NPCQE_07

NOVEL INTERMEDIATES, PROCESS FOR THEIR PREPARATION AND PROCESS FOR THE PREPARATION OF CoQlO EMPLOYING THE SAID

NOVEL INTERMEDIATES

Field of Invention

The present invention relates to an improved process for the preparation of Coenzyme Q. Coenzyme QlO or CoQlO has the chemical name 2- [(all -trans)- 3, 7,ll,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.

side chain

1

The invention also provides new intermediates useful for the preparation of CoQlO and processes for their preparation.

Background of the Invention

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).

As depicted above CoQlO 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, CoQO ₁ 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. The key step in the synthesis of CoQlO is in the addition of the remaining isoprene unit.

One of the processes given in literature for the addition of the remaining isoprene unit is to modify isoprene compound of formula 4 to an active building block of "chloroisoprenyl sulphone " compound of formula 5.

4 5

Literature method of synthesis of chloroisoprenyl sulphone compound of formula 5 is by heating isoprene of formula 4 (0.0846 mmols), benzene sulphonyl chloride (0.086 mmols), cuprous chloride (0.846 mmols) and triethyl amine hydrochloride (0.086 mmols) in acetonitrile (0.079 mols), at reflux temperature for 2 hours and quenching in cold methanol. The crude product of formula 5 is recrystallized from 95% ethanol to obtain compound of formula 5 in 42% yield (J. Org. Chem. 35,4217(1970).

The present inventors have observed that following the above procedure the reaction does not go to completion under the above condition and results in poor yield (30- 40%) of the crude product.

In another method, benzenesulphonyl chloride (50 mmol), isoprene (100 mmol), cuprous chloride (2.5 mmol) and triethylamine hydrochloride (2.5 mmol), were heated to 60° C for 15 hours, cooled and quenched in methylene dichloride. The compound of formula 5 was isolated by distilling out solvent and crystallizing in 95% ethanol in 90% yield (J. Org. Chem. 68, 7925(2003)).

Both the processes as mentioned herein above do not mention about the positional isomers of compound of formula 5a and cis isomer of compound of formula 5b, that are formed during the synthesis (J. Org. Chem. 41 3287(1976)).

5a 5b

As reported in J.Org.Chem.41 3287 (1976), total yield of 95% is obtained for the mixture of all the three compounds of formula 5, 5a and 5b respectively. Mixture of 5 and 5a in the ratio of 4:1 is obtained in 74 % yield. Purification of the desired compound 5 from the crude is obtained with drastic yield loss in 33.5 % yield only (J. Org. Chem. 41 3287(1976)).

Thus an industrially economical process in which the formation of the unwanted isomers is minimized is presently lacking.

Chloroisoprenyl sulphone compound of formula 5 is reacted with "benzoquinone nucleus" compound of formula 6 where R is protecting group to form CoQ ₁ sulphone of formula 7. Compound of formula 6 is made from CoQ o compound of formula 2 in three steps.

Choice of protecting group is a major contributing factor in the synthesis of CoQlO. The protecting groups used in literature for the synthesis of CoQlO using chloroisoprenyl sulphone of formula 5 are -CH ₂ OCH ₂ CH ₂ OCH ₃ and -CH ₃ respectively.

CoQl sulphone compound of formula 7 is reacted with solanesyl bromide to form CoQlO sulphone, compound of formula 8, which is desulphonated to form compound of formula 9 followed by deprotection and oxidation to form CoQlO of formula 1.

Desulphonation of compound of formula 8 where R is -CH ₂ OCH ₂ CH ₂ OCH ₃ or -CH ₃ uses modified Bouvelut-Blanc method of sodium and ethanol and THF as solvent, at 10-12 ⁰ C.

Deprotection involves (i) 48% hydrobromic acid at 50 ⁰ C, (ii) Methanolic Hydrochloric acid (BuU.Chem.Soc. Japan, 55, 1325 (1982)).

The critical parameter associated with the synthesis of CoQlO involving the above route is selection of protecting groups that can be (i) synthesized cost effectively, (ii) deprotected easily under mild condition and (iii) oxidized readily. The synthesis of compound of formula 6 where R is -CH ₂ OCH ₂ CH ₂ OCH ₃ requires methoxyethoxymethyl chloride. Methoxyethoxymethyle chloride is a costly reagent and the requirement of two equivalents per one equivalent of the compound adds to the cost.

