Indian Journal of Chemistry Vol. 52B, October 2013, pp 1299-1312 A novel process for synthesis of Atovaquone Bhairab N Roy*, Girij P Singh, Piyush S Lathi, Manoj K Agrawal, Rangan Mitra & Anurag Trivedi Chemical Research Department, Lupin Research Park, Survey No 46/A & 47/A, Nande Village, Mulshi Taluka, Pune 411 042, India E-mail: [email protected]Received 3 June 2013; accepted (revised) 13 August 2013 A stereospecific efficient process for synthesis of atovaquone i.e. trans-2-[4-(4-chlorophenyl)cyclohexyl ]-3-hydroxy- 1,4-naphthalenedione and its cis isomer from commercially available raw materials such as α-tetralone and 4-(4- chlorophenyl)cyclohexanone is described. Keywords: Atovaquone, cis-atovaquone, 1-tetralone, Mukaiyama aldol reaction Atovaquone is the hydroxy-1,4-naphthoquinone analog of Coenzyme Q10 and has an antipneumo- cystic activity 1 . It is mainly prescribed for treatment of Pneumocystis carinii pneumonia as well as for malaria, toxoplasmosis and carcinoma or fibro- sarcoma 2-4 . The mechanism of action involves the inhibition of mitochondrial electron transport in cytochrome bc 1 complex of the parasite, which is linked to pyrimidine biosynthesis 5 . Described herein is a novel stereospecific route for synthesis of atovaquone 1 as well as cis-atovaquone 2 from readily available and economic starting materials. Existing route of synthesis of Atovaquone Strategy adopted in the literature for synthesis of atovaquone i.e. trans-2-[4-(4-chlorophenyl)cyclo- hexyl]-3-hydroxy-1,4-naphthalenedione 1 essentially consisted of free radical substitution on 1,4-naphtho- quinone derivatives by 1-chloro-4-cyclohexylbenzene radical either by thermal or photochemical irradiation. Although the precursors used for obtaining 1-chloro- 4-cyclohexylbenzene radical were different, however condensation was carried out by employing the principle of Hunsdiecker decarboxylative condensation 5 (Scheme I). Overall yields for the reported methods were poor (in the range of 20-40%), and a mixture of cis/trans isomers of atovaquone was obtained, which required further separation through fractional crystallization employing a large volume of solvents to obtain the active pharmaceutical ingredient i.e. trans isomer 5-9 . After filing patent applications for the present work 10,11 (PCT/IB2011/001507, 28 th June 2011; PCT/IB2011/002134, 14 th Sep.2011), an elegant synthesis of atovaquone 1 was disclosed in WO 2012/080243 A2 (published on 21 st June 2012), which involved condensation between 1H-2- benzopyran-1,4-(3H)-dione and 4-(4-chloropheyl)- cyclohexanecarbaldehyde 12,13 .
Transcript
Indian Journal of Chemistry Vol. 52B, October 2013, pp 1299-1312
A novel process for synthesis of Atovaquone
Bhairab N Roy*, Girij P Singh, Piyush S Lathi, Manoj K Agrawal, Rangan Mitra & Anurag Trivedi
Chemical Research Department, Lupin Research Park, Survey No 46/A & 47/A, Nande Village, Mulshi Taluka, Pune 411 042, India
Received 3 June 2013; accepted (revised) 13 August 2013
A stereospecific efficient process for synthesis of atovaquone i.e. trans-2-[4-(4-chlorophenyl)cyclohexyl ]-3-hydroxy-1,4-naphthalenedione and its cis isomer from commercially available raw materials such as α-tetralone and 4-(4-chlorophenyl)cyclohexanone is described.
