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Title:
ERYTHROMYCIN A 9-O-PSEUDOSACCHARINYLOXIME DERIVATIVES AND PROCESS FOR THE PREPARATION OF CLARITHROMYCIN USING THE SAME
Document Type and Number:
WIPO Patent Application WO/2004/007518
Kind Code:
A1
Abstract:
The present invention relates to new erythromycin A 9-O-pseudosaccharinyloxime derivatives represented by Formula 1, and to a new method for preparing 6-O-methylerythromycin A (clarithromycin) as macrolide compound, represented by Formula 2, using the same: wherein R1 is hydrogen or a methyl group, and R2 is a trimethylsilyl group.

Inventors:
SHIN DONG-SEONG (KR)
RYOO UI-SANG (KR)
AN SEUNG-HO (KR)
Application Number:
PCT/KR2003/000813
Publication Date:
January 22, 2004
Filing Date:
April 22, 2003
Export Citation:
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Assignee:
KOREA UNITED PHARM INC (KR)
SHIN DONG-SEONG (KR)
RYOO UI-SANG (KR)
AN SEUNG-HO (KR)
International Classes:
C07H17/08; (IPC1-7): C07H17/08
Domestic Patent References:
WO1998004574A11998-02-05
Foreign References:
KR20010100197A2001-11-14
KR20020039951A2002-05-30
JPH11310592A1999-11-09
US5844105A1998-12-01
Attorney, Agent or Firm:
Kim, Hong-gyun (637-20 Yoksam-Don, Kangnam-Ku Seoul 135-080, KR)
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Claims:
What Is Claimed Is :
1. Erythromycin A 9pseudosaccharinyl derivatives represented by Formula 1 : wherein R1 is hydrogen or a methyl group, and R2 is hydrogen or a trialkylsilyl group.
2. The derivatives of Claim 1, wherein R1 is hydrogen, and R2 is a trimethylsilyl group.
3. The derivatives of Claim 1, wherein Ri is methyl, and R2 is a trimethylsilyl group.
4. A method for preparing clarithromycin, which comprises the steps of: reacting erythromycin A 90oxime derivatives of Formula 3 with pseudosaccharidinyl chloride of Formula 4 to give erythromycin A 90pseudosaccharinyloxime of Formula la, wherein R is trimethylsilyl; methylating the compound of Formula la with a methylating agent such that the 6hydroxy group of the compound of Formula la is substituted with the 6 methoxy group, thereby synthesizing 60methyl erythromycin A 90pseudosaccharinyloxime derivatives of Formula 1b ; and deprotecting the compound of Formula 1b to give clarithromycin of Formula 2:.
5. The method of Claim 4, wherein the step of preparing the compound of Formula la is carried out using pseudosaccharinyl chloride of Formula 4 at 1.0 2.0 equivalents relative to the compound of Formula 3 in an aprotic polar solvent in the presence of 1.02. 0 equivalents relative to the compound of Formula 4.
6. The method of Claim 4, wherein the step of methylating the compound of Formula la is carried out using a methylating agent selected from the group consisting of methane iodide, dimethyl sulfate and diazomethane, at 1.010 equivalents relative to the compound of Formula la, in an aprotic polar solvent in the presence of a base or Lewis acid.
7. The method of Claim 4, wherein the step of deprotecting the compound of Formula lb is carried out by reacting the compound of Formula 1b with formic acid or acetic acid of 12 equivalents and sodium hydrogen sulfite of 25 equivalents relative to the compound of Formula lb, in aqueous alcohol solution at a temperature of room temperature to the boiling point of the solvent, so that all the protecting groups are simultaneously removed in one reactor.
Description:
ERYTHROMYCIN A 9-O-PSEUDOSACCHARINYLOXIME DERIVATIVES AND PROCESS FOR THE PREPARATION OF CLARITHROMYCIN USING THE SAME

Technical Field The present invention relates to new erythromycin A 9- O-pseudosaccharidinyloxime derivatives represented by Formula 1, and a new method for preparing 6-0-methyl- erithromycin A (clarithromycin), as a macrolide compound, represented by Formula 2, using the same: wherein R1 is hydrogen or a methyl group, and R2 is a trimethylsilyl group.

Background Art Clarithromycin is a semi-synthetic macrolide antibiotic, which was first disclosed in Japanese Patent Laid-Open Publication No. Sho 57-2298 (laid-open date: January 1, 1982). This compound shows excellent antibacterial activity against various bacteria, such as gram-positive bacteria, some gram-negative bacteria, Mycoplasma, Helicobactor pylori, Chlamidia and the like, which cause a disease in human or mammal.