Deprotection of the two methoxyethoxymethyl groups in compound of formula 9 where R is-CH ₂ OCH ₂ CH ₂ OCH ₃ also requires drastic condition for deprotection that leads to impurity formation.

The synthesis of CoQlO from compound of formula 9 where R is -CH ₃ requires expensive reagent of eerie ammonium nitrate for oxidation step (J. Org. Chem. 68,

7925 (2003)).

The present inventors observed that the oxidation also results in side reactions with yield loss and therefore is not cost effective.

Use of CoQlO in broadband medical application is increasing day by day. The key point in the synthesis of CoQlO is the choice of the building blocks of i)"isoprene unit", (ii) "the benzoquinone nucleus" and (iii) "the polyprenyl side chain". A cost effective process of preparing CoQlO can be made only with the suitable "building blocks" which are made economically. An industrially viable process is currently lacking.

Keeping the above facts in mind, the present inventors have explored various alternatives for the preparation of CoQlO. The present inventors have developed the following improved novel processes and novel intermediates

1. Improved process for the preparation of the "benzoquinone nucleus" - the head group of CoQlO. The process has also resulted in producing novel intermediates. These aspects have been made the subject of our co-pending Indian patent application No. 803/MUM/2005

2. Improved processes for the preparation of solanesyl bromide and solanesyl acetone, the key intermediates for the preparation of the "polyprenyl side chain" of CoQlO. Such processes have been made the subject matter of our co-pending Indian patent application No. 804/MUM/2005

3. Improved process for the preparation of CoQlO, by coupling of the polyprenyl side chain of ten isoprene units, with the head group "benzoquinone nucleus". Such scheme of synthesis has been made the subject matter of our co-pending Indian patent application No. 805/MUM/2005 4. An improved process for the preparation of CoQlO ₁ by condensation of one isoprene unit to the head group "benzoquinone nucleus" to form novel intermediate CoQi ₁ which is coupled with solanesyl bromide. Such scheme of synthesis has been made the subject matter of our co-pending Indian patent application No. 806/MUM/2005

The present invention disclosed in this application relates to an improved process for the preparation of CoQlO ₁ by condensation of one isoprene unit to the head group "benzoquinone nucleus" to form novel intermediate CoQ _1, which is coupled with solanesyl bromide.

Objective of the invention

The main objective of the present invention is to provide an improved process for the preparation of CoQlO of the formula 1, given herein above and overcoming the drawbacks of the hitherto known processes.

Another objective of the present invention is to provide an improved process for the preparation of CoQlO of the formula 1 given herein above which is useful for industrial application.

Another objective of the present invention is to provide a novel intermediate, namely, CoQl sulphone of the formula 11 which is also useful for the preparation of CoQlO

Another objective of the present invention is to provide a novel intermediate, namely, CoQlO sulphone of the formula 12 useful for the preparation of CoQlO

Still another objective of the present invention is to provide a process for the preparation of novel intermediate namely, CoQi sulphone of the formula 12 which is simple, cost effective and commercially applicable.

Yet another objective of the present invention is to provide a process for the preparation of novel intermediate namely CoQlO sulphone of the formula 12 wherein the yield is 80% and the purity is 98%, useful for the preparation of CoQlO . Yet another objective of the present invention is to provide an improved process for the preparation of chloroisoprenyl sulphone compound of formula 5

Detailed Description of the Invention

The present invention for the preparation of CoQlO has been developed based on using chloroisoprene sulphone as building block of one isoprene unit, using protecting groups such as methoxyethoxy methyl and methyl groups to form the building block of benzoquinone nucleus, and solanesyl bromide as a building block with nine isoprene units.

