Field of the Invention:
The invention relates to a novel process for preparation of 2-[trans-4-(4'-
chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone I.e. Atovaquone [I]. This
invention also provides a novel process for preparation of 2-[cis-4-(4'-
chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone and process for
isomerization of 2-[cis-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-
naphthoquinone to 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-
naphthoquinone in presence of a Lewis acid.
Background of the Invention:
2-[Trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone [CAS No.
95233-18-4], which is also called Atovaquone [I], has antipneumocystic activity and
is used in the treatment of Pneumocystis cariniipneumonia, as disclosed in US patent
number US 4981874. Further uses of Atovaquone as a therapeutic agent for malaria,
toxoplasmosis and carcinoma or fibrosarcoma are disclosed in US patent number US
5206268, US 5856362 and US 5567738, respectively. The mechanism of action for
Atovaquone involves the inhibition of mitochondrial electron transport in cytochrome
bc1 complex of the parasite, which is linked to pyrimidine biosynthesis (Tetrahedron
Lett, 1998, 39 7629).

There are only few reports available for the synthesis of Atovaquone employing
various synthetic alternatives essentially based on Hunsdiecker decarboxylative
condensation, which proceeds through a radical mechanism. However, the overall
yield of the desired product in almost all the reported processes is exceedingly poor
i.e. economically far away from being attractive. Details of the reported syntheses are
discussed hereinafter.
The method for synthesis of Atovaquone disclosed in US Patent No. 5,053,432
describes Hunsdiecker decarboxylative condensation between (4-(4-chlorophenyl)
cyclohexane 1-carboxylic acid and 2-chloro 1,4-naphthoquinone in presence of silver
nitrate and ammonium persulfate to obtain 2-chloro-3-[4-(4-chloro-phenyl)-
cyclohexyl]-[1,4]naphthoquinone, which was converted to (cis/trans)-2-hydroxy-3-[4-
(4-chloro-phenyl)-cyclohexyl]-[1,4]naphthoquinone and on further re-crystallization
through acetonitrile, the desired product i.e. trans-2-hydroxy-3-[4-(4-chloro-phenyl)-
cyclohexyl]-[1,4]naphthoquinone was obtained (Scheme 1). The disadvantage with
this process is that overall yield is very low (4-5 %) and it requires expensive catalyst
such as silver nitrate. Moreover, it also requires a number of purification steps in
different solvents to obtain the desired product, thereby, rendering this process
economically not viable for manufacturing.

The improved process for the Hunsdiecker decarboxylative condensation precursor
i.e. oxalate mono acids in presence of ammonium persulfate, silver nitrate and phase
transfer catalyst, Adogen® 464 to obtain 2-chloro-3-[4-(4-chloro~phenyl)-
cyclohexyl]-[1,4]naphthoquinone has been reported by Williams and Clark
[Tetrahedron Letters, 1998, 39, 7629-7632], which was subsequently converted to
Atovaquone. This process reports 43% overall yield for 2-chloro-3-[4-(4-chloro-
phenyl)-cyclohexyl]-[1,4]naphthoquinone. On further re-crystallization through
acetonitrile, desired product i.e. trans-2-hydroxy-3-[4-(4-chloro-phenyl)-cyclohexyl]-
[1,4]naphthoquinone was obtained (Scheme 2). Besides lower overall yield, this
process also requires the expensive catalyst, silver nitrate hence rendering this process
not attractive for large scale manufacturing.

WO 229/007991 A2 disclosed a method for synthesis of Atovaquone through
formation of intermediates via Hunsdiecker decarboxylative condensation between
1,4-naphthoquinone and 4-(4-chlorophenyl) cyclohexane 1-carboxylic acid in
presence of silver nitrate and ammonium persulfate to obtain 2-[4-(4-chloro-
phenyl)cyclohexyl]-1,4-naphthoquinone, which was further converted to 2-[4-(4-
chloro-phenyl)cyclohexyl]-2,3-dichloro-2,3-dihydro-1,4-naphthoquinone by using
acetic acid and chlorine followed by conversion to 2-chloro-3-[4-(4-chloro-phenyl)-
cyclohexyl]-[1,4]naphthoquinone, which was further converted to Atovaquone
through base catalyzed hydrolysis (Scheme 3). Over all yield for the first step is very
poor (20%) and moreover, chlorine gas was used in the second step. Hence, this
process is not a practical process for commercial scale for obvious reasons.

WO 2010/ 0001379A1 disclosed a method for synthesis of Atovaquone. In this
process trans-4-(4-chlorophenyl)cyclohexane-l-carboxylic acid was reacted with N-
hydroxy pyridine-2(1H)-thione in presence of DCG to obtain trans-2-thioxopyridin-
1(2H)-yl-4-(4-chlorophenyl)-cyclohexane carboxylate, which was further reacted with
1,4-napthoquinone under ultra violet irradiation with 400W halogen lamp to obtain 2-
[4-(4-chlorophenyl)cyclohexyl]-3-(pyridine-2-ylthio) naphthalene-1,4 dione which
was further hydrolyzed in presence of base followed by isomer separation to obtain
Atovaquone (Scheme 4). However, besides higher material cost, the overall yield of
the desired isomer is only 12% from the geometric isomer mixture i.e. from
penultimate to ultimate.

