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WO2012153162A1 - Nouveau procédé de préparation d'atovaquone - Google Patents

Nouveau procédé de préparation d'atovaquone Download PDF

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WO2012153162A1
WO2012153162A1 PCT/IB2011/001507 IB2011001507W WO2012153162A1 WO 2012153162 A1 WO2012153162 A1 WO 2012153162A1 IB 2011001507 W IB2011001507 W IB 2011001507W WO 2012153162 A1 WO2012153162 A1 WO 2012153162A1
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chlorophenyl
cyclohexyl
dihydronaphthalen
trans
compound
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Bhairab Nath Roy
Girij Pal Singh
Piyush Suresh Lathi
Manoj Kunjabihari Agrawal
Rangan Mitra
Anurag TRIVEDI
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Lupin Ltd
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Lupin Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C46/00—Preparation of quinones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/06—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation
    • C07C37/07—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by conversion of non-aromatic six-membered rings or of such rings formed in situ into aromatic six-membered rings, e.g. by dehydrogenation with simultaneous reduction of C=O group in that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/24—Halogenated derivatives
    • C07C39/42—Halogenated derivatives containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/513—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an etherified hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C07C45/66—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups by dehydration
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C46/00—Preparation of quinones
    • C07C46/02—Preparation of quinones by oxidation giving rise to quinoid structures
    • C07C46/06—Preparation of quinones by oxidation giving rise to quinoid structures of at least one hydroxy group on a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
    • C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C50/00—Quinones
    • C07C50/26—Quinones containing groups having oxygen atoms singly bound to carbon atoms
    • C07C50/32—Quinones containing groups having oxygen atoms singly bound to carbon atoms the quinoid structure being part of a condensed ring system having two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the invention relates to a novel process for preparation of 2-[trcms-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone i.e. Atovaquone [I].
  • This invention also provides a novel process for preparation of 2-[cw-4-(4'-chlorophenyl)cyclohexyl]-3- hydroxy-l ,4-naphthoquinone and process for isomerization of 2-[c/s-4-(4'- chlorophenyl)cyclohexyl] -3 -hydroxy- 1 ,4-naphthoquinone to 2-[tr ns-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone in presence of a Lewis acid.
  • Atovaquone 2-[ r «5-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l ,4-naphthoquinone [CAS No. 95233-18-4], which is also called Atovaquone [I], has antipneumocystic activity and is used in the treatment of Pneumocystis carinii pneumonia, 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 bci complex of the parasite, which is linked to pyrimidine biosynthesis (Tetrahedron Lett, 1998, 39 7629).
  • 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]-l,4- naphthoquinone, which was further converted to 2-[4-(4-chloro-phenyl)cyclohexyl]-2,3- dichloro-2,3-dihydro-l,4-naphthoquinone by using acetic acid and chlorine followed by conversion to 2-chloro-3-[4-(4-chloro-phenyl)-cyclohexyl]-[l,4]naphthoquinone, which was further converted to Atovaquone
  • WO 2010/001378 Al disclosed a method for conversion of c 5-2-(4-(4-chlorophenyl)- 3 -hydroxy- 1 ,4-naphthoquione to trara-2-(4-(4-chlorophenyl)-3 -hydroxy- 1 ,4-naphthoquione in the presence of strong acids such as sulphuric acid and methansulphonic acid.
  • 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 'c/V isomer of Atovaquone and process for converting 'c/V isomer of Atovaquone to pharmaceutically active form i.e. 'trans ' ' isomer in presence of a Lewis acid.
  • 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)-l -hydroxy cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [IV] through Mukaiyama aldol condensation of (l ,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-l -enyl)-3,4-dihydronaphthalen-l (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-
  • Yet another object of the present invention is synthesis of the novel compound 2- bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l (2H)-one [VII] from 2-(4- (4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(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-l-ol [VIII] from 2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3 ,4-dihydronaphthalen- l(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-l,4-dione [IX] from 2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-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-l-ol from 'trans ' isomer of 2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol through an innovative crystallization process.
  • Yet another object of the present invention is synthesis of cw-2-(4-(4- chlorophenyl)cyclohexyl)naphthalene-l,4-dione [XII] from cis-2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol [XI] through oxidation.
  • Yet another object of the present invention is synthesis of cis isomer of Atovaquone from c/s-2-(4-(4-chlorophenyl)cyclohexyl)naphthalene-l ,4-dione [XII].
