Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF CLARITHROMYCIN FORM-II

Abstract

The present invention relates to an improved process for the prepar of Clarithromycin Form-II from Erythromycin base without attachment of any oxime based synthesis and also relates to a process for the synthesis of 2',3' -Bis (Benzyloxycarbonyl) Erythromycin A with optimal use of catalysts in the reductive formylation of 3-N- demethyl, 6-0-methyl erythromycin A without involving laborious processes.

Full Text

The present invention relates to an improved, high yielding and cost effective process for the preparation of clarithromycin, without the involvement of any oxime based synthesis. Background of the invention: The general methods of preparing clarithromycin, processes as per scheme lin fig 1, involves: 1. Protecting the hydroxy group at the T position and methyl group of the dimethyl amino group at the 3' position in Erythromycin- A with suitable protective group. 2. Introducing suitable side chains in the 9-carbonyI Group of Erythromycin A. Protecting the 4"-Hydroxy of Erythromycin A with suitable protective group. 3. Methylating the 11-hydroxy of the protected Erythromycin-A with suitable methylating agent. 4. Deprotecting the 6-O-methyl Erythromycin -A derivative in multiple step to obtain 6-O-methyl Erythromycin -A. 5. Conversion of 6-O-Methyl Erythromycin-A to the desired Polymorph. Prior Art US 4,331,803 describes a process for making clarithromycin from Erythromycin-A by converting erythromycin A to its 2\ 3'-bis-benzyloxycarbonyl derivative followed by methylation using methyl iodide in the presence of a base such as an alkali metal hydride, butyl lithium/diisopropyl or sodium/potassium amide. The methylation reaction is carried out using 5-10 moles of methyl iodide and 1-2 moles of 2\ 3"-bis-benzyloxycarbonyl derivative at temperatures ranging from -78°C to room temperature preferably from -15°C to 5°C. The solvents used include polar aprotic solvents such as N,N-Dimethylformamide, N,N-Dimethylacetamide, Dimethylsulfoxide or their mixture with THF. Purification of the methylated product is carried out by using column chromatography, removal of the benzyloxycarbonyl protecting groups by hydrogenolysis and remethylation of the 3'-N by reductive formylation. The yield of clarithromycin is about 6%. E.H. Flynn et al. in Journal of the American Chemical Society, 77,3104 (1955), describe a method for preparation of 2', 3'-bis-benzyloxycarbonyl Erythromycin derivatives, removal of the Benzyloxycarbonyl group by hydrogenolysis and reductive methylation with excess amount of formaldehyde. US 4,672,109 describes a modification of this process in which the 9-carbonyl group of 2\ 3*-bis-benyloxycabonyl derivative is protected as an alkyl oxime prior to 6-methylation to increase the regioselectivity of the methylation in the 6 position. The modified process requires seven process steps, including chromatographic purification, and the yield is still relatively low, about 13%. Canadian patent CA 1,226,279 discloses a method for preparing 6-0-methyl-2,-0, N-bis (benzyloxycarbonyl)-N-demethylerythromycin A which comprises by methylating 2-0, N-bis (benzyloxycarbonyl)-N-demethylerythromycin A with a methylating agent in the presence of potassium hydroxide or sodium hydroxide in a polar aprotic solvent. The compound, 6-0-methyl-2*-0, N-bis (benzyloxycarbonyl)-N-dimethyl erythromycin A, produced in this manner is purified using column chromatography which is time consuming and laborious. The purified compound is subjected to catalytic reduction to eliminate benzyloxycarbonyl groups at the 2,-0- and N-positions. Subsequent to this, an aqueous