Synthesis of similar type of compound i.e. 2-(4-t-butylcyclohexyl)-3-hydroxy-1,4-
naphthoquinone by employing Hunsdiecker decarboxylative condensation between 2-
chloro-1,4 naphthoquinone and 4-t-buytlcyclohexane-l-carboxylic acid was reported
in EP 0077551 B1 and by Hudson et al(Eur. J. Med. Chem. 1986, 21, 271-275).
Moreover, isomerization of cis-2-(4-t-butylcyclohexyl)-3-hydroxy-1, 4-
naphthoquinone to trans-2-(4-t-butylcyclohexyl)-3-hydroxy-1, 4-naphthoquinone in
presence of concentrated sulphuric acid was also reported (Scheme 5). This
established the fact that in the presence of a strong acid such as sulphuric acid,
benzylic proton a to the naphthoquinon ring gets abstracted and leads to
thermodynamically more stable geometric isomer.
WO 2010/001378 Al disclosed a method for conversion of cis-2-(4-(4-chlorophenyl)-
3-hydroxy-1,4-naphthoquione to trans-2-(4-(4-chlorophenyl)-3 -hydroxy-1,4-
naphthoquione in the presence of strong acids such as sulphuric acid and
methansulphonic acid.
Hence, it is evident from prior art that the processes reported in the literature for the
industrial synthesis of Atovaquone are at present not industrially feasible processes
with respect to cost and efficiencies, use of toxic chemicals and eco-hazardous
operations. Hence, there is need for an eco-friendly, "green", cost effective, easy-to-
operate, industrial-scale synthesis of Atovaquone.
The present inventors have found a novel, cost effective, operation friendly, green
process for preparation of the title compound. This invention also provides a novel
process for preparation of 'cis' isomer of Atovaquone and process for converting 'cis'
isomer of Atovaquone to pharmaceutically active form i.e. 'trans' isomer in presence
of a Lewis acid.
Objects of the Invention:
Thus an object of this invention is to provide a novel cost effective and efficient
process for the synthesis of Atovaquone [I].
Another object of the present invention is synthesis of the novel compound 2-(4-(4-
chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [IV] through
Mukaiyama aldol condensation of (1,2-dihydronaphthalen-4-yloxy)trimethylsilane
[II] with 4-(4-chlorophenyl)cyclohexanone [III] and further conversion of the
Mukaiyama adduct to Atovaquone [I].
Yet another object of the present invention is synthesis of the novel compound 2-(4-
(4-chlorophenyl)cyclohex-1-enyl)-3,4-dihydronaphthalen-1(2H)-one[V] from 2-(4-(4-
chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [IV] through
dehydration and further conversion of it to Atovaquone [I].
Yet another object of the present invention is synthesis of the novel compound 2-(4-
(4-ehlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [VI] from 2-(4-(4-
chlorophenyl)cyclohex-1-enyl)-3,4-dihydronaphthalen-1(2H)-one [V] through
hydrogenation in presence of noble metal catalysts and further conversion of it to
Atovaquone [I].
Yet another object of the present invention is synthesis of the novel compound 2-
bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [VII]
from 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [VI]
through ketone bromination and further conversion of it to Atovaquone [I].
Yet another object of the present invention is synthesis of the novel compound 2-(4-
(4-chlorophenyl)cyclohexyl)naphthalen-1-ol [VIII] from 2-bromo-2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [VII] through
aromatization in presence of base and further conversion of it to Atovaquone [I].
Yet another object of the present invention is synthesis of the novel compound 2-(4-
(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione [DC] from 2-(4-(4-
chlorophenyl)cyclohexyl)naphthalen-1-ol [VIII] through oxidation and further
conversion of it to Atovaquone [I].
Yet another object of the present invention is separation of 'cis' isomer of 2-(4-(4-
chlorophenyl)cyclohexyl)naphthalen-1-ol from 'trans' isomer of 2-(4-(4-
chlorophenyl)cyclohexyl)naphthalen-1-ol through an innovative crystallization
process.
Yet another object of the present invention is synthesis of cis-2-(4-(4-
chlorophenyl)cyclohexyl)naphthalene-1,4-dione [XII] from cis-2-(4-(4-
chlorophenyl)cyclohexyl)naphthalen-1-ol [XI] through oxidation.
Yet another object of the present invention is synthesis of cis isomer of Atovaquone
from cis-2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione [XII].
Yet another object of the present invention is isomerization of "cis" isomer of
Atovaquone to trans isomer of Atovaquone [I] in presence of a Lewis /Bronsted acid
such as titanium tetrachloride, Sulfuric acid, triflic acid, methansulphonic acid.
Summary of Invention:
One aspect of the present invention is to provide 2-[trans-4-(4'-
chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone, i.e. Atovaquone [I]
through a novel, cost effective, green, and eco-friendly process, without
separation of any diastereomers or geometric isomers of intermediates obtained
during the reactions
A process for preparation of 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-
1,4-naphthoquinone, i.e. Atovaquone [I] comprising the steps of-
a) condensing (l,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4-
chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic solvent
to obtain 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen-
1(2H)-one [IV]
b) dehydration of 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one [IV] in organic solvent and in presence of acid
such as pTSA to obtain diastereomeric mixture of 2-(4-(4-
chlorophenyl)cyclohex-1-enyl)-3,4-dihydronaphthalen-1(2H)-one[V]
c) hydrogenation of 2-(4-(4-chlorophenyl)cyclohex-1-enyl)-3,4-
dihydronaphthalen-1(2H)-one[V] with platinum oxide to obtain cis/trans
mixture of 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-
one[VI]
d) optional selective crystallization of cis/trans mixture of 2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [VI] to separate
the 'cis' and 'trans' isomers of 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one[VI]
e) ketone bromination of cis/trans mixture of 2-(4-(4-chlorophenyl)cyclohexyl)-
3,4-dihydronaphthalen-1(2H)-one [VI] to obtain cis/trans mixture of 2-bromo-
2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1 (2H)-one [VII]
f) in absence of step (d) Optional selective crystallization of 2-bromo-2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [VII] to separate
the 'cis' and 'trans' isomers of 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-
3,4-dihydronaphthalen-1(2H)-one [VII]
g) elimination of cis/trans mixture of 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-
3,4-dihydronaphthalen-1(2H)-one [VII] with a strong base to give cis/trans
mixture of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol[VIII]
h) in absence of step (f) optionally crystallizing 2-(4-(4-
chlorophenyl)cyclohexyl)naphthalen-1-ol [VIII] to separate the 'cis' and
'trans' isomers of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol [VIII]
i) oxidizing 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol [VIII] to obtain 2-
(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione [IX]
j) base catalyzed epoxidation of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-
1,4-dione [IX] to la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-
2,7(1 aH,7aH)-dione [X] in presence of hydrogen peroxide
k) acid catalyzed hydrolysis of la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-
b]oxirene-2,7(laH,7aH)-dione [X] to obtain 2-[trans-4-(4'-
chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone [I]
Another aspect of the present invention is to provide separation of 'cis' and 'trans'
isomer of intermediates VI, VII and VIII through selective crystallization in an
appropriate solvent.
Another aspect of the present invention is to provide a method for converting 2-[cis-4-
(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone to 2-[trans-4-(4'-
chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone in presence of Lewis/
Bronsted acid
Another aspect of the present invention is to provide process for preparation of
compound 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen-
1(2H)-one [IV] comprising condensation of (l,2-dihydronaphthalen-4-
yloxy)trimethylsilane [II] with 4-(4-chlorophenyl)cyclohexanone [III] in presence of
Lewis acid in organic solvent
Another aspect of the present invention is to provide, a highly efficient and
atomeconomic process for synthesis of compound [III] i.e. 4-(4-
chlorophenyl)cyclohexanone
The process for making compound of formula (III), as provided comprises the steps
of-
a) Preparation of (4-chlorophenyl) magnesium bromide (Grignard reagent) by
reacting l-bromo-4-chlorobenzene (i) with magnesium turnings in presence of
catalytic amount of iodine
b) reacting (4-chlorophenyl) magnesium bromide with 1,4-cyclohexanedione
monoethylene ketal (ii) to obtain 8-(4-chlorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol
(iii)
c) dehydration reaction of 8-(4-chlorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (iii) in
organic solvent and in presence of p-TSA and ethylene glycol to obtain 4-(4-
chlorophenyl)-cyclohex-3-enone monoethylene ketal (iv)
d) hydrogenation of 4-(4-chlorophenyl)-cyclohex-3-enone monoethylene ketal (iv) in
presence of noble metal catalyst such as palladium on carbon, platinum oxide,
preferentially palladium on carbon to obtain compound 4-(4-chlorophenyl)-
cyclohexanone monoethylene ketal (v)
e) deketalization of 4-(4-chlorophenyl)-cyclohexanone monoethylene ketal (v) in
presence of pTSA in mixture of acetone: water to obtain 4-(4-chlorophenyl)
cyclohexanone [III]
Another aspect of the present invention is to provide process for synthesis of 2-[cis-4-
(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone comprising the steps of-
ay converting Cis-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol (XI), to
cis-4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (XII) in presence of
sulphuric acid /sodium nitrite or sodium bromate/acetic acid or acetic
acid/hydrogen peroxide or ruthenium chloride/hydrogen peroxide/acetic acid
b) converting cis-4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (XII)
to cis-1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(1aH,7aH)-
dione (XIII) in presence of hydrogen peroxide and base.
c) converting cis-1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-
2,7(1aH,7aH)-dione (XIII) to give cis isomer of Atovaquone in presence of
sulfuric acid.
Another aspect is to provide a process for isomerization of cis-Atovaquone i.e. 2-[cis-
4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone to trans-Atovaquone
i.e. 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone in
presence of Lewis acid
Further aspects of the invention are to provide the following compounds:
a) 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen-1(2H)-one
[IV]
b) 2-(4-(4-chlorophenyl)cyclohex-1-enyl)-3,4-dihydronaphthalen-1(2H)-one[V]
c) 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [VI]
d) 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-1(2H)-one
[VII]
e) 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol [VIII]
f) 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione [IX]
g) la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione [X]
Brief description of accompanying Figures:
Figure I: Process for synthesis of Atovaquone [I] without separation of any
diastereomers or geometric isomers of intermediates obtained during the reaction.
Figure II: Process for synthesis of 'cis' isomer of Atovaquone [XIV] from cis-2-(4-
(4-chlorophenyl)cyclohexyl)naphthalen-1-ol [XI]
Figure III: Process for isomerization of 'cis' isomer of Atovaquone [XIV] to
Atovaquone [I] i.e. desired "trans 'isomer in presence of Lewis acid.
Figure IV: High yielding process for synthesis of key intermediate i.e. 4-(4-
chlorophenyl)cyclohexanone [III].
Figure V: The ORTEP diagram of. trans-2-(4-(4-chlorophenyl)-1-
hydroxycyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [IV]
Figure VI: The ORTEP diagram of cis-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-
dihydronaphthalen-1 (2H)-one
Figure VII: The ORTEP diagram of trans-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-
ol
Detailed Description of the Invention
The present invention relates to process for preparation of Atovaquone [I] as
described in the scheme of reactions in Figure I.
(l,2-Dihydronaphthalen-4-yloxy)trimethylsilane (II) was condensed with 4-(4-
chlorophenyl)cyclohexanone (III) in presence of titanium tetrachloride in an organic
solvent such as dichloromethane to give trans-2-(4-(4-chlorophenyl)-1-
hydroxycyclohexyl)-3,4-dihydronaphthalen-1(2H)-one (IV). Compound (IV) on
dehydration in presence of p-TSA in an organic solvent such as toluene gave a
mixture of diastereomers of 2-(4-(4-chlorophenyl)cyclohex-1-enyl)-3,4-
dihydronaphthalen-1(2H)-one (V), which on further hydrogenation using platinum
oxide in organic solvent such as ethyl acetate, acetone preferably acetone gave
cis/trans-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one (VI).
Compound (VI) was further reacted with bromine in presence of acetic acid in an
organic solvent such as diethyl ether to give tis/trans-2-bromo-2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one (VII). Compound (VII)
was then treated with potassium tert-butoxide in organic solvent such as
dimethoxyethane to get cis/trans,-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol
(VIII), which was further converted to cis/trans-4-(4-
chlorophenyl)cyclohexyl)naphthalene-1,4-dione (IX) in presence of any of the
following combination of reagents: sulphuric acid /sodium nitrite or sodium
bromate/acetic acid or acetic acid/hydrogen peroxide or ruthenium chloride/hydrogen
peroxide/acetic acid. This was subsequently converted to cis/trans-1a-(4-(4-
chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione (X) in presence
of hydrogen peroxide and base such as sodium carbonate. Compound (X) on
hydrolysis with sulfuric acid gave Atovaquone (I).
The present invention also relates to separation of 'cis' and 'trans' isomer of
intermediates VI, VII and VIII through selective crystallization in an appropriate
solvent. The pure 'cis' and 'trans' isomers of intermediates VI, VII and VIII are
respectively converted into pure 'cis'and ''trans'isomer of intermediate [X] by means
of the chemistry described in scheme A. Furthermore, pure 'tis' and 'trans 'isomer of
intermediate [X] were respectively converted to 2-[tis-4-(4'-
chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone [XIV] (Figure II) and 2-
[trans-4-(4'-chlorophenyl)cyclohexyl] -3 -hydroxy- 1,4-naphthoquinone [I] i.e.
Atovaquone [I] through acid catalyzed hydrolysis
Cis-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol (XI), was converted to cis-4-
(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (XII) in presence of any of the
following combination of reagents: sulphuric acid /sodium nitrite or sodium
bromate/acetic acid or acetic acid/hydrogen peroxide or ruthenium chloride/hydrogen
peroxide/acetic acid, which was subsequently converted to cis-1a-(4-(4-
chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(1aH,7aH)-dione (XIII) in
presence of hydrogen peroxide and base such as sodium carbonate. Compound (X)
on hydrolysis with sulfuric acid gave cis-Atovaquone (XIV). (reaction Scheme of
Figure II)
A method for converting 2-[cis-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-
naphthoquinone to 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-
naphthoquinone in presence of Lewis/ Bronsted acid is also provided (reaction
Scheme of Figure III)
Cis- Atovaquone or mixture of cis/trans-Atovaquone was converted to trans-
Atovaquone in presence of Lewis acid such as titanium tetrachloride, in organic
solvent such as dichloromethane.
Another aspect of the present invention is to provide , a highly efficient and atom
economic process for synthesis of compound [III] i.e. 4-(4-
chlorophenyl)cyclohexanone which is described below (reaction Scheme of Figure
IV)
1 -Bromo-4-chlorobenzene (i) was reacted with magnesium turnings in presence of
catalytic amount of iodine in organic solvent such as tetrahydrofuran to obtain
corresponding Grignard reagent, which was further reacted with 1,4-
cyclohexanedione monoethylene ketal (ii) to obtain 8-(4-chlorophenyl)-1,4-dioxa-
spiro[4.5]decan-8-ol (iii) in an average 90 % isolated yield. Compound (iii) was
dehydrated in presence of pTSA and ethylene glycol in organic solvent such as
toluene to obtain 4-(4-chlorophenyl)-cyclohex-3-enone monoethylene ketal (iv) in
93% isolated yield, which was further hydrogenated in presence of noble metal
catalyst such as palladium on carbon, platinum oxide, preferentially palladium on
carbon to obtain compound 4-(4-chlorophenyl)-cyclohexanone monoethylene ketal
(v). Compound (v) was deketalized in presence of pTSA in mixture of acetone: water
(50:50). After completion of deketalization, acetone was evaporated under reduced
pressure to obtain aqueous slurry, which was added to dilute sodium bicarbonate
solution and resulting mixture was cooled to 5 °C to obtain 4-(4-chlorophenyl)
cyclohexanone [III] as light yellow solid in 88 % yield .
The addition of ethylene glycol played a crucial role in improving the yield of
compound (iv). In the absence of ethylene glycol, not only the yields were found to be
lower but also formation of innumerable number of impurities, rendering difficulty in
crystallization of (iv).
The invention is described in further details below
A) Process for synthesis of Atovaquone [I]
Step 1 of Figure I
Mukaiyama aldol condensation is very well studied and widely used in organic
synthesis. Mukaiyama aldol condensation is generally carried out in presence of
Lewis acid or Lewis base in a polar aprotic solvent preferably halogenated solvent
such as DCM at temperature range of -70 to 0 °C. Lewis acids such as TiCl4
(Mukaiyama, T. et al. Chem. Lett. 1973, 1011.; Mukaiyama, T. et al. J. Am. Chem.
Soc. 1974, 96, 7503.; Mukaiyama, T. et al Chem. Lett. 1975, 741); BF3.Et2O
(Nakanura, E. et al. J. Am. Chem. Soc. 1977, 99, 961.; Sugimura, H. et al. Synlett.
1991, 153.); SnCl4 (Mukaiyama, T. et al. Org. Synth. 1987, 65, 6) and Lewis bases
such as CaCl2 (Denmark, S. E. et al. Ace. Chem. Res 2000, 32, 432; Hosomi, A. et al.
J. Am. Chem. Soc. 2002, 124, 536), Lithium amide (Mukaiyama, T. et al. Chem. Lett.
2002, 182) have been reported for Mukaiyama aldol condensation.
Mukaiyama aldol condensation of (l,2-dihydronaphthalen-4-yloxy)trimethylsilane of
formula [II] with 4-(4-chlorophenyl)cyclohexanone [III] was carried out in presence
of Lewis acid such as titanium tetrachloride in organic solvent such as
dichloromethane at temperature -60 to -35 °C; preferably at -60 °C under inert
atmosphere, (Stepl of Figure 1). After completion of reaction, titanium tetrachloride
was quenched by adding chilled water at 0 °C. Organic layer was separated and
washed with 5 % aqueous solution of sodium bicarbonate and brine. Evaporation of
organic solvent afforded the crude trans-2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-
3,4-dihydronaphthalen-1(2H)-one, which was further re-crystallized from ethyl
acetate to obtain pure trans-2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one [IV] in 85 % isolated yield.
The structure of compound [IV] has been established from single crystal X-ray
diffraction studies. The crystals are monoclinic (a = 9.9256Å, b= 10.6118 Å,
c=16.9116 Å; a=90 °, ß=98.4140 °, ?=90 °) having a space group of P21/c, and Z=4.
The ORTEP diagram of compound [IV] shows that the hydroxyl group has an axial
conformation, whereas other bulky groups in 1, 4 position of the cyclohexane ring
have equatorial conformation (Figure V). The hydrogen atoms of the hydroxyl group
form a hydrogen bond with carbonyl oxygen of the ketone functionality of the 1-
tetralone moiety.
Step 2 of Figure I
Mukaiyama aldol condensation product i.e. trans-2-(4-(4-chlorophenyl)-1-
hydroxycyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [IV] was dehydrated in
presence of acids such as sulfuric acid, p-toluene sulfonic acid, methane sulfonic acid
and triflic acid preferably p-toluene sulfonic acid in solvents such as dichloromethane,
toluene, benzene; preferably toluene at temperature of about 25 to 110 °C, preferably
60 °C, which gave the diastereomeric mixture of 2-(4-(4-chlorophenyl)cyclohex-1-
enyl)-3,4-dihydronaphthalen-1(2H)-one [V].
The corresponding tetra substituted a,p-unsaturated ketone, would apparently be
thermodynamically most stable and expected as the desired product on dehydration,
however, surprisingly compound [V] was obtained as the sole product presumably
due to steric considerations. Compound [V] was characterized by NMR, IR and MS
and further HPLC analysis showed that it is a mixture of two diastereomers [A] and
[B].
At this stage no attempt was made to separate these stereoisomers and they were
hydrogenated to obtain 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-
I(2H)-one (VI).
Step 3 of Figure I
Dehydrogenation of cyclic ketones to arenes or phenolic compounds is well known in
literature. Springer et al has reported dehydrogenation of 1-tetralone or substituted 1-
tetralone derivatives to corresponding naphthalene and corresponding 1-naphthol
derivatives in presence of palladium on carbon (J.Org.Chem. 1971, 36(5) 686-689).
Hence, hydrogenation of compound (V) was ruled out in presence of palladium on
carbon, palladium hydroxide on carbon or Raney nickel and therefore hydrogenation
was carried out in presence of 1 wt % loading of platinum oxide in mild hydrogen
pressure (2-3 kg/cm2) to obtain 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-
dihydronaphthalen-1 (2H)-one (VI).
2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one (VI) exists in cis
and trans isomers, which was further confirmed by HPLC analysis and NMR
spectroscopy.
Cis and trans isomers of 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-
1(2H)-one were separated through selective crystallization as it was observed that in
cyclohexane, one isomer was more soluble that the other isomer and after
recrystallizations in cyclohexane, one isomer was obtained in the pure form. Single
crystal was obtained from the pure isomer and structure was assigned through a X-ray
single crystal analysis and it was observed that obtained pure compound is cis-2-(4-
(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one and it shows that the
crystals are monoclinic (a = 9.1928 A, b=10.9073 Å, c=17.7399 Å; a=90 °,
ß=97.1320 °, ?=90 °), having a space group of P21/c, and Z=4.
The ORTEP diagram of cis-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-
1(2H)-one, where bulky groups in 1, 4 position of the cyclohexane ring have axial -
equatorial conformation is shown in figure VI.
At this stage, geometric isomers of (4-(4-chlorophenyl)cyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one were not separated for further transformations and were
carried forward as such as shown in Figure I.
Step 4 of Figure I
Cis/trans -2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one (VI)
was converted into cis/trans-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one (VII) through ketone bromination method i.e. bromine
and acetic acid.
Here also, if required, the geometric isomer of compound [VII] can be separated
through selective crystallization from methanol to obtain pure cis and trans isomers of
compound [VII] which could be further converted into respective i.e. cis and trans
isomer of Atovaquone as per the process described in Figure I.
Step 5 of Figure I
P-bromo substituted 1-tetralone derivatives to corresponding substituted 1-naphthol
derivative in presence of base such as triethylamine, piperidine, morpholine and
cyclohexylamine was reported (Tetrahedron Letter 2005, 46, 4187-92; JACS,1957,
79, 230). When cis/trans-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one (VII) was treated with of the above reported bases,
desired product was not obtained. Therefore, cis/trans-2-bromo-2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one (VII) was treated with
comparatively stronger base like alkoxides such as potassium fer/-butoxide, sodium
methoxide and sodium ethoxide to obtain corresponding 1-naphthol derivative i.e.
cis/trans-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol (VIII).
Cis and trans isomers of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol (VIII) were
separated through selective crystallization as it was observed that in cyclohexane, one
isomer was more soluble that the other isomer and after recrystallizations in
cyclohexane, one isomer was obtained in the pure form. Single crystal was obtained
from the pure isomer and structure was assigned through a X-ray single crystal
analysis and it was observed that obtained pure compound is trans-2-(4-(4-
chlorophenyl)cyclohexyl)naphthalen-1-ol and it shows that the crystals are
monoclinic (a = 13.3526 Å, b=7.9000 Å, c=16.5550 Å; a=90 °, ß=96,95. °, ?=90 °),
having space group of P21/c and Z value 4.
The ORTEP diagram of trans-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol,
where bulky groups in 1, 4 position of the cyclohexane ring have equatorial
conformation conformation is shown in figure VII.
DSC melting point for trans 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol is
195.14°C
Step 6 of Figure I
Arnold and Larson have reported oxidation of naphthalene derivatives in presence of
acetic acid and hydrogen peroxide to afford corresponding quinone derivatives
(Synthetic Communication, 1940, 250-252). However, there is no report of oxidation
of 1-naphthol derivatives to corresponding quinone derivatives under similar
conditions.
When compound (VIII) was treated with hydrogen peroxide in acetic acid according
to the reaction conditions reported in the abovementioned paper, it was observed that
the reaction was sluggish and dark red coloured byproducts were also obtained. But,
when bromide ion was added in the same reaction mixture, reaction was completed in
4 h, gave 50 % yield for compound (IX) and although the crude product was dark red
coloured, number of byproducts was comparatively less. However, column flash
chromatography was necessary for the separation of pure compound (IX) from crude
product.
It was also observed that addition of bromide ion improves the rate of reaction
presumably because of in situ oxidation of bromide ion by hydrogen peroxide to
bromate and hence we thought of carrying out the reaction in presence of sodium
bromate and acetic acid.
In spite of dearth of any literature procedure of such oxidation, compound (VIII) was
oxidized in presence of sodium bromate/ acetic acid which yielded 66 % of compound
(IX).
Alternatively, compound (VIII) was also converted into compound (IX) in presence of
RuCl3/acetic acid and hydrogen peroxide (Tetrahedron Letter, 1983, 5249-5252).
Patel et al (Tetrahedron 2007, 63, 4067) has reported conversion of ?-tocopherol to
corresponding ortho-quinone derivative via 5-nitroso-?-tocopherol intermediate as
shown in scheme 6.
Presumably this occurred by a concerted hydrogen transfer from phenolic hydroxyl
functionality to nitroso group via a six member transition state i.e. intramolecular
tautomerism