For example, methods for preparing clarithromycin are disclosed in European Patent Nos. 147,062, 158,467, 195,960, and 260,938, and US Patent Nos. 4,990, 602,5, 837,829, 5,929, 219,5, 892,008, 5,864, 023, and 5,852, 180.

Erythromycin A has a plurality of highly reactive hydroxy groups in a molecule thereof, and a ketone group at the 9-position in the molecule thereof tends to form an intramolecular acetal to produce a new hydroxy group. Thus, in synthesizing clarithromycin from erythromycin A, direct methylation of the 6-hydroxy group results in formation of an excessive amount of various undesired by-products in addition to the 6-methoxy group so that it is very difficult for clarithromycin to be commercially isolated and purified.

For this reason, as the most commercially useful method among the prior methods as described above, there can be mentioned a method wherein erythromycin 9-oxime derivatives are formed and the 6-hydroxy group is then substituted with the 6-methoxy group. In this case, the hydroxy group of the oxime moiety needs to be protected with a suitable substituent before methylation of the 6- hydroxy group.

The methods for synthesizing clarithromycin according to the prior art will now be described in further detail.

First, there can be mentioned a method disclosed in European Patent No. 158,467. In this method, as shown in Scheme 1, the oxime's hydroxy group of erythromycin A 9- oxime is introduced with a benzyl group and the like, and the 2'-hydroxy group and the 3'-dimethylamino group are protected with a benzyloxycarbonyl group, after which the 6-hydroxy group is methylated and the protecting group and the oxime group are then removed, thereby obtaining clarithromycin.

[Scheme 1] y. CBz OBn gzCO.., HO,. No T r>Ho<. . o< ;- HO HO 0 0', oc 'ORz 'OH 'OMe < bMe erythromycin A 9-oxime derivatives clarithromycin

However, benzyloxycarbonyl chloride used in this method is used in an excess amount, and also is an expensive, unstable, severely irritating compound.

Furthermore, in removing benzyloxycarbonyl chloride after the methylation reaction, additional steps are required, in which hydrogenation reaction unsuitable for mass production needs to be conducted, and then the methyl group left upon introduction of the benzyloxycarbonyl group into the 3'- amino group needs to be reproduced.

Second, there can be mentioned a method disclosed in European Patent No. 195,960. In this method, as shown in Scheme 2, derivatives are synthesized in which all the oxime's hydroxy group of erythromycin A 9-oxime, the 2'- hydroxy group and the 3'-dimethylamino group are protected with a benzyl group. Then, the 6-hydroxy group is methylated, and the protecting group and the oxime group are removed to give clarithromycin.

[Scheme 2] I-'bu r0 s*Bn si*-Bn I),.,.-clacithromycin HOI Hp t. 10 °. >-'OH 0'-""OH HO s HO t 0"0

However, this method likewise has problems in that the hydrogenation reaction unsuitable for mass production needs to be carried out in order to remove the protecting group, and the 2'-protecting group remains as an impurity even after the end of reaction without being easily removed.

Third, there can be mentioned a method disclosed in European Patent No. 260,938. In this method, as shown in Scheme 3, the oxime's hydroxy group of erythromycin A 9- oxime is protected with a benzyl group or a substituted benzyl group in a manner similar to Scheme 2, but the 2'- and 4"-hydroxy groups are protected with an easily removable silyl group. Then, the protecting group and the 9-oxime group are removed, thereby obtaining clarithromycin.

However, in this method, the hydrogenation reaction unstable for mass production needs to be likewise carried out in order to remove the protecting group and the oxime group.

[Scheme 3] wN r ^wN.. H°8-; zoo N Tlll,, O HOM < HOs HO ol HO,,.'..... HO,.,,, fl O'v,, HO.. '. w. dJ °O''r clarithromycin HO hp O) r^ ) TMS TMS Q TMS bM OMe t) M*''&Mt

Fourth, there can be mentioned a method disclosed in US Patent No. 5,837, 829. In this method, as shown in Scheme 4, all the oxime's hydroxy group of erythromycin A 9-oxime and the 2'-and 4"-hydroxy groups are protected with an easily removable silyl group, after which a methyl group is introduced into the 6'-hydroxy group, and then, the protecting group and the oxime group are removed to give clarithromycin.

