WO2007129268A2 - Procédé amélioré pour la synthèse de coq10 - Google Patents

Procédé amélioré pour la synthèse de coq10 Download PDF

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Publication number
WO2007129268A2
WO2007129268A2 PCT/IB2007/051675 IB2007051675W WO2007129268A2 WO 2007129268 A2 WO2007129268 A2 WO 2007129268A2 IB 2007051675 W IB2007051675 W IB 2007051675W WO 2007129268 A2 WO2007129268 A2 WO 2007129268A2
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WIPO (PCT)
Prior art keywords
formula
compound
och
coq
reaction
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Ceased
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PCT/IB2007/051675
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English (en)
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WO2007129268A3 (fr
Inventor
Mita Roy
Abhay Atmaram Upare
Hariharan Sivaramakrishnan
Ganesh Baburao Wagh
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Piramal Enterprises Ltd
Original Assignee
Nicholas Piramal India Ltd
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Application filed by Nicholas Piramal India Ltd filed Critical Nicholas Piramal India Ltd
Publication of WO2007129268A2 publication Critical patent/WO2007129268A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/28—Preparation of ethers by reactions not forming ether-oxygen bonds from acetals, e.g. by dealcoholysis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/48—Preparation of compounds having groups
    • 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
    • C07C46/08—Preparation of quinones by oxidation giving rise to quinoid structures of at least one hydroxy group on a six-membered aromatic ring with molecular oxygen

