FIELD OF THE INVENTION This invention relates to processes for making clarithromycin and the products used in these processes; e. g., erythromycin A 9-alkylidenehydrazones, erythromycin A 9- alkyl-and 9-arylsulfonylhydrazones, erythromycin A 9-N-alkylhydrazones and erythromycin A 9-N, N-dialkylhydrazones.

BACKGROUND OF THE INVENTION Clarithromycin is a semi-synthetic macrolide antibiotic marketed under the name Biaxin (R) in the United States. It is indicated for the treatment of mild to moderate infections caused by susceptible strains of certain microorganisms under certain conditions, including pharyngitis/tonsillitis due to Streptococcus Pyogenes, acute maxillary sinusitis due to Haemophilus Influenzae, Moraxella Catarrhalis, or Streptococcus Pneumoniae, acute bacterial exacerbation of chronic bronchitis due to Haemophilus Influenzae, Moraxella Catarrhalis, or Streptococcus Pneumoniae, pneumonia due to Mycoplasma Pneumoniae, or Streptococcus Pneumoniae, uncomplicated skin and skin structure infections due to Staphylococcus Aureus, or Streptococcus Pyogenes, disseminated mycobacterial infections due to Mycobacterium Avium, or Mycobacterium Intracellulare. Clarithromycin, in combination with omeprazole capsules, is indicated for the treatment of patients with an active duodenal ulcer associated with H. Pylori infection.

Clarithromycin is 6-O-methyl erythromycin A. However, it has not been possible to directly methylate erythromycin A selectively at the 6 position. See, for example, S. Morimoto et al., J. Antibiotics 37,187 (1984) in which direct methylation yielded a combination of 6-O-methyl, 11-0-methyl, and 6,11-dimethylated erythromycin A, in an overall yield of 79% and a ratio of approximately 4: 1: 6. It has been found, however, that various protecting groups can not only prevent methylation at the protected sites, but can influence the relative amounts of methylation at unprotected sites. See Y. Watanabe, J.

Antibiotics 46,647 (1993) and the patents discussed below. Clarithromycin and erythromycin A have the following chemical structures: 0 C OHH3 H3C\ C H3 OH 6 _ _HO CH CH"o H3C < O 4° XCH3 O LOCHS CH3 CH3 0 OH CH3 4" Clarithromycin 0 H3C 11'CH3 OHOHCHs OH-CH3 HO HOT--7 CH3CH2' 110OCH3 oCH3 OH CH3 Erythromycin A

U. S. 4, 331,803 describes a process for making clarithromycin from erythromycin A by converting erythromycin A to it's 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 or sodium amide, column chromatography, removal of the benzyloxycarbonyl protecting groups by hydrogenolysis and remethylation of the 3'-N by reductive formylation. The total yield is low, about 6 %.

U. S. 4,672,109 describes a modification of this process in which the 9- carbonyl group of a 2', 3'-bis-benzyloxycarbonyl 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 7 process steps, including chromatographic purification, and the yield is still relatively low, about 13%.

U. S. 4,680,386 also describes a modification of the process of the'109 patent in which the 9-carbonyl group is protected as a benzylated oxime rather than an alkyl oxime.

The reported yield from erythromycin A is about 24%.

U. S. 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 5, the overall yield is about 30%. See also Y.

Watanbe et al., Heterocycles 36 (2), 243 (1993), disclosing the benzylated oxime route.

Y. Watanabe et al., J. Antibiotics 46,1163 (1993) discloses that benzyl chloroformate, used to generate the 2'-0,3'-N-bis (benzyloxycarbonyl) protecting groups, is severely irritating and toxic. In that paper and in EP 260,938, a route is disclosed which avoids the use of benzyl chloroformate, in which the 2'and 4"hydroxy groups are silylated with trimethylsilyl chloride and trimethylsilyl imidazole after oximation and benzylation of the oxime OH, which also appears to increase the regiospecificity of the 6-OH methylation.

The overall yield from erythromycin A is about 34%.

