Field of Invention:
The present invention describes an environment friendly process for the synthesis of 4,5-
dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-carbaldehyde (rheinal) from 1,8-
dihydroxy-3-hydroxymethyl-anthraquinone (aloe emodin) via aerial oxidation in
presence of organometallic catalysts. Such organometallic catalysts are selected from
oxovanadium (IV), copper (II) and, enzyme containing copper (II).
Background of the Invention:
4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-carbaldehyde (compound I), has a
diversified synthetic utility in synthesis of various pharmacologically active
anthraquinone derivatives. e.g.US5,480,873 describes various anthraquinone derivatives
useful for modifying cell functions and are indicated for use in the treatment of skeletal
diseases, diabetis and related complications. Most of these anthraquinone derivatives are
routed through compound of formula I.
Besides, compound of formula I would have a potential utility in synthesis of diacerhein
(compound II, described in French patent No. 2508798), an important therapeutic
candidate useful in treatment of degenerative diseases of joints, such as osteoarthritis and
connective tissue matrix diseases, such as osteoporosis and rheumatoid arthritis.
A key intermediate of diacerhein viz. 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-
anthracene-2-carboxylic acid (compound III) can be prepared from compound of formula
T through well documented oxidation reactions employing heptavalent Mn such as
potassium permanganate (CN 101104583) , sodium hypochlorite (J.Org. Chem. 71
(2006) 9291-9296), sodium perborate (Tetrahedron 45 (1989) 3299-3306). The stated
approach would be an environmentally benign approach when compared to the one
reported in WO A-98 56750, involving chromium based catalyst. Hexavalent chromium
compounds such as chromic anhydride and dichromate are known for high toxicity and
carcinogenicity as well as harmful effect on environment.
Practice of chromium based process for preparation of diacerhein, would require a very
cumbersome and tedious process for purification to remove the chromium traces (which
is mandatory as per the FDA/ICH guidelines) as described in EP-A-0-636 602, WO-A-
00/68179, WO-A-98/56750, WO-A-01/96276, WO-A-2004/050601. The said
purification processes are complex, multi-step and involve use of toxic solvents &
reagent, and result in decreased yields of diacerein.
To overcome the described drawbacks related to chromium based process EP- 1666446,
reports chromium free oxidation using sodium nitrite and 12-14 volume of sulfuric acid
to arrive at the compound of formula III. Hence in large scale synthesis it could create
difficulty in effluent handling.

In view of the facts discussed above there is a need for development of economical, eco-
friendly and hazard-free process for preparation of compound of formula I, which in turn
would lead to an economical, eco-friendly and hazard-free process for diacerhein and
other pharmacologically active anthrequinone derivatives.
Various synthetic approaches has been reported in the literature to overcome some of the
problems related to the process for preparation of compound of formula I as provided
below.
US 5,480,873 describes a process for preparation of 'I' through modified Swern
oxidation of l,8-Dihydroxy-3-hydroxymethyl-anthraquinone also known as aloe emodin
(Compound IV) by employing sulphur trioxide-pyridine complex in dry dimethyl
sulphoxide. The by-products of above reaction are dimethyl sulfide, carbon monoxide,
carbon dioxide and when alkyl amine is used as base gives alkylammonium chloride as
byproduct. Byproducts generated during the Swern oxidation are dimethyl sulfide and
carbon monoxide both toxic and volatile. Further, dimethyl sulfide is a highly volatile
liquid with an unpleasant odour.

CN 101104583 describes a process for preparation of T by oxidation of compound IV
via well documented literature methods such as chromium trioxide-pyridine complex,
pyridine chlorochromate, pyridine dichromate, Dess-Martin catalyst etc. It is to be noted
that any oxidation with Cr (IV) would produce Cr (III) salts which are not
environmentally benign and require special effluent treatment.
Compound of formula T is also known to be obtained from the extract of Rheum emodi
as described in Indian Journal of Chemistry, 38 (1999) 749-751. However, isolation using
column chromatography, use of large volume of solvents and low yield render the
process less attractive for large scale manufacture.
Mitter et al reported in Journal of the Indian Chemical Society 9 (1932) 375 a synthetic
process of compound of formula T involving reduction/hydrogenation of 4,5-diacetoxy-
9,10-dioxo-9,10-dihydro-anthracene-2-carbonyl chloride (compound V). Compound V is
in turn prepared by chlorination of compound 'II' involving reaction with thionyl
chloride. The reduction process involves use of palladium charcoal catalyst poisoned with
barium sulfate; otherwise untreated catalyst is too reactive and gives over reduction
products. Hence this could not be a desirable industrial process.

