Synthetic method

Details Synthetic method Synthetic method

2000-12-15

2001-11-20

Pryor, Alton (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

Polycyclo ring system containing anthracene configured ring...

Reexamination Certificate

active

06320063

ABSTRACT:

The invention relates to a process for the preparation of AQ4 and derivatives thereof including AQ4N, a bis-bioreductive agent with of value in the treatment of cancer.
AQ4N is an anthraquinone, and would normally be synthesised by oxidation of AQ4 (3):
AQ4N is in fact a prodrug and the reverse reaction occurs in vivo, reductive metabolism in hypoxic cells giving the active agent, AQ4, in its protonated form. The prodrug is non-toxic, making its synthesis in large quantities desirable.
AQ4 has been prepared previously by the method of Scheme 1 (
J. Chem. Soc
. 1937, 254
; J. Med. Chem
. 1979, 22
; Synth. Comm
. 1995, 25, 1893).
Alternatively, 1,8-diamino-4,5-dihydroxyanthraquinone (U.S. $14/1 g: Aldrich Chemical Co., Gillingham, England) can be substituted for 1 in Scheme 1. We have also prepared 3 by the route as shown in Scheme 1, and found that the leuco compound 2 was formed in low purity but was too unstable to be purified. Subsequent direct use of this led to impure 3, which required extensive column chromatography to obtain material pure enough to crystallise. The overall yield of 3 from 1 was 33% (of 90-97% purity) following one column/crystallisation cycle, and 25% (of 98% purity) following a second column/crystallisation cycle. The expense of the starting material 1 and the difficulty of the chromatography (requiring much time and large volumes of solvents because of the insolubility of 3) does not make this a very viable large-scale synthesis to provide compound of the purity required.
We used this route to make 3 in 5 g quantity. This took a great deal of effort, to give 3 in 25% overall yield, at ca. 97% purity (impurity profile; small amounts of several unknown products). The cost of starting material 1 (4 kg) to make 1 kg of AQ4N was approximately £5000 at catalogue prices. While the cost is perhaps acceptable, this route is not operationally suitable for large-scale synthesis.
An alternative synthesis of 3 has been reported from the 1,4-difluoro compound 4 (Scheme 2
; J. Med. Chem
. 1991, 34, 2373). We confirmed the reported results, obtaining a 78% yield of 3 (94% pure before recrystallisation, with no major impurities). This reaction is suitable for scale-up, and it seems likely that material of adequate purity could be obtained by recrystallisation. The analogous dichloro compound 5 gave only trace amounts of 3 (Scheme 2), and the protected dibenzyl ether 6 was no better, indicating that the use of 4 was mandatory in this route.
Synthesis of the key intermediate 4 was thus investigated. Successful halogen exchange has been reported (
Synth. Comm
. 1985, 15, 907) for the 1,4-dichloro-anthraquinone 7 (7→8; Scheme 3), but this was not successful with the required analogues 5 or 6 (Scheme 3).
Another reported synthesis of 4 has been via the difluorophthalic anhydride 9 (
Synth. Comm
. 1995, 20, 2139), and we verified this synthesis, obtaining an 89% yield of pure 4 (Scheme 4).
Operationally this is the best method, but the cost of starting material 9 (2 kg) is prohibitive (U.S. $230,000 at catalogue price, if available in this quantity). Syntheses of this also have to be considered. Two syntheses have been reported, In Scheme 5 (
Synth. Comm
. 1990, 20, 2139), the overall yield of 9 is 40% from the acid chloride 10 (U.S. $24/5 g: Aldrich Chemical Co.). The overall yield is good, but the cost of 10
(while much less than 9) is still high, and the 4-step synthesis will add to costs. especially the BuLi step. Cost of staring material 10 (5 kg) is prohibitive (U.S. $24,000 at catalogue price, if available in this quantity).
Scheme 6 outlines a synthesis from cheap 2,3-dimethylaniline 14 (U.S. $53/500 g: Aldrich Chemical Co.). Fluorination followed by nitration gave 16 (
J. Chem. Soc
. 1963, 5554). This was converted to 17 and then by a second fluorination to 18, followed by oxidation with nitric acid to the previously-mentioned 13 (see Scheme 5).
The lower cost starting material for Scheme 6 would probably be offset by the much lower overall yield reported (8%). This is largely due to a low yield (30%) in the 17→18 conversion.
A study of diverse reports (
Syn. Lett
. 1990, 339
; J. Org. Chem
. 1993, 58, 261
; Het. Chem
. 1995, 32, 907) suggests an alternative synthesis (Scheme 7).
The tetrachlorophthalic anhydride (19) is cheap (U.S. $63/3000 g: Aldrich Chemical Co.), and can be dechlorinated in two successive reactions to give the dichlorophthalic anhydride 21 in 45-60% overall yield. The well-defined conditions listed are required to achieve clean product in each case. A single step from 19→21 does not work well, due to the differing requirements for the separate dechlorinations. The products (19, 20, 21) are not distinguishable by TLC, requiring NMR to determine purities. While 21 is also commercially available it is expensive (U.S. $59/1 g: Aldrich Chemical Co.), and it is probably cheaper to make it by the above method. The dichloro compound 21 has been reportedly converted into the desired difluoro analogue 9 in ca. 60% yield using KF (Bergmann et al.;
J. Chem. Soc
. 1964, 1194), but few details were given. However, it is difficult to repeat the reaction using the sketchy reported conditions, owing to sublimation of the anhydride 21 at 250° C. Alternative methods using solvents give only very low yields. This problem would have to be solved for this route to be viable.
Synth. Comm., 1990, 20, 2139 uses the difluorophthalic anhydride 9 but does not mention the Bergmann et al. paper (
J. Chem. Soc
. 1964, 1194). Instead, it notes “development of a practical synthesis of [3,6-difluorophthalic anhydride]”. This implies that the previous Bergmann et al. method is not practical. They then develop a quite different (but longer) route to this compound (Scheme 5, above).
The same authors, in an earlier paper (
Synth. Comm
. 1985, 15, 907), do specifically reference the Bergmann et al. paper. They then go on to develop two alternative routes to the next compound in the synthesis (compound 4, above), bypassing the need to make 3,6-difluorophthalic anhydride. This again implies that the Bergmann et al. method to make this compound is not practical.
We have now solved this problem by using a nitrogen atmosphere and repeated remelting of the sublimate to obtain useful results.
Thus the present invention provides a process for the preparation of the compound AQ4 of formula 3:
or a salt or N-oxide thereof, including the step:
Preferably the reaction is carried out using a nitrogen atmosphere.
Any method of mixing the reaction to ensure even heating and maximum contact between the melt of 21 and the inorganic fluoride may be used. However, preferably the reaction mixture is heated to cause sublimation of solid, with frequent remelting of the sublimate back into the reaction mixture. Gentle stirring internally aids reaction.
The reaction is preferably conducted over a layer of powdered anhydrous KF and/or NaF, and more preferably a mixture of anhydrous KF and NaF. Preferably the mixture of KF and NaF contains from 10% to 60% by weight of NaF and from 90% to 40% by weight of KF, and more preferably around 17% by weight of NaF and around 83% by weight of KF.
Preferably the reaction mixture includes:
5
parts by weight dichlorophthalic
anhydride (21);
10 to 25 especially around 20,
parts by weight KF; and
2 to 6 especially around 4
parts by weight NaF.
The reaction is preferably conducted at a temperature of 260-270° C.
The above reaction step is a critical step and very dependent on conditions that were not reported by Bergmann et al.;
J. Chem. Soc
. 1964, 1194). Thus on a small scale (10 g), a bath temperature of 245-250° C. works better than 260-270° C., giving a cleaner product and a higher yield. However, on a 100 g scale this temperature range did not work well, with the reaction only going part way. Because the reaction is heterogeneous (the compound 21 melts but the KF does not), efficient heat transfer is critical, and the margin between incomplete reaction (less than 260° C.) and rapid decomposition (greater than 270° C.) is very

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