Title of Invention

NOVEL INTERMEDIATES, PROCESS FOR THEIR PREPARATION AND PROCESS FOR THE PREPARATION OF CoQ10 EMPLOYING THE SAID NOVEL INTERMEDIATES

Abstract

The present invention relates to an improved process for the preparation of Coenzyme Q. Coenzyme Q10 or CoQ10 has the chemical name 2-[(all-trans)- 3,7,11,15,19,23,27,31,35,39-decamethyl-2, 6, 10, 14, 18, 22, 26, 30, 34, 38-tetracontadecaeny1]-5,6-dimethoxy-3-methyl-1,4-benzoquinone and has the formula 1. The invention also provides new intermediates useful for the preparation of CoQ10 and process for their preparation.

Full Text

FORM-2 THE PATENTS ACT 1970 (Act 39 of 70) COMPLETE SPECIFCATION (Section 10) NOVEL INTERMEDIATES, PROCESS FOR THEIR PREPARATION AND PROCESS FOR THE PREPARATION OF CoQ10 EMPLOYING THE SAID NOVEL INTERMEDIATES NICHOLAS PIRAMAL INDIA LTD., A COMPANY REGISTERED UNDER INDIAN COMPANY'S ACT 1956, LOCATED AT, NICHOLAS PIRAMAL TOWER, GANPATRAO KADAM MARG, LOWER PAREL, MUMBAI- 400013, MAHARASHTRA, INDIA. The following specification particularly describes the nature of this invention and the manner in which it is to be performed Field of Invention The present invention relates to an improved process for the preparation of Coenzyme Q. Coenzyme Q10 or CoQ10 has the chemical name 2- [(all -trans)- 3, 7,11,15,19,23,27,3l,35,39-decamethyl-2, 6, 10, 14, 18, 22, 26, 30, 34, 38 -tetracontadecaenyl]-5,6-dimethoxy -3- methyl -1,4-benzoquinone and has the formula 1. The invention also provides new intermediates useful for the preparation of CoQ10 and processes for their preparation. Background of the Invention This coenzyme is present in virtually in 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" Elsvier/ North -Holland Biomedical Press, New York, 1986; "Coenzyme Q: Bioechemistry, Bioenergetics, and clinical Applications of Ubiquinone" Wiley, New York, 1985; " Coenzyme Q, Molecular Mechanism in Health and Disease" CRC press). As depicted above CoQ10 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, CoQ10,of the formula 2. O 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 CoQ10 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. 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 was recrystallized from 95% ethanol to obtain compound 5 in 42% yield (J. Org. Chem. 35,4217(1970). We 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 process 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 CoQi 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 CoQ 10. The protecting groups used in literature for the synthesis of CoQ 10 using chloroisoprenyl sulphone of formula 6 are -CH 2OCH2 CH 2OCH 3 and -CH3 respectively. CoQl sulphone compound of formula 2 is reacted with solanesyl bromide to form CoQ 10 sulphone, compound of formula 8, which is desulphonated to form compound of formula 9 followed by deprotection and oxidation to form CoQ 10 of formula L MeO MeO MeO S02Ph Me0 MeO MeO Desulphonation of compound of formula 8 where R is -CH2OCH2CH2OCH3 or -CH3 uses modified Bouvelut-Blanc method of sodium and ethanol and THF as solvent, at 10-12°C. Deprotection involves (i) 48% hydrobromic acid at 50°C, (ii) Methanolic Hydrochloric acid (Bull.Chem.Soc. Japan 55.1325(1982)). The critical parameter associated with the synthesis of CoQ10 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 -CH2OCH2CH2OCH3 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-CH20CH2CH2 OCH3 also requires drastic condition for deprotection that leads to impurity formation. The synthesis of CoQ10 from compound of formula 9 where R is -CH3 requires expensive reagent of eerie ammonium nitrate for oxidation step (J. Org. Chem.68, 7925(2003)). We observed that the oxidation also results in side reactions and yield loss and therefore not cost effective. Use of CoQ10 in broadband medical application is increasing day by day. The key point in the synthesis of CoQ10 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 CoQ 10 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, we have explored various alternatives for the preparation of CoQ10. Our above-mentioned efforts have resulted in developing the following improved novel processes and novel intermediates 1. Improved process for the preparation of the "benzoquinone nucleus" - the head group of CoQ10. The process has also resulted in producing novel intermediates. These aspects have been made the subject of our co pending 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 C CoQ10. Such processes have been made the subject matter of our co pending application 804/MUM/2005 3. Improved process for the preparation of CoQ10, by coupling of the polyprenyl side chain of ten isoprene units, with the head group "bezoquinone nucleus". Such scheme of synthesis has been made the subject matter of our co pending application no 805/MUM/2005 4. An improved process for the preparation of CoQ10, by condensation of one isoprene unit to the head group "benzoquinone nucleus" to form novel intermediate C0Q1, which is coupled with solanesyl bromide. Such scheme of synthesis has been made the subject matter of our co pending application no 806/MUM/2005 The present invention disclosed in this application relates to an improved process for the preparation of CoQlO , by condensation of one isoprene unit to the head group "benzoquinone nucleus" to form novel intermediate CoQlO, 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 above 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 above which is useful for industrial application. Another objective of the present invention is to provide a novel intermediate, namely, CoQlO sulphone of the formula 11. which is also useful for the preparation of CoQlO MeO MeO T ^" v S02Ph 11 OMe 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 MeO MeO OMe 12 Still another objective of the present invention is to provide a process for the preparation of novel intermediate namely, CoQlO 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 CoQ10 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 CoQ10 has been developed based on using chloroisoprene sulphone as building block of one isoprene unit, using protecting groups 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 CoQ10 of the formula 1 MeO O MeO, which comprises: 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. 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°C to 50°C for a period of 1 to 6 hours to obtain compound of formula 12, iii. desulphonating the compound of the formula 12 using sodium/ethanol in an inert solvent at a temperature in the range of-40°C to 20°C for a period of 16 to 24 hours to obtain the compound of formula 13, iv. deprotecting the compound of the formula 13, 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°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 vi. isolating the compound of formula (1) formed by conventional methods. Scheme -1 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°C to 60 ° C in acetonitrile, quenching the resultant reaction, extracting the product with a chlorinated solvent, evaporating the solvent CoQlO sulphone of the formula il 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°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 application 805/MUM/2005. The mole 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 CoQi 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°C to 50°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°C to 20°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 bromide, 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°C to 50°C for a period of 2 to 6 hours. Zinc salt 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 or the preparation of CoQ 10 which comprises, (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°C to 60 ° C in acetonitrile, quenching the resultant reaction, 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 0.02 to 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. Using the ratio of 1:1;2-1.3 and cuprous iodide a higher yield and purity is effected unlike the prior art where a higher ratio is used and the yield is less. According to yet another embodiment of the present invention there is provided a novel intermediate H. S02Ph 11 OMe which is useful for the preparation of CoQ10. According to yet another embodiment of the present invention there is provided a process for the preparation of novel intermediate of the formula H. MeO S02Ph MeO OMe which is useful for the preparation of CoQ10, which comprises, (i) reacting the Grignard reagent of formula 10 11 O O MeO MeO' ^ ^MgBr OMe with chloroisoprenyl sulphone of formula 5 10 Ph02S 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 12 OMe which is useful for the preparation of CoQ10. 