Scaiano et al. reported in Chem Commum. (2006) 4401-4403 a photochemical oxidation
of 2-(hydroxymethyl) anthraquinone [VI] to 2-formyl- 9, 10-dihyroxyanthracene [VII]
Quantum efficiency of this process is low and hence, it could not be utilized for
manufacture of compound of formula I.

Hence there is a need for development of an eco-friendly i.e. "green" and cost effective
synthesis of compound 'I'.
Oxidation of alcohol to corresponding aldehyde in presence of metal catalyst with
molecular oxygen is well documented in Tetrahedron 62 (2006) 8227-8241. It is
advantageous because oxygen is inexpensive, readily available, and ultimately produces
benign byproducts such as water.
Several metals such as cobalt, copper, gold, iron, palladium ruthenium and vanadium as
organometallic complex are known for oxidizing alcohol to the respective aldehyde.
However, several challenges exist in the development of metal-catalyzed aerobic alcohol
oxidations. This includes identification of specific metal catalyst, optimization of reaction
temperatures, pressures of oxygen and catalyst loading, etc. Also nature of metal complex
plays a crucial role for oxidation of alcohol. The other key challenge is functional group
tolerance and the ability to oxidize an alcohol preferentially in the presence of other
functional groups susceptible to oxidation. Hence, there is a need of research for
identification of the metal catalysts and optimization of reaction conditions, which would
lead towards a cost effective process. This invention provides that.
Oxidation of protected phenolic alcohol is very well reported with TEMPO (2,2,6,6-
Tetramethylpiperidine-1-oxyl)/ Cu(II) catalyzed system as well as organometallic
catalysts obtained from Vanadium [Synthesis, (1996) 1153-1174; Tetrahedron Letters,
2006 (47) 922-926; J. Org. Chem. 72 (2007) 7030-7033; Org. Lett. 6 (2004) 217-219; J.
Org. Chem. 71(2006) 7087-7090]. It could be rationalized that phenolic group is
protected to prevent the oxidation of phenolic 'OH' function, which is likely to give the
semiquinone derivative. Since, our system contains the anthraquinone backbone which is
much deactivated system. Hence, it was thought that oxidation of phenolic 'OH' function
would be less vulnerable and thus could be advantageous because of avoidance of the
protection and deprotection of phenolic 'OH', which would be technologically superior
as well as economically more feasible over prior art.
However, there are, no report of oxidation of free hydroxy anthraquinone primary alcohol
to the corresponding hydroxy anthraquinone aldehyde with TEMPO catalyzes system as
well as organometallic catalyst obtained from Vandadium.
Hydroxy anthraquinones are known to form complex with various simple metal salts,
such as copper, cadmium, nickel, iron, vanadium and cobalt called as, "lake" complexes
of formula 'VIII'. (Russian Journal of Coordination Chemistry, 2004, (30) 360-364;
JACS, 1919 (41) 2081-2083). Hence, it is very challenging to develop a process for
oxidation of alcohol function attached to hydroxy anthraquinones. The present invention
provides that.

Objects of the invention
Thus the object of the present invention is to provide cost effective, hazard-free and eco-
friendly process for preparation of 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-
carbaldehyde, i.e. compound of formula I of high purity.
A further object of the present invention is to provide an improved and cost effective
industrial process for the preparation of compound of formula I that produces minimum
by-products.
Summary of Invention:
The present invention provides a process for preparation of 4,5-Dihydroxy-9,10-dioxo-
9,10-dihydro-anthracene-2-carbaldehyde T by employing aerial oxidation in presence of
organometallic catalysts has been described. The said metal catalysts are selected from
Oxovanadium (IV)/DABCO (l,4-diazabicyclo[2.2.2]octane), Copper (II)/TEMPO and
enzyme containing Copper (II)/TEMPO. To our surprise we found that reaction
conducted in presence of a peroxy compound such as m-chloroperbenzoic acid (mCPBA),
the rate of reaction increases approximately two fold and often increases the overall yield.

