Phthalazine derivate

Phthalic anhydride and diethyl phthalate are easily converted with hydrazine into 4-hydroxyphthalazin-l(2/f)-one. Its substituted derivatives have been prepared using substituted hydrazines, substituted phthalic anhydrides, or diesters or disodium salts of substituted phthalic acids (Scheme 81). However, condensation of phenylhydrazine with phthalic anhydride gives only a small amount of the corresponding phthalazine, the main product being 2-anilinophthalimide. This can be rearranged in the presence of base into the phthalazine derivative. For the preparation of 2,3-disubstituted derivatives, 1,2-disub-stituted hydrazines are reacted with the appropriate phthalic anhydrides or phthaloyl chlorides. Derivatives of 4-amino- or 4-hydrazino-phthalazin-l(2iT)-one have been prepared either from the corresponding monothiophthalimide and 3-aminoisoindolin-3-one (1S4) or from ethyl 2-cyanobenzoate (155) and hydrazine hydrate (Scheme 82). Similarly,... 

Quinoxalinyl, 4-cinnolinyl, and 1-phthalazinyl derivatives, which are all activated by a combination of induction and resonance, have very similar kinetic characteristics (Table XV, p. 352) in ethoxylation and piperidination, but 2-chloroquinoxaline is stated (no data) to be more slowly phenoxylated. In nucleophilic substitution of methoxy groups with ethoxy or isopropoxy groups, the quinoxaline compound is less reactive than the cinnoline and phthalazine derivatives and more reactive than the quinoline and isoquinoline analogs. 2-Chloroquinoxaline is more reactive than its monocyclic analog, 2-chloropyrazine, with thiourea or with piperidine (Scheme VI, p. 350). 

Cyclocondensation of 2-aroylbenzoic acid 223 with hydrazine gave the phthalazine derivative 224, which was alkylated with ethyl chloroacetate in aqueous sodium hydroxide or pyridine to give the N-substituted derivative 225. Condensation of the latter with hydrazine afforded the hydra-zide 226, which could be cyclized to give the 2//[l,2,4]triazino[3,4-a]phthalazin-3(4tf)-one 227 (91MI3). 

Several applications of established ring-closure methodologies have been applied for the syntheses of the benzo-logues of the triazolopyridazine ring system - all these refer to cyclization to [l,2,3]triazolo[3,4- ]phthalazine derivatives. In Table 13, such products are shown together with yields and literature references. The product in entry 8 is somewhat outstanding in this list these compounds have been synthesized by solid-phase methodology, and the yields refer to the amounts of the crude products mostly of 90% purity. 

Table 13 [1,2,3]Triazolo[3,4-a]phthalazine derivatives obtained by established ring-closure techniques, including yields and literature references...

Figure 1.12). It is beyond the scope of the present review article to discuss all of the findings of these studies in detail. However, in general, it can be stated that also these CSPs may reveal valuable complementary selectivity profiles for particular classes of chiral solutes. This may apply to an even greater extent to CSPs based on Sharpless phthalazine-derived cinchona alkaloids (see Figure 1.9) (type IV CSPs bottom) [38,59] and mutants thereof (N.M. Maier and W. Lindner, in preparation). They partly showed exceptionally high enantioselectivities for some specific applications (vide infra). 

Other functionalized supports that are able to serve in the asymmetric dihydroxylation of alkenes were reported by the groups of Sharpless (catalyst 25) [88], Sal-vadori (catalyst 26) [89-91] and Cmdden (catalyst 27) (Scheme 4.13) [92]. Commonly, the oxidations were carried out using K3Fe(CN)g as secondary oxidant in acetone/water or tert-butyl alcohol/water as solvents. For reasons of comparison, the dihydroxylation of trons-stilbene is depicted in Scheme 4.13. The polymeric catalysts could be reused but had to be regenerated after each experiment by treatment with small amounts of osmium tetroxide. A systematic study on the role of the polymeric support and the influence of the alkoxy or aryloxy group in the C-9 position of the immobilized cinchona alkaloids was conducted by Salvadori and coworkers [89-91]. Co-polymerization of a dihydroquinidine phthalazine derivative with hydroxyethylmethacrylate and ethylene glycol dimethacrylate afforded a functionalized polymer (26) with better swelling properties in polar solvents and hence improved performance in the dihydroxylation process [90]. 