  • Yet another object of the present invention is isomerization of "cw" 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.
  • a Lewis /Bronsted acid such as titanium tetrachloride, Sulfuric acid, triflic acid, methansulphonic acid.
  • One aspect of the present invention is to provide 2-[trans-4-(4'- chlorophenyl)cyclohexyl]-3-hydroxy-l,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-[/r «5-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,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)-l-hydroxycyclohexyl)-3,4-dihydronaphthalen-l(2H)- one [IV]
  • step (d) in absence of step (d) optional selective crystallization of 2-bromo-2-(4-(4- chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [VII] to separate the 'tis ' and 'trans ' isomers of 2-bromo-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one [VII]
  • step (f) in absence of step (f) optionally crystallizing 2-(4-(4- chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII] to separate the 'tis ' and 'trans' isomers of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol [VIII]
  • 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-l,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
  • Another aspect of the present invention is to provide process for synthesis of 2-[cis-4- (4'-chlorophenyl)cyclohexyl]-3-hydroxy-l ,4-naphthoquinone comprising the steps of- a) converting C s-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-ol (XI), to cis-4-(4- chlorophenyl)cyclohexyl)naphthalene-l,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
  • 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- [tra «5-4-(4'-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone in presence of Lewis acid
  • 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 'tis ' isomer of Atovaquone [XIV] from cis-2-(4- (4-chlorophenyl)cyclohexyl)naphthalen- 1 -ol [XI]
  • Figure III Process for isomerization of 'tis ' isomer of Atovaquone [XIV] to Atovaquone [I] i.e. desired i trans ' isomer in presence of Lewis acid.
  • Figure V The ORTEP diagram of. tra «s-2-(4-(4-chlorophenyl)-l- hydroxycyclohexyl)-3 ,4-dihydronaphthalen- 1 (2H)-one [IV]
  • Figure VI The ORTEP diagram of cw-2-(4-(4-chlorophenyl)cyclohexyl)-3,4- dihydronaphthalen-l(2H)-one
  • Figure VII The ORTEP diagram of tra «5-2-(4-(4-chlorophenyl)cyclohexyl)naphthalen- l-ol
  • the present invention relates to process for preparation of Atovaquone [I] as described in the scheme of reactions in Figure I.
  • the present invention also relates to separation of 'tis ' and 'trans ' isomer of intermediates VI, VII and VIII through selective crystallization in an appropriate solvent.
  • the pure 'tis ' and 'trans ' isomers of intermediates VI, VII and VIII are respectively converted into pure 'tis ' and 'trans ' isomer of intermediate [X] by means of the chemistry described in scheme A.
  • Cis- Atovaquone or mixture of c/Vtra/is-Atovaquone was converted to trans- Atovaquone in presence of Lewis acid such as titanium tetrachloride, in organic solvent such as dichloromethane.
  • Lewis acid such as titanium tetrachloride
  • 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)
  • 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 TiCl 4 (Mukaiyama, T. et al. Chem.
  • 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.
  • Mukaiyama aldol condensation product i.e. tra «5-2-(4-(4-chlorophenyl)-l- hydroxycyclohexyl)-3,4-dihydronaphthalen-l(2H)-one [IV] was dehydrated in presence of acids such as sulfuric acid, /?-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 1 10 °C, preferably 60 °C, which gave the diastereomeric mixture of 2-(4-(4-chlorophenyl)cyclohex-l-enyl)-3,4-dihydronaphthalen- l(2H)-one [V].
  • acids such as sulfuric acid, /?-toluene sulf
  • Cis and trans isomers of 2-(4-(4-chlorophenyl)cyclohexyl)-3,4-dihydronaphthalen- l(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.
  • 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.
  • Cis and trans isomers of 2-(4-(4-chlorophenyl)cyclohexyl)naphthalen-l-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.
  • compound (VIII) was also converted into compound (IX) in presence of RuCl 3 / 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-y-tocopherol intermediate as shown in scheme 6.
  • 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 «-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, 1 188, 1 140, 1093, 919, 860, 845, 737 cm “1 .
  • reaction mass was again cooled to - 55°C and at this temperature, a solution of (l,2-dihydronaphthalen-4-yloxy)trimethylsilane (11 1.3 g, 0.515 mol) in dichloromethane (1 L) was added and allowed to stir at -55 °C for lh. 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.
  • 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 %.
  • Example 7 Synthesis of c/s /ra/ii-4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (IX) in presence of acetic acid/ hydrogen peroxide
  • Example 9 Synthesis of 4-(4-chlorophenyl)cyclohexyl)naphthalene-l,4-dione (IX) in presence of sodium nitrite/ 50% aqueous sulphuric acid.
  • FTIR (KBr): 3370, 3078, 2944, 2928, 2900, 2859, 1695, 1594, 1490, 1451 , 1306, 1287, 1157, 1089, 944, 886, 801 , 725 cm -1 .
  • Cis isomer of Atovaquone (0.5 g) was dissolved in dichloromethane (20 mL) and T1CI4 (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.
  • Example 13 Conversion of "cw” isomer of Atovaquone to "fra/is” 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.
  • 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.