U. S. describes a modification of the process of EP 260,938 utilizing specific oxime derivatives. The yield based on erythromycin A is about 39%.

U. S. 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-bis (O-trimethylsilyl)-Erythromycin A 9-oxime, and 2', 4", (O- trimethylsilyl) erythromycin A-6,9-hemiketal.

WO 97/19096 describes a process for 6-O-alkylation of erythromycin A 9- oxime derivatives (among other substrates) by using a combination of a weak organic base, such as trimethylamine, pyridine, N-methylpyrrolidine, N-methyl piperidine and a strong base, such as alkali metal hydride, alkali metal hydroxide, or alkali metal alkoxides.

Erythromycin A 9-hydrazone was reported in 1956 by M. V. Sigal et. al., J.

Am. Chem. Soc. 78,388 (1956). Erythromycin A 9-hydrazone and Erythromycin A 9- isopropylidinehydrazone are disclosed in DE 1966310. U. S. 4,957,905 also discloses 9-N- substituted derivatives of erythromycins, including 9-isopropylidenehydrazone, and claims pharmaceutical compositions containing them useful for treating bacterial infections in humans and animals. However, the'905 patent does not describe the O-methylation of such hydrazones, nor the use of such hydrazones to synthesize clarithromycin or its derivatives.

The'905 patent also states that"the 9-keto group of erythromycin reacts only sluggishly with hydrazine itself and does not react with substituted hydrazines such as phenyl hydrazine and semicarbazide" (citing M. V. Sigal, Jr., et al, J. Amer. Chem Soc. 78,388-395 (1956)) (col. 2, lines 22-27).

SUMMARY OF THE INVENTION It has now been found that clarithromycin may be synthesized from erythromycin A by way of an alkylidenehydrazone or an arylsulfonylhydrazone.

Regioselectivity of methylation is high, and yields of the methylation step are comparable to the best reported oxime-based syntheses; the reagents (hydrazine hydrate and, for example, acetone or p-toluene sulfonyl chloride) are inexpensive, and unlike the previously reported clarithromycin syntheses utilizing silyl protecting groups, silylation may be accomplished without the use of the relatively expensive trimethylsilyl imidazole. It has also been found that clarithromycin may beneficially be prepared from erythromycin A 9-N- alkylidenehydrazones, erythromycin A 9-N-alkylsulfonylhydrazones, erythromycin A 9-N- arylsulfonylhydrazones, erythromycin A 9-N-alkylhydrazones and erythromycin A 9-N, N- dialkylhydrazones.

DETAILED DESCRIPTION OF THE INVENTION In a first embodiment of the invention, synthesis of clarithromycin starts with the preparation of erythromycin A 9-hydrazone (Compound II in the chemical synthesis illustrated below), which has been described in the literature. Commonly used reagents for hydrazone formation may be used, including hydrazine, hydrazine hydrate, hydrazine sulfate, hydrazine acetate, hydrazine hydrochloride, hydrazine dihydrochloride, and hydrazine hydrobromide. The preferred reagent is hydrazine hydrate.

The hydrazone group may then be protected with a group selected from alkylidenes or arylsulfonyls (Compounds IIIa and IIIb in the chemical synthesis illustrated below). Alkylidenehydrazones are formed preferably as alkylidene addition compounds with a ketone or aldehyde of up to 7 carbon atoms, preferably acetone or methyl ethyl ketone; of diaryl ketones, preferably benzophenone or alkyl-or halogeno-substituted benzophenones, of dicycloalkylketones, preferably with six or fewer carbon atoms in the rings, such as

dicyclohexylketone; and of cycloalkylaryl ketones such as cyclopentylphenylketone.

Preferably, the alkylidene group is isopropylidene, derived from reaction with acetone or a source of acetone such as 2,2-dimethoxypropane.

Arylsulfonylhydrazones may be formed by the reaction of an erythromycin A 9-hydrazone with an arylsulfonylhalide, such as benzene sulfonyl chloride or p-toluene sulfonyl chloride. Alternatively, arylsulfonyl hydrazones of erythromycin A or its derivatives may be formed directly by the reaction of Erythromycin A with arylsulfonyl hydrazides.

