WO2013014486A1 - Synthèse perfectionnée de 2-(4-(4-chlorophényl)cyclohex-1-ényl)-3,4-dihydronaphtalèn-1(2h)-one ; intermédiaire pour atovaquone - Google Patents

Synthèse perfectionnée de 2-(4-(4-chlorophényl)cyclohex-1-ényl)-3,4-dihydronaphtalèn-1(2h)-one ; intermédiaire pour atovaquone Download PDF

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WO2013014486A1
WO2013014486A1 PCT/IB2011/002134 IB2011002134W WO2013014486A1 WO 2013014486 A1 WO2013014486 A1 WO 2013014486A1 IB 2011002134 W IB2011002134 W IB 2011002134W WO 2013014486 A1 WO2013014486 A1 WO 2013014486A1
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chlorophenyl
compound
cyclohexyl
dihydronaphthalen
reaction
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Bhairab Nath Roy
Girij Pal Singh
Piyush Suresh Lathi
Manoj Kunjabihari Agrawal
Rangan Mitra
Aunrag 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
    • 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
    • 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
    • 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
    • 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
    • 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
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/62—Halogen-containing esters
    • C07C69/63—Halogen-containing esters of saturated acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
    • C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/32—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by aldehydo- or ketonic radicals
    • 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

  • DIHYDRONAPHTHALEN-H2HVONE AN INTERMEDIATE FOR ATOVAQUONE
  • the invention relates to a novel process for preparation of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one, key intermediate for synthesis of Atovaquone [I].
  • Atovaquone 2-[7>a «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).
  • This invention describes a) Genesis of poor yield of compound (V) from compound (VI) and, b) An alternative chemistry which is efficient, easily operable, high yielding process for synthesis of compound (V) from compound (VI).
  • an object of this invention is to provide a novel cost effective and efficient process for the synthesis of an intermediate of Atovaquone i.e. 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one (V).
  • Another object of the present invention is synthesis of the novel compound 4-(4- chlorophenyl)- 1 -( 1 -oxo- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate (XIa) through esterifcation of 2-(4-(4-chlorophenyl)-l-hydroxycyclohexyl)-3,4- dihydronaphthalen-l(2H)-one (IV) with trifluro acetic anhydride.
  • Yet another object of the present invention is synthesis of the compound 2-(4-(4- chlorophenyl)cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one (V) from 4-(4- chlorophenyl)- 1 -( 1 -oxo- 1 ,2,3 ,4-tetrahydronaphthalen-2-yl)cyclohexyl 2,2,2-trifluoroacetate (XIa) through E2 elimination (elimination, bimolecular) of trifluro acetyl functionality.
  • An aspect of the present invention is to provide compound 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen-l(2H)-one (V), a key intermediate for synthesis of Atovaquone through a novel, cost effective, green, and eco-friendly process.
  • Fig 1 Scheme showing rate of protonation of compound (IV) for formation of compound (A) & (B) via path [A] and [B]
  • Fig 3 Scheme showing that in path B; oxygen of carbonyl functionality was protonated, which through “retro-aldoV reaction gives a-tetralone (XII) & 4-(4- chlorophenyl)cyclohexanone (III) DETAILED DESCRIPTION OF THE INVENTION
  • selection of a base for carrying out esterification reaction was limited to only organic amine, which only polarizes hydroxyl function such as pyridine, N,N- di/sopropylethylamine, etc.
  • the synthesis of compound (V) from compound (IV) comprised of the following two steps 1) synthesis of compound (XIa) from compound (IV) in 90% isolated yield (example 1) and 2) synthesis of compound (V) from compound (XIa) in 90% isolated yield (example 7).
  • overall isolated yield for compound (V) from compound (IV) comes to 81 %, which is 31% more than that obtained by the process reported in our co-pending PCT application PCT/IB2011/001507(Example 10; yield 50%).
  • reaction mass was cooled to 0 °C and trifluoroacetic anhydride (22.2 g, 0.1 1 mol) in dichloromethane (50 mL) was added into it in a dropwise manner over a period of 30 min.
  • the resultant mixture was stirred at room temperature 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 HC1 soln. (10 mL) and after separation and drying with anh. Na 2 S0 4 solvent was evaporated to afford the desired product as an off-white solid (18.3 g, 96 % yield).
  • FTIR (neat): 3027, 2946, 2934, 2874, 1768, 1688, 1600, 1491, 1443, 1372, 1218, 1165, 1 154, 1090 cm '1 .
  • FTIR (neat): 3022, 3060, 2958, 2935, 2888, 2832, 1638, 1600, 1485, 1359, 1337, 1251 , 1 188, 1140, 1093, 919, 860, 845, 737 cm 4 .
  • Example 8 Synthesis of 2-(4-(4-chlorophenyl) cyclohex-l-enyl)-3,4-dihydronaphthalen- l(2H)-one (V) in presence of DABCO
  • Example 16 Synthesis of cis/trans-2-(4-(4-ch!orophenyl)cyclohexyl)naphthalen-l-ol (VIII) and method for separation of cis and trans isomers
  • 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 17 Synthesis of 4-(4-chlorophenyl)cyclohexyl)naphthaIene-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 .
  • FTIR (KBr): 3375, 2958, 2924, 2853, 1659, 1646, 1625, 1594, 1490, 1369, 1344, 1277, 1248, 1216, 1089, 998, 822, 727, 656, 530 cm -1 .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Inorganic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention porte sur un procédé de préparation de 2-(4-(4-chlorophényl)cyclohex-1-ényl)-3,4-dihydronaphtalèn-1(2H)-one (V), intermédiaire clé pour la synthèse d'Atovaquone [I]. Le procédé de préparation du composé (V) comprend les étapes de : i) réaction de 2-(4-(4-chlorophényl)-1-hydroxycyclohexyl)-3,4-dihydronaphtalèn-1(2H)-one (IV) avec de l'anhydride trifloro acétique en présence d'une base dans un solvant organique pour produire un composé de la formule (XIa) ; ii) élimination de la fonctionnalité trifluoroacétyle du composé (XIa) dans un solvant organique et en présence d'une base organique pour donner le composé de la formule (V). L'invention concerne également un procédé de préparation du composé (XIa) comprenant les étapes de : i) réaction de 2-(4-(4-chlorophényl)-1-hydroxy cyclohexyl)-3,4-dihydronaphtalèn-1(2H)-one (IV) avec de l'anhydride trifluro acétique en présence d'une base organique dans un solvant organique. L'invention porte également sur un autre procédé de préparation du composé (V) à partir du composé (XIa) comprenant une réaction d'élimination du composé (XIa) à fonctionnalité trifluoroacétyle dans un solvant organique et en présence d'une base organique.
PCT/IB2011/002134 2011-07-28 2011-09-14 Synthèse perfectionnée de 2-(4-(4-chlorophényl)cyclohex-1-ényl)-3,4-dihydronaphtalèn-1(2h)-one ; intermédiaire pour atovaquone Ceased WO2013014486A1 (fr)