The mechanistic implication of the above transformation was noted and compound
(VIII) was converted to the corresponding nitroso derivative by treating with sodium
nitrite and 50 % aqueous sulphuric acid in organic solvent such as 1,4-dioxane at
temperature 25 to 75 °C; preferably at 70 °C which, to our satisfaction yielded
compound (IX) in quantitative yield (step 6 of figure I). Interestingly, in the present
case the tautomerism is intermolecular not intramolecular.
There was improvement in the yield as compared to earlier methods but to obtain pure
compound (IX) column chromatography could not be avoided in all processes.
Step 6 and 7 of Figure I
Compound (IX) was converted to compound (X) in presence of hydrogen peroxide
and base such as sodium carbonate (J. Org Chem, 1952, 74 3910-3915), which was
further hydrolyzed in presence of a Bronsted acid such as sulfuric acid to obtain
compound (I) (J. Org Chem, 1952, 74 3910-3915; US 5,053,432). Crude product was
further re-crystallized from acetonitrile to obtain Atovaquone [I] in 99 % purity as
shown by HPLC analytical method described in US monograph for relative substance
and resolution of Atovaquone, wherein no cis isomer was observed.
B) Process for synthesis of cis-Atovaquone [XIV]
Geometric isomers of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol [VIII] i.e. cis
and trans isomer were separated through selective crystallization in presence of
cyclohexane, where cis-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol (XI) was
soluble in cyclohexane and trans-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol
precipitated out.
cis-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol (XI) was converted into 2-[cis-
4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone (XIV) i.e. cis isomer
of Atovaquone, as shown in Figure II through employing chemistry as described in
steps 6 and 7 and further hydrolysis of compound [XIII] in presence of sulphuric acid.
C) Process for isomerization of cis- Atovaquone to trans-Atovaquone [I]
Isomerization of 'cis' isomer of Atovaquone to 'trans' isomer of Atovaquone was
carried out in presence of a Lewis acid such as titanium tetrachloride.
Nomenclatures used for the compounds mentioned herein are as understood from the
CambridgeSoft® ChemOffice software ChemDraw Ultra version 6.0.1.
Analytical Methods:
The purity was determined by HPLC using a Shimadzu LC 2010 system equipped
with a column (Purosphere star RP-18e (4.6 x 150mm), 5 urn), column oven
temperature 25 °C and UV visible detector (UV at 340nm). Mobile phase was buffer:
acetonitrile (55:45) with flow rate 3.0 mL-1, injection volume 20 µl. NMR spectra
were obtained at 200 and 400 MHz Bruker instruments, with CDCl3 as solvent unless
otherwise stated. Chemical shifts (S) are given in ppm relative to tetramethylsilane (5
= 0 ppm). IR spectra were recorded on Perkin Elmer Spectrum (Model: Spectrum
100) and absorption bands are given in cm-1. DSC was recorded on Perkin Elmer
model Diamond DSC at the rate of 10 °C/min, and endothermic peak was recorded in
0 C and ?H is reported in J/g. Crystal structure of the single crystal was measured on
Bruker Smart Apex CCD diffractometer having software SHELXTL-PLUS at
temperature 293 (2) K and wavelength 0.71073 Å and ? range for data collection is
1.56 to 28.40°.
Example 1: Synthesis of (1,2-dihydronaphthalen-4-yloxy)trimethylsilane (II)