formaldehyde solution is added to the mixture so that a further catalytic reduction takes place to effect N-methylation of the compound. As formamides are known to poison the Pd/C catalyst, the consumption of Pd/C is high, thereby increasing the cost of the process. US 4,680,386 also discloses a modification of the process of the US 4,672,109 patent in which the 9-carbonyl group is protected as a benzylated oxime rather than an alkyl oxime. LIS 4, 670,549 is an improvement on the process of the '386 patent, in which the same alkylating reagent is used for alkylating the 9-oxime, 3'-amine and 2'-hydroxyl groups. The number of steps is reduced to five. EP 260,938 discloses a synthetic route in which the 2'and 4' hydroxyl group are silylated with trimethylsilyl chloride and trimethylsilyl imidazole after oximation and benzylation ;>f the oxime OH, which also appears to increase the regioselectivity of the 6-OH nethylation. US 4,990,602 discloses a modification of the process of EP 260,938 utilizing specific sxime derivatives. US 4,610,910 describes silylated erythromycin A derivatives and procedures for making them. In only two of the silylated compounds described is the 9-carbonyl protected, 2'-9-i)is(O-trimethylsilyl) erythromycin A-9-Oxime and 2',4",9,11,12- pentakis(0-trimethyl silyl) erythromycin A-6, 9-hemiketal. PCT Publication No. WO 99/40097 describes a process for making clarithromycin and he products used in these processes; e.g., erythromycin A 9-alkylidenehydrazones, erythromycin A 9-alkyl-and 9-arylsulfonylhydrazones, erythromycin A 9- N-alkyl lydrazones and erythromycin A 9-N, N-dialkylahydrazones. Essentially clarithromycin is synthesized from erythromycin A by way of an alkylidenehydrazone or an irylsulfonylhydrazone. Regioselectivity of methylation is high and yields of the nethylation step are comparable of the best report oxime-based synthesis. 3P 1,097,938 Al discloses a method of preparing pure Form II crystals of Clarithromycin comprising steps of: (a) treating Clarithromycin with Formic Acid in an Organic Solvent ;o give crystalline Clarithromycin format (b) neutralizing the clarithromycin formate with i base in a mixture of water and a water miscible organic solvent. 2P 1,134,229 A2 discloses a method for preparing high purity clarithromycin of Form II crystals comprising the steps of: protection the 9-oxime hydroxyl group of erythromycin A 9-oxime or a salt thereof with a tropyl group and the T -and 4"-hydroxy groups with trimethylsilyl groups; reacting 2' -4"-0-bis (trimethylsilyl) erythromycin A 9-0-tropyloxime with a methylation agent; removing the protective groups and the oxime group of 2'-4"-Obis (trimethylsilyl)-6-0-methyl) erythromycin A 9-O-tropyloxime to obtain crude clarithromycin; treating the crude clarithromycin with methanesulfoinc acid in a mixture of a water-miscible organic solvent and water to obtain crystalline clarithromycin mesylate trihydrate; and neutralizing the crystalline clarithromycin mesylate trihydrate with aqueous ammonia in a mixture of a water-miscible organic solvent and water without the involvement of oxime based synthesis. US 5,858,986 describe the crystal Form-I of clarithromycin and a process for its preparation. US 5,945,405 describe the novel Form-0 solvate of clarithromycin and a process for its preparation. US 5,844,105 describes a process for the preparation of clarithromycin Form-II comprising converting erythromycin A to 6-O-methyl erythromycin A and treating the 6-O-methyl erythromycin A with a number of common organic solvents or a mixtures of common organic solvents. Further, these patents also describe the heating of Form-0 or I of clarithromycin