Atovaquone is the hydroxy-1,4-naphthoquinone analog of Coenzyme Q10 and has an antipneumo-cystic activity1. It is mainly prescribed for treatment of Pneumocystis carinii pneumonia as well as for malaria, toxoplasmosis and carcinoma or fibro-sarcoma2-4. The mechanism of action involves the inhibition of mitochondrial electron transport in cytochrome bc1 complex of the parasite, which is linked to pyrimidine biosynthesis5. Described herein is a novel stereospecific route for synthesis of atovaquone 1 as well as cis-atovaquone 2 from readily available and economic starting materials.
Existing route of synthesis of Atovaquone
Strategy adopted in the literature for synthesis of atovaquone i.e. trans-2-[4-(4-chlorophenyl)cyclo-hexyl]-3-hydroxy-1,4-naphthalenedione 1 essentially consisted of free radical substitution on 1,4-naphtho-quinone derivatives by 1-chloro-4-cyclohexylbenzene radical either by thermal or photochemical irradiation.
Although the precursors used for obtaining 1-chloro-4-cyclohexylbenzene radical were different, however condensation was carried out by employing the principle of Hunsdiecker decarboxylative condensation5 (Scheme I).
Overall yields for the reported methods were poor
(in the range of 20-40%), and a mixture of cis/trans isomers of atovaquone was obtained, which required further separation through fractional crystallization employing a large volume of solvents to obtain the active pharmaceutical ingredient i.e. trans isomer5-9.
After filing patent applications for the present work10,11 (PCT/IB2011/001507, 28th June 2011; PCT/IB2011/002134, 14th Sep.2011), an elegant synthesis of atovaquone 1 was disclosed in WO 2012/080243 A2 (published on 21st June 2012), which involved condensation between 1H-2-benzopyran-1,4-(3H)-dione and 4-(4-chloropheyl)-cyclohexanecarbaldehyde12,13.
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Results and Discussion
Strategy adopted here was to develop the carbon framework of atovaquone through Mukaiyama aldol condensation between silyl enol ether of α-tetralone and 4-(4-chlorophenyl)cyclohexanone, which was further transformed to atovaquone 1 as well as cis-atovaquone 2 through high yielding reaction sequence.
The overall schematic process for synthesis of atovaquone 1 is shown in Scheme II and Scheme III
describes the process for synthesis of cis-atovaquone 2. Although the process for synthesis of compound 4
is already known, herein is reported an improvement in the existing process to obtain the same in higher yield viz. 90% (70% reported)5 (Scheme IV).
Mukaiyama aldol reaction is essentially only the condensation between a silyl enol ether and an aldehyde14. There is only one report, by Reddy15 et al on the condensation between silyl enol ether of α-tetralone and acetone in presence of titanium tetrachloride to give the corresponding aldol in 85% yield, but no work has been reported for cyclic ketones such as substituted cyclohexanone.
To our satisfaction, Mukaiyama aldol condensation of (1,2-dihydronaphthalen-4-yloxy)trimethylsilane 3 with 4-(4-chlorophenyl)cyclohexanone 4 gave trans-2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-di-hydronaphthalen-1(2H)-one 5, which on recrystal-
lization from ethyl acetate yielded pure trans-2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydrona-phthalen-1(2H)-one 5 in 85% isolated yield.
The structure of compound 5 has been established from single crystal X-ray diffraction studies. The ORTEP diagram (Figure 1) of compound 5 shows that the hydroxyl group has an axial conformation, whereas, p-chloro phenyl and α-tetralone in 1,4 position of the cyclohexane ring have equatorial conformation and crystals are monoclinic [(a = 9.9256Å, b=10.6118 Å, c=16.9116 Å; α=90°, β=98.4140°, γ=90°) space group of P21/c, and Z=4].
Brønsted acid catalyzed dehydration of compound 5 was first attempted for obtaining compound 6, but the yield for compound 6 was only 50%. This was because of considerable retro aldol reaction, which yielded α-tetralone and 4-(4-chlorophenyl)cyclohexa-none as products. Amongst the acids tried for dehydration such as sulfuric acid, p-toluene sulfonic acid (p-TSA), methane sulfonic acid and triflic acid, only p-toluene sulfonic acid gave the corresponding olefin 6 in 50% yield, whereas, with other acids unidentified products were obtained.