To a reactor equipped with reflux condenser, nitrogen bubbler, dropping funnel and
thermo-pocket, were charged a-tetralone (270.0 g, 1.85 mol) and triethylamine (514.0
g, 5.08 mol) at room temperature under nitrogen atmosphere. After stirring at room
temperature for 15 min, trimethyl silyl chloride (541.0 g, 5.0 mol) was added drop
wise over a period of 30-40 min while maintaining nitrogen atmosphere and stirred
for around 1h at room temperature. Sodium iodide (369.0 g, 2.46 mol) was dissolved
in acetonitrile (2.2 L) at RT and added to the reaction mass slowly while maintaining
an internal temperature not more than 40 °C. The resultant reaction mass was allowed
to stir at room temperature for 2h. TLC was checked at this point for product
formation and in case the reaction was found to be incomplete, an additional 1 mol
equivalent of triethylamine was added to the reaction mass. On complete consumption
of reactants, the reaction mass was poured into ice water (3 L) and extracted with n-
pentane (2x 1 L). After separating, the organic layer was dried over anhydrous
potassium carbonate and solvent evaporated to give product as a brown oil (402.0 g,
96% yield). Generally yield of the product ranges from 90 to 97 %.
FTIR (neat): 3022, 3060, 2958, 2935, 2888, 2832, 1638, 1600, 1485, 1359, 1337, 1251,
1188,1140,1093,919,860,845,737 cm-1.
1H NMR (CDCl3, 200 MHz): d 1.85 (s, 9H), 3.89-3.94 (m, 2H), 4.34-4.38 (t, 2H), 6.79
(s, 1H), 8.69-8.81 (m, 3H), 9.0-9.02 (d, 1H).
MS (EI): C13H18OSi: 218.1127; [M+H]+: 219.10
Example 2: Synthesis of 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-
dihydronaphthalen-l(2H)-one (IV)