Accordingly, the present invention provides a process for the preparation of CoQ 10 of the formula 1

said process comprising the steps of: i. reacting the Grignard reagent of formula 10 (as described herein below) with chloroisoprenyl sulphone of formula 5 in the presence of a copper salt and a solvent under inert atmosphere, at a temperature in the range of

-25° C to 40° C for a period of 2 to 4 hours, quenching the resultant reaction, extracting the product with a water immiscible solvent to give compound of formula 11,

11. condensing compound of formula ll_with solanesyl bromide of formula 3a in the presence of a base and a solvent at a temperature in the range of - 50 ⁰ C to 50 ⁰ C for a period of 1 to 6 hours to obtain compound of formula 12,

111. desulphonating the compound of the formula 12 using sodium/ethanol in an inert solvent at a temperature in the range of -40 ⁰ C to 20 ⁰ C for a period of 16 to 24 hours to obtain the compound of formula 13,

IV. deprotecting the compound of the formula 13 _j by HBr or zinc halide / acetic acid in the presence of a chlorinated solvent at a temperature in the range of 15°C to 50 ⁰ C for a period of 2 to 6 hours, quenching the reaction mixture in aqueous medium and extracting the resulting mixture by a water immiscible solvent, evaporating the solvent to obtain the compound of formula 14, v. oxidising the compound of formula 14 by conventional method to form compound of formula 1 and

Vl. isolating the compound of formula (1) formed by conventional methods. The process explained above is shown in scheme- 1 below:

Chloroisoprenyl sulphone of the formula 5 may be obtained by reacting isoprene with benzenesulphonyl chloride and triethylamine hydrochloride in presence of cuprous halide preferably cuprous iodide at a temperature in the range of 40 ⁰ C to 60 ° C in acetonitrile, quenching the resultant reaction, extracting the product with a chlorinated solvent, and evaporating the solvent

CoQ ₁ sulphone of the formula 11 may be obtained by coupling the Grignard reagent 10 with chloroisoprenyl sulphone 5 in the presence of cuprous salt such as cuprous chloride, cuprous iodide, cuprous sulfate and the like; a solvent such as diethylether, tetrahydrofuan, dioxan and the like at a temperature in the range of -25°C to 40 ⁰ C for a period of 2 to 4 hours. The Grignard reagent may be prepared by any known method as well by the method described in our co-pending India patent application No. 805/MUM/2005. The molar ratio of cuprous salt to the Grignard reagent used may vary from 1:0.1 to 1:1.0, preferably 1:0.7.

The condensation of solanesyl bromide of formula 3a with CoQ ₁ sulphone compound of the formula 11 may be carried out in the presence of a base such as potassium tertiary butoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide and the like; solvent such as N,N-dimethyl formamide, tetrahydrofuran, diisopropyl ether and the like at a temperature in the range of -50 ⁰ C to 50 ⁰ C for period of 1 to 6 hours. Purification at this stage is not needed and proceeded to the next step of desulphonation thereby further making the process not only simple but also cost effective for commercial production.

The desulphonation of the compound of the formula 11 to obtain compound of formula 12 may be carried out by using sodium and ethanol in an inert solvent such as tetrahydrofuran, diethylether, xylol and the like at a temperature in the range of -40 ⁰ C to 20 ⁰ C for a period of 16 to 24 hours.

Deprotection of the compound of the formula 12 to get the compound of the formula 13 may be carried out using 48% hydrogen bromide solution or with a mild Lewis acid preferably zinc halide, such as zinc chloride, zinc bromide and the like in a chlorinated solvent such as methylene chloride, chloroform or carbon tetrachloride at a temperature in the range of 15 ⁰ C to 50 ⁰ C for a period of 2 to 6 hours. Zinc halide may be used in the molar ratio of 1:1 to 1:5.

The oxidation of the formula 13 may carried out by known method of using Ferric chloride in isopropanol,

According to an embodiment of the present invention there is provided an improved process for the preparation of chloroisoprenyl sulphone compound of formula 5

useful for the preparation of CoQ ₁₀ , said process comprising the steps of:

(i) Reacting isoprene of formula 4

4 with benzenesulphonyl chloride and triethylamine hydrochloride in presence of cuprous halide preferably cuprous iodide at a temperature in the range of 40 ⁰ C to 60 ° C in acetonitrile, quenching the resultant reaction mixture, extracting the product with a chlorinated solvent, evaporating the solvent to give compound of formula 5,

(ii) isolating and purifying the compound of formula 5 by conventional methods.