In case of Lewis acid catalyzed dehydration using titanium (IV) chloride and zirconium (IV) chloride, only retro-aldol product was obtained in quantitative yield (Scheme V).
Scheme I — Existing route of atovaquone 1
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Scheme II
Scheme III — Process for synthesis of cis-atovaquone 2
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Thus, it was decided to change the approach to base catalyzed E2 deacetoxylation, for which preparation of acetoxy and sulfonate esters were attempted with acetic anhydride, methane sulfonyl chloride, triflic anhydride, toluene sulfonyl chloride and trifluoroacetic anhydride. Only, trifluoroacetic anhydride gave the corresponding ester i.e. 4-(4-chlorophenyl)-1-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate 5a as a crystal-line solid in 95% isolated yield.
4-(4-Chlorophenyl)-1-(1-oxo-1,2,3,4-tetrahydrona-phthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate 5a when subjected to E2 elimination with DABCO, gave compound 6 in an isolated yield of 90%. Thus, overall yield for synthesis of compound 6 was improved by more than 40%, compared to E1 elimination.
Because of thermodynamic considerations (tetra substituted olefin and long conjugation) as well as kinetic considerations (high acidity of proton α to carbonyl function), it was expected that compound [A′] would be the sole product either by E1 or E2
elimination. Surprisingly, no trace of compound [A′] was found and compound 6 was obtained as a product. The formation of compound 6 could be rationalized by fast [1,5] sigmatropic re-arrangement after formation of compound [A′] (Scheme VI).
HPLC and NMR analysis of compound 6 shows that it was mixture of isomers, postulated as mixture of cis and trans as shown in Scheme VII. When compound 6 was subjected to HPLC analysis on CHIRALCEL OJ-H column, two sets of peaks i.e. peak 1 and peak 2 were obtained respectively. NMR spectra of both peaks 1 and 2 showed that it was still a mixture of isomers.
Hence, compound in peak 1 was separated on AMYLOZE-2 column and gave two more sets i.e. compound in peak 1A and compound in peak 1B. However, compound in peak 2 could not be separated on the same column. Thus, compound in peak 2 was separated on CHIRALPAK IA column, which gave two more set of compound in peak 2A and compound in peak 2B.
Br
Cl O
OO
ClO
O
HO
+ ClO
OMg/THF
95%
PTSA
Toluene93%
(i) H2 , Pd/C EtOAc
(ii) PTSA, Water88%
Cl O
4 Scheme IV — High yielding process for synthesis of compound 4
Figure 1 — The ORTEP diagram of trans-2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen-1(2H)-one 5
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Compound obtained from peak 1B and peak 2B
gave good single crystals. ORTEP diagram of compound in peak 1B showed that the single crystals (Figure 2) are dimeric and monoclinic [(a = 34.913Å, b=5.7690 Å, c=20.540 Å; α=90°, β=124.88°, γ=90°), Z=4, formula weight-673.68]
and ORTEP diagram compound in peak 2B showed that the single crystals (Figure 3) are dimeric and monoclinic [(a = 34.795Å, b=5.806 Å, c=20.4620 Å; α=90°, β=124.67°, γ=90°), Z=4, formula weight-673.68]. Single crystal X-ray diffraction data for these compounds was complex and dimer
Scheme V — Comparison of various processes for dehydration of compound 5
Scheme VI — Sigma-tropic re-arrangement of compound 6
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Scheme VII — Isomer of compound 6
Figure 2 — The ORTEP diagram of compound 6 in peak 1B
Figure 3 — The ORTEP diagram of compound 6 in peak 2B
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in nature; thus, it was not possible to conclude anything about stereoisomers.
Palladium and nickel catalyzed dehydrogenation of cyclic ketones to phenolic compounds has been reported16. Hence, hydrogenation was carried out in presence of platinum oxide under mild hydrogen pressure (2-3 kg/cm2) to obtain a mixture of cis and trans-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydro-naphthalen-1(2H)-one 7 (50:50) in quantitative yield.