Detailed Description
The invention embodies transition metal complex catalyzed oxidation of benzylic
hydroxyl group of compound of formula IV to corresponding aldehyde of formula I,
having purity of 98%.
According to one embodiment of the invention, oxidation of compound 'IV to
corresponding aldehyde T was performed in presence of organometallic catalysts
obtained from Oxovanadium (IV), Copper (II), Cobalt (II) and Iron (III); preferably with
Oxovanadium (IV) and Copper (II).
It was observed that rate of reaction and conversion is more with oxovanadium such as
VO(acac)2 (Vanadyl acetylacetonate, compound of formula IX) as compared to other
metal complexes such as copper, cobalt and iron.

It is well documented that VO(acac)2/DABCO/O2 oxidize alcohol to the corresponding
aldehyde (Tetrahedron 62 (2006) 8227-8241). However, it is to be noted that there are no
report of oxidation of hydroxy antraquinone alcohol to the corresponding aldehyde using
such catalyst.
The mechanism for VO (acac)2 catalyzed oxidation has been rationalized as initial
oxidation of V(IV) to V(V) by O2 followed by the attack of alcohol to form a V-alkoxide
Elimination of the alkoxide would result in product formation and V(III), which could
then be reoxidized by O2 to reform the active V(V). mCPBA helps in re-oxidation of
V(III). It is depicted in the Scheme 2.

Scheme2 Reaction mechanism of VO(acac)2 catalyzed oxidation
There was no significant improvement in the rate as well as conversion of compound TV
to compound T by increasing the oxygen pressure. However, it was observed that
addition of mCPBA in the VO(acac)2 /DABCO/O2 catalyzed reaction increases the rate of
reaction of compound [II] to compound [I], which is apparently due to homogenous
source of oxygen in the form of mCPBA.
TEMPO (tetramethylpiperidinyloxyl radical) and its derivatives is versatile oxidant, large
number of reports are documented for oxidation of alcohols to corresponding aldehyde
are well documented (Synthesis (1996) 1153-1174). For example, TEMPO with aqueous
sodium hypochlorite (Adv. Synth. Catal. 346 (2004) 1051-1071); TEMPO with
stoichimetric iodine (Organic Letters 5 (2003) 285-287); TEMPO with simple Cu (II)
salts and Cu (II) complexes (Tetrahedron Letters, 2006 (47) 922-926) in presence of O2.
However, it is to be noted that there are, no report of oxidation of hydroxy antraquinone
alcohol to the corresponding aldehyde in presence of TEMPO catalyzes systems.
It has to be emphasized that TEMPO catalyzed oxidation in presence of simple salts does
not oxidize the hydroxy anthraquinone alcohol to corresponding aldehyde. But TEMPO
along with Cu(II) complex such as Cu (II) salen H4 complex (compound of formula X)
oxidizes the hydroxy anthraquinone alcohol (compound IV) to corresponding hydroxy
anthraquinone aldehyde (compound I).

Reaction mechanism for Cu (II) salen H4 is - it undergoes ligand exchange to form a Cu-
alkoxide that binds with TEMPO. The Cu-TEMPO intermediate can proceed to the
aldehyde via hydrogen atom abstraction by TEMPO. Molecular oxygen is proposed to
reoxidize TEMPOH to TEMPO followed by reoxidation of Cu (I) by TEMPO
(Tetrahedron Letters, 2006 (47) 922-926).

Scheme3 Reaction mechanism of Cu (II) salen H4/TEMPO/O2 catalyzed oxidation
Addition of 10 mole % of mCPBA in the Cu (II) Salen H4 /TEMPO/ O2 catalytic system
increases the rate of reaction and conversion of compound 'IV to compound 'I'. This is
due to homogenous sources of oxygen in the form of mCPBA but there was no increase
in rate as well as conversion by increasing the oxygen pressure.
Laccases (EC 1.10.3.2, p-diphenol:dioxygen oxidoreductase, compound XI) belong to
multinuclear copper-containing oxidases. They catalyse the monoelectronic oxidation of
substrate at the expence of molecular oxygen (Trends in Biotechnology, 2006 (24) 219-
226). Copper (in laccase enzyme) has two N2 ligands from two histidines and one oxygen
ligand (Journal of Biological Chemistry, 2005). However, it is to be noted that there are,
no report of oxidation of hydroxy antraquinone alcohol to the corresponding aldehyde.