[Scheme 4] TOD OT8DMS JF OTBOMS t OTBD 5 TMB OTB S TMSOs'r N-. m. ,..-. w HO)", >HOs O g) °"2eOs ° s darithromycin HO ^ "o U., y,. L., O HO HO 4MB OMe However, this method has a problem in that the silyl group used as the protecting group is very unstable in water, such that the methylation reaction of the 6-hydroxy <BR> <BR> group requires an extreme anhydrous Another problem is that the silyl group has very high flammability so that sodium hydride, which is difficult to be handled in mass production, needs to be used as a base.

Another method for preparing clarithromycin is disclosed in European Patent No. 272,110 and US Patent No.

4,990, 602. As shown in Scheme 5, the core of this method is to convert the oxime's hydroxy group of erythromycin A 9-oxime with easily removable acetal derivatives. Then, the 2'-and 4"-hydroxy groups are protected with a silyl group, and the 6'-hydroxy group is introduced with a methyl group, after which the protecting group and the oxime group which became unnecessary are removed to give clarithromycin.

[Scheme 5] tk N qz N' Ni Ni TMSQ.,. HO, l. 0, Nez no,, t HO"SM O 0><°is < clitiomycin HO' O, Oe,, p p' iI "OTMS 0 '"OTMS OMe OMe Although this method can be regarded as the most advanced method in terms of process yield, or selectivity to the 6-hydroxy group in methylation, it has problems in that total yield is only less than 40%, and the acetal derivatives for protection of the oxime's hydroxy group is used in an excessive amount of less than 10 equivalents.

Another problem is that, when the acetalization is maintained at an extreme anhydrous condition, the completion of the reaction is difficult so that process yield is reduced. In addition, it has a problem in that selectivity to the 6-position in methylation is only less than 90% such that various impurities produced together are not easily removed.

Korean Patent Laid-Open Publication Nos. 2001-47939 and 2001-10096 disclose methods for preparing clarithromycin from erythromycin using N-oxide according to Scheme 6.

[Scheme 6] 0 0 N N HC H Ho HO", *sNoAo---HO", ot clSithromycin "o-L, L"° vu ou Wo O ro 2 zozo orme These methods are simple methods wherein a methyl group is introduced into the 6-hydroxy group without protection of the 2'-and 4"-hydroxy groups, after which oxidation of N-oxide, and if necessary, removal of the 9- oxime, are carried out to give clarithromycin. However, these methods for preparing clarithromycin using the N- oxide intermediate have problems in that total yield is very low (less than 20%), and competitive by-products are caused at a large amount upon oxidation for introducing N- oxide and reduction for removing N-oxide such that these by-products are not easily removed. For these reasons, these methods are unsuitable for commercial use.

Korean Patent Laid-Open Publication Nos. 2000-57013 and 2001-100197 discloses new protecting groups for erythromycin A 9-oxime. In the method according to Korean Patent Laid-Open Publication No. 2000-57013,1, 3- benzodithiol-2-yilium as a protecting group is introduced into erythromycin A 9-oxime by means of 1, 3-benzodithiol-2-

ylium tetrafluoroborate. In the method according to Korean Patent Laid-Open Publication No. 2001-100197, a tropyl group as a protecting group is introduced into the oxime's hydroxy group by means of tropylium tetrafluoroborate. As a reagent for introducing these new protecting groups, tetrafluoroborate is used which contains extremely toxic fluorine and requires significant cares in its preparation and handling, and disposal of its waste. Moreover, since these protecting groups are not easily available commercially, there is an inconvenience in that the protecting groups must be prepared separately for use.

Also, because of this separate preparation, the protecting groups cause environmental pollution and have disadvantages with respect to their preparation process.

Disclosure of Invention An object of the present invention is to develop an intermediate useful for the preparation of clarithromycin and to provide a new, industrially applicable method by which clarithromycin is prepared at high yield in an efficient and simple manner using the developed intermediate.

Therefore, the present inventors have continued to study in an attempt to develop a new synthetic intermediate capable of solving the problems occurring in the above- mentioned techniques for the preparation of clarithromycin, and as a result, found that, when a pseudosaccharinyl group is introduced into the 9-oxime's hydroxy group of erythromycin A 9-oxim derivatives, selectivity to the 6- hydroxy group in methylation of the hydroxy group reaches the highest level, and also reaction yield reaches the

highest level. Furthermore, it was found that, when the pseudosaccharinyl group is introduced into the 9-oxime's hydroxy group, all protecting groups can be removed by only one step after methylation, to isolate clarithromycin as the desired product. On the basis of these points, the present invention was perfected.