Isomers of compound 7 were separated through selective crystallization from cyclohexane. Cis-isomer of compound 7 was highly soluble in cyclohexane whereas trans-isomer 7 was very less soluble.
Single crystal could be obtained from one of the pure isomers and structure was assigned through X-ray single crystal diffraction analysis. It was observed that this isomer was cis-2-(4-(4-chlorophenyl)-cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one having monoclinic crystal structure [(a = 9.1928 Å, b=10.9073 Å, c=17.7399 Å; α=90°, β=97.1320°, γ=90°), space group of P21/c, and Z=4 (Figure 4) and the other isomer obtained was trans isomer as evident from molecular weight and other spectroscopic data.
Compound 7 was converted to 2-bromo-2-(4- (4-chlorophenyl)cyclohexyl)-3, 4-dihydronaphthalen-1(2H)-one 8 with bromine and acetic acid. In this case also, mixture of isomers was obtained and was
Figure 4 — The ORTEP diagram of cis-2-(4-(4-chlorophenyl)-cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one 7
separated through selective crystallization from methanol. One isomer of compound 8 was highly soluble in methanol whereas the other isomer of 8 was very less soluble.
Aromatization of β-bromo substituted 1-tetralone derivatives to corresponding 1-naphthol derivatives has been reported in presence of organic as well as inorganic bases17,18. However, in case of mixture of compound 8, organic bases such as triethylamine, piperidine, morpholine and cyclohexylamine failed to give desired product and only with inorganic bases like alkoxides such as potassium tert-butoxide, sodium methoxide and sodium ethoxide, 1-naphthol derivative i.e. cis and trans-2-(4-(4-chlorophenyl)-cyclohexyl)naphthalen-1-ol 9 (50:50) could be obtained in good yield. In this case also, separation of cis and trans isomers of compound 9 was achieved through selective crystallization from cyclohexane; the cis-isomer of compound 9 was highly soluble in cyclohexane and trans-isomer 9 was very less soluble.
Single crystal diffraction analysis for one isomer shows that this isomer was trans-2-(4-(4-chloro-phenyl)cyclohexyl)naphthalen-1-ol having monocle-nic crystal structure [(a = 13.3526 Å, b=7.9000 Å, c=16.5550 Å; α=90°, β=96.95°, γ=90°), space group of P21/c and Z value 4] (Figure 5). Other isomer was cis isomer as evident from molecular weight and other spectroscopic data.
Various reagent combinations for oxidation of naphthol to quinone have been reported such as a) hydrogen peroxide in acetic acid19, b) sodium bromate and acetic acid20, c) RuCl3/ acetic acid and hydrogen peroxide21, but none of the above reported methods gave more than 50% yield and are mostly associated with some dark red colored impurity, probably quinone coupling product. Only in presence of sodium nitrite and sulfuric acid, compound 9 was converted to compound 10 in 70% isolated yield22,23.
Compound 10 was converted to 1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7
Figure 5 — The ORTEP diagram of trans-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol 9
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(1aH,7aH)-dione 11 in presence of hydrogen peroxide and a base such as sodium carbonate, which was further hydrolyzed in presence of concentrated sulfuric acid24 to obtain Atovaquone, which was further recrystallized from ethyl acetate to obtain Atovaquone in 99% purity as per HPLC analytical data.
When cis and trans mixture (50:50) of 1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7 (1aH,7aH)-dione 11 was treated with dilute sulfuric acid, it gave mixture of cis/trans –atovaquone (50:50).
Similarly, pure cis-2-(4-(4-chlorophenyl)cyclo-hexyl)naphthalen-1-ol 9 was converted to corres-ponding epoxide compound 11, which upon treatment with dilute sulfuric acid gave only cis-Atovaquone, which was confirmed by HPLC analysis with authentic cis-isomer.