at a temperature ranging from 70° C to 110°C for a prolonged period to prepare Form-II crystals. There is long felt need in the industry to develop cost effective, efficient and commercially viable process by the non-oxime route for the preparation of clarithromycin. Summary of the invention: The object of the invention is to provide for improved high yielding and cost effective process for the preparation of Clarithromycin Form-II from Erythromycin base without attachment of any functional group at the 9-Carbonyl Position and without involvement of any oxime based synthesis. It is yet another object of the invention is to provide a process for the synthesis of 2'33'-Bis (benzyloxycarbonyl) erythromycin A. It is yet another object of the invention is to provide a process for the optimal use of catalysts in the reductive formylation of 3-N-demethyl, 6-O-methyl erythromycin A without involving laborious processes such as column chromatography as described in the prior art. It is yet another object of the invention is to provide a process for the optimal use of catalysts in the reductive formylation of 3-N-demethyl, 6-O-methyl erythromycin A. It is yet another object of the invention is to provide alternate process for hydrogenolysis of 2\3',Bis (benzyloxycarbonyl) 6-O-methyl erythromycin A. It is yet another object of the invention is to provide a process for the preparation of pharmaceutical grade of" Clarithomycin Form- II". Brief description of the accompanying drawings: Fig.l: Synthetic scheme of Clarithromycin by prior art Fig.2: Synthetic scheme of Clarithromycin by this invention Fig.3: XRD of Crude Clarithromycin before oxalate salt preparation Fig.4: XRD of wet Clarithromycin Fig.5: XRD of Clarithromycin after drying Fig.6: XRD of Standard Clarithromycin Form-II Detailed description of the invention: Thus in accordance with this invention, as per scheme II in fig.2, 1. Erythromycin A is reacted with benzylchloroformate in the presence of Sodium Bicarbonate in Tetrahydrofuran (THF) medium at about 30° C to 60°C for 6hrs to obtain 2\ 3',Bis (benzyloxycarbonyl) N-demethyl erythromycin A. 2. 2\ 3\Bis (benzyloxycarbonyl) N-demethyl erythromycin A is then reacted with methyl Iodide at about 0°C to 15°C in the presence of alkali metal base such as sodium hydride for 0.5 to 2 hrs in a mixture of tetrahydrofuran and dimethyl sulfoxide to obtain 2 * ,3' -Bis (benzyloxycarbonyl) N-demethyl-6-O-methyl erythromycin A. 3. 2\ 3*,Bis (benzyloxycarbonyl) N-demethyl-6-O-methyl erythromycin A is then converted to Clarithromycin by hydrogenolysis (reaction time of 0.5 to 1.5 hr at temperature range of 25°C to 50°C) using H2, with Pd/C or Raney Nickel catalyst, in ethanol-water / methanol-water mixture respectively, followed by reductive formylation (reaction time of 2 to 6 hrs with a temperature range of 25°Cto 50°C) with formaldehyde using Pd/C or sodium borohydride, . in ethanol-water/methanol-water. 4. Optionally hydrogenolysis of 2\ 3'-Bis (benzyloxycarbonyl)-N-demethyl -6-0-methyl erythromycin A using H2, with Pd/C or Raney Nickel catalyst, in Ethanol / Methanol water mixture respectively, followed by reductive formylation with Formaldehyde using Pd/C or Sodium borohydride, in Ethanol-Water/Methanol-Water. Further conversion to clarithromycin salt is carried out by reaction with organic acids such as oxalic acid, citric acid, fumaric acid, maleic acid etc., in any one of the solvents selected from ethyl acetate or water miscible organic solvents such as acetone, methanol, ethanol, isorpopanol, acetonitrile, tetrahydrofuran, DMF or mixtures thereof. Clarithromycin oxalate/citrate/ fumarate /maleate etc is converted to clarithromycin