Scheme 4 Reaction mechanism of Laccase/TEMPO/O2 catalyzed oxidation
The active from of TEMPO is the oxidized product; called oxoammonium ion, which is
formed by laccaseox- Laccaseox is generated by oxidation of laccase through oxygen.
Oxoammonium ion oxidizes the alcohol to aldehyde liberating back the inactive form of
TEMPO (VI) that again gets oxidized. (J. Mol Cat. B: Enzymatic 37 (2005) 79-83).
Although it has been reported that Co(II), Fe(III) salen H4 complex (compound XII and
XIII respectively) along with oxygen oxidizes primary benzylic alcohol to the
corresponding aldehyde, but in our system no oxidation product was observed, a fact
which is difficult to rationalize.

However, Cu (II) salen H4 complex is an efficient oxidizing catalyst in presence of
oxygen/ air more as in presence of a peroxy acid such as m-chloroperbenzoic acid,
peroxyacetic acid, peroxybenzoic acid, preferably m-chloroperbenzoic acid
The said salen H4 complexes were made by the procedure reported in literature.
(Tetrahedron Letters, 2006 (47) 922-926), which is schematically shown in Scheme 5

Scheme 5. Synthesis of Metal Salen H4 complex
The Schiff base is obtained by reaction of an aromatic aldehyde with the diamine.
The aromatic aldehyde is selected from salicylaldehyde or substituted salicylaldehyde;
preferably salicylaldehyde.
The diamine component in the Schiff base is aliphatic, substituted aliphatic or cyclic
diamine such as ethylene diamine, 1, 2-cyclohexane diamine; preferably ethylene
diamine, 1,2-cyclohexyldiamine
Oxovanadium (IV) is in the organometallic complex such as, Oxovanadium (IV)
acetylacetonate.
The acetylacetonate is simple acetylacetonate or substituted acetylacetonate.
Compound 'IV' with DABCO and in the presence of Oxovanadium (IV) compounds,
such as VO(acac)2 and molecular oxygen or air as oxidizing agent gives the Compound
'I' in quantitative yield. Wherein, VO(acac)2 is available from Sigma Aldrich co or could
be prepared by literature method (Inorg. Synth. 1957; 5: 113-116).
Compound 'IV with 1, 4-Diazabicyclo [2.2.2] octane (DABCO) and in the presence of
Oxovanadium (IV) compounds, such as VO(acac)2, m-chloroperbenzoic acid and
molecular oxygen or air as oxidizing agent gives the Compound T also in quantitative
yield but the rate increases 2 fold.
Compound 'IV' with oxaammonium ion, in particular 2,2,6,6 - tetramethyl piperdin-1
oxyl (TEMPO) and in the presence of Cu (II) complexes such as Cu (II) Salen-H4 [IX]
(Tetrahedron Letter, 2006, 47, 923-926) and oxygen gives the Compound 'I'.
The so obtained compound of formula 'I' could be further purified and un-reacted
alcohol 'IV can be recycled to obtain compound 'I'.
Compound 'IV with oxaammonium ion, in particular 2,2,6,6 - tetramethyl piperdin-1
oxyl (TEMPO) and in the presence Cu (II) containing enzymes such as laccase 'XI'
(Trends in Biotechnology, 2006, 24, 219-226) gives the Compound 'I' and compound
'III'. Further purification of mixture of compound 'I' and 'III' is achieved by column
chromatography as per condition described in example 4.
Useful enzymes for oxidiation of alcohol compound to aldehyde and or carboxylic acid
may thus include oxidative enzyme, including laccase. Such enzyme may be obtained
from a variety of natural sources, including animal organs and microorganisms.
Particularly useful laccase include enzyme derived from the microorganism Trametes
versicolor such as available from Sigma-Aldrich co.
The oxidation reaction for obtaining compound T with metal catalyst is carried out in
solvent such as 1,4 dioxane, dimethyl formamide, dimethyl sulfoxide and N-methyl
pyrrolidine; preferably reaction is performed in 1,4- dioxane.
The oxidation reaction for obtaining compound 'I' with metal catalyst is carried out in
mixture of solvent such as water and 1,4 dioxane (1:1).
The oxidation reaction for obtaining compound T with laccase enzyme is carried out in
buffer having pH range 4-6; preferably at pH 5.
Reaction is generally employ VO(acac)2 as catalyst, loading of catalyst is about 5% to 20