12 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 .0. rH 12 OMe which is useful for the preparation of CoQ10, which comprises, (i) condensing compound of formula 11 O. S02Ph 11 OMe with solanesyl bromide of formula 3a in the presence of a base and a solvent at a temperature in the range of-50°C to 50°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°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 jU. (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 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 COQ1 of formula 11 Cooled the reaction mixture obtained in step (i) above to 15 to 20 °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°C to get COQ1 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 COQ1 of formula 11 Cooled the reaction mixture obtained in step (i) above to 15 to 20 °C and was added anhydrous cuprous chloride 20g, 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°C to get COQ1 crude. The crude was purified by column chromatography to yield 106 g (75 % of theory, HPLC 98%) of compound of formula lL 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°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°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°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°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°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°C to obtain a pale yellow viscous oil of compound of formula 12. Yield 301 g (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°C. Ethanol 108 g and sodium 31g was added at -25 °C to - 30°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°C. The residue obtained was purified by column chromatography to yield 137 g of compound of formula 13 fYield 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 6.0hours at 40-45°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°C and cooled slowly to 10°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°C. Ethanol 108 g and sodium 31g was added at -25°C to - 30°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°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°C and held for 4.0 hrs, quenched the excess HBr using sodium bicarbonate and filtered through hyflo, to the clear IPA solution containing CoQ10 Hydroquinone added ferric chloride 78.0g 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°C and cooled slowly to 25 °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. CoQ10 was obtained in good overall yield as well purity. 2. Purification steps were avoided thereby making the process economical. Claims: 1. A process for the preparation of CoQ 10 of the formula 1 which comprises: i. reacting the Grignard reagent of formula 10 10 with chloroisoprenyl sulphone of formula 5 PhO 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_, XL S02Ph 11 ii. 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°C to 50°C for a period of 1 to 6 hours to obtain compound of formula 12, 8 H 12 desulphonating the compound of the formula 12 using sodium/ethanol in an inert solvent at a temperature in the range of -40°C to 20°C for a period of 16 to 24 hours to obtain the compound of formula 13, iTH 13 deprotecting the compound of the formula 13^ 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°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 H, OH 10-H 14 oxidising the compound of formula 14 by conventional method to form compound of formula I and isolating the compound of formula (1) formed by conventional methods. Improved process for the preparation of chloroisoprenyl sulphone compound of formula 5 Ph02S useful for the preparation of CoQ !0 which comprises, Reacting isoprene of formula 4 with benzenesulphonyl chloride and triethylamine hydrochloride in presence of cuprous halide preferably cuprous iodide at a temperature in the range of 40°C to 60 ° C in acetonitrile, quenching the resultant reaction, extracting the product with a chlorinated solvent, evaporating the solvent to give compound of formula 5, isolating and purifying the compound of formula 5 by conventional methods. S02Ph Novel intermediate of formula 11 MeO MeO OMe useful for the preparation of CoQ 10. 11 Novel intermediate of formula 12 OMe useful for the preparation of CoQ 10. 12 5. A process according to claim 1 for the novel intermediate of formula 11, which comprises: (i) reacting the Grignard reagent of formula 10 OMe with chloroisoprenyl sulphone of formula 5 10 PhO 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. 6. A process according to claim 1 for the novel intermediate of formula 12, which comprises: (i) condensing compound of formula 11 0 11 MeO S02Ph MeO OMe with solanesyl bromide of formula 3a in the presence of a base and a solvent at a temperature in the range of -50°C to 50°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. 7. The process as claimed in claims 1 and 5, wherein the copper salt used in step (i) is selected from cuprous chloride, cuprous iodide and cuprous sulfate. 8. The process as claimed in claims 1 and 5, wherein die solvent in step (i) is selected from diethylether, tetrahydrofuan and dioxan. 9. The process as claimed in claims 1 and 6, wherein the base used in step (ii) is selected from potassium tertiary butoxide, sodium ethoxide, sodium hydroxide and potassium hydroxide. 10. The process as claimed in claims 1 and 6, wherein the solvent in step (ii) is selected from N,N dimethyl formamide, tetrahydrofuran and diisopropyl ether. 11. The process as claimed in claim 1, wherein the inert solvent in step (iii) is selected from tetrahydrofuran, diethylether and xylol. 12. The process as claimed in claim 1, wherein die zinc halide in step (iv) is selected from zinc bromide and zinc bromide. 13. The process as claimed in claim 1, wherein the chlorinated solvent used in step (iv) is selected from methylene chloride, chloroform and carbon tetrachloride. 14. The process as claimed in claim 2, wherein the cuprous halide used in step (i) is selected from cuprous chloride and cuprous iodide. 15. The process as claimed in claim 1, wherein the mole ratio of cuprous salt to the Grignard reagent used in step (i) is 1:0.1 to 1:1.0, preferably 1:0.7. 16. The process as claimed in claim 2, wherein in step (i) the molar ratio of benzene sulphonyl chloride and isoprene is 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 is in the range of 1:01 to 1:0.2 preferably 1:0.08 to 1:0.15. Dated this 5m day of April 2006 (Dr. H. Sivaramakrishnan) President Nicholas Piramal Research Centre Nicholas Piramal India Limited Applicant Abstract The present invention relates to an improved process for the preparation of Coenzyme Q. Coenzyme Q10 or CoQlO has the chemical name 2- [(all -trans)- 3, 7,11,15,19,23,27,3 l,35,39-decamethyl-2, 6, 10, 14, 18, 22, 26, 30, 34, 38 -tetracontadecaenyl]-5,6-dimethoxy -3- methyl -1,4-benzoquinone and has the formula 1. Benzoquinone** Nucleus Meo Polyprenyl side chain O MeO. 1 The invention also provides new intermediates useful for the preparation of CoQlO and processes for their preparation.