Preparation of chloroisoprenyl sulphone compound of formula 5 may be carried out by reacting benzene sulphonyl chloride with isoprene in presence of triethylamine hydrochloride in acetonitrile. The molar ratio of benzene sulphonyl chloride and isoprene may be taken in the range of 1:1 to 1:2 preferably 1:1.2 to 1:1.3. Molar ratio of benzene sulphonyl chloride to triethylamine hydrochloride may be varied from 1:01 to 1:0.2 preferably 1:0.08 to 1:0.15. Catalyst used for the reaction may be cuprous iodide. Molar ratio of benzene sulphonyl chloride to cuprous iodide may be varied from 1:0.01 to 1:0.05 preferably 1:0.02 to 1:0.03. Reaction may be quenched in ammonium chloride solution and the product extracted in chlorinated hydrocarbon solvent. The solvent may be evaporated and the product compound of formula 5 may be isolated in alcohol preferably methanol or isopropanol.

Unlike the prior art, the present invention utilizes benzene sulphonyl chloride and isoprene in a ratio of 1:1.2 to 1:1.3 and cuprous iodide as a catalyst, which results in higher yield and better purity.

According to yet another embodiment of the present invention there is provided a novel intermediate of formula 11

which is useful for the preparation of CoQlO.

According to yet another embodiment of the present invention there is provided a process for the preparation of novel intermediate of the formula 11

which is useful for the preparation of CoQlO, said process comprising the steps of: (i) reacting the Grignard reagent of formula 10

with chloroisoprenyl sulphone of formula 5

in the presence of copper salt and a solvent under inert atmosphere, at a temperature in the range of -25° C to 40° C for a period of 2 to 4 hours, quenching the resultant reaction, extracting the product with a water immiscible solvent to give compound of formula 11,

(ii) isolating and purifying the compound of formula 11 formed by conventional methods.

According to yet another embodiment of the present invention there is provided a novel intermediate of formula 12

which is useful for the preparation of CoQlO.

According to another embodiment of the present invention, there is provided a process for the preparation of the novel intermediate compound of the formula 12

which is useful for the preparation of CoQlO, said process comprising the steps of: (i) condensing compound of formula 11

with solanesyl bromide of formula 3a

in the presence of a base and a solvent at a temperature in the range of -50 ⁰ C to 50 ⁰ C for a period of 1 to 6 hours, quenching the resultant reaction, extracting the product with a water immiscible solvent to give compound of formula 12

(ii) isolating and purifying the compound of formula 12 formed by conventional methods.

The details of the various reactions conditions of the processes described above and those preferred ones are given below. The details of the process of the present invention are given in the Examples below which are provided for illustration only and therefore they should not be construed to limit the scope of the invention

Example 1 Preparation of Chloroisoprenyl Sulphone compound of formula 5

Benzene sulphonyl chloride 50 g , isoprene 31.5 g , cuprous iodide 1.0 g, triethylamine hydrochloride 7.8 g were taken in acetonitrile 135 ml and heated to 50 - 60 ⁰ C for 15 hrs. The reaction was diluted with methylene dichloride and washed with aqueous ammonium chloride solution. The methylene dichloride layer was dried over anhydrous sodium sulphate, filtered and evaporated under vacuum. Methanol was added to the residue to precipitate the solid (41 g , HPLC 83%)

Example 2

Preparation of Chloroisoprenyl Sulphone compound of formula 5 Benzene sulphonyl chloride 50 g , isoprene 23 g , cuprous iodide 1.0 g, triethylamine hydrochloride 3.9 g were taken in acetonitrile 135 ml and heated to 50 -60 ° C for 15 hrs. The reaction was diluted with methylene dichloride and washed with aqueous ammonium chloride solution. The methylene dichloride layer was dried over anhydrous sodium sulphate, filtered and evaporated under vacuum . Methanol was added to the residue to precipitate the solid (62 g , HPLC 83%)

Example 3

Preparation of Chloroisoprenyl Sulphone of formula 5

Benzene sulphonyl chloride 50 g, isoprene 23 g, cuprous iodide 1.0 g, triethylamine hydrochloride 3.9 g were taken in acetonitrile 135 ml and heated to 50 -60 ° C for 15 hrs. The reaction was diluted with methylene dichloride and washed with aqueous ammonium chloride solution. The methylene dichloride layer was dried over anhydrous sodium sulphate, filtered and evaporated under vacuum . Methanol was added to the residue to precipitate the solid (64 g) which was purified in isopropanol to obtain compound of formula 5 (32 g, HPLC 97%)