Definitions

  • Coenzyme Qio or CoQio has the chemical name 2- [(all -trans)- 3, 7,l l,15,19,23,27,31,35,39-decamethyl-2, 6, 10, 14, 18, 22, 26, 30, 34, 38 - tetracontadecaenylJ-S ⁇ -dimethoxy -3- methyl -1,4-benzoquinone and has the formula 1.
  • This coenzyme is present in virtually every cell in the human body and is known as the "miracle nutrient”. It plays a vital role in maintaining human health and vigor and is involved in mitochondrial processes such as respiration, maintenance of heart muscle strength, enhancement of the immune system, quenching of free radical in the battle against ageing to name a few ("The miracle nutrient coenzyme” Elsevier/ North - Holland Biomedical Press, New York, 1986; “Coenzyme Q: Biochemistry, Bioenergetics, and clinical Applications of Ubiquinone” Wiley, New York, 1985; “ Coenzyme Q, Molecular Mechanism in Health and Disease” CRC press).
  • CoQ 10 of the formula 1 comprises mainly of two moieties (i) the head group - "benzoquinone nucleus” and (ii) the "polyprenyl side chain” with ten isoprene units.
  • the source of benzoquinone nucleus is 2,3-dimethoxy-5-methyl benzoquinone, CoQ 0, of the formula 2.
  • the source of the polyprenyl side chain is solanesol, a naturally occurring alcohol, containing nine isoprene units and having the formula 3 where X is -OH.
  • One of the process involves condensing solanesyl bromide of nine isoprene units (compound of formula 3 where X is -Br ) with CoQ 1 sulphone compound of formula 4 where R 1 and R 2 represents protecting groups,
  • the next stage of the synthesis of CoQ 10 involves removal of the sulphone to form compound of formula 6, which is deprotected and oxidized subsequently to form CoQ 10 compound of formula 1.
  • the key problem in synthesis by the above mentioned scheme is desulphonation.
  • the sulphone is readily removed by reductive desulphonation by dissolving metal viz. sodium in THF/ ethanol or Li in ethylamine or methylamine (Chem.Soc.Chem Commun.(1982) 153, Bull. Chem. Soc. Jpn. 55 1325(1982) our co-pending Indian patent application No. 706/MUM/2006).
  • Ceric Ammonium nitrate is an expensive reagent and used 1.2 times that of the starting material compound of formula 6 and therefore makes the process cost ineffective.
  • the present inventors have observed that the oxidation is not selective and gives rise to side reactions and generates impurities, and column purification cannot be avoided.
  • CoQi sulphone compound of formula 4 where Ri and R 2 are -CH 3 is not suitable for synthesis of CoQi 0 for industrial production.
  • the protecting group is a major contributing factor in CoQi 0 synthesis.
  • 2-methoxyethoxymethyl is reported to be of industrial use (Synthesis 469 (1981), US 4,270,003 (1981)).
  • Literature does not specify the extent of positional isomer formed in desulphonated product compound of formula 6 (Ri and R 2 as methoxyethoxymethyl and Ri as methoxyethoxymethyl and R 2 as methyl respectively).
  • the present inventors have observed around 35% of positional isomers compound of formula 6 (Ri and R 2 as methoxyethoxymethyl and Ri as methoxyethoxymethyl and R 2 as methyl respectively) were formed.
  • the respective isomers do not get separated in thin layer chromatography or high pressure liquid chromatography.
  • the oxidation is done with isomers of compound of formula 6 (Ri and R 2 as methoxyethoxymethyl and Ri as methoxyethoxymethyl and R 2 as methyl respectively) and there is a substantial yield loss in purification after oxidation.
  • the pharmacopeal passing CoQi 0 can be obtained around 35 % yield only from the condensed compound of formula 5. This makes the process, which has the potential of industrial application as cost ineffective.
  • Literature reports deprotection of compound of formula 6 (Ri and R 2 as methoxyethoxymethyl and Ri as methoxyethoxymethyl and R 2 as methyl respectively) to form CoQ 10 hydroquinone compound of formula 6 (where R 1 and R 2 are hydrogen) and in-situ oxidation of CoQ 1 O hydroquinone to form CoQ 1 O compound of formula 1.
  • the oxidation was carried out in-situ in presence of methanolic potassium hydroxide solution in presence of oxygen.
  • Solanesol is obtained from natural sources namely tobacco and potatoes.
  • Solanesol in tobacco is very less ( ⁇ 2%) and for using it as a starting material for the preparation of CoQ 10 it requires a purity of minimum 95 %, which increases the cost of solanesol.
  • the industrially feasible process would require the consumption coefficient of solanesol to be minimised.
  • the key point in the synthesis of CoQ 10 is the choice of building block for "the benzoquinone nucleus” which features i) functional group for chain elongation and ii) protecting groups.
  • One such "building block” for "the benzoquinone nucleus” utilizes i) CoQ 1 sulphones as nucleophilic functionality and ii) methoxyethoxymethyl and methoxyethoxymethyl and methyl, as protecting groups.
  • the corresponding ⁇ - sulphonyl stabilized carbanions serve as nucleophilic partner in carbon carbon bond formation to obtain the desired carbon skeleton of CoQ 10 sulphone, with sulphone at carbon 4 of the polyprenyl chain.
  • the sulphone has the advantage of easy removal and the drawback of inferior regioselectivity, at the end of reaction.
  • the present invention relates to the improved process of i) desulphonation of CoQ 10 sulphone with sulphone at carbon 4, containing dimethoxyethoxymethyl and monomethoxyethoxymethyl as protecting group and ii) oxidation of CoQlO hydroquinone to CoQ 1 O
  • the main objective of the present invention is to provide an improved process for the desulfonation of CoQlO sulphone of formula 5 to provide compound of formula 6 overcoming the drawbacks of the hitherto known process.
  • Another objective of the present invention is to provide an improved process for the preparation of CoQ 10 of the formula 1, given above overcoming the drawbacks of the hitherto known processes
  • Yet another objective of the present invention is to provide an improved process for the preparation of CoQ 1O of the formula 1 given above which is useful for industrial application.
  • the present invention provides a process for the preparation of a compound of formula 6
  • Desulphonation of the compound of the formula 5 to obtain compound of formula 6 may be carried out by using lithium triethyl borohydride in a solvent selected from tetrahydrofuran, hexane, dioxane, xylol and the like in the presence of a catalyst such as 1,3-bis diphenyl phosphinopropane palladium chloride, at a temperature in the range of -10 0 C to 25°C for a period of 0.5 to 3 hours.
  • a catalyst such as 1,3-bis diphenyl phosphinopropane palladium chloride
  • Deprotection of the compound of the formula 6 to get the compound of the formula 7 may be carried out using 48% hydrogen bromide in an alcohol such as ethanol, isopropyl alcohol, n-butyl alcohol and the like at a temperature in the range of 25 0 C to 100 0 C for a period of 0.5 to 3 hours.
  • an alcohol such as ethanol, isopropyl alcohol, n-butyl alcohol and the like at a temperature in the range of 25 0 C to 100 0 C for a period of 0.5 to 3 hours.
  • the oxidation of the formula 7 may be carried out by known method of using ferric chloride at a molar ratio that is less than 1:1 in isopropanol as solvent in the presence of oxygen.
  • the undesired positional isomer is restricted to not more than 10% in the desulfonation reaction unlike the prior art where about 35% of the undesired positional isomer is obtained.
  • the present invention provides for decreasing the molar quantity of ferric chloride, which increases the purity of the oxidized product and thereby increase the yield of CoQio.
  • Lithium triethyl borohydride IM solution in THF (12.5 ml) was added to the mixture over a period of 30 minutes. The reaction was continued for 1 hour at 0 - 5 ° C. The reaction was quenched in saturated ammonium chloride solution and THF layer separated.
  • Lithium triethyl borohydride IM solution (142 ml) in THF was added to the mixture over a period of 30 minutes. The reaction was continued for 1 hour at 0 - 5 ° C. The reaction was quenched in saturated ammonium chloride solution and THF layer separated. The THF layer was distilled to obtain the title compound (36 g) in 92 % yield (purity 90%).
  • Lithium triethyl borohydride IM solution (142 ml) in THF was added to the mixture over a period of 30 minutes. The reaction was continued for 1 hour at 0 - 5 ° C. The reaction was quenched in saturated ammonium chloride solution and THF layer separated. The THF layer was distilled to obtain the title compound (36 g) in 92 % yield (purity 90%).
  • Lithium triethyl borohydride IM solution (109 ml) in THF was added to the mixture over a period of 30 minutes. The reaction was continued for 1 hour at 0 - 5 ° C. The reaction was quenched in saturated ammonium chloride solution and THF layer separated. The THF layer was distilled to obtain the title compound (36 g) in 92 % yield (purity 90%).