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IN1010/KOL/2011 2011-07-28
IN1010KO2011 2011-07-28

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4981874A (en) 1988-08-16 1991-01-01 Latter Victoria S Medicaments
US5206268A (en) 1988-08-16 1993-04-27 Burroughs Wellcome Co. Medicaments
US5567738A (en) 1992-08-07 1996-10-22 Glaxo Wellcome Inc. Use of 2-(4-(4-chlorophenyl)cyclohexyl)-3-hydroxy-1,4-Naphthoquinone for the treatment of cancer
US5856362A (en) 1994-09-02 1999-01-05 Glaxo Wellcome Inc. Medicaments for the treatment of toxoplasmosis
WO2008122988A1 (fr) * 2007-04-05 2008-10-16 Cadila Healthcare Limited Procédé de préparation de l'atovaquone et conversion de l'isomère cis en isomère trans

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4981874A (en) 1988-08-16 1991-01-01 Latter Victoria S Medicaments
US5206268A (en) 1988-08-16 1993-04-27 Burroughs Wellcome Co. Medicaments
US5567738A (en) 1992-08-07 1996-10-22 Glaxo Wellcome Inc. Use of 2-(4-(4-chlorophenyl)cyclohexyl)-3-hydroxy-1,4-Naphthoquinone for the treatment of cancer
US5856362A (en) 1994-09-02 1999-01-05 Glaxo Wellcome Inc. Medicaments for the treatment of toxoplasmosis
WO2008122988A1 (fr) * 2007-04-05 2008-10-16 Cadila Healthcare Limited Procédé de préparation de l'atovaquone et conversion de l'isomère cis en isomère trans

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"March's Advanced Organic Chemistry, 6th edition,", WILEY INTERSCIENCE, pages: 1103 - 1105
"March's Advanced Organic Chemistry, 6th edition,", WILEY INTERSCIENCE, pages: 1477 - 1501
TETRAHEDRON LETT, vol. 39, 1998, pages 7629
WILLIAMS D R ET AL: "Synthesis of Atovaquone", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 39, no. 42, 15 October 1998 (1998-10-15), pages 7629 - 7632, XP004134267, ISSN: 0040-4039, DOI: 10.1016/S0040-4039(98)01691-8 *

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