Example 4

Preparation of compound of formula 11 (i) Preparation of Grignard reagent of formula 10 Suspended 12 g of magnesium in tetrahydrofuran 550 ml and heated to 40 - 45 ⁰ C. Then, added a pinch of iodine and 2,3,4-trimethoxy-5-bromo-6-methylhydroquinone methoxyethoxymethyl ether 150 g slowly until initiation of Grignard reagent takes place. After completion of addition maintained the reaction for 2.0 hrs at the same temperature, (ii) Preparation of COQl of formula 11 Cooled the reaction mixture obtained in step (i) above to 15 to 20 ⁰ C and was added anhydrous cuprous chloride 40 g, followed by chloroisoprenyl sulphone 70.0 g in THF 800 ml, maintained the reaction at the same temperature for 3.0 hrs and quenched the reaction in ammonium chloride and extracted the product in isopropyl ether, washed the isopropyl ether layer with water, saturated sodium chloride solution and dried under sodium sulphate and distilled isopropyl ether under vacuum at 50 ⁰ C to get COQl crude. The crude was purified by column chromatography to yield 113 g (80% of theory, HPLC 98%) of compound of formula 11

Example 5 Preparation of compound of formula 11

(i) Preparation of Grignard reagent of formula 10

Suspended 12 g of magnesium in tetrahydrofuran 550 ml and heated to 40 - 45°C. Then, added a pinch of iodine and 2,3,4-trimethoxy-5-bromo-6-methylhydroquinone methoxyethoxymethyl ether 131 g slowly until initiation of Grignard reagent takes

place. After completion of addition maintained the reaction for 2.0 hrs at the same temperature.

(ii) Preparation of COQl of formula 11

Cooled the reaction mixture obtained in step (i) above to 15 to 20 ⁰ C and was added anhydrous cuprous chloride 2Og, followed by chloroisoprenyl sulphone 70 g in THF

800 ml, maintained the reaction at the same temperature for 3.0 hrs and quenched the reaction in ammonium chloride and extracted the product in isopropyl ether, washed the isopropyl ether layer with water, saturated sodium chloride solution and dried under sodium sulphate and distilled isopropyl ether under vacuum at 50 ⁰ C to get COQl crude. The crude was purified by column chromatography to yield 106 g (75 % of theory, HPLC 98%) of compound of formula IL

Example 6

Preparation of compound of formula 12 Dissolved Solanesyl bromide 222 g prepared by the process given in literature in THF 700 ml. Dissolved compound of formula 11 (190 g) prepared by the process described in Example 5 in THF (1.0 litre) and DMF (190 ml) and added to the solution of solanesyl bromide. Cooled the reaction mixture to - 30 ° C to - 35° C. To the reaction mixture was added potassium tertiary butoxide 40.5g at - 30 ° C to - 35° C. Maintained for 1.0 hour at -20 ⁰ C to - 30 ° C and raised the contents of the flask to room temperature. Reaction was continued for 1.0 hour at the same temperature and quenched in ammonium chloride solution. The product was extracted with hexane, dried over anhydrous sodium sulphate and distilled under vacuum at 50 ⁰ C to obtain a pale yellow viscous oil of compound of formula 12. Yield 325 g (92 %, HPLC purity 88 %).

Example 7

Preparation of compound of formula 12

Dissolved Solanesyl bromide 222 g prepared by the process given in literature in THF 700 ml. Dissolved compound of formula 11 (190 g) prepared by the process described in Example 5 in THF (1.0 litre) and DMF (190 ml) and added to the solution of solanesyl bromide. Cooled the reaction mixture to - 30 ° C to - 35° C. To the reaction mixture was added potassium tertiary butoxide solution 40.5g in 300 ml THF over a period of 20 minutes at - 30 ° C to - 35° C. Maintained for 1.0 hour at -

20 ⁰ C to - 30 ° C and raised the contents of the flask to room temperature. Reaction was continued for r 1.0 hour at the same temperature and quenched in ammonium chloride solution. The product was extracted with hexane, dried over anhydrous sodium sulphate and distilled under vacuum at 50 ⁰ C to obtain a pale yellow viscous oil of compound of formula 12_Yield 327 g (92 %, HPLC purity 88 %).

