An improved method for the preparation of 4,5-diaminochrysazin

Article abstract of DOI:10.1080/00397910903457324

4,5-Diaminochrysazin was prepared from chrysazin by ethylation and nitration followed by reaction with hydroiodic acid (HI). Treatment of 1,8-diethoxy-4,5-dinitroanthraquinone with HI resulted not only in O-deethylation, but also in reduction of nitro groups with more than 95% yield. This is a unique finding and is reported for the first time with a definite improvement over literature methods and is suitable for scale-up. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903457324

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An Improved Method for the Preparation
of 4,5-Diaminochrysazin
P. Hareesh Kumar a , G. Venkateshwara Rao a , B. Narayanaswamy a
& G. Chandrasekara Reddy a
a Vittal Mallya Scientific Research Foundation , Bangalore, India
Published online: 05 Nov 2010.
To cite this article: P. Hareesh Kumar , G. Venkateshwara Rao , B. Narayanaswamy & G.
Chandrasekara Reddy (2010) An Improved Method for the Preparation of 4,5-Diaminochrysazin,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 40:23, 3501-3505, DOI: 10.1080/00397910903457324
To link to this article: http://dx.doi.org/10.1080/00397910903457324
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Synthetic Communications1, 40: 3501–3505, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903457324
AN IMPROVED METHOD FOR THE PREPARATION
OF 4,5-DIAMINOCHRYSAZIN
P. Hareesh Kumar, G. Venkateshwara Rao,
B. Narayanaswamy, and G. Chandrasekara Reddy
Vittal Mallya Scientific Research Foundation, Bangalore, India
4,5-Diaminochrysazin was prepared from chrysazin by ethylation and nitration followed by
reaction with hydroiodic acid (HI). Treatment of 1,8-diethoxy-4,5-dinitroanthraquinone
with HI resulted not only in O-deethylation, but also in reduction of nitro groups with more
than 95% yield. This is a unique finding and is reported for the first time with a definite
improvement over literature methods and is suitable for scale-up.
Keywords: Anthraquinone; deethylation; ethylation; nitration; reduction
Amino and hydroxyanthraquinones have long been found use in anticancer therapy
as exemplified by drugs Ametantrone and Mitoxantrone[1] and also in dyestuff
industry.[2] In our on going programme[3] of making new anticancer molecules, an
attempt to prepare new derivatives of mitoxantrone has been initiated. In this endea-
vor, we prepared 4,5-diaminochrysazin (1,8-dihydroxy-4,5-diaminoanthraquinone) as
a key intermediate for making various aminoanthraquinone derivatives. In the litera-
ture, several methods have been tried to make various 4,5-daminocrysazin derivatives
mainly as dye intermediates: (a) racting a mixture of 1,8-diamino-4-hydroxy-and
1,5-diamino-4-hydroxy anthraquinone with manganous oxide in sulfuric acid[4] to
get a mixture of products (b) bromination of 1,8-diamino anthraquinone and hydroly-
sis in presence of boric acid[5] to get halogen substituted products (c) nitration of chry-
sazin followed by bromination and subsequent reduction with alkaline glucose,[6] or
iron powder,[7] (d) reacting 1,8-dinitroanthraquinone with fuming sulfuric acid and
reduction[8] to get a mixture of products (e) reducing a mixture of 1,5-dinitro-4,8-
dihydroxy and 1,8-dinitro-4,5-dihydroxy anthraquinone with iron in sulfuric acid[9]
and catalytic hydrogenation of 4,5-dinitro and 4,7-dinitro chrysazin in presence of
sulfuric acid with catalyst Pd=C or Pt=C,[10] (f) direct nitration of chrysazin and
insitu catalytic reduction of nitration liquors over Pt=C[11] to get a mixture of
1,8-dihydroxy-4,5-dinitro & 1,8-dihydroxy-2,5-dinitroanthraquinone, (g) reduction
of 1,8-dihydroxy-4,5-dinitro anthraquinone and or 1,5-dihydroxy-4,8-dinitro
Received August 12, 2009.
Address correspondence to G. Chandrasekara Reddy, Vittal Mallya Scientific Research
Foundation, #94=3 & 94=5, 23rd Cross, 29th Main, BTM II Stage, Bangalore-560076, India. E-mail:
gcreddy@vmsrf.org
3501