To a reactor equipped with, over head stirrer, reflux condenser, nitrogen bubbler,
dropping funnel and thermo-pocket, was charged 4-(4-chlorophenyl)cyclohexanone (
85.0 g, 0.41 mol) under a positive nitrogen pressure at 25 °C. Freshly dried
dichloromethane (850 mL) was added to dissolve the material and the reaction mass
was cooled to -35 °C. A 1 molar solution of titanium tetrachloride (85.4 g, 0.45 mol)
in dry dichloromethane (550 mL) was added drop wise to the reaction mass. After
compete addition of titanium tetrachloride reaction mixture was warmed to 0 °C and
stirred for 1 h. Reaction mass was again cooled to -55°C and at this temperature, a
solution of (l,2-dihydronaphthalen-4-yloxy)trimethylsilane (111.3 g, 0.515 mol) in
dichloromethane (1 L) was added and allowed to stir at -55 °C for 1h. After which,
again reaction mixture was warmed to 0°C and then quenched with ice water (2500
mL) under vigorous stirring and diluted with dichloromethane (3000 mL). Organic
layer was separated and washed with saturated sodium bicarbonate solution (500 mL)
and brine. After stripping off the DCM layer under reduced pressure, the residue was
suspended in ethyl acetate (300 mL) and resultant slurry was refluxed for 1h and
cooled to RT. Resultant solid were filtered off to give the product as off-white solid.
(122.3 g, 84.9 % yield). Generally yield of the product ranges from 78 to 85 %.
FTIR (neat): 3441, 2945, 2927, 2858, 1654, 1598, 1397, 1230, 1046, 962, 840, 751,
610 cm-1.
1H NMR (CDCl3, 400 MHz): d 1.55(t, 1H), 1.68-1.79 (m, 4H), 1.91-2.02 (m, 2H), 2.04-
2.11 (m,2H), 2.32-2.36 (dd, 1H), 2.45 (t, 1H), 2.68 (dd, 1H), 3.05(d, 2H), 4.98 (s, 1H
(OH)), 7.20- 7.3.7 (m, 6H), 7.52 (t,lH), 8.04 (d,lH); 13C NMR (CDCl3, 100 MHz): d
25.5, 28.6, 28.9, 29.5, 32.0, 35.7, 43.6, 57.1, 72.8, 126.8, 127.5, 128.3, 128.4, 128.5,
131.4, 133.1, 133.9, 144.2, 145.7, 202.8; MS (EI): C22H23C102 : 354.86; [M]+: 355.85;
DSC peak at 167.85 °C (10°C/min)
PXRD [2?] (Cu Ka1 = 1.54060 Å, Ka2 = 1.54443 Å, Kß .= 1.39225 Å; 40 mA, 45
kV): 8.07, 8.81, 8.93, 9.76, 10.51, 15.60, 17.29, 17.44, 19.10, 19.32, 20.84, 22.96,
24.37,27.96,29.55,
Example 3: Synthesis of 2-(4-(4-chlorophenyl) cyclohex-1-enyl)-3,4-
dihydronaphthalen-1(2H)-one (V)

2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen-1 (2H)-one
(122.0 g, 0.0.345mol) was charged in a reactor equipped with overhead stirrer, reflux
condenser and thermo-pocket. Toluene (2 L) was added to suspended the material and
p-toluene sulfonic acid (3.05 g, 2.5 mol%) was added to the reaction mass which was
then heated to 60 °C and stirred for 2h. Progress of reaction was monitored on TLC.
After completion of reaction, reaction mass was cooled to RT and solvent was
evaporated under pressure to obtain residue. To the residue, was added ethyl acetate
(1500 mL) and washed with sat. NaHCO3 soln. and brine followed by evaporation of
solvent to give crude product which was further recrystallised from methanol to
obtain white solid compound (V) (55.2 g, 50%). Generally yield of the product ranges
from 45 to 56%.
FTIR (neat): 3020, 3045, 2920, 2894, 2863, 2839, 1683, 1597, 1491, 1218, 1088, 818,
747. cm-1.
1H NMR (CDCl3, 400 MHz): d 1.79-1.96 (m, 2H), 2.16-2.34 (m, 6H), 2.83-2.87 (m,
1H), 3.18 (s, 2H), 3.19-3.24 (m, 1H), 5.58 (d, 1H), 7.17-7.35 (m, 6H), 7.49 (t, 1H), 8.08
(d,lH); 13C NMR (CDCl3, 100 MHz): d 27.0 (27.2), 28,3 (28.5), 28.8, 29.8 (29.9), 33.4
(33.5), 39.3(39,4), 55.7(56.0), 124.1 (124.2), 126.7, 127.4 (127.5), 128. 3 (128.31), 128.4 *
(128.5), 128.7, 131.5, 132.8 (132.9), 133.4, 136.0 (136.1), 144.0 (144.1), 145.4 (145.5),
198.8 (198.9); MS (EI): C22H21C10: 336.12; [M+H]+: 337.10 DSC peak at 136.02. °C
(10°C/min)
Example 4: Synthesis of cis/trans-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-
dihydronaphthalen-l(2H)-one (VI)

2-(4-(4-chlorophenyl) cyclohex-1-enyl)-3, 4-dihydronaphthalen-1(2H)-one (51.0g,
0.151 mol) was dissolved in acetone (1.1 L) at RT and transferred to a Parr autoclave
reactor. Platinum oxide (0.097 g, 3 mol %) was added to the reaction mass and
flushed twice with nitrogen and once with hydrogen. Subsequently, a hydrogen
pressure of 5 kg/cm was maintained for 4-5h at RT after which the platinum black
was filtered off through a Celite bed. The mother liquor was evaporated under
reduced pressure to give crude product which was re-crystallized from methanol to
give product as white solid (43.29g, 90% yield). Generally yield of the product ranges
from 85 to 95%.
Cis/trans-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one (10 g)
was suspended in cyclohexane (100 mL) and stirred for 1 h. cis-2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one was soluble in
cyclohexane and trans-2-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-
l(2H)-one remained insoluble (4.8 g). Single crystal was generated from cyclohexane
layer which contain cis-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-
l(2H)-one (Figure VI).
FTIR(neat): 2917, 2887, 2850, 1681, 1491, 1294, 1089, 1012, 749, 530 cm-1.
1H NMR (CDCl3, 400 MHz): d 1.24-1.28 (m, 1H), 1.44-1.59 (m, 3H), 1.74-1.85 (m,
3H), 1.90-196 (m, 3H), 2.02-2.09 (m, 2H), 2.19-2.27 (m, 1H), 2.99-3.09 (m, 2H), 7.14-
7.24 (m, 2H), 7.25-7.35 (m, 5H), 7.47-7.5 (t,1H), 8.05-8.07 (d,1H); MS (EI): C22H23ClO
: 338.15 [M+H]+: 339.00; DSC peak at 82.95 °C (10°C/min)
Example 5: Synthesis of cis/trans-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one (VII) and method for separation of cis and trans
isomers

Cis/trans-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one (43,2
g, 0.127 mol) was charged into a reactor equipped with thermo-pocket and dropping
funnel. Acetic acid (86.4 g) and diethyl ether (1.5 L) were added and the reaction
mass was cooled to 0 °C. Bromine (24.5 g, 0.153 mol) was dissolved in diethyl ether
(100 mL) and added drop wise to the reaction mass at 0 °C. The resultant orange
solution was stirred at 0 °C for lh and gradually the temperature was allowed to
increase to 15-20 °C when the reaction mass started decolourizing, after which
reaction temperature was allowed to increase upto 25 °C. After completion of
reaction, dichloromethane (300 mL) was added to dissolve solid, if any, precipitated
during the reaction. Organic layer was washed with water (2 x 500 mL) and then with
aqueous solution of 5% sodium thiosulphate (500 mL). Solvent was removed from the
reaction mass under reduced pressure to obtain product as white solid (53.1 g, 99 %).
Generally yield of the product ranges from 95 to 99 %.
Cis/trans-2 -bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1 (2H)-
one (39 g) was suspended in methanol (100 mL) and stirred for 1 h. cis-2-bromo-2-
(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one was soluble in
methanol and trans-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one remained insoluble. Pure trans-2-bromo-2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one was obtained through
filtration as white solid (19 g) and major cis-2 bromo-2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one was obtained after
evaporation of solvent under reduced pressure as sticky semi-solid material (21 g).
Trans-2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one
FTIR (neat): 2929, 2850, 1687, 1599, 1490, 1454, 1292, 1234, 1090, 1013, 916, 810,
747,631 cm-1.
1H NMR (CDCl3, 400 MHz): d 1.29-1.33 (m, 1H), 1.44-1.48 (m, 1H), 1.58-1.65 (m,
2H), 1.83-1.91 (m, 2H), 2.06-2.09 (d, 1H), 2.25-2.31 (m, 1H), 2.38-2.54 (m, 3H), 2.70-
2.76 (t, 1H), 2.93-2.97 (d, 1H), 3.27-3.31 (m, 1H), 7.15-7.17 (d, 2H), 7.27-7.30 (m, 3H),
7.37-7.41 (t, 1H) 7.52-7.56 (t,lH), 8.18-8.20 (d,lH) ; 13C NMR (CDCl3, 100 MHz): d
27.0, 28.3, 29.1, 31.5, 33.9, 34.2, 43.9, 44.2, 74.7,' 127.1, 128.1, 128.3, 128.4, 128.6,
128.9, 129.1, 130.3, 131.6, 133.8, 142.5, 145.2,
DSC: peak at 182.95 °C
Example 6: Synthesis of cis/trans-2-(4-(4-chlorophenyl)cyclohexyI)naphthalen-1-
ol (VIII) and method for separation of cis and trans isomers