Example 8

Preparation of compound of formula 12

Dissolved Solanesyl bromide 222 g prepared by the process given in literature in THF 700 ml. Dissolved compound of formula 11 (190 g ) prepared by the process described in Example 5 in THF (1.0 litre) and DMF (190 ml) and added to the solution of solanesyl bromide. Cooled the reaction mixture to - 30 ° C to - 35° C. To the reaction mixture was added potassium tertiary butoxide 46.7 g at - 30 ° C to - 35° C. Maintained for 1.0 hour at -20 ⁰ C to - 30 ° C and raised the contents of the flask to room temperature. Reaction was continued for r 1.0 hour at the same temperature and quenched in ammonium chloride solution. The product was extracted with hexane, dried over anhydrous sodium sulphate and distilled under vacuum at 50 ⁰ C to obtain a pale yellow viscous oil of compound of formula 12. Yield 301g (85 %, HPLC purity 88 %).

Example 9

Preparation of compound of formula 1

Compound of formula 12 prepared by the process described in Example 8 (200 g) was taken in THF 1.0 litre and cooled to -25°C to - 30 ⁰ C. Ethanol 108 g and sodium 3 Ig was added at -25°C to - 30 ⁰ C. Reaction was maintained for 22 hrs at the same temperature. Excess sodium in the reaction mixture was destroyed by adding methanol and the reaction mixture quenched in ammonium chloride solution and extracted with hexane. Hexane layer was dried over anhydrous sodium sulphate and distilled under vacuum at 50 ⁰ C. The residue obtained was purified by column chromatography to yield 137 g of compound of formula 13_(Yield 69 % , Purity 99 %). Dissolved compound of formula 13 in 685 ml methylene chloride . Zinc bromide (159.7 g) was added and stirred at room temperature for 3 hours. After completion of reaction filtered the reaction mass, and neutralised with sodium bicarbonate solution. The organic layer was distilled under vacuum to obtain compound of formula 14 as a

viscous oil (130 g). The compound of formula 14 was dissolved in isopropyl alcohol 1300 ml and oxidized using ferric chloride 146.7 g in water 74 ml. The reaction mixture was stirred for ό.Ohours at 40-45 ⁰ C and quenched with water and extracted with hexane. The hexane layer was dried over anhydrous sodium sulphate, filtered and distilled under vacuum to obtain compound of formula 1 a dark red viscous oil, which was dissolved in isopropanol at 50 ⁰ C and cooled slowly to 10 ⁰ C to get a pale yellow solid which was filtered and washed with sufficient quantity of IPA.

Example 10 Preparation of compound of formula 1

Compound of formula 12 prepared by the process described in Example 8 (200 g) was taken in THF 1.0 litre and cooled to -25°C to - 30 ⁰ C. Ethanol 108 g and sodium 31g was added at -25 ⁰ C to - 30 ⁰ C. Reaction was maintained for 22 hrs at the same temperature. Excess sodium in the reaction mixture was destroyed by adding methanol and the reaction mixture quenched in ammonium chloride solution and extracted with hexane. Hexane layer was dried over anhydrous sodium sulphate and distilled under vacuum at 50 ⁰ C. The residue obtained was purified by column chromatography to yield 137 g of compound of formula 13_(Yield 69 %, Purity 99 %). Dissolved compound of formula 13 (100 g) in 1.0 lit isopropyl alcohol and added catalytic quantity of cone. HBr warmed to 50 ⁰ C and held for 4.0 hrs, quenched the excess HBr using sodium bicarbonate and filtered through hyflo, to the clear IPA solution containing CoQlO Hydroquinone added ferric chloride 78.Og in water 35 ml, stirred for 3.0hrs and quenched with water and extracted with hexane, washed the hexane layer with water, and dried the hexane layer under sodium sulphate, distilled the hexane under vacuum and obtained a dark red viscous oil which is dissolved in IPA 525ml at 50 ⁰ C and cooled slowly to 25 ⁰ C to get a pale yellow solid which was filtered and washed with sufficient quantity of IPA, recrystallized from ethanol Yield - 41g,Purity - 98%

Advantages

1. CoQlO was obtained in good overall yield as well purity.

2. Purification steps were avoided thereby making the process economical.