The present invention provides erythromycin A 9-O- pseudosaccharinyl derivatives of Formula lb useful for synthesis of clarithromycin, which is obtained by reacting erythromycin A 9-oxime represented by Formula 3, or 2', 4"- disubstitutd derivatives of erythromycin A 9-oxime, with pseudosaccharinyl chloride represented by Formula 4, to give a new compound represented by Formula la, and conducting 6-O methylation of the compound of Formula la :

wherein R2 is a trimethylsilyl group.

Moreover, the present invention provides a new method by which clarithromycin is synthesized from the compound of Formula 1 at high yield in an economic manner. The method of the present invention comprises the steps of: reacting 2', 4"-O-bis (trimethylsilyl) erythromycin A 9-0-oxime of Formula 3 with pseudosaccharinyl chloride of Formula 4 in an aprotic polar solvent in the presence of a base, to obtain 2', 4"-0-bis (trimethylsilyl) erythromycin A 9-O- pseudosaccharinyloxime of Formula la ;

methylating the compound of Formula la with a methylating agent selected from the group consisting of methane iodide, dimethyl sulfate and diazomethane, in an aprotic polar solvent such that the 6-hydroxy group is substituted with the 6-methoxy group, thereby synthesizing 2', 4"-O-bistrimethylsilyl-6-0-methyl-etythromycin A-9-O- pseudosaccharinyloxime derivatives of Formula 1b ; and heating the compound of Formula 1b in a solvent mixture of water and organic solvent in the presence of organic or inorganic acid, so that all the protecting groups are removed, thereby obtaining clarithromycin of Formula 2.

Hereinafter, the present invention will be described in detail.

The present invention provides erythromycin A 9-O- pseudosaccharinyloxime derivatives of Formula 1 as described above. These compounds are new, and useful for the preparation of clarithromycin which is widely used as an antibiotic. For example, the erythromycin A 9-O- pseudosaccharinyloxime derivatives of Formula 1 can be easily prepared by reacting 2', 4"-0- bis (trimethylsilyl) erythromycin A 9-oxime of Formula 3 with pseudosaccharinyl chloride of Formula 4 in a suitable aprotic polar solvent in the presence of a base. 2'/4g-0~ bis (trimethylsilyl) erythromycin A 9-oxime used in this reaction can be easily prepared by a well known silylation method (for example, a method illustrated in Korean Patent Laid-Open Publication No. 10-1999-48084) using commercially available erythromycin A 9-oxime.

In this reaction, the amount of pseudosaccharinyl chloride is more than one equivalent, and preferably 1-2 equivalents, relative to 2'/4ff-0- bis (trimethylsilyl) erythromycin A 9-oxime.

The aprotic polar solvent that can be used in this reaction includes an ethereal solvent, such as

tetrahydrofuran, dimethoxyethane and 1,4-dioxane, an amide- based solvent, such as dimethylformamide and diethylformamide, an aprotic polar solvent, such as acetonitrile, dimethylsulfoxide and tetramethylenesulfone, and a mixture of two or more of the aprotic polar solvents.

Any solvent may be used if it does not adversely affect the reaction. The solvent can be used at the minimum amount required to dissolve the reactants in view of economical efficiency.

Also, in order to promote the reaction, a base can be used. Examples of the base include inorganic bases, including sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and sodium hydroxide, and organic bases, including alkoxide such as potassium t-butoxide, and tert-amine, such as pyridine, triethylamine, tripropylamine, diethylisopropylamine, tributylamine, 1, 8- diazabicyclo [5.4. 0] undec-7-ene, 1, 5-diazabicyclo [4.3. 0] non- ene and 1, 4-diazabicyclo [2.2. 2] octane. The base can be used at 1.0-2. 0 equivalents, and preferably 1.0-1. 2 equivalents, relative to pseudosaccharinyl chloride of Formula 4. Furthermore, the reaction can be usually carried out at a temperature of 0 °C to the boiling point of the solvent. Preferably, the reaction is carried out at 0 to 50 °C in view of reaction rate and the economic efficiency of a process.

The synthesized erythromycin A 9-O- pseudosaccharinyloxime derivatives of Formula la is useful in preparing clarithromycin by methylation of the 6-hydroxy group. In synthesizing clarithromycin from the compound of Formula lb, the 6-hydroxy group is substituted with the 6-

methoxy group to give the compound of Formula lb, and the protecting groups are then removed, thereby obtaining the desired product.

In preparing the compound of Formula 1b by methylating the 6-hydroxy group of the erythromycin A 9-O- pseudosaccharinyl derivatives of Formula la, the compound of Formula la is treated with a methylating agent, such as methyl iodide, dimethyl sulfate or diazomethane, in a suitable solvent in the presence of a suitable base or catalyst.