Potassium tert-butoxide (31.2 g, 0.278 mol) was charged into a reactor containing
dimethoxyethane (500 mL) at room temperature. Temperature of the reaction mass
was increased to 40 °C and to this was added a solution of cis/trans-2-bromo-2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one (53.0 g, 0.126 mol) in
dimethoxyethane (500 mL). Temperature of the reaction mass was further increased
to 80°C and was allowed to stir for 1.5 h at this temperature. Progress of reaction was
monitored on TLC. After completion of reaction, reaction mass was cooled to RT and
solvent was evaporated under reduced pressure and 10% aqueous solution of
hydrochloric acid (180 mL) was added to the residue. The resultant mixture was
extracted with DCM (150 mL) and evaporated to give crude product (47.0 g).
Generally average yield of the product ranges from 70 to 80 %.
Mixture of cis/trans-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol (25 g) was
suspended in cyclohexane and stirred for 1 h. cis-2-(4-(4-
chlorophenyl)cyclohexyl)naphthalen-1-ol was soluble in cyclohexane and trans-2-(4-
(4-chlorophenyl)cyclohexyl)naphthalen-1-ol remained insoluble. Pure trans-2-bromo-
2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one was obtained
through filtration as light orange solid (7.5 g) and major cis-2-bromo-2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one was obtained after
evaporation of solvent under reduced pressure as sticky semi-solid material (11 g).
Obtained major cis-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol was further
purified by column chromatography to obtain pure cis,-2-(4-(4-
chlorophenyl)cyclohexyl)naphthalen-1-ol as sticky semi-solid brown colored material
(7g).
Trans-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol
FTIR (neat): 3563, 3016, 2928, 2853, 2400,, 1492, 1263,1216, 1094, 807, 768,755 cm"
1H NMR (CDCl3, 400 MHz): d 1.63-1.85 (m, 4H), 2.06-2.09 (m, 4H), 2.68-2.70 (t, 1H),
3.03-3.08 (t, 1H), 7.15-7.17(d, 2H), 7.27-7.30 (m, 3H), 7.37-7.41 (t, 1H) 7.82-7.84
(d,lH), 8.12-8.14 (d,lH); 13C NMR (CDCl3, 100 MHz): d 33.18, 34.58, 37.01, 43.51,
76.73, 127.1, 128.3, 129.0, 129.1, 130.3, 131.6, 133.8, 145.71, 147.24 MS (EI):
C22H21ClO: 336.12; [M-H]-: 335.20
DSC: peak at 195.14°C
PXRD [2?] (Cu Ka1 = 1.54060 Å, Ka2 = 1.54443 Å, Kß = 1.39225 Å; 40 mA, 45
kV): 10.76, 12.38, 13.00, 13.33, 13.76, 14.37, 15.51, 16.10, 17.41, 17.73, 18.71,
19.67, 20.05, 21.36, 22.39, 23.04, 23.40, 24.02, 24.56, 26.11, 27.72, 28.97, 30.01,
31.78
Example 7: Synthesis of cis/trans-4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-
dione (IX) in presence of acetic acid/ hydrogen peroxide

To 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol (1.2 g, 3.5 mmol) taken in a RB
flask, was added acetic acid (20 mL) and stirred for 15 min at RT. Temperature of the
reaction mass was increased to 80 °C and a 30% solution of H2O2 (5 mL) was added
to it drop wise over a period of 30 min at 80 °C and stirred for another 30 min. After
cooling to RT, water (50 mL) was added to the reaction mass. The resultant mixture
was extracted with DCM (3.x 100 mL), dried over anhydrous Na2SO4 and evaporated
to give crude product which was purified by column chromatography to give pure
product as yellow solid. (0.4 g, 32% yield)
FTIR (neat): 3310, 2926, 2856, 1662, 1614, 1594, 1492, 1449, 1329, 1305, 1261, 1251,
1091, 1012, 937, 822, 779, cm-1.
13C NMR (CDCl3, 100 MHz): d 26.92, 27.74, 29.81, 32.16, 33.93, 34.41, 36.21, 38.73,
43.39, 125.96, 126.00, 126.75, 126.46, 128.18, 128.46, 128.52, 128.62, 131.46, 131.68,
131.85, 131.9, 132.45, 132.53, 133.13, 133.67, 133.71, 134.11, 143.50, 145.28, 155.17,
155.64, 184.74, 184.90, 185.33,
Example 8: Synthesis of 4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione
(IX) in presence of acetic acid/hydrogen peroxide/potassium bromide

To 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol (1.0 g, 2.9 mmol) taken in a RB
flask, were added acetic acid (20 mL) and potassium bromide (1.0 g, 8.4 mmol) and
stirred for 15 min at RT. Temperature of the reaction mass was increased to 80 °C and
a 30% solution of H2O2 (5 mL) was added to it dropwise over a period of 30 min at 80
°C and stirred for another 30 min. After cooling to RT, water (50 mL) was added to
the reaction mass. The resultant mixture was extracted with DCM (3x 100 mL), dried
over anhydrous Na2SO4 and evaporated to give crude product which was purified by
column chromatography to give pure product as yellow solid. (0.52 g, 50% yield)
Example 8: Synthesis of 4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione
(IX) in presence of sodium bromate/ acetic acid

2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol (5.1 g, 15.1 mmol) was added to
acetic acid (70 mL) and resulting reaction mass was heated to 60 °C. Sodium bromate
(1.5 g, 10 mmol) was added to the above reaction mixture and stirred for 1 h at 80 °C.
Water (15 mL) was added to the reaction mixture and stirred for an additional 2 h at
80 °C. The reaction mixture was cooled to RT and water (200 mL) was added to it.
The resultant mixture was extracted with dichloromethane (2 x 300 mL). Combined
organic layer was dried over anhydrous Na2SO4 and evaporated to give crude product
which was purified by column chromatography (stationary phase: Silica gel and
mobile phase: 2% ethyl acetate in cyclohexane) to give pure product as yellow solid.
(3.5 g, 66 % yield)
Example 9: Synthesis of 4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione
(IX) in presence of sodium nitrite/50% aqueous sulphuric acid.

To a stirred solution of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol (42.3 g,
125.9 mmol) in 1,4-dioxane (850 mL) were added 50 % aqueous sulphuric acid (170
mL) and sodium nitrite (17.4 g, 251.7mmol) at 5 °C and temperature of the resultants
reaction mixture was increased to 80 °C and stirred for another 2 h. After cooling to
RT, water (50 mL) was added to the reaction mass and extracted with ethyl acetate
(3x 500 mL), dried over anhydrous Na2SO4 and solvent was evaporated to crude
product, which was further purified by column chromatography (stationary phase:
Silica gel and mobile phase: 2% ethyl acetate in cyclohexane) to give pure product as
yellow solid. (30.3 g, 70%)
Example 10: Synthesis of cis/trans-1a-(4-(4-
chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione(X)

4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (13.5 g, 38.5 mmol) was
charged into a reactor along with 1,4-dioxane (135 mL) at RT. To this were added
sodium carbonate (4.5 g, 42.4 mmol) and a 30% soln. of H2O2 (5.23 g, 154.0 mmol)
and the reaction mass was refluxed for 30 min. After cooling the reaction mass to RT,
water (50 mL) was added and extracted with ethyl acetate (3*300 mL). Solvent was
removed under reduced pressure to give product as off-white solid (13.7 g, 96%
yield).
FTIR (KBr): 3370, 3078, 2944, 2928, 2900, 2859, 1695, 1594, 1490, 1451, 1306,
1287,1157,1089,944,886,801,725 cm-1.
1H NMR (CDCl3, 400 MHz): 5 1.28-1.41 (m, 2H), 1.56-1.62 (t, 2H), 1.9 (s, 4H),
3.96 (s, 1H) 7.16-7.18(d, 2H), 7.28-7.29 (d, 2H), 7.76-7.78 (t, 2H) 7.97-7.98 (d,2H),
8.03-8.05 (d,2H) ;13C NMR (CDCl3, 100 MHz): d26.6, 29.3, 33.3, 33.4, 34.3, 37.7,
43.3, 57.7, 58.2, 66.3, 66.9, 126.5, 126.6, 127.6, 128.4, 128.5, 131.5, 131.6, 132.8,
134.3, 134.6, 143.2, 145.2, 191.5, 192.1
Example 11: Synthesis of Atovaquone [I]

To 1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione
(13.5g, 1.6 mmol) taken in a reactor was added cone. H2SO4 (135 mL) and stirred for
5 h at RT. Water (2 L) was added to the reaction mass and extracted with DCM
(3*200 mL). Solvent was evaporated under reduced pressure to give crude product
which was further re-crystallized from acetonitrile to obtain pure compound as a
yellow solid (10 g, 74% yield).
FTIR (KBr): 3375, 2958, 2924, 2853, 1659, 1646, 1625, 1594, 1490, 1369, 1344,
1277,1248,1216,1089,998,822,727,656,530 cm-1.
1H NMR (CDCl3, 400 MHz): d 1.58 (q, 2H), 1.75 (d, 2H), 1.96 (d, 2H), 2.16-2.20 (m,
2H), 2.63 (t, 1H), 3.16 (t, 1H), 7.18 (d, 2H), 7.28 (d, 2H), 7.48 (s, 1H), 7.68 (t, 1H), 7.76
(t,lH), 8.07 (d, 1H), 8.13 (d, 1H); 13C NMR (CDCl3, 100 MHz): d29.18, 34.34, 34.46,
34,64, 43.22, 126, 127, 127.25, 128.43, 129.19, 129.31, 131.45, 132.86, 133.12, 135.02,
146.05, 152.98, 181.80, 184.56; MS (EI): C22H19ClO3: 366.1023; [M+Naf: 388.95, [M-
H]-: 365.30; DSC peak at 220.44 °C (10°C/min)
PXRD [2?] (Cu Ka1 = 1.54060 Å, Ka2 = 1.54443 Å, Kß = 1.39225 Å; 40 mA, 45
kV): 7.30, 9.70, 10.79, 11.11, 11.83, 15.43, 16.16, 16.89, 17.39, 22.93, 24.62, 24.68,
25.35,26.18,26.84,28.52,28.70,29.52,30.68,34.23,36.84.
Example 12: Conversion of "cis" isomer of Atovaquone to "trans" isomer of
Atovaquone in presence of Titanium tetrachloride.
Cis isomer of Atovaquone (0.5 g) was dissolved in dichloromethane (20 mL) and
TiCl4 (0.5 mL)was added to it at RT. Resulting reaction mixture was heated to 40 °C
and stirred for 24 h. Reaction was monitored for conversion of cis isomer of
Atovaquone to trans isomer at different intervals. After 24 h, HPLC analysis showed
the cis to trans ratio as 50:50.
HPLC Retention time for cis isomer: 19.33 min
HPLC Retention time for trans isomer: 22.66 min
Example 13: Conversion of "cis" isomer of Atovaquone to "trans''' isomer of
Atovaquone in presence of Sulphuric acid.
Cis/trans Atovaquone (0.5 g) was added in sulphuric acid (10 mL) at RT and stirred
for 2 h, after which the reaction mixture was poured in ice water and product was
extracted with dichloromethane, which was analyzed on HPLC as per resolution
method given in US pharmacopoeia.
HPLC Retention time for cis isomer: 19.33 min
HPLC Retention time for trans isomer: 22.66 min
Example 14: Synthesis of csi-4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-
dione (XII) in presence of Sodium Nitrite/ sulphuric acid