%; preferably VO(acac)2 loading of about 5% is used.
Reaction is generally employ Cu (II) salen-H4 as catalyst, loading of catalyst is about
10% to 30%; preferably Cu (II) salen-H4 loading of about 10% is used.
Reaction is generally employ laccase enzyme loading of about 10% to about 30%;
preferably enzyme loading of about 10% is used
Organometallic catalyzed oxidation is carried out over a wide range of temperature. For
example, the reaction may be carried out at temperature of about 75 °C to 100 °C, but
typically carried out at 90 °C.
Enzymatic reaction is carried out at temperature of 25 to 50 °C, but typically carried out
at 25 °C.
The oxidation is carried out over wide range of oxygen pressure, it was observed that rate
of reaction does not have any effect with increasing oxygen pressure hence preferable
oxygen pressure is 1 -2 bar.
Unreacted alcohol 'IV is recovered from crude product by column chromatography
using silica gel as stationary phase and hexane: ethyl acetate (1:1) as mobile phase, which
could be recycled, thereby improving the "atom economy" of the overall process.
The present invention is illustrated in more detail by referring to the following Examples,
which are not to be construed as limiting the scope of the invention.
Example 1:
Process of preparation of 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-
carbaldehyde from 1,8-Dihydroxy-3-hydroxymethyl-anthraquinone through
VO(acac)2- DABCO/ O2 oxidation in 1,4 dioxane as solvent
A par autoclave reactor was charged with 200 ml of 1,4 Dioxane to that aloe-emodin
(85% purity) (3 g) , VO (acac)2 (0.150 g), DABCO (0.200 g) were added and stirred at
room temperature for 15 min. Reactor was purged with oxygen gas for 5 min and then 1
bar oxygen pressure was maintained in reactor. The resulting mixture was stirred at 90 °C
for 8 h. Reaction was monitored by TLC (1:1, hexane/ethyl acetate). After complete
disappearing of starting material (normally after 8hr), reaction mixture was cooled to RT
and filtered to remove insoluble material. Filtrate was then poured in 1L of ice cool water
to obtain the product. After filtering and washing with water (200 ml), the collected
brown solid was dried at 45° C. in vacuo. Isolated yield: 2 g (79%); Melting point: 202
- 205 °C (Literature melting point 200 °C; USP. 5,480,873); Compound I: 1H NMR
(200MHz, DMSO4 d6): d 7.38-8.09 (m, Ar), 10.10(s, Ar-CHO), 11.98-11.95 (m, Ar-
OH); IR Spectra (cm-1): 1699, 1673, 1630, 1265.
Example2
Process of preparation of 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-
carbaldehyde from 1,8-Dihydroxy-3-hydroxymethyl-anthraquinone through
VO(acac)2- DABCO/mCPBA/O2 oxidation in 1,4 dioxane as solvent
A par autoclave reactor was charged with 200 ml of 1,4 Dioxane to that aloe-emodin
(1.5g) (85% purity), VO (acac)2 (0.075g), DABCO (0.100 g) and mCPBA (0.100g) were
added and stirred at room temperature for 15 min. Reactor was purged with oxygen gas
for 5 min and then 1 bar oxygen pressure was maintained in reactor. The resulting
mixture was stirred at 90 °C for 5 h. Reaction was monitored by TLC (1:1, hexane/ethyl
acetate). After complete disappearing of starting material (normally after 5hr), reaction
mixture was cooled to RT and filtered to remove insoluble material.. Workup was done
as per given in the example 1. Isolated yield: 1.05 g (82%)
Example 3
Process of preparation of 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-
carbaldehyde from 1,8-Dihydroxy-3-hydroxymethyl-anthraquinone through
VO(acac)2- DABCO/ O2 oxidation in 1,4 dioxane: water (1:1) as reaction media
A par autoclave reactor was charged with 100 ml of 1,4 Dioxane and 100 ml of water to
that aloe-emodin (3 g) (85% purity), VO (acac)2 (0.150 g), DABCO(0.200 g) were added
and stirred at room temperature for 15 min. Reactor was purged with oxygen gas for 5
min and then 1 bar oxygen pressure was maintained in reactor. The resulting mixture was
stirred at 90 °C for 24 h. Reaction was monitored by TLC (1:1, hexane/ethyl acetate).
After complete disappearing of starting material (normally after 8hr), reaction mixture
