP240017). Acid 19 with formamide gives trioxo PP 3 (04CCT413) whereas condensation with 9-isothiocyanatoacridine (analogously to the formation of 4, path B) leads to thiono PP 21 (04MI2).
Scheme 5 Huang et al. (12TL7154) have recently published regioselective syntheses of mono-, bis-, and tris-N-substituted PP tetraones with diversified substitution. Scheme 6 discloses, starting from uracil-4-carboxylic ester 22, the essential steps of alkylation/cyclization or alkyl-introducing cyclization. This way, urea-mediated cyclization of mono- and dialkyluracils gave products 23 and 24, respectively, in moderate yields under relatively forcing conditions (solid-phase reaction at 210 °C). For the more difficult approach to trisubstituted PPs2  25a and b, a smooth and efficient palladium-catalyzed cascade reaction enabled simultaneous cyclization and N-3 functionalization by means of monoalkyl urea species.
Scheme 6
Scheme 7

2.5. Synthesis from Nitroorotic Acid

Processes have been developed to prepare tetraoxo PP (4) from nitroorotic acid (26, Scheme 7) without isolating intermediates (10MIP1) and to synthesize alkylated PPs 23 and 24 in a similar way (08WOP127591).

2.6. Synthesis from Pyrimido[5,4-d] [1,3]oxazines

Substituted oxo PPs are accessible from 5-aminopyrimidine-4-carboxylic acid (27a) derivatives (as depicted above) via pyrimidooxazines, too (Scheme 8). For instance, isovaleramide 27b on cyclizing yields oxazinone 28, and subsequent condensation with benzylamine gives PP 29 (03WOP103575). Analogous reactions of aminoorotic acid 19 lead to oxazinone 30 and, for instance, amine 31 (02MI4) or to styryl derivative 32 (90JME1721).

2.7. Synthesis from Purines

The ring transformation of purines to give PPs (cf. 82MI1; 92HC(24/4)149, p. 167) by an ANRORC-type mechanism has been further developed extensively, especially by Portuguese and British chemists. Generally, 9-arylpurines having a C-N functionality in the 6-position, on nucleophilic attack at the imidazole ring by ammonia or amines, yield 4-amino- or 4-imino-8-arylamino PPs. These reactions often compete with a simple modification of the purine substituents and are very sensitive to the experimental conditions. Thus, 6-cyanopurine 35 (Scheme 9) and methylamine furnish, depending on the conditions, 4-imino PP 36 (01JCS(P1)2532) or Dimroth rearrangement product 37 (09H(78)2245). Other examples include the formation of 4-imino PPs 38 and 39 and stable amino tautomer 40 (07EJO1324).
Scheme...