Isomerization of cis-2-(4-(4-chlorophenyl)-3-hydroxy-1,4-naphthoquione to trans-2-(4-(4-chloro-phenyl)-3-hydroxy-1,4-naphthoquione has been reported only in the presence of concentrated sulfuric acid and methansulphonic acid9,25. When the same was attempted with titanium tetrachloride, it gave a mixture of cis and trans atovaquone. Moreover, the rate of reaction was considerably slower.
Analytical Methods The purity was determined by HPLC using a
Shimadzu LC 2010 system equipped with a column (Purosphere star RP-18e (4.6 × 150 mm), 5 µm), column oven temperature 25°C and UV-visible detector (UV at 340 nm). 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 using Bruker instruments, with CDCl3 as solvent unless otherwise stated. Chemical shifts (δ) are given in ppm relative to tetramethylsilane (δ = 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 °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 θ range for data collection is 1.56 to 28.40°.
Synthesis of (1,2-dihydronaphthalen-4-yloxy)tri-
methylsilane 3 To a reactor equipped with reflux condenser,
nitrogen bubbler, dropping funnel and thermo-pocket,
were charged α-tetralone (270.0 g, 1.85mol) and triethylamine (514.0 g, 5.08 mol) at RT under nitrogen atmosphere. After stirring at RT for 15 min, trimethylsilyl 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 1 h at RT. 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 of not more than 40°C. The resultant reaction mass was allowed to stir at RT for 2 h. 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 (2×1 L). After separation, 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%.
Activated magnesium turnings (92.2 g, 3.84 mol) were charged into 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 the 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 the 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 the resulting reaction mixture was heated at 50°C for 1 h. Thereafter, the reaction mixture was quenched with aqueous solution of ammonium chloride and the solvent was evaporated to obtain crude 8-(4-chlorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol, which was suspended in dilute hydrochloric acid (6 L) and stirred for 30 min and
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after filtration, a white solid was obtained as product (764.0 g, 93% yield). Generally, yield of the product ranges from 88 to 95%.
8-(4-Chlorophenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (750.0 g, 2.8 mol) was charged in a reactor equipped with Dean-Stark condenser and thermo-pocket. Toluene (15 L) was added to the suspended material and p-toluene sulfonic acid (15.95 g, 3 mol%) and ethylene glycol (250 mL, 2.8 mol) were added to the reaction mass which was then heated to 110°C and stirred for 6 h. Reaction was monitored by TLC and after complete consumption of starting material, reaction mass was cooled to RT. 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. The resulting suspension was filtered to obtain yellow solid (669.0 g, 93% yield). Generally, yield of the product ranges from 90 to 97%.
4-(4-Chlorophenyl)-cyclohex-3-enone monoethyl-ene 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 which was then flushed twice with nitrogen and once with hydrogen. Subsequently, a hydrogen pressure of 5-7 kg/cm2 was maintained for 7 h at RT. Reaction was monitored on TLC. After completion of reaction, palladium on carbon was filtered through a Celite bed. The mother liquor was concentrated under reduced pressure to
give crude product as light yellow semi solid of 4-(4-chlorophenyl)-cyclohexanone monoethylene ketal.
Crude 4-(4-chlorophenyl)-cyclohexanone mono-ethylene ketal 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 3 h after which it was cooled to RT. Acetone was evaporated under reduced pressure and the 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%.
To a reactor equipped with overhead 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 dichloro-methane (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, the 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 (1,2-dihydronaphthalen-4-yloxy)trimethyl-silane (111.3 g, 0.515 mol) in dichloromethane (1 L) was added and allowed to stir at ‒55°C for 1 h. Thereafter, the reaction mixture was again warmed to 0°C and then quenched with ice water (2500 mL) under vigorous stirring and diluted with dichloro-methane (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 the resultant slurry was refluxed for 1 h 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%.