was cooled to RT and filtered to remove insoluble material. Workup was done as per
given in the example 1. Isolated yield: 1.8gm (70%)
Example-4
Process of preparation of 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-
carbaldehyde from l,8-Dihydroxy-3-hydroxymethyl-anthraquinone through Cu(II)
Salen H4/TEMPO/O2 oxidation.
A par autoclave reactor was charged with 100 ml of 1,4 Dioxane to that aloe-emodin (1
g) (85% purity), Cu(II) Salen H4 (0.150g), TEMPO (0.150g) were added and stirred at
room temperature for 15 min. Reactor was purged with oxygen gas for 5 min and then 1
bar oxygen pressure was maintained in reactor. The resulting mixture was stirred at 95 °C
for 8 h and then reaction mixture was cooled to RT and filtered to remove insoluble
material. Filtrate was then poured in 1L of ice cool water to obtain the product. After
filtering and washing with water (200 ml), the collected brown solid was dried at 45° C.
in vacuo. Crude product was further purified by column chromatography using mobile
phase hexane: ethyl acetate (1:1) to obtain the pure aldehyde and unreacted compound II
could be reused to obtain compound I. Isolated yield: 0.2g (24%)
Example-5
Process of preparation of 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-
carbaldehyde from l,8-Dihydroxy-3-hydroxymethyl-anthraquinone through Cu(II)
Salen H4/TEMPO/O2/mCPBA oxidation.
A par autoclave reactor was charged with 100 ml of 1,4 Dioxane to that aloe-emodin (1.5
g) (85% purity), Cu(II) Salen-H4 (0.075g), TEMPO (0.075g), mCPBA (0.100 g) were
added and stirred at room temperature for 15 min. Reactor was purged with oxygen gas
for 5 min and then 1 bar oxygen pressure was maintained in reactor. The resulting
mixture was stirred at 95 °C for 8 h. Workup and purification of crude product was done
as per given in example 4 Isolated yield: 0.74 (58%)
Example-6
Process of preparation of 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-
carbaldehyde from 1,8-Dihydroxy-3-hydroxymethyl-anthraquinone through
through Laccase/TEMPO/O2
A par autoclave reactor was charged with 10 mmole sodium acetate buffer of pH 5
(100ml) to that aloe-emodin (3gm) (85% purity), laccase from T. versicolor (0.5gm),
TEMPO (0.9 g) were added and stirred at room temperature for 15 min. Reactor was
purged with oxygen gas for 5 min and then 1 bar oxygen pressure was maintained in
reactor. The resulting mixture was stirred at 25 °C for 96 h. Reaction was monitored by
HPLC gives 34 % carboxylic acid and 48% aldehyde and 15 % un-reacted aloe emodin.
Workup and purification of crude product was done as per given in example 4.
Chromatographic Condition:
Instrument: HPLC equipped with Pump, Injector, UV detector and Recorder.
Column: Inertsil ODS 3V (4.6 x 150mm), 5µm
Flow rate: 1.0 mL/minute.
Detector: UV at 254nm.
Example-7
Process of preparation of 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-
carbaldehyde from 1,8-Dihydroxy-3-hydroxymethyl-anthraquinone through Cu(II)
(OAc)2/ TEMPO/O2 oxidation in 1,4 dioxane as a solvent
A par autoclave reactor was charged with 200ml of 1,4 Dioxane to that aloe-emodin
(2gm) (85% purity), Cu(II) (OAc)2 (0.075gm), TEMPO (0.56g) were added and stirred at
room temperature for 15 min. Reactor was purged with oxygen gas for 5 min and then 1
bar oxygen pressure was maintained in reactor. The resulting mixture was stirred at 90 °C
for 8 h. Reaction was monitored by TLC (1:1, hexane/ethylacetate) and no oxidative
product was observed.
Example-8
Process of preparation of 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-
carbaldehyde from 1,8-Dihydroxy-3-hydroxymethyl-anthraquinone through
TEMPO/I2 oxidation in 1,4 dioxane as a solvent
A reactor was charged with 100ml of 1,4 Dioxane to that aloe-emodin (3gm) (85%
purity) was added and in that aqueous solution of sodium bicarbonate (1 gm in 10ml of
deionzied water) added. Solid iodine (5.78gm) was added to above reaction mixture in
one portion followed by TEMPO (0.150gm) and stirred at room temperature for 15 min.