The hydrazone group may also be protected with an alkylsulfonyl. The alkyl group of the alkylsulfonyl may be a straight or branched alkyl group containing 1-7 carbon atoms. A preferred alkylsulfonyl group is a methylsulfonyl group.

The erythromycin A 9-alkylidenehydrazone or erythromycin A 9-alkyl-and arylsulfonylhydrazone may be represented by the following formula A: wherein Rla and R, b may both be H, or may be together =CR5R6 wherein R5 and R6 are selected from the group consisting of H, alkyl or halogeno-substituted alkyl of up to 7 carbons, and aryl of up to 6 carbon atoms, with one or more substituents on the aryl group selected from the group consisting of H, alkyl, phenyl, and halogeno; or, additionally, Rla may be H; when Ria is H, R, b is R7SO2-, R7 is aryl with one or more substituents on the aryl group selected from the group consisting of H, alkyl, phenyl, and halogeno or R, is a straight or branched alkyl group containing 1-7 carbon atoms; R, and R3 are selected from the group

consisting of H, RgR9R, oSi, and R"CO; R8, R9, Rio and R,, are selected from the group consisting of alkyl, aryl, and aralkyl; R4 is selected from the group consisting of H and CH3, with the proviso that where Ria and Rib are both H, or where Rla and R, b together are =C (CH3) 2, and R, and R3 are both H, R4 is CH3.

The hydroxy groups other than the 6-hydroxy group of erythromycin A 9- alkylidenehydrazone, erythromycin A 9-alkylsulfonylhydrazone and erythromycin A 9- arylsulfonylhydrazone may then be protected to produce hydroxy protected erythromycin A 9-alkylidenehydrazone, hydroxy protected erythromycin A 9-alkylsulfonylhydrazone and hydroxy protected erythromycin A 9-arylsulfonylhydrazone. For example, the hydroxy groups may be silylated using conventional techniques to produce Compounds IVa and IVb in the chemical synthesis illustrated below. While other silylation reagents may be used, such as chlorotrimethylsilane, chlorodimethylethylsilane, chlorodimethylisopropylsilane, chlorodimethyl-octylsilane, chlorodimethylvinylsilane, chlorodimethylphenylsilane, chlorotriisopropylsilane, chloro-t-butyldimethylsilane and hexamethyldisilazane, it has been found that the trimethylsilyl group is effective, and that 2', 4" bis (trimethylsilyl) ation may be accomplished without the use of the more expensive trimethylsilyl imidazole, used in previously reported syntheses of clarithromycin, in apparently quantitative yield. Protective groups other than silyl may be used, for example, acetyl and acyl groups. Preferred acylation reagents are acetyl chloride, acetic anhydride, benzoyl chloride, and benzoic anhydride.

Methylation at the 6-OH position of the hydroxy protected erythromycin A 9- alkylidenehydrazone, hydroxy protected erythromycin A 9-alkylsulfonylhydrazone and hydroxy protected erythromycin A 9-arylsulfonylhydrazone may be performed conventionally, with a methylating reagent such as methyl iodide, methyl bromide, methyl chloride, dimethyl sulfate, methyl p-toluene sulfate, or methyl methanesulfonate, and a base such as sodium hydride, butyl lithium or potassium hydroxide. The reaction can be carried out in aprotic solvents, such as DMSO, THF and DMF.

This methylation produces hydroxy protected clarithromycin 9- alkylidenehydrazone, hydroxy protected clarithromycin 9-alkylsulfonylhydrazone and hydroxy protected clarithromycin 9-arylsulfonylhydrazone such as Compounds Va and Vb (as set forth in the chemical synthesis illustrated below).