To a stirred solution of cis-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol (0.5 g,
1.4 mmol) in 1,4 dioxane (20 mL) were added 50 % aqueous sulphuric acid (10 mL)
and sodium nitrite (0.2 g, 2.9mmol) at 5 °C and temperature of the resultant reaction
mixture was increased to 80 °C and stirred for 2 h. After cooling to RT, water (50 mL)
was added to the reaction mass and extracted with DCM (3x 100 mL), dried over
anhydrous Na2SO4 and evaporated to give crude product which was purified by
column chromatography (stationary phase: Silica gel and mobile phase: 2% ethyl
acetate in cyclohexane) to give pure product as yellow solid. (0.34 g)
1H NMR (CDCl3, 400 MHz): d 1.71-1.75 (m, 2H), 1.84-1.96 (m, 4H), 2.04-2.06 (m,
2H), 6.82 (s, 1H), 7.23-7.30 (dd, 4H), 7.73-7.75 (m, 2H), 8.06-8.12 (dd, 2H) ; 13C NMR
(CDCl3, 100 MHz): d 27.73, 27.84, 29.80, 34.41, 38.74, 127.1, 128.3, 129.0, 129.1,
130.3, 131.6, 133.8, 143.49, 1555.18,
Example 15: Synthesis of 4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione
(XII) in presence of Sodium bromate/ acetic acid

To a stirred solution of cis-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol (5.0 g,
15 mmol) in acetic acid (75 mL) was added sodium bromate (1.48 g, 9.8 mmol) at 25
°C and resulting reaction mixture was stirred for another 30 min at 80 °C after which
the reaction mixture was cooled to RT. Water (50 mL) was added to the reaction
mass and extracted with DCM (3x 100 mL), dried over anhydrous Na2SO4 and
solvent evaporated to give crude product which was purified by column
chromatography (stationary phase: Silica gel and mobile phase: 2% ethyl acetate in
cyclohexane) to give pure product as yellow solid. (3.0g, 58 % yield)
Example 16: Synthesis of 1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-
b]oxirene-2,7(1aH,7aH)-dione (XIII)

Cis-4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (1.85 g,) was charged into a
reactor along with 1,4-dioxane (20 mL) at RT. Sodium carbonate (0.2 g, 2.0 mmol)
was added to the above reaction mixture and a 30% soln. of H2O2 (1.5 ml, 20.0 mmol)
was added drop wise and the reaction mass was heated to 80 °C and stirred at that
temperature for 30 min. After cooling the reaction mass, water (50 mL) was added
and extracted with ethyl acetate (100 mL). Solvent was removed under reduced
pressure to give crude product as yellow solid (1.7 g, 90 % yield).
Example 17: Synthesis of cis-Atovaquone [XIV]

Cis-1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione
(1.7 g, 4.7 mmol) was taken in a reactor and to it was added dilute H2SO4 (10 mL)
and stirred for 20 min at RT. Water (100 mL) was added to the reaction mass and
extracted with DCM (100 mL). HPLC analysis confirms cis-Atovaquone.
Retention time for cis-Atovaquone: 19.23 min
Example 18: Synthesis of 8-(4-chlorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (iii)

Activated magnesium turnings (92.2g, 3.84 mol) were charged to a nitrogen dried reactor
equipped with reflux condenser, nitrogen bubbler, thermo pocket and side arm addition
funnel. Dry THF (2.0 L) and catalytic amount of iodine were added and reactor was
gently heated. 1-Bromo 4-chlorobenzene (674.0 g, 3.52 mol) solution in THF (2 L) was
added slowly into the above reaction mass at 50 °C to obtain corresponding Grignard
reagent. To this Grignard reagent, solution of 1,4 cyclohexanedione mono-ethylene ketal
(500.0 g, 3.20 mol) in THF (2 L) was added at 40-50 °C and resulting reaction mixture
was heated at 50 °C for 1 h, after which the reaction mixture was quenched with aqueous
solution of ammonium chloride and solvent was evaporated to obtain crude 8-(4-
chlorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (v), which was suspended in dilute
hydrochloric acid (6 L) and stirred for 30 min and after filtration, white solid was
obtained as product (764.0 g, 93% yield). Generally yield of the product ranges from 88
to 95%.
1H NMR (CDCl3, 400 MHz): d 1.49 -1.69 (d, 2H), 1.72-1.78 (d, 2H), 2.08-2.19 (m, 4H),
3.96-4.03 (m, 4H), 7.28-7.37 (m 2H), 7.41-7.48 (m,2H). 13C NMR (CHCI3, 100 MHz):
£30.6, 36.5,64.2, 64.3, 72.2, 108.2, 125.9, 128.6, 132.6, 147.0.
PXRD [2?] (Cu Ka1 = 1.54060 Å, Ka2 =. 1.54443 Å, Kß = 1.39225 Å; 40 mA, 45
kV): 8.09, 8.96, 12.30, 14.84, 16.43, 17.60, 17.93, 18.88, 20.92, 22.29, 24.70, 15.59,
30.02,30.31
Example 19: Synthesis of 4-(4-chlorophenyl)-cyclohex-3-enone monoethylene
ketal (iv)

8-(4-chlorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (750.0 g, 2.8mol) was charged in a
reactor equipped with Dean-Stark condenser and thermo-pocket. Toluene (15L) was
added to suspended the material and p-toluene sulfonic acid (15.95 g, 3mol%) and
ethylene glycol (250 mL, 2.8 mol) were added to the reaction mass which was then
heated to 110 °C and stirred for 6h. Reaction was monitored by TLC and after
complete consumption of starting material; reaction mass was cooled to room
temperature. Solvent was evaporated under reduced pressure to obtain crude product,
which was suspended in 1% aqueous sodium bicarbonate solution (1.5 L) and stirred
for 1 h. Resulting suspension was filtered to obtain yellow solid (669.0 g, 93 % yield).
Generally yield of the product ranges from 90 to 97 %.
FTIR(neat): 2877,1644,1495,1243,1123,1024cm-1.
1H NMR (CDCl3, 400 MHz): d 1.91 -1.94 (t, 2H), 2.47 (s, 2H), 2.62-2.63 (t, 2H), 4.02
(s, 4H) 5.99 (s, 1H), 7.25- 7.33 (m, 4H); 13C NMR (CHCl3, 100 MHz): d27.8, 31.2,
36.1, 64.5, 107.5, 212.5, 122.1, 126.4, 128.2, 132.5,
Example 19: Synthesis of 4-(4-chlorophenyl)-cyclohexanone [HI]