When the methylating agent, such as methyl iodide or dimethyl sulfate, is used to conduct 6-O methylation of the compound of Formula la, the amount of the methylating agent is suitably 1-10 equivalents relative to the compound of Formula la, in view of reaction rate and the degree of formation of by-products. Preferably, the methylating agent is used at 1.0-5. 0 equivalents relative to the compound of Formula la. The reaction can be usually carried out at a temperature of 0 °C to the boiling point of the solvent, and preferably 0-50 °C.

Furthermore, when diazomethane is used as the methylating agent, it can be used at 1-10 equivalents relative to the compound of Formula la, and added repeatedly at 1-2 equivalents each time in view of the progression of the reaction. The methylation reaction can be used at a temperature of 0 °C to the boiling point of the solvent, and preferably 0-50°C. In order to greatly promote the progression of the reaction, a conventional Lewis acid may be used as a catalyst.

After methylation, the compound of Formula 1b is deprotected according to a conventional deprotection

process, thereby isolating and purifying clarithromycin as the desired product. In other words, clarithromycin can be synthesized and isolated by a method wherein the pseudosaccharinyl group, the silyl group, the oxime group and the like are isolated stepwise from the compound of Formula 1b or simultaneously removed in one reactor without isolation of the intermediate. In view of the economic efficiency and expediency of a process, there is preferably used the method wherein the protecting groups are simultaneously removed in one reactor.

The pseudosaccharinyl group can be completely removed by treatment with an acid or base of a suitable concentration in a suitable solvent. Similarly, the oxime and silyl groups can be completely removed by treatment with an acid or base.

If the protecting groups are removed stepwise, the pseudosaccharinyl derivatives are first removed by treatment with dilute hydrochloric acid, dilute sulfuric acid, formic acid or the like while removing the trimethylsilyl group, after which the 9-oxime group is removed by means of sodium sulfite, thereby obtaining clarithromicin as the desired product.

If all the protecting groups are removed in one reactor, in view of the shortening and economical efficiency of a process, the 9-pseudosaccharinyl derivatives are first treated with formic acid or the like in a suitable solvent to remove the pseudosaccharinyl group and the silyl group, and then, sodium sulfite is added to the reaction solution to remove the 9-oxime group, thereby obtaining clarithromycin as the desired product.

In preparing clarithromycin by methylating erythromycin A 9-0-pseudosaccharinyloxime derivatives

according to the present invention, the process is carried out in a gentle manner, the pseudosaccharinyl group is easily introduced and isolated, and also clarithromycin as the desired product is easily isolated.

Best Mode for Carrying Out the Invention The present invention will hereinafter be described in further detail by examples. It should however be borne in mind that the present invention is not limited to or by the examples. In the examples, temperature is given in Celsius (°C).

Preparation 1: 2', 4"-O-bis (trimethylsilyl) erythromycin A 9-oxime 50 g of erythromycin A 9-oxime and 4.63 g of ammonium chloride were dissolved in 200 ml of dimethylformamide. To the solution, 38.7 g of hexamethyldisilazane was added dropwise at a temperature of 30-40 °C for 20 minutes. The mixture was stirred for 5 hours at the same temperature, followed by cooling to room temperature, after which 23.3 ml of an aqueous 4N-sodium hydroxide solution was added.

After additional stirring for one hour at room temperature, the stirred material was dissolved by addition of 200 ml of pure water and 20 g of salt, and the solution was stirred for two hours at less than 10 °C. The produced solid was filtered, washed with 100 ml of pure water and 100 ml of hexane in order, and then air-dried for 12 hours at 50 °C, thereby obtaining 53.65 g (90%) of 2//4"~0~ bis (trimethylsilyl) erythromycin A 9-oxime as a white powdered solid.

Preparation 2: Pseudosaccharinyl chloride 5 g of saccharin was suspended in 20 ml of benzene chloride. 6.8 g of phosphorous pentachloride was added to the suspension, which was then heated for 2 hours at 130 °C.

The heated solution was cooled to less than 10 °C and stirred for 1 hour. The produced solid of the reaction solution was filtered and recrystallized from 15 ml of benzene, thereby obtaining 5 g (91%) of pseudosaccarinyl chloride as a white solid.