The hydroxy protected clarithromycin 9-alkylidenehydrazone, hydroxy

protected clarithromycin 9-alkylsulfonylhydrazone and hydroxy protected clarithromycin 9- arylsulfonylhydrazone may then be deprotected, e. g., desilylated with conventional desilylation reagents, such as tetrabutylammonium fluoride or in the presence of acids to give Compounds VIa and VIb (as set forth in the chemical synthesis illustrated below). This deprotection results in the formation of clarithromycin 9-alkylidenehydrazone, clarithromycin 9-alkylsulfonylhydrazone and clarithromycin 9-arylsulfonylhydrazone.

Clarithromycin may then be formed from the clarithromycin 9- alkylidenehydrazone or the clarithromycin 9-alkyl-and 9-arylsulfonylhydrazone by conversion of the 9-alkylidenehydrazone and the 9-alkyl-and 9-arylsulfonylhydrazone groups to a 9-keto group. This conversion may be a one or two step sequence. For example, in the two step sequence, reaction with hydrazine removes the alkylidene group yielding clarithromycin 9-hydrazone (Compound VII in the chemical synthesis illustrated below). The 9-hydrazone may then be converted into clarithromycin (Compound VIII in the chemical synthesis illustrated below) with NaOCI, CuCl,, Br, with CH3COOH and benzeneselninic anhydride. Alternatively, the alkylidene or alkyl-and arylsulfonylhydrazone protecting group <BR> <BR> <BR> <BR> <BR> can be removed in one step (Compound VI-Compound VIII). For example, the isopropylidenehydrazone group can be removed in a single step by treatment with cupric salts, such as cupric chloride, cupric acetate, and cupric sulfate, preferably cupric chloride.

The isopropylidenehydrazone group can also be removed in a single step with bromine in acetate buffer. These steps have not been optimized. Some examples of the process of the invention are set forth below in Examples 1 through 11.

In a second embodiment of the invention, erythromycin A (Compound I in the chemical synthesis illustrated below) is reacted with an alkylhydrazine or a dialkylhydrazine to form the resulting erythromycin A 9-N-alkylhydrazone or erythromycin A 9-N, N- dialkylhydrazone, respectively. For example, erythromycin A is reacted with dimethylhydrazine or methylhydrazine to provide erythromycin 9-N, N-dimethylhydrazone or erythromycin 9-N-methylhydrazone.

The alkyl group of the alkylhydrazine may be a straight or branched chain alkyl group containing from 1-7 carbon atoms. Each of the alkyl groups in the dialkylhydrazine may also be a straight or branched chain alkyl group containing 1-7 carbon atoms. Such alkyl groups include, for example, methyl, ethyl, propyl and butyl groups, etc.

Thus, the alkyl group of the erythromycin A 9-N-alkylhydrazone or erythromycin A 9-N, N- dialkylhydrazone may be a straight or branched alkyl group of 1-7 carbon atoms.

Clarithromycin may then be prepared from erythromycin A 9-N- alkylhydrazone and erythromycin A 9-N, N-dialkylhydrazone. For example, erythromycin A 9-N-alkylhydrazone and erythromycin A 9-N, N-dialkylhydrazone may then be subjected to the same steps for preparation of clarithromycin as outlined above (in regard to the first embodiment) and illustrated below. Such a process may include the following steps: (a) conversion of erythromycin A into erythromycin A 9-N-alkylhydrazone or erythromycin A 9-N, N-dialkylhydrazone; (b) hydroxy group protection of erythromycin A 9-N- alkylhydrazone or erythromycin A 9-N, N-dialkylhydrazone to form hydroxy group protected erythromycin A 9-N-alkylhydrazone or hydroxy group protected erythromycin A 9-N, N- dialkylhydrazone; (c) methylation of hydroxy group protected erythromycin A 9-N- alkylhydrazone or hydroxy group protected erythromycin A 9-N, N-dialkylhydrazone to form hydroxy group protected 6-O-methyl erythromycin A 9-N-alkylhydrazone or hydroxy group protected 6-O-methyl erythromycin A 9-N, N-dialkylhydrazone; (d) replacement of hydroxy group protection from hydroxy group protected 6-O-methyl erythromycin A 9-N- alkylhydrazone or hydroxy group protected 6-O-methyl erythromycin A 9-N, N- dialkylhydrazone with hydrogen; and (e) removal of the 9-N-alkylhydrazone or 9-N, N- dialkylhydrazone group followed by formation of a 9-keto group.