4-(4-Chlorophenyl)-cyclohex-3-enone monoethylene ketal (291.0 g, 1.15 mol) was
dissolved in ethyl acetate (2.3 L) at RT and transferred to a Parr autoclave reactor.
Palladium on carbon (9.0 g, 3 wt %) was added to the reaction mass and flushed twice
with nitrogen and once with hydrogen. Subsequently, a hydrogen pressure of 5-7
kg/cm2 was maintained for 7h at RT. Reaction was monitored on TLC; after
completion of reaction, palladium on carbon was filtered through a Celite bed. The
mother liquor was evaporated under reduced pressure to give crude product as light
yellow semi solid of 4-(4-Chlorophenyl)-cyclohexanone monoethylene ketal (v).
Crude 4-(4-Chlorophenyl)-cyclohexanone monoethylene ketal (v) was suspended in
50:50 acetone: water (1000 mL) at 25 °C and p-TSA (11.5 g, 5 mol %) was added to
it. The reaction mass was heated to 70 °C and stirred for 3h after which it was cooled
to RT. Acetone was evaporated under reduced pressure and resultant slurry was added
to sodium bicarbonate solution and stirred for 30 min at 5 °C and filtered off to afford
pure product as off-white solid (198.0 g, 88 % yield). Generally yield of the product
ranges from 80 to 90 %.
FTIR(neat): 2939,1712,1490,1164,1091,1013,833 cm-1.
1H NMR (CDCl3, 200 MHz): d 1.85 -1.93 (m, 2H), 2.18-2.22 (m, 2H), 2.49-2.59 (m,
4H) 2.98-3.05 (m, 1H), 7.14-7.19 (m, 2H), 7.25-7.30 (m, 2H); 13C NMR (CHCl3, 100
MHz): d 33.8, 41.3, 42.1, 128.0, 128.4, 132.2, 143.2, 210.7; DSC (10 °C/min): Peak at
63.39 °C
We Claims:
1) A process to prepare 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-
naphthoquinonnamely Atovaquone [I] comprising the steps of-
i) condensing (1,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4-
chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic solvent
to obtain 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen-
1(2H)-one[IV]
ii) dehydration of 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one [IV] in organic solvent and in presence of acid
such as pTSA to obtain diastereomeric mixture of 2-(4-(4-
chlorophenyl)cyclohex-1-enyl)-3,4-dihydronaphthalen-1(2H)-one[V]
iii) hydrogenation of 2-(4-(4-chlorophenyl)cyclohex-1-enyl)-3,4-
dihydronaphthalen-1(2H)-one[V] with PtO2 to obtain cis/trans mixture of 2-
(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [VI]
iv) optional selective crystallization of cis/trans mixture of 2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [VI] to separate
the 'cis' and 'trans' isomers of 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one
v) ketone bromination of cis/trans mixture of 2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [VI] to obtain
cis/trans mixture of 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one [VII]
vi) in absence of step (d) optional selective crystallization of 2-bromo-2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [VII] to separate
the 'cis' and ' trans' isomers of 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-
3,4-dihydronaphthalen-1(2H)-one [VII]
vii) elimination of cis/trans mixture of 2-bromo-2-(4-(4-
chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [VII] with a
strong base to give cis/trans mixture of 2-(4-(4-
chlorophenyl)cyclohexyl)naphthalen-1-ol [VIII]
viii) in absence of step (f) optionally crystallizing 2-(4-(4-
chlorophenyl)cyclohexyl)naphthalen-1-ol [VIII] to separate the 'cis' and
'trans' isomers of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol [VIII]
ix) oxidizing cis/trans mixture of 2-(4-(4-
chlorophenyl)cyclohexyl)naphthalen-1-ol [VIII] to obtain cis/trans mixture of
2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione [IX]
x) base catalyzed epoxidation of cis/trans mixture of 2-(4-(4-
chlorophenyl)cyclohexyl)naphthalene-1,4-dione [IX] to cis/trans mixture of
1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(laH,7aH)-dione
(X) in presence of hydrogen peroxide
xi) acid catalyzed hydrolysis of cis/trans mixture of 1a-(4-(4-
chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(1aH,7aH)-dione (X) to
obtain 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-
naphthoquinone [I]
2) The process according to Claim 1 step i) wherein the Lewis acid used is
titanium tetrachloride.
3) The process according to claim 1 step ii), wherein the dehydrating agent is
selected from the group of Bronsted acids consisting of p-toluene sulfonic
acid, methane sulfonic acid and triflic acid.
4) The process according to claim 1 step ii), wherein organic solvent is selected
from the group consisting of dichloromethane, toluene and benzene.
5) The process according to claim 1step iv) wherein the solvent used for
selective crystallization is cyclohexane.
6) The process according to claim 1 step v), wherein the bromination is carried
out with bromine in acetic acid in diethyl ether.
7) The process according to claim 1step vi) wherein the solvent used for
selective crystallization is methanol.
8) The process according to claim 1 step vii) wherein strong base used is
selected from the group consisting of potassium t-butoxide, sodium
methoxide and sodium ethoxide.
9) The process according to claim 1 step viii) wherein solvent used for selective
crystallization is cyclohexane.
10) The process according to claim 1 step ix) wherein oxidation reaction is
carried out by acetic acid/H2O2 or acetic acid/NaBrO3 or sulfuric acid/NaNO2
or RuCl3/AcOH/H2O2.
11) The process according to claim 1 step x) wherein epoxidation reaction is
carried out by sodium bicarbonate and hydrogen peroxide.
12) The process according to claim 1 step xi) wherein hydrolysis is carried out by
sulfuric acid.
13) A compound 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one [IV].
14) Compound 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one [IV] adapted for use in preparation of 2-[trans-
4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone [I].
15) A process to prepare compound 2-(4-(4-chlorophenyl)-1-
hydroxycyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [IV] comprising
condensation of (1,2-dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-
(4-chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic
solvent.
16) The process according to claim 15, wherein Lewis acid used is titanium
tetrachloride.
17) The process according to claim 15, wherein the compound 2-(4-(4-
chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen-1(2H)-one [IV]
is obtained in trans configuration.
18) The compound according to claim 17, adapted for use in preparation of 2-
[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone [I].
19) A compound 2-(4-(4-chlorophenyl)cyclohex-1-enyl)-3,4-dihydronaphthalen-
1(2H)-one[V].
20) The process according to claim 1step ii) wherein the compound (V) is
obtained in a diastereomeric mixture of [A] and [B]

21) The compound according to claim 19, adapted for use in the preparation of 2-
[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone [I].
22) A compound (l,2-dihydronaphthalen-4-yloxy)trimethylsilane [II]
23) A compound 4-(4-chlorophenyl)cyclohexanone [III]
24) A compound 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-
1(2H)-one [VI]
25) The compound according to claim 24, adapted for use in preparation of 2-
[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone [I]
26) A compound 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-
dihydronaphthalen-1 (2H)-one [VII]
27) The compound according to claim 26, adapted for use in preparation of 2-
[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone [I]
28) A compound 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol [VIII]
29) The compound according to claim 28, adapted for use in preparation 2-[trans-
4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone [I]
30) A compound 2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione [IX]
31) The compound according to claim 30, adapted for use in preparation of 2-
[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone [I]
32) A compound la-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-
2,7(1aH,7aH)-dione (X)
33) The compound according to claim 32, adapted for use in preparation of 2-
[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone [I]
34) A process for making a compound of formula (III), comprising the steps of-
a) Preparation of (4-chlorophenyl)magnesium bromide (Grignard reagent) by
reacting l-bromo-4-chlorobenzene with magnesium turning in presence
catalytic amount of iodine
b) reacting (4-chlorophenyl)magnesium bromide with 1,4-cyclohexanedione
monoethylene ketal to obtain 8-(4-chlorophenyl)-1,4-dioxa-spiro[4.5]decan-8-
ol)
c) dehydration of 8-(4-chlorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol in
toluene and in presence of p-TSA and ethylene glycol to obtain 4-(4-
chlorophenyl)-cyclohex-3-enone monoethylene ketal
d) hydrogenating 4-(4-chlorophenyl)-cyclohex-3-enone monoethylene ketal
in presence of noble metal catalyst such as palladium on carbon, platinum
oxide, to obtain compound 4-(4-chlorophenyl)-cyclohexanone monoethylene
ketal
e) deketalization of 4-(4-chlorophenyl)-cyclohexanone monoethylene ketal in
presence of pTSA in mixture of acetone: water to obtain 4-(4-chlorophenyl)
cyclohexanone [III]
35) A process for making a compound of formula (XIV), comprising the steps of-
a) a process to convert cis,-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol
(XI), to cis- 4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (XII) in
presence of sulphuric acid /sodium nitrite or sodium bromate/acetic acid or
acetic acid/hydrogen peroxide or ruthenium chloride/hydrogen peroxide/acetic
acid
b) a process to convert cis-4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-
dione (XII) to cis-1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-
2,7(1aH,7aH)-dione (XIII) in presence of hydrogen peroxide and sodium
bicarbonate.
c) a process of converting cis-1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-
b]oxirene-2,7(laH,7aH)-dione (XIII) to give cis isomer of Atovaquone in
presence of sulfuric acid.
36) A process of isomerization of cis isomer of Atovaquone to trans-Atovaquone (2-
[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone) in presence of
Lewis acid.
37) The process according to claim 36, wherein the Lewis acid used is titanium
tetrachloride.

Provided is a process of preparation of 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-
hydroxy-1,4-naphthoquinone, i.e. Atovaquone [I] which is cost effective, green, and
eco-friendly process, without separation of any diastereomers or geometric isomers of
intermediates obtained during the reactions. Also provided is separation of 'cis' and
'trans' isomer of intermediates VI, VII and VIII through selective crystallization in an
appropriate solvent. A method for converting 2-[cis-4-(4'-chlorophenyl)cyclohexyl]-
3-hydroxy-1,4-naphthoquinone to 2-[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-
1,4-naphthoquinone in presence of Lewis/ Bronsted acid is also provided. A process
for preparation of compound 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-
dihydronaphthalen-1(2H)-one [IV] comprising condensation of (1,2-
dihydronaphthalen-4-yloxy)trimethylsilane [II] with 4-(4-
chlorophenyl)cyclohexanone [III] in presence of Lewis acid in organic solvent. The
invention also encompasses a highly efficient and atomeconomic process for synthesis
of compound [III] i.e. 4-(4-chlorophenyl)cyclohexanone as well as a process for
synthesis of 2-[cis -4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone.
Further provided is a process for isomerization of cis-Atovaquone i.e. 2-[cis-4-(4'-
chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone to trans-Atovaquone i.e. 2-
[trans-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone in presence of
Lewis acid