Form- II pure crystals by treating the clarithromycin oxalate/citrate/fumatare/maleate etc., with a mixture of water, aqueous ammonia and a water miscible organic solvent selected from methanol, ethanol, iso-propanol, acetone, ethyl acetate etc. The wet clarithromycin is dried at about 60°C to about 65°C under vacuum to yield Clarithromycin Form II. Example-1: Preparation of 2% 3'-Bis (benzyloxycarbonyl) N-demethyl erythromycin: To a mixture of tertahydrofuran (88g) and benzyl chioroformate (75g) and sodium bicarbonate (37.5g) in the flask, 50g Erythromycin (0.068 Mol) is added at a temperature ranging from 40°C to 50°C and stirred at 55°C for 3 to 6 hrs. Tetrahydrofuran is then distilled off, 200ml toluene is added to obtain 90-100g crude 2',3'-Bis (benzyloxycarbonyl) N-demethyl erythromycin A. HPLC purity of this is 90-95%. Crude 2\3'-Bis (benzyloxycarbonyl) N-demethyl erythromycin A is purified with 200ml methylene chloride and 400ml D.M. water; the sodium bicarbonate is allowed to dissolve in water while 2',3'-Bis (benzyloxycarbonyl) N-demethyl erythromycin A dissolves in methylene chloride. The solvent is then distilled off and 150 ml Acetone is charged into the flask. 2',3'-Bis (benzyloxycarbonyl) N-demethyl erythromycin A is crystallized out of acetone at temperature ranging 0-10°C over 1-2 hrs as a wet cake, which is dried to obtain 48-50 g or pure 2\3'-Bis (benzyloxycarbonyl) N-demethyl erythromycin A. HPLC purity of 2\3'-Bis (benzyloxycarbonyl) N-demethyl erythromycin A is more than 99% and melting range is 190°C to 200°C. Second crop of 2',3'-Bis (benzyloxycarbonyl) N-demethyl erythromycin A is isolated by concentration of mother liquor and re-crystallized in acetone (0-5°C) to obtain pure 2\3'-Bis (benzyloxycarbonyl) N-demethyl erythromycin A. HPLC purity of 99% and melting range is 190° C to 200°C are obtained. Example-2: Preparation of I'^^N-Bis^enzyloxycarbony^N-demethyl^-O-methyl -erythromycin A: In a 1:1 mixture of 400 ml of dry tetrahydroforan and DMSO, 50g of 2\3'-Bis (benzyloxycarbonyl) N-demethyl erythromycin A is dissolved, cooled to about 1°C to about 12°C under nitrogen. 7.98 g methyl iodide is added under stirring. 1.17 g of sodium hydride of purity 55% to 65% is added in small portions. The reaction takes about 1 hr to go to about 65% to 75% completion. After the reaction completion, 10 ml of dimethyl amine (40% aqueous solution) is added to neutralize excess CH3I in about 30 Min. The product is extracted in methylene chloride and the aqueous layer containing the inorganic impurities is drained off. The solvent is then distilled off. 50 ml of methyl iso butyl ketone is added into the reaction mass, stirred at room temperature for about 3 hrs & the resulting mixture is filtered to isolate 5 to 6 g of the unreacted 2\3'-Bis (benzyloxycarbonyl) N-demethyl erythromycin A. The filtrate containing the product is concentrated under a reduced pressure to obtain 2\3'-N-Bis (benzyloxycarbonyl) N-demethyl-6-O-methyl-erythromycin A having 55% to 65% purity by HPLC, with melting point of 115°C - 130°C. Example-3 Preparation of 6-O-Methyl Erythromycin A (Clarithromycin); 50 g of 2\3'-N-Bis (benzyloxycarbonyl) N-demethyl-6-0-methyl~erythromycin A obtained from Example-2 is dissolved in a mixture of 188 ml ethanol and 12 ml water. A mixture of 6.60g sodium acetate, 4.0 ml of acetic acid and 25 ml water is added to reactants. Catalytic reduction is performed for about 1 hr at 30°C to 40°C with H2 gas with 3.0g of 10% Pd/C. After the reaction, 32 ml of 37% aqueous formaldehyde solution is added and reductive formylation is continued for about 4hrs. After the reaction, the catalyst is filtered off and the pH of