Reaction was monitored by TLC (1:1, hexane/ethylacetate) and no oxidative product was
observed.
Example-9
Process of preparation of 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-
carbaldehyde from 1,8-Dihydroxy-3-hydroxymethyl-anthraquinone through Fe (III)
salen H4/ O2 oxidation in 1,4 dioxane as a solvent
A par autoclave reactor was charged with 200ml of 1,4 Dioxane to that aloe-emodin
(3gm) (85% purity), Fe (III) salen (0.150gm), were added and stirred at room temperature
for 15 min. Reactor was purged with oxygen gas for 5 min and then 1 bar oxygen
pressure was maintained in reactor. The resulting mixture was stirred at 90 °C for 8 h.
Reaction was monitored by TLC (1:1, hexane/ethylacetate) and no oxidative product was
observed.
Example-10
Process of preparation of 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2-
carbaldehyde from 1,8-Dihydroxy-3-hydroxymethyl-anthraquinone through Co (II)
salen H4/ O2 oxidation in 1,4 dioxane as a solvent
A par autoclave reactor was charged with 200ml of 1,4 Dioxane to that aloe-emodin
(2gm) (85% purity), Co (II) salen (0.120gm), were added and stirred at room temperature
for 15 min. Reactor was purged with oxygen gas for 5 min and then 1 bar oxygen
pressure was maintained in reactor. The resulting mixture was stirred at 90 °C for 8 h.
Reaction was monitored by TLC (1:1, hexane/ethylacetate) and no oxidative product was
observed.
We Claim:
1. A process for preparation of 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-
2-carbaldehyde from l,8-Dihydroxy-3-hydroxymethyl-anthraquinone comprising
of aerial oxydation of l,8-Dihydroxy-3-hydroxymethyl-anthraquinone at oxygen
pressure of about 1 to 2 bar in presence of a transition metal complex, a co-
catalyst and optionally an oxidizing agent in an organic solvent such as 1,4
dioxane, water or mixtures thereof at a temperature ranging between 25 to 100°C,
isolation by appropriate process and optional purification of the product.
2. The process as claimed in claim 1, wherein a transition metal complex is Vanadyl
acetylacetonate and a co-catalyst is l,4-diazabicyclo[2.2.2]octane.
3. The process as claimed in claim 2 wherein loading of Vanadyl acetylacetonate
catalyst is about 5% to 20 % of substrate.
4. The process as claimed in claim 1, wherein a transition metal complex is Copper
(II) salen H4 complex and a co-catalyst is 2,2,6,6-Tetramethylpiperidine-l-oxyl.
5. The process as claimed in claim 4 wherein loading of catalyst is about 10% to
30% of substrate.
6. The process as claimed in claim 1, wherein a transition metal complex is laccase
enzyme and a co-catalyst is 2,2,6,6-Tetramethylpiperidine-l-oxyl.
7. The process as claimed in claim 6 wherein loading of laccase enzyme loading is
about 10% to about 30% of substrate.
8. The process as claimed in claim 1 wherein the oxygen pressure maintained
between 1 and 2 bar.
9. The process as claimed in claim 1 wherein an oxidizing agent is selected from
peroxyacids such as metachloroperbenzoic, perbenzoic acid and peraceticacid.
10. The process as claimed in claim 2 wherein an oxidizing agent is selected from
peroxyacids such as metachloroperbenzoic acid, perbenzoic acid and
peraceticacid.
11. The process as claimed in claim 4 wherein an oxidizing agent is selected from
peroxyacids such as metachloroperbenzoic acid, perbenzoic acid and
peraceticacid.
12. The process as claimed in claim 6 wherein an oxidizing agent is selected from
peroxyacids such as metachloroperbenzoic acid, perbenzoic acid and
peraceticacid.

A process for preparation of 4,5-Dihydroxy-9,10-dioxo-9,10-dihydro-anthracene-2- carbaldehyde from l,8-Dihydroxy-3-hydroxymethyl-anthraquinone comprising of aerial oxydation of l,8-Dihydroxy-3-hydroxymethyl-anthraquinone at oxygen pressure of about 1 to 2 bar in presence of a transition metal complex, a co-catalyst and optionally an
oxidizing agent in an organic solvent such as 1,4 dioxane, water or mixtures thereof at a
temperature ranging between 25 to 100°C, isolation by appropriate process and optional
purification of the product.