The following is an illustration of the chemical synthesis of preparing clarithromycin according to the first embodiment of the invention. 0 H Ha NNHy R1a p OH H3 CHgN-R H3C., N'H3C CHg N tb CH3 OH.. CH3 H H3C CH3 Oa OH CH3 CoHH Oh3, OH..H, N OCH3 H3C CH3 (COH 3 0 0OCH3 CH3CH2"0 0 C 0-\OH CHa L-CHs CH : n\. OH Chu p OH CH3 (CH3 cl3 OH CHa-.1, CH3 CH3 1 erythromycinA 11 erythromyclnA9hydrazone Illa erythromyclnA 9-isopropylidenehydrazone or Illb erythromycinA 9-arylsuifonylhydrazone R"R7e R1e . N R Nue HgC CH3 N N R N, N-Rie HaC CH3 H3C CH3 H3C CH3 3C CH H3 CHg HgC,, H'OH OCH3 H"3 OH OH H3 CH3 OH.. CHOO N H3w OH..HgR ? N H3w OH.. CHgRO NI OH OH CH2'0'*0OCH3 3CH2"0 0OCH3 CH3CH2 00'0 OCH3 OCHg OCHg.. OCH3 OH OR3-OR3 CH3 CH3 CH3 3 Va Vb. Z, 4", 9-protected clarithromycin Na, IW. 2', 4", 9 protected erythromycin A Vb. clarithromysm 9-alkylidenehydrazone or Vlb. clarithromycin 9 arylsulfonylhydrazone 0 N-NH2 H3C CH3 H3C CH3 Ot'ri'OCH, HC CH''-''OH/CHs N HCH3 N CH3CH20IH3C oCH3 OH--CHg N OH..Hg, N", pH3 _..... p CH3 CH3CH2"0 0 OCH3 OCH3 CH3 CH3 o OH CH3 CH3 , OH CH3 0 OH CH3 CH3 Vil. clarithromycin 9-hydrazone VIII. clarithromycin

In the first embodiment, R, a and R, b may both be H, or may be together =CRSR6 wherein R5 and R6 are selected from the group consisting of H, alkyl or halogeno-substituted alkyl of up to 7 carbons, and aryl of up to 6 carbon atoms, with one or more substituents on the aryl group selected from the group consisting of H, alkyl, phenyl, and halogeno, or R, a may be H; when RI is H, R, b is R7SO2-, R7 is aryl with one or more substituents on the aryl group selected from the group consisting of H, alkyl, phenyl, and halogeno; R2 and R3 are selected from the group consisting of H, R8R9RloSi, and RCO; R8, Rg, R, o and R,, are selected from the group consisting of alkyl, aryl, and aralkyl; R4 is selected from the group consisting of H and CH3, with the proviso that where Rla and R, b are both H, or where RI a and Rlb together are =C (CH3) 2, and R, and R3 are both H, R4 is CH3.

The foregoing illustration also shows, in part, the chemical synthesis of the second embodiment of this invention. That is, instead of preparing erythromycin A 9- isopropylidenehydrazone or erythromycin A 9-arylsulfonylhydrazone (as in the first embodiment), erythromycin A 9-N-alkylhydrazone or erythromycin A 9-N, N- dialkylhydrazone is prepared. Clarithromycin may then be prepared from erythromycin A 9-N-alkylhydrazone or erythromycin A 9-N, N-dialkylhydrazone using the same steps of 2', 4"protection, 6-O-methylation, deprotection, 9-N-alkylhydrazone or 9-N, N-dialkylhydrazone removal and formation of a 9-keto group as illustrated in the schematic.