2-(4-(4-Chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihydronaphthalen-1(2H)-one (122.0 g, 0.0.345 mol) was charged into a reactor equipped with overhead stirrer, reflux condenser and thermo-pocket. Toluene (2 L) was added to suspend the material and p-toluenesulfonic acid (3.05 g, 2.5 mol%) was added to the reaction mass which was then heated to 60°C and stirred for 2 h. Progress of reaction was monitored on TLC. After completion of reaction, the reaction mass was cooled to RT and the solvent was evaporated under reduced pressure to obtain the residue. To the residue, was added ethyl acetate (1500 mL) and the organic layer washed with sat. NaHCO3 soln. and brine followed by evaporation of solvent to give crude product which was further re-crystallized from methanol to obtain white solid compound (55.2 g, 50%). Generally, yield of the product ranges from 45 to 56%.
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, was charged 2-(4-(4-chlorophenyl)-1-hydroxycyclohexyl)-3,4-dihy-dronaphthalen-1- (2H)-one (15.0 g, 0.04 mol) and dissolved in dichloromethane (150 mL) at RT. To the above solution were added pyridine (8.4 g, 0.11 mol) and DMAP (0.3 g, 2.0 mmol). The reaction mass was cooled to 0°C and trifluoroacetic anhydride (22.2 g, 0.11 mol) in dichloromethane (50 mL) was added into it in a drop-wise manner over a period of 30 min. The resultant mixture was stirred at RT for 3 h after which DM water (300 mL) was added to it, followed by organic layer separation. The organic layer was washed with 1M HCl soln. (10 mL) and after separation and drying with anhydrous Na2SO4, the solvent was evaporated to afford the desired product as an off-white solid (18.3 g, 96 % yield).
Synthesis of 2-(4-(4-chlorophenyl) cyclohex-1-enyl)-
3,4-dihydronaphthalen-1(2H)-one 6 in presence of
DABCO
To a reactor equipped with reflux condenser, dropping funnel and thermo-pocket, were charged 4-(4-chlorophenyl)-1-(1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate (5.0 g, 0.01 mol) and DABCO (3.1 g, 0.027 mol) and dissolved in toluene (50 mL) at RT. The reaction mass was refluxed for 5 h after which it was cooled and toluene removed under reduced pressure. To the resultant residue was added 1 M HCl (20 mL) and the mass extracted with dichloromethane (2×50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to obtain the desired product which was recrystallized from methanol to give product as white solid (3.3 g, 90% yield).
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Synthesis of cis/trans-2-(4-(4-chlorophenyl)cyclo-
hexyl)-3,4-dihydronaphthalen-1(2H)-one 7 and
method for separation of cis and trans isomers 2-(4-(4-Chlorophenyl)cyclohex-1-enyl)-3,4-dihydro-
naphthalen-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/cm2 was maintained for 4-5 h at RT after which the platinum black was filtered off through a Celite bed. The mother liquor was concentrated 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 85to 95%.
cis/trans-2-(4-(4-Chlorophenyl)cyclohexyl)-3,4-di-hydronaphthalen-1(2H)-one (10 g) was suspended in cyclohexane (100 mL) and stirred for 1 h. cis-2-(4-(4-Chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one was soluble in cyclohexane and trans-2-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphtha-len-1(2H)-one remained insoluble (4.8 g). Single crystal was generated from cyclohexane layer which contain cis-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-di-hydronaphthalen-1(2H)-one.
Synthesis of cis/trans-2-bromo-2-(4-(4-chlorophenyl)-
cyclohexyl)-3,4-dihydronaphthalen-1(2H)-one 8 and
method for separation of cis and trans isomers
cis/trans-2-(4-(4-Chlorophenyl)cyclohexyl)-3,4-di-hydronaphthalen-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 1 h and gradually the temperature was allowed to increase to 15-20°C when the reaction mass started decolourizing. Thereafter, reaction temperature was allowed to increase upto 25°C. After completion of reaction, dichloromethane (300 mL) was added to
dissolve solids, if any, precipitated during the reaction. Organic layer was washed with water (2 × 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)cyclohex-yl)-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-di-hydronaphthalen-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-dihydro-naphthalen-1(2H)-one was obtained after evaporation of solvent under reduced pressure as sticky semi-solid material (21 g).