the filtrate is adjusted with IN sodium hydroxide solution. The mixture is extracted with Methylene dichloride and the solvent is evaporated. The residue is slurried in 300 ml of Acetone. The impurity 6,11, Dimethyl Erythromycin A is then filtered off and solid residue from the filtrate Acetone is evaporated in vacuum & the residue is crystallized in 150ml of methanol to obtain 10.10g of Crude 6-O-Methyl Erythromycin A. Crude 6-O-Methyl Erythromycin A is crystallized from ethanol to give 6.0 to 7.0 g of pure 6-0- Methyl Erythromycin A. £xample-4 'reparation of Clarithromycin Form-II via Clarithromycin oxalate: 20 g wet Clarithromycin crude (on dry basis 100 g) is suspended in 1250 ml of Acetone, lie suspension is heated to 50°C and 20.20 g Oxalic acid dihydrate is added and refluxed 0 min. The solution is slowly cooled to room temperature & stirred for 2 hrs, then the esulting crystals were filtered & dried for 8 hr. at 67°-75°C to give 104-108g of Clarithromycin oxalate. 0 g of Clarithromycin oxalate is dissolved in 500 ml Methanol and filtered. The filtrate s heated to 55°C and 800 ml Aqueous Ammonia is added. The mass is then refluxed for 5 min and 2000 ml of D.M. water is added at 55°C. The solution is slowly cooled to 3om temperature & stirred for 6 Hrs, The resulting crystals were filtered & dried under acuum at 8-10 hrs at 55°C to give 42-44 g of Clarithromycin Form-II. Example 5, reparation of Clarithromycin Form-II via Clarithromycin oxalate: 20g wet Clarithromycin crude (on dry basis 100 g) is suspended in 1250 ml of Acetone, he suspension is heated to 50°C and 20.2 g Oxalic acid dihydrate is added and refluxed )r 30 min. The solution is slowly cooled to room temperature & stirred for 2 hrs, then le resulting crystals were filtered & dried for 8 hr. at 67°-75°C to give 104-108g of larithromycin oxalate. 0 g of Clarithromycin oxalate is dissolved in 500 ml Methanol and filtered. The filtrate i heated to 55°C and 90 ml of Triethylamine is added. The mass is then refluxed for 15 tin and 2400 ml of D.M. water added at 55°C. The solution is slowly cooled to room raiperature & stirred for 6 Hrs. The resulting crystals were filtered & dried under acuum at 8-10 hrs at 55°C to give 42 - 44 g of Clarithromycin Form-II. The present invention has the following advantages over prior art: 1. Meets the long felt need of the industry to develop cost effective, efficient and commercially viable process by the non-oxime route for the preparation of clarithromycin. 2. The yield of the intermediate, 2'-3'-N-Bis (Benzyloxycarbonyl) N-Demethyl Erythromycin A, is enhanced to over 80% as against the reported yield of 55% in the prior art. 3. It avoids the use of unsafe solvents such as benzene, chloroform, ether etc. 4. The quality of benzylchloroformate used in the present invention is reduced significantly by 60% to 80%, as compared to the prior art. 5. The reaction temperature for the methylation step is carried out at temperature 1-15°C as compared to around -10 to -12°C as in the prior art. 6. The laborious chromatographic process forthe isql^^ 3'-N-Bis (Benzyloxycarbonyl) N-Demethyl Erythromycin A, is replaced by a simple work-up process using solvents such as methyl isobutyl ketone, acetone, methylene chloride etc. giving yields of around 80% as compared to around 41% in the prior art. 7. The use of Pd/C catalyst has dramatically been reduced by 50% in one of the process options viz. hydrogenolysis and reductive formylation carried out in two steps with Pd/C in the first step and sodium borohydride in the second step. It is now possible to recycle of Pd/C in this process option, thereby reducing the cost substantially. 