The present invention is now described in more detail by reference to the following examples, but it should be understood that the invention is not construed as being limited thereto. Unless otherwise, indicated herein, all parts, percents, ratios and the like are by weight. As used below in the examples"chromatographic purity"or"% pure by chromatography"means the fraction of the uv (ultraviolet) absorption attributable to the HPLC peak corresponding to the product as a percent of the total absorption of all relevant peaks.

Example 1: Synthesis of Erythromycin A 9-Hydrazone Hydrazine hydrate (79 mL, 1.6 moles) was added to a solution of Erythromycin A (100 g, 0.14 moles) in methyl alcohol (500 mL). 5 mL of 32% (w/v) hydrochloric acid was added dropwise to the homogeneous solution over five minutes at 20- 25°C. The reaction mixture was stirred for 9 hours at 50°C. The solvent was evaporated,

ethyl acetate was added, and the mixture was extracted with water (2 x 200 mL). The organic phase was dried with MgS04 and then evaporated, affording 108 g crude product. The product was identified by'H-NMR,'3C NMR, and mass spectroscopy.'H-NMR (d6-DMSO, 500 <BR> <BR> <BR> <BR> MHZ)-8H-2.19 (6H, s NMe,), 3.19 (3H, s, 3"-OCH3).''CMR (D6-DMSO, 90 MHZ-8c- 30.1 (Cg), 166.9 (C=NNH2), 174.5 (C,), 48.9 (3"-OCH3) mass spectra (FAB)-748.3 (MH+).

Example 2: Synthesis of Erythromycin A 9-Isopropylidenehydrazone 108 g crude Erythromycin A 9-hydrazone was dissolved in 540 mL acetone and stirred at room temperature for 6 hours. The solvent was evaporated and dried to yield 106 g of Erythromycin A 9-isopropylidenehydrazone, 87.5% pure by chromatography.'H- <BR> <BR> <BR> <BR> <BR> NMR (d6-DMSO, 500 MHZ)-6H-1.83 (3H, s, =N-N=C (CH3) 2)), 2.00 (3H, s, (3H, s, =N- N=C (CH3) ,), 2.21 (6H, s, NMe,) 3.21 (3H, s, 3"-OCH3).3CMR (D6-DMSO, 90 MHZ-°c ~ 30.7 (C8), 162.5 (C=N-N=C (CH3) 2), 177. 3 (C=N-N=C (CH3) 2), 174.5 (C,), 49.0 (3"-OCH3) mass spectra (FAB)-788.4 (MH+).

Example 3: Silylation of Erythromycin A 9-Isopropylidenehydrazone Erythromycin 9-isopropylidenehydrazone A (59 g, 74.8 mmoles) was dissolved in ethyl acetate (1 L) and then, imidazole (42.9 g, 0.6 moles) was added.

Trimethylchlorosilane (37.4g, 0.3 moles) was dropped into the homogenous solution within 10 minutes. The reaction mixture was stirred for 1 hour at room temperature under nitrogen atmosphere. The reaction mixture was quenched with cold water (1 L) and phases were separated. The organic phase was extracted with brine solution (2x200 mL), and subsequently dried with MgS04 and filtered. The solvent was removed under vacuum to afford 69.7 g of the product, 2', 4"-bis (trimethylsilyl) erythromycin A 9- isopropylidenehydrazone, 86.8% pure by chromatography. The product was identified by'H- <BR> <BR> <BR> <BR> NMR, CMR and mass spectroscopy.'H-NMR (d6=DMSO, 500 MHZ)-OH-0.04 (9H, s, Si (CH3) 3), 0.09 (9H, s, Si (CH3) 3), 1.81 (3H, s, =N-N=C (CH3) 2), 1.98 (3H, s, =N-N=C (CH3) 2), 2.14 (6H, s, NMe2), 3.20 (3H, s, 3"-OCH3).''C-NMR (d6-DMSO, 90 MHZ)-6,-I. 0 (Si (CH3)), 1.2 (Si (CH3)), 29.1 (C3), 49.1 (3"-OH3), 162.2 (C=N-N=C (CH3) 2), 177.0 (C=N-N=C (CH3) 2).

Mass spectra (FAB)-932.5 (MH+).