Example 1 : Preparation of 2', 4"-0- bis (trimethylsilyl) erythromycin A 9-O- pseudosaccharinyloxime 5 g of 2', 4"-0-bis (trimethylsilyl) erythromycin A 9- oxime was dissolved in 35 ml of pyridine and cooled to a temperature of 0-5 °C. To the mixture, 1.35 g of pseudosaccharinyl chloride was added and stirred for 3.5 hours at the same temperature. To the stirred material, 30 ml of pure water and 70 ml of hexane were added, and stirred for 5 minutes and then extracted. The organic layer was washed twice with 30 ml of saltwater, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, thereby obtaining 5.39 g (91%) of 2', 4"-O-bis (trimethylsilyl) erythromycin A 9-O- pseudosaccharinyloxime as a foamy solid.

5.39 g of the obtained foamy 2', 4"-0- bis (trimethylsilyl) erythromycin A 9-0- pseudosaccharinyloxime was dissolved in 45 ml of acetone, and cooled to a temperature of 0-5 °C. To the cooled material, 60 ml of pure water of the same temperature was added slowly with stirring for one hour. Then, the

produced solid was filtered and dried under reduced pressure for 8 hours at room temperature, thereby obtaining 4.31 g (80%) of 2', 4"-0-bis (trimethylsilyl) erythromycin A 9-0-pseudosaccharinyloxime as a white solid.

1H-NMR (CDC13, ppm): 7.79-7. 67 (m, 4H), 5.04 (d, 1H), 4.82 (d, 1H), 4.41 (d, 1H), 3308 (s, 3H), 2.28 (s, 6H), 0.10 (s, 9H), 0.08 (s, 9H).

Example 2: Preparation of 2', 4"-O-bistrimethylsilyl-6- O-methylerythromycin A 9-O-pseudosaccharinyloxime 2 g of 2', 4"-0-bis (trimethylsilyl) erythromycin A 9-O- pseudosaccharinyloxime was dissolved in 35 ml of tetrahydrofuran and cooled to a temperature of 0-5 °C, to which 0.32 g of BF3-etherate was then added. To the mixture, 31.6 ml of 3% diazomethane in ethylether was added in four steps at 1.5-hour intervals. The resulting material was stirred for two hours at the same temperature, after which the white floating material was removed by filtration and the filtrate was concentrated at 20 °C. The residue was dissolved in 30 ml of dichloromethane, washed with 20 ml of pure water and 20 ml of 10% saltwater in order, and then concentrated by evaporation under reduced pressure, thereby obtaining 1.84 g (91%) of 2', 4"-O-bistrimethylsilyl-6-O- methyl erythromycin A 9-0-pseudosaccharinyloxime as a foamy solid. 1 g of the obtained solid was purified by silica gel chromatography to give 0.85 g (85%) of pure 2', 4"-O- bistrimethylsilyl-6-O-methylerythromycin A 9-O- pseudosaccharinyloxime. lH-NMR (CDCI3 ppm) : 7. 79-7. 67 (m, 4H), 3. 30 (s, 3H), 3.23 (s, 3H), 2.20 (s, 6H), 0.06 (s, 9H), -0.09 (S, 9H)

Example 3: Preparation of 6-O-methylerythromycin A 9- oxime 5.0 g of 2', 4"-O-bistrimethylsilyl-6-0- methylerythromycin A 9-0-pseudosaccharinyloxime was dissolved in 10 ml of methanol, to which 43.3 g of formic acid was then added. The mixture was heated under reflux for 4 hours. The solution was cooled to room temperature, and added with 10 ml of pure water, and then adjusted to a pH of 10-11 with an aqueous solution of 5N-sodium hydroxide.

Then, the solution was cooled to a temperature of 0-5 °C, stirred for one hour, and filtered. The obtained solid was washed with 5 ml of cold pure water to give 3.2 g (90%) of the white title compound. 1 g of the resulting solid was purified by silica gel chromatography to give 0.9 g (90%) of the pure title compound.

1H-NMR (CDCI3, ppm) : 5.09 (dd, 1H), 4.93 (d, 1H), 4.43 (dd, 1H), 4. 01 (m, 1H), 3.77 (s, 1H), 3.64 (d, 1H), 3. 45 (m, 1H), 3.33 (m, 1H), 3.32 (S, 3H), 3.20 (m, 1H), 3.09 (s, 3H), 3.01 (m, 1H), 2.87 (m, 1H), 2.56 (m, 1H), 2.40 (m, 1H), 2.31 (m, 2H), 2.28 (s, 6H), 2. 00-1. 80 (m, 3H), 1.41 (m, 1H), 1. 24-1. 07 (m, 27H), 1. 13 (s, 3H), 0.85 (t, 3H) Example 4: Preparation of 6-0-methylerythromycin acetate 2 g of 2', 4"-O-bis (trimethylsilyl) erythromycin A 9-O- pseudosaccharinyloxime was dissolved in 35 ml of well-dried dimethylformamide and cooled to a temperature of 0-5 °C.