Synthesis of cis/trans-2-(4-(4-chlorophenyl)cyclo-
hexyl)naphthalen-1-ol 9 and method for separation
of cis and trans isomers 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 RT. 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 concentrated 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)cyclo-hexyl)naphthalen-1-ol (25 g) was suspended in cyclo-hexane and stirred for 1 h. cis-2-(4-(4-Chlorophenyl)-cyclohexyl)naphthalen-1-ol was soluble in cyclo-hexane and trans-2-(4-(4-chlorophenyl)cyclohexyl)-naphthalen-1-ol remained insoluble. Pure trans-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol was obtained through filtration as light orange solid (7.5 g) and major cis-2-(4-(4-chlorophenyl)cyclohexyl)-naphthalen-1-ol was obtained after evaporation of solvent under reduced pressure as sticky, semi-solid material (11 g). Obtained major cis-2-(4-(4-chloro-phenyl)cyclohexyl)naphthalen-1-ol was further puri-fied by column chromatography to obtain pure cis-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-1-ol as sticky semi-solid brown colored material (7 g).
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 the mass 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 (3×100 mL), dried over anhydrous Na2SO4 and concetrated to give crude product which was purified by column chromatography to give pure product as yellow solid (0.4 g, 32% yield).
2-(4-(4-Chlorophenyl)cyclohexyl)naphthalen-1-ol (5.1 g, 15.1 mmol) was added to acetic acid (70 mL)
ROY et al.: SYNTHESIS OF ATOVAQUONE
1311
and the resulting reaction mass was heated to 60°C. Sodium bromate (1.5 g, 10 mmol) was added to the above reaction mixture and the mass 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 (2×300 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated to give crude product which was purified by column chromatography (stationary phase: silica gel (100-200 mesh) and mobile phase: 2% ethyl acetate in cyclohexane) to give pure product as yellow solid (3.5 g, 66% yield).
Synthesis of cis/trans-4-(4-chlorophenyl)cyclo-
hexyl)naphthalene-1,4-dione 10 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 resultant reaction mixture was increased to 80°C and the mass stirred for another 2 h. After cooling to RT, water (50 mL) was added to the reaction mass and extracted with ethyl acetate (3 × 500 mL), dried over anhydrous Na2SO4 and solvent was evaporated to obtain 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%).
Synthesis of cis/trans-1a-(4-(4-chlorophenyl)-
cyclohexyl)naphtho[2,3-b]oxirene-2,7(1aH,7aH)-
dione 11
4-(4-Chlorophenyl)cyclohexyl)naphthalene-1,4-di-one (13.5 g, 38.5 mmol) was charged into a reactor along with 1,4-dioxane (135 mL) at 25°C. 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 the mass extracted with ethyl acetate (3×300 mL). Solvent was removed under reduced pressure to give the product as off-white solid (13.7 g, 96% yield).
To 1a-(4-(4-chlorophenyl)cyclohexyl)naphtho[2,3-b]oxirene-2,7(1aH,7aH)-dione (13.5g, 1.6 mmol) taken in a reactor was added conc. 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 recrystallized from acetonitrile to obtain pure compound as a yellow solid (10 g, 74% yield).
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, 2.9 mmol) at 5°C and temperature of the resultant reaction mixture was increased to 80°C and stirred for 2 h. After cooling to 25°C, water (50 mL) was added to the reaction mass and extracted with DCM (3 × 100 mL), dried over anhydrous Na2SO4 and the solvent was evaporated to give crude product which was purified by column chromatography (stationary phase: silica gel (100-200 mesh) and mobile phase: 2% ethyl acetate in cyclohexane) to give pure product as yellow solid (0.34 g).