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

Abstract

L'invention concerne un procédé amélioré pour la préparation de la coenzyme Q. La coenzyme Q10 ou CoQ10 porte le nom chimique suivant : 2- [(all -trans)- 3, 7,l l,15,19,23,27,31,35,39-décaméthyl-2, 6, 10, 14, 18, 22, 26, 30, 34, 38 -tétracontadécaényl]-5,6-diméthoxy -3-méthyl -1,4-benzoquinone et est représentée par la formule 1.
PCT/IB2007/051675 2006-05-05 2007-05-04 Procédé amélioré pour la synthèse de coq10 Ceased WO2007129268A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN705/MUM/2006 2006-05-05
IN705MU2006 2006-05-05

Publications (2)

Publication Number Publication Date
WO2007129268A2 true WO2007129268A2 (fr) 2007-11-15
WO2007129268A3 WO2007129268A3 (fr) 2009-04-23

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2007/051675 Ceased WO2007129268A2 (fr) 2006-05-05 2007-05-04 Procédé amélioré pour la synthèse de coq10

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WO (1) WO2007129268A2 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2435466A1 (fr) * 1978-08-02 1980-04-04 Kuraray Co Derives de l'hydroquinone et leur procede de preparation
EP1700838A1 (fr) * 2005-03-11 2006-09-13 Gnosis S.p.A. Procédé de préparation de la coenzyme Q10

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WO2007129268A3 (fr) 2009-04-23

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