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  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Cette invention concerne un procédé de préparation de 2-[trans- 4-(4'-chlorophényl)cyclohexyl]-3-hydroxy-1,4-naphtoquinone, c.à.d. d'Atovaquone [I] qui est un procédé économique, écologique et respectueux de l'environnement, sans séparation des diastéréomères ou des isomères géométriques des intermédiaires obtenus au cours des réactions ; la séparation des isomères « cis » et « trans » des intermédiaires VI, VII et VIII par cristallisation sélective dans un solvant approprié ; un procédé de conversion d'une 2-[cis-4-(4'-chlorophényl)cyclohexyl]-3-hydroxy- 1,4-naphtoquinone en 2-[trans-4-(4'-chlorophényl)cyclohexyl]-3-hydroxy- l,4-naphtoquinone en présence d'un acide de Lewis/Bronsted ; et un procédé de préparation d'un composé de 2-(4-(4-chlorophényl)-1-hydroxy-cyclohexyl)- 3,4-dihydronaphtalén-1-(2H)-one [IV] comprenant la condensation d'un (1,2-dihydronaphtalén-4-yloxy)-triméthylsilane [II] avec une 4-(4-chlorophényl)cyclohexanone [III] en présence d'un acide de Lewis dans un solvant organique. Cette invention concerne également un procédé de synthèse très efficace et économique en atomes d'un composé [III], c.à.d. d'une 4-(4-chlorophényl)cyclohexanone ainsi qu'un procédé de synthèse d'une 2-[cis-4-(4'-chlorophényl)-cyclohexyl]-3-hydroxy-l,4-naphtoquinone. Un procédé d'isomérisation de cis-Atovaquone, c.à.d. d'une 2-[cis-4-(4'-chlorophényl)cyclohexyl]-3-hydroxy-l,4-naphtoquinone, en trans-Atovaquone, c.à.d. 2-[trans-4-(4'-chlorophényl)cyclohexyl]- 3-hydroxy-1,4-naphtoquinone en présence d'un acide de Lewis est également décrit.
PCT/IB2011/001507 2011-05-12 2011-06-28 Nouveau procédé de préparation d'atovaquone Ceased WO2012153162A1 (fr)

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CN103570520A (zh) * 2013-08-21 2014-02-12 山东鲁抗舍里乐药业有限公司 一种苯醌类化合物、其制备方法及其应用
CN103570521A (zh) * 2013-08-21 2014-02-12 山东鲁抗舍里乐药业有限公司 一种阿托伐醌的制备方法
CN106397522A (zh) * 2015-07-31 2017-02-15 中国人民解放军军事医学科学院毒物药物研究所 3,7‑二（叔丁基二甲基硅基氧基）‑6‑烯‑5β‑胆烷‑24‑酸甲酯
CN110724155A (zh) * 2019-11-11 2020-01-24 北京华素制药股份有限公司 一种羟考酮羟醛二聚体的制备方法
CN111643670A (zh) * 2020-05-29 2020-09-11 新疆医科大学 能量双调控药物及其制备方法和应用

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103570520A (zh) * 2013-08-21 2014-02-12 山东鲁抗舍里乐药业有限公司 一种苯醌类化合物、其制备方法及其应用
CN103570521A (zh) * 2013-08-21 2014-02-12 山东鲁抗舍里乐药业有限公司 一种阿托伐醌的制备方法
CN106397522A (zh) * 2015-07-31 2017-02-15 中国人民解放军军事医学科学院毒物药物研究所 3,7‑二（叔丁基二甲基硅基氧基）‑6‑烯‑5β‑胆烷‑24‑酸甲酯
CN110724155A (zh) * 2019-11-11 2020-01-24 北京华素制药股份有限公司 一种羟考酮羟醛二聚体的制备方法
CN111643670A (zh) * 2020-05-29 2020-09-11 新疆医科大学 能量双调控药物及其制备方法和应用

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