The solution was added with 87 mg of 60% sodium hydride and stirred for 20 minutes at the same temperature. To the stirred material, 286 mg of dimethyl sulfate was added, and the mixture was stirred for 5 hours at the same temperature.

The stirred solution was added with 20 ml of water and 35 ml of ethyl acetate and stirred, and the organic layer was isolated. The organic layer was washed with 10 ml of pure water and 10 ml of 10% saltwater, respectively, and then concentrated by evaporation under reduced pressure to yield 1.84 g (91%) of foamy 2', 4"-O-bistrimethylsilyl-6-0- methylerythromycin A 9-0-pseudosaccharinyloxime. The foamy crude product was dissolved in a mixture of 10 ml ethanol and 10 ml pure water, and added with 0.2 g of formic acid and 0.8 g of sodium hydrogen sulfite, and then heated under reflux for 4 hours. After cooling to room temperature, the resulting material was added with 10 ml of pure water and 20 ml of ethyl acetate, and stirred well while it was adjusted to a pH of 10-11 with an aqueous solution of 5N- sodium hydroxide. The organic layer was isolated, washed with 10 ml of pure water, and then dried over anhydrous magnesium sulfate. At 10 °C, 0.30 g of acetic acid diluted in 2 ml of ethyl acetate was added dropwise to the resulting solution which was then stirred for two hours at the same temperature. The resulting solid was filtered, washed with ethyl acetate, and then air-dried for 12 hours at 40 °C to yield 0.9 g (620) of 6-0-methylerythromycin A acetate as a while solid.

Melting point: 219-220 °C.

1H-NMR (CDCI3, ppm) : 5.05 (dd, 1H), 4.91 (d, 1H), 4.46 (d, 1H), 4.01 (m, 1H), 3.76 (s, 1H), 3.74 (dd, 1H), 3.67 (d, 1H), 3.54 (m, 1H), 3.33 (s, 3H), 3.04 (s, 3H), 2.02 (s, 3H), 1.41 (s, 3H), 0.85 (t, 3H) Example 5: Preparation of 6-0-methylerythromycin A (clarithromycin)

1 g of 6-0-methylerythromycin A 9-oxime was dissolved in a mixture of 5 ml ethanol and 5 ml pure water, and added with 90.7 mg of formic acid and 409 mg of sodium hydrogen sulfite, and then heated under reflux for 4 hours. After being cooled to room temperature, the solution was added with 5 ml of pure water and 10 ml of ethyl acetate, and neutralized with sodium carbonate. The organic layer was isolated, washed with 5 ml of pure water, dried over anhydrous magnesium sulfate, and then concentrated by evaporation under reduced pressure. The residue was recrystallized from 7 ml of ethanol to give 0.623 g (63.5%) of clarithromycin in crystal form (crystal form I).

Example 6: Preparation of 6-0-methylerythromycin A acetate 5.0 g of 2', 4"-O-bistrimethylsilyl-6-0- methylerythromycin A 9-0-pseudosaccharinyloxime was dissolved in a mixture of 25 ml ethanol and 25 ml pure water, and added with 0.5 g of formic acid and 2.0 g of sodium hydrogen sulfite, and then heated under reflux for 4 hours. After being cooled to room temperature, the resulting material was added with 25 ml of pure water and 50 ml of ethyl acetate, and stirred well while it was adjusted to a pH of 10-11 with an aqueous solution of 5N- sodium hydroxide. The organic layer was isolated, washed with 25 ml of pure water, and then dried over anhydrous magnesium sulfate. At 10 °C, 0.83 g of acetic acid diluted in 5 ml of ethyl acetate was added dropwise to the resulting solution which was then stirred for two hours at the same temperature. The resulting solid was filtered, washed with ethyl acetate, and then air-dried for 12 hours

at 40 °C to yield 3.07 g (88%) of 6-O-methylerythromycin acetate as a while solid.

Melting point : 220~221C 1H-NMR (CDCI3, ppm) : 5.05 (dd, 1H), 4.91 (d, 1H), 4.46 (d, 1H), 4.01 (m, 1H), 3.76 (s, 1H), 3.74 (dd, 1H), 3.67 (d, 1H), 3.54 (m, 1H), 3.33 (s, 3H), 3.04 (s, 3H), 2.02 (s, 3H), 1.41 (s, 3H), 0.85 (t, 3H) Example 7: Preparation of 6-O-mathylerythromycin A acetate 3.0 g of 6-0-methylerythromycin was dissolved in a mixture of 9 ml chloroform and 1 ml methanol, to which 0.275 ml of acetic acid was then added dropwise for 10 minutes at room temperature. The solution was stirred for 20 minutes at room temperature, and added with 25 ml of hexane, and then additionally stirred for 10 minutes. The produced solid was filtered, washed with 10 ml of hexane, and then air-dried for 3 hours at 60 °C to give 3.16 g (97. 5%) of the title compound.