Example 4: Methylation of 2', 4'-bis- (trimethylsilyl) Erythromycin A 9- Isopropylidenehydrazone 2', 4'-bis- (trimethylsilyl) Erythromycin A 9-isopropylidenehydrazone (85 g, 89.9 mmoles) was dissolved in a 1: 1 mixture of DMSO: THF (1.7 L). The solution was cooled to 2-3 °C and methyl iodide (70 g, 0.5 moles) and powdered KOH (22.4 g, 0.4 moles) were added in four equal portions every fifteen minutes. The reaction mixture was stirred for 75 minutes at room temperature, and was made basic (pH-10) with dimethyl amine 60% aqueous solution (24 mL) and water (24 mL) and stirred for another 90 minutes. Water was added to the reaction mixture (0.6 L) and was extracted with hexane (3.6 L). The organic phase was washed with water (0.4 L) and subsequently with brine (0.4 L). Then, it was dried with MgSO4 and filtered. The solvent was removed under vacuum to afford 81.3 g of the product. The crude product was dissolved in 1.2 L of acetonitrile and refluxed for 5 minutes, the turbid solution filtered and stirred at 0-5 °C for 1 hour. The precipitate was filtered and washed with cold acetonitrile (2x80 mL) and was then dried at high vacuum to yield 38.6 g of 2', 4"-bis- (trimethylsilyl)-6-methoxy erythromycin A 9-isopropylidenehydrazone (that is, 2', 4'-bis- (trimethylsilyl) clarithromycin 9-isopropylidenehydrazone) with 85.1% chromatographic purity.

Example 5: Desilylation of 2', 4"-bis- (trimethylsilyl)-6-methoxy Erythromycin A 9- Isopropylidenehydrazone 2', 4"-bis- (trimethylsilyl)-6-methoxy Erythromycin A 9- isopropylidenehydrazone (38.6 g, 41 mmoles) was stirred with a 1 M tetrabutylammonium fluoride solution (309 mL) in THF for 1 hour. The THF was removed under vacuum and the solid was dissolved in ethyl acetate (2.3 L) and then extracted with water (2x0.8 L)) and brine solution (0.7 L). The solid was triturated with water (0.4 L) at room temperature for 1 hour, filtered, washed with water (2x40 mL) and then dried under high vacuum to afford 32.8 g of <BR> <BR> <BR> <BR> the product with 86.2% chromatographic purity.'H-NMR (CDCI3,500 MHZ)-OH-1. 91 (3H, s, =N-N=C (CH3) 2), 2.03 (3H, s,--N-N=C (CH3) 2), 2. 33 (6H, s, Né2), 2.93 (3H, s, 6- OCH3), 3.29 (3H, s, 3"-OCH3).'3C-NMR (CDCI ;, 90 MHZ)-°c-29.3 (C8), 163.4 (C=N- N=C (CH3) 2), 179.3 (C=N-N=C (CH3) 2). Mass spectra (FAB)-802.7 (MH+).

Example 6: Preparation of Clarithromycin 9-Hydrazone 6-Methoxy erythromycin A 9-isopropylidenehydrazone (32.8 g, 43 mmoles) was dissolved in ethanol (820 mL) and refluxed with hydrazine hydrate (33.8 g, 0.7 moles) for 3 hours. Water (490 mL) was added and the heterogeneous mixture was evaporated to a third of its volume under vacuum. The precipitate was filtered and washed with water (2x50 mL), and then dried under high vacuum to afford 25.2 g of clarithromycin 9-hydrazone.'H- NMR (CDCl3,500 MHZ)-OH-2.33 (6H, s, NMe2), 3.19 (3H, s, 6-OCH3), 3.32 (3H, s, 3"- OCH3).'3C-NMR (CDC13, 90 MHZ)-8-29.0 (C8), 167.7 (C=NNH2), 174.9 (C,), 49.4 (3"- OCH3), 51.7 (6-OCH3). Mass spectra (FAB)-762.5 (MH+).

Example 7: Preparation of Clarithromycin From