8. The reaction time has been significantly reduced in hydrogenolysis compared to prior art. 9. The process offers the option for the formation of the salts such as the oxalate, citrate, maleate, fumarate etc at the last stage of the process to enable a direct conversion to Clarithromycin Form-II. This is superior compared to prior art option of heating Form-0 or I of clarithromycin at a temperature ranging from 70 to 110°C for a prolonged period of time to prepare Form-II crystals, which has the problem of low productivity. 10. The invention offers a purer pharmaceutical grade of clarithromycin with high yields, by reducing the quantum of impurities in the methylation reaction and a work up procedure for isolation of major impurities. We claim: 1. An improved, high yielding and cost effective process for the preparation of clarithromycin, without the involvement of any oxime based synthesis comprising steps ■ Reacting Erythromycin A with benzylchloroformate to obtain 2\ 3',Bis (benzyloxycarbonyl) 6-O-methyl erythromycin A ■ Reacting 2', 3\Bis (benzyloxycarbonyl) 6-O-methyl erythromycin A with Methyl Iodide to obtain 2 \3' -bis(benzyloxycarbonyl)-N-demethyl Clarithromycin ■ Converting 2', 3' -bis (benzyloxycarbonyl) N-demethyl 6-O-methyl erythromycin A to Clarithromycin by hydrogenolysis ■ Further converting Clarithromycin to Clarithromycin Salt ■ Treating the Clarithromycin Oxalate / Citrate / Fumarate / Maleate, to form Clarithromycin Form-II 2. A process for the preparation of 2\ 3',Bis (benzyloxycarbonyl) 6-O-methyl erythromycin A wherein Erythromycin A is reacted with benzylchloroformate in the presence of Sodium bicarbonate in Tetrahydrofuran (THF) medium at about 30°C to 60°C for about 6hrs to 8hrs 3. A process as claimed in claim 1, wherein 2\ 3',Bis (benzyloxycarbonyl) 6-O-methyl erythromycin A is reacted with Methyl Iodide at about 0 to 15°C in the presence of alkali metal base such as Sodium hydride for 0.5 to 2 hrs in a mixture of Tetrahydrofurn and Dimethyl Sulfoxide to obtain 2',3'-Bis (benzyloxycarbonyl) N- demethyl 6-O-methyl erythromycin A 4. A process as claimed in claim 1, wherein the hydrogenolysis is carried out with Pd/C or Raney nickel catalyst at temperature of 25 to 50°C in Ethanol-water / Methanol-water mixture for 0.5 to 1.5 hrs followed by reductive formylation for 2 to 6 hrs at temperature of about 250C to about 50°C with Formaldehyde using Pd/C or Sodium borohydride, in Ethanol-water/Methanol-Water. 5. A process as claimed in claim 1 wherein the Clarithromycin Salt is prepared by reaction of Clarithromycin with organic acids such as Oxalic Acid/Citric Acid/Fumaic Acid/Maleic Acid etc. in solvents selected from acetone, methanol, ethanol, Isorpopanol, ethyl acetate, acetonitrile, tetrahydrofuran, N, N, dimethyl formamide or any other water miscible organic solvent. 6. A process as claimed in claim 1 wherein Clarithromycin Form II is prepared by treating the Clarithromycin salts such as the Oxalate/Citrate/Fumatare/Maleate, with a mixture of Water, Triethyl Amine or water, aqueous ammonia and a water miscible organic solvent selected from methanol, ethanol, isopropanol, acetone, ethyl acetate, followed by drying at about 60°C to about 65°C under vacuum.

Documents:

660-mas-2002- abstract.pdf

660-mas-2002- claims duplicate.pdf

660-mas-2002- claims original.pdf

660-mas-2002- correspondence others.pdf

660-mas-2002- correspondence po.pdf

660-mas-2002- description complete duplicate.pdf

660-mas-2002- description complete original.pdf

660-mas-2002- description provisional.pdf

660-mas-2002- drawings.pdf

660-mas-2002- form 1.pdf

660-mas-2002- form 3.pdf

660-mas-2002- form 4.pdf

660-mas-2002- form 5.pdf