Example 8: Preparation of 6-0-methylerythromycin A (clarithromycin) crystal (crystal form 2) 0.60 g of clarithromycin obtained in Example 4 was suspended in a mixture of 2 ml ethanol and 2 ml pure water, and dissolved by addition of 44.2 mg of formic acid, followed by filtration. The filtrate was heated to a temperature of 50-55 °C, and added with 1.2 ml of 28% ammonia water at the same temperature, and then cooled to less than 10 °C. At the same temperature, the resulting material was stirred for two hours, and the produced solid was filtered. The obtained solid was washed with 3 ml of a

2: 1 mixture of pure water and ethanol, and air-dried for 12 hours at 45-50 °C to give powdered clarithromycin (crystal form 2).

1H-NMR (CDCI3, ppm) : 5.02 (dd, 1H), 4.90 (d, 1H), 4.41 (d, 1H), 4.00 (m, 1H), 3.78 (s, 1H), 3.64 (m, 1H), 3.57 (m, 2H), 3.33 (s, 3H), 3.20 (m, 1H), 3. 07-2. 95 (m, 2H), 3.01 (S, 3H), 2.87 (m, 1H), 2.58 (m, 1H), 2.40 (m, 1H), 2.37 (m, 2H), 2. 28 (s, 6H), 2. 00-1. 80 (m, 3H), 1.41 (m, 1H), 1. 24-1. 07 (m, 27H), 1.13 (s, 3H), 0.85 (t, 3H) Example 9: Preparation of 6-0-methylerythromycin A (clarithromycin) crystal (crystal form II) 5.0 g of clarithromycin acetate obtained by the method as described in Example 5 or 6 was dissolved in a mixture of 20 ml ethanol and 20 ml pure water, followed by filtration. The filtrate was heated to a temperature of 50-55 °C, and added with 1.2 ml of 28% ammonia water at the same temperature, and then cooled to less than 10 °C. At the same temperature, the resulting material was stirred for two hours, and the produced solid was filtered. The obtained solid was washed with 3 ml of a 2: 1 mixture of pure water and ethanol, and air-dried for 12 hours at 45-50 °C to give 4.31 g (93%) of powdered clarithromycin (crystal form II).

Industrial Applicability As described above, the present invention provides the method for preparing 6-0-methylerythromycin A using the erythromycin A 9-0-pseudosaccharinyl derivatives. The method of the present invention has the following effects

and inventive steps as compared to the prior art.

First, in the present invention, saccharin, which is inexpensive and widely used as food additives due to its secured safety, is used as a protecting group for the hydroxy group, so that 6-0-methylerythromycin can be prepared in an economical manner as compared to the prior art utilizing other expensive protecting groups.

Second, the present invention shows high selectivity to 6-O in methylation, and thus, minimizes production of by-products to make the isolation and purification of the desired product very easy. In other words, the present invention is advantageous in that it shows high selectivity to 6-O of more than 91% in 6-O methylation, so that side reactions are significantly reduced and thus the isolation and purification of the desired product become easy.

Third, all the protecting groups, including the oxime protecting group, the oxime group, and the 2'-and 4'- position protecting groups, are simultaneously removed by only one reaction, so that a reaction process is significantly shortened. High-pressure hydrogenation required to remove the benzyl group and the like used in the prior art is carried out in a very limited manner in view of its technical property, and has a risk of explosion and the like, and is not easily completed such that significant cares and efforts are required for the isolation and purification of a product. However, in the present invention, the pseudosaccharinyl group is completely removed even by weak acids, and the oxime and silyl groups and the like, which remains after removal of the protecting group in the prior art, are simultaneously removed in the same reactor. For this reason, the present invention has an effect in that a preparation process is

greatly shortened.

Fourth, in the present invention, clarithrothromycin produced after removal of all the protecting groups can be obtained intact or after conversion into the form of an acid addition salt. Since this acid addition salt can be easily converted into crystal form II of clarithromycin by neutralization (see, WO 98-04574), the present invention is highly advantageous with respect to a preparation process, as compared to the prior art wherein crystal form II of clatithromycin is prepared by a multi-step process.