1,4-dione (1.85 g,) was charged into a reactor along with 1,4-dioxane (20 mL) at 25°C. 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).
Synthesis of cis-Atovaquone 2
cis-1a-(4-(4-Chlorophenyl)cyclohexyl)naphtha-[2,3-b]oxirene-2,7(1aH,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 25°C. Water (100 mL) was added to the reaction mass and extracted with DCM (100 mL). HPLC analysis24 confirmed cis-Atovaquone, having identical retention time with authentic sample. Retention time26 for cis-Atovaquone: 19.33 min.
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 25°C. 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 Retention26 time for cis isomer: 19.33 min and retention time for trans isomer: 22.66 min.
References 1 Latter V S & Gutteridge W E, US Patent 4981874, 1991. 2 Latter V S, Gutteridge W E & Hudson A T, US Patent
5206268, April 04, 1993. 3 Hudson A T, US Patent 5856362, January 05, 1999. 4 Hudson A T, US Patent 5567738, October 22, 1996. 5 Williams D R & Clark M P, Tetrahedron Lett, 39, 1998, 7629. 6 Hudson A T & Randall A W, US Patent 5053432, October 01,
1991. 7 Saralaya S S, Somashekar S H, Shashiprabha, Kanakamajalu
S, Ranganathan K R, Ananthalakshmi V & Jeyaraman G, PCT
Int Appl WO 2009/122432A2, October 08, 2009. 8 Kumar A, Dike S Y, Mathur P, Nellithanath B T, Sharma B,
Kore S S & Buchude V S, PCT Int Appl WO 2009/007791A2, January 01, 2009.
9 Zhu F, Qiao H & Bekhazi M, PCT Int Appl WO 2010/ 0001379 A1, January 07, 2010.
10 Roy B N, Singh G P, Lathi P S, Agrawal M K, Mitra R & Trivedi A, PCT Int Appl WO 2012/153162, November 15, 2012.
11 Roy B N, Singh G P, Lathi P S, Agrawal M K, Mitra R & Trivedi A, PCT Int Appl WO 2013/014486, January 31, 2013.
12 Dwyer A N, Gordon A, & Urquhart M, PCT Int Appl
WO 2012/080243 A2, June 21, 2012. 13 Britton H, Catterick D, Dwyer A N, Gordon A H, Leach S G,
McCormick C, Mountain C E, Simpson A, Stevens D R, Urquhart M W J, Wade C E, Warren J, Wooster N F & Zilliox A, Org Process Res Dev, 16, 2012, 1607.
14 Mukaiyama T, Banno K & Narasaka. K, J Am Chem Soc, 96, 1974, 7503.
15 Mitra R B, Muljiani Z & Reddy G B, Synth Commun, 16, 1986, 1099 – 1108.
16 Springer J M, Hinman C W, Flanagan P W K, Hamming M C & Linder D E, J Org Chem 36, 1971, 686.
17 Bekaert A, Provot O, Rasolojaona O, Alami M & Brion J, Tetrahedron Lett, 46, 2005, 4187.
18 Hassner A, Cromwell N H & Davis S J, J Am Chem Soc, 79, 1957, 230.
19 Arnold R T & Larson R, J Org Chem, 5, 1940, 250. 20 Rastogi R P & Srivastava P K, Indian J Chem, 24A, 1985,
999. 21 Ito S, Aihara K & Matsumoto M, Tetrahedron Lett, 24, 1983,
5249. 22 Henderson G G & Boyd R, J Chem Soc, 97, 1910, 166. 23 Patel A, Liebner F, Mereiter K, Nestscher T & Rosenau T,
Tetrahedron, 63, 2007, 4067. 24 Nakanishi K & Fieser L F, J Am Chem Soc, 74, 1952, 3910. 25 Antonio N, Mara S, Annibale S & Stefano M, PCT Int Appl
WO 2008/139290 A1, November 10, 2008. 26 Atovaquone USP monograph, USP 35/NF 30, 2012, Vol 2,
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