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706-mum-2006-correspondance-receivced.pdf

706-mum-2006-correspondence 1(21-5-2007).pdf

706-mum-2006-correspondence 2(12-6-2009).pdf

706-MUM-2006-CORRESPONDENCE(12-5-2009).pdf

706-MUM-2006-CORRESPONDENCE(12-6-2009).pdf

706-mum-2006-description (complete).pdf

706-mum-2006-form 1(6-6-2006).pdf

706-mum-2006-form 13(12-5-2009).pdf

706-MUM-2006-FORM 18(12-6-2009).pdf

706-MUM-2006-FORM 2(TITLE PAGE)-(17-8-2012).pdf

706-mum-2006-form 2(title page)-(5-5-2006).pdf

706-mum-2006-form 3(21-5-2007).pdf

706-mum-2006-form-1.pdf

706-mum-2006-form-2.pdf

706-mum-2006-form-3.pdf

706-MUM-2006-MARKED COPY(17-8-2012).pdf

706-MUM-2006-PCT-IB-326(12-5-2009).pdf

706-MUM-2006-PCT-ISA-237(12-5-2009).pdf

706-MUM-2006-RECEIPT(IPO)-(12-6-2009).pdf

706-MUM-2006-REPLY TO EXAMINATION REPORT(17-8-2012).pdf

706-MUM-2006-SPECIFICATION(AMENDED)-(17-8-2012).pdf

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