Chemical Class Phthalazine derivative I Clinical Pharmacology ... 

As with ciimolines, phthalazines were also prepared most frequently through condensations of hydrazine derivatives and carbonyl-containing compounds. For example, Monneret and co-workers reported the condensation of dialdehyde 148 with hydrazine to produce phthalazine derivative 149, an advanced intermediate in the preparation of anticancer analogs of etoposide <99T12805>. 

A similar transformation was reported using a polyfunctional phthalazine derivative (7.2.) 4 It is interesting to note that the transmetalation of the borane was not selective with respect to the pyridyl group, formation of the product resulting from the transfer of the ethyl group was also observed. 

For steric reasons, the reaction of enamines with 1,4-diarylpyridazino-[4,5-d]pyridazines (260) takes place only with the unsubstituted pyridazine ring (91T3959). Numerous enamines were used in the reaction with 260. Among other products, a series of phthalazine derivatives was obtained. An efficient approach to isoquinoline derivatives is based on the reaction... 

For a number of substrate classes these new AQN ligands are superior to the phthalazine-derived ones, that is, most vinylic and allylic compounds are dihydroxylated with significantly higher enantioselectivities. For example, using (DHQD)2AQN in the AD of allyl tosylate gives... 

A method has been reported for the solid-phase synthesis of tetrazolo[5,1 -tf]phthalazine derivatives 501 based on the cyclization of resin-bound chlorophthalazines 500 with NaN3 in l-methyl-2-pyrrolidinone (NMP) at 120°C (Scheme 63) <2005TL3107>. 

Up to 1994, no reaction involving derivatives of pyridazino[3,4-c]pyridazines has been reported. Only some reactions and the synthesis of compound (1) as a key intermediate in the synthesis of pyridazino[3,4,5-tffe]phthalazine derivatives (2)-(4) has been described <82CJC1214>. 

A similar reaction sequence is expected from some other phthalazine derivatives, such as methoxy (88) and aminophthalazines,05 e.g., Scheme 10. 

Janda s phthalazine derivative (13) [13 b] and the pyridazine derived ligand (14) developed by Bolm [15] almost reach the yield and enantiomeric excess achieved with the original catalytic system in a homogenous reaction ( er -butanol/ water or acetone/water) [12 b]. After addition of diethyl ether or ferf-butyl methyl ether, the polymer-bound ligand is precipitated quantitatively. Thereby, the product as well as the ligand... 

The strategy is impressively simple the phthalazine derivative 15 can readily be prepared from quinine in one step. Being a divinyl derivative, it can be submitted as a cross-linking unit in the radical polymerization of methyl methacrylate (MMA) or 2-hydroxy methacrylate (HEMA). Thereby, an immobilized (DHQ-PHAL) derivative 16 is obtained, which is suited for the asymmetric dihydroxylation of frantr-stilbene (>99 % ee) and ( )-cinnamic acid methyl ester (>99 % ee. Table 1). The insoluble catalyst can be recovered by simple filtration, and its repeated... 

Ju Y, Varma RS (2005) Microwave-assisted cyclocondensation of hydrazine derivatives with alkyl dihalides or ditosylates in aqueous media syntheses of pyrazole, pyrazolidine and phthalazine derivatives. Tetrahedron Lett 46 6011-6014... 

Preparative Methods the acetate is prepared from dihydroquinidine and the p-chlorobenzoate is commercially available. The phthalazine-derived bis(dihydroquinidine) ligand is commercially available. A formulation of the standard reactants for the asymmetric dihydroxylation (AD-mix-p) on the small scale has been developed and is commercially available. AD-mix-p (1 kg) consists of potassium osmate (0.52 g), the phthalazine-derived ligand (5.52 g), K3Fe(CN)6 (700 g), and powdered K2CO3 (294 g). 

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