3502
P. H. KUMAR ET AL.
anthraquinone with hydrazine hydrate[12] or with mixed reducing sugars.[13] (h)
reduction of 1,8-dimethoxy-4,5-dinitroanthraquinone with Pd=C or Pt=C at 125 ꢀC
to give 4,5-diaminochrysazin.[14] Chang and Cheng[15] reported nitration of chrysazin
to give a mixture of 4,5-dinitrochrysazin and 4,7-dinitrochrysazin in 85:15 ratio and
subsequently reduced the mixture with iron powder. Shimazu et al.[16] prepared a
mixture of 4,5-diaminochrysazin and 1,5-dihydroxy-4,8-diaminoanthraquinone from
a mixture of dimethylcrysazin and 1,5-dimethoxy anthraquinone by the nitration
of 1,5- and or 1,8-dimethoxy anthraquinone and then reduction with metal=acid
followed by hydrolysis in sulfuric acid at 40–160 ꢀC. All these methods were evaluated
carefully as they lead either to a mixture of products with less purity and yields or
economically not attractive. Because of demand for highly pure 4,5-diaminochrysazin
in pharmaceutical synthesis, selective nitration and reduction methods were studied
extensively in this laboratory. This article describes (1) ethylation of chrysazin to
increase the solubility of chrysazin in subsequent nitration step, (2) an efficient and
regioselective nitration of 1,8-diethoxychrysazin, (3) obtaining pure 1,8-diethoxy-4,5-
dinitroantraquinone without purification and (4) reduction of nitrogroups and
de-ethylation in a single step. This process thus illustrates the significant improvement
over literature methods avoiding the usage of Pd=C or Pt=C and suitability for
scale-up.
RESULTS AND DISCUSSION
Direct nitration of chrysazin according to a classical procedure,[17,18] including
addition of phosphoric acid,[19] resulted in so many regioisomers with unreacted chry-
sazin and that the desired 4,5-dinitrochrysazin could not be easily isolated. Of other
nitrating systems,[20] such as nitronium tetrafluoroborate and trifluroacetyl nitrate,
altering the molar ratio of nitrating reagent and the reaction solvent had no effect
on the selective preparation of 4,5-dinitrochrysazin.[21] After numerous experiments,
it was found that protection hydroxyl group of chrysazin (2) and nitration leads to an
increase in the solubility of 1,8-diethoxyanthraquinone (3) in sulfuric acid and to give
selectively the desired nitrated product 1,8-diethoxy-4,5-dinitroanthraquinone (4) in
good yield and purity. This pure diethoxy dinitroanthraquinone on treatment with
hydroiodic acid gave 4,5-diaminochrysazin (1) in high yield and purity (Scheme 1).
EXPERIMENTAL
Melting points were determined on an Acro melting-point apparatus and uncor-
rected. Infrared (IR) spectra were recorded on a Thermo Nicolet Fourier Transform
1
(FT)-IR instrument in KBr discs. H NMR spectra were recorded on a Bruker
200-MHz instrument. All chemical shift values are reported in d units downfield from
tetramethylsilane (TMS) as internal standarad. Mass spectra (MS) were recorded on a
Micromass Q-TOF microTM (USA) instrument with AMPS Max 10=6A system.
Preparation of 1,8-Diethoxyanthraquinone (3)
To a stirred solution of compound 2 (50 g, 34.6 mmol) in N,N-Dimethyl
formamide (500 ml) was added potassium carbonate (250 g, 1811 mmol) and diethyl

PREPARATION OF 4,5-DIAMINOCHRYSAZIN
3503
Scheme 1. Preparation of 4,5-diaminochrysazin.
sulfate (260 g, 1688 mmol) and heated to 100 ꢀC slowly over a 2-hour period. The
reaction mixture was then poured into water, filtered, washed with water and dried
to get the product 3. (60 g, 97%); mp > 170 ꢀC (decomposition). IR (KBr) tmax 2978,
2878, 1674, 1585, 1438, 1396, 1315, 1284, 1230, 1115, 1061, 1014, 895, 791, 741 cmꢁ1
;
1H NMR (200 MHz, CDCl3): d 1.55 (6 H, t, J ¼ 7.0 Hz), 4.25 (4 H, q, J ¼ 7.0 and
13.9 Hz), 7.27 (2 H, d, J ¼ 7.6 Hz), 7.59 (2 H, t, J ¼ 8.0 Hz), 7.84 (2 H, d, J ¼ 7.6 Hz);
HRMS (ESþ) m=z calcd. for C18H16O4 (M þ H)þ 297.1127, Obs. 297.1115.
Preparation of 1,8-Diethoxy-4,5-dinitroanthraqunone (4)
To a stirred solution of sulfuric acid (339 ml) and boric acid (11 g, 177.9 mmol)
which was maintained at a temperature of 0 to þ2 ꢀC, charged compound 3 (22 g,
74.3 mmol) and then added pre-cold nitrating mixture (Nitric acid, 11 ml,
172.3 mmol and sulfuric acid (13 ml) in 100 ml water) over a period of 2 hours. Reac-
tion mixture was quenched with ice-cold water, filtered, and dried to get the product
4 (28 g, 97.6%); mp > 250 ꢀC(decomposition); IR (KBr) tmax 2978, 2878, 1693, 1593,
1
1527, 1416, 1358, 1300, 1230, 1107, 1022, 926, 822, 795, 733, 694 cmꢁ1; H NMR
(200 MHz, DMSO-d6); d 1.42 (6H, t, J ¼ 6.6 Hz), 4.31 (4 H, q, J ¼ 6.0 and 8.0 Hz),
7.63 (2 H, d, J ¼ 8.0 Hz), 8.14 (2 H, d, J ¼ 8.0 Hz); HRMS (ESþ) m=z calcd. For.
C18H14N2O8 (M þ Na) 409.0648. Obs. 409.0651.
Preparation of 4,5-Diaminochrysazin (1)
Compound 4 (5 g, 12.9 mmol) in hydroiodic acid (40 ml, 292.41 mmol) was
heated to 100 ꢀC for 3 hours and quenched with ice-cold alkaline solution to get

3504
P. H. KUMAR ET AL.
the compound 1, which was filtered and dried (3.4 g, 97.1%); mp > 300 ꢀC
(Decomposition); IR (KBr) tmax 3400, 3305, 1570, 1516, 1207, 833, 551, 455,
cmꢁ1
;
1H NMR (200 MHz, DMSO-d6); d 7.14 (2H, d, J ¼ 10 Hz), 7.28 (2H, d,
J ¼ 10 Hz), 7.94 (4 H, brs), 12.78 (2 H, s).
ACKNOWLEDGMENTS
The authors thank Dr. Anil Kush, CEO, Vittal Mallya Scientific Research
Foundation, for his encouragement and Mr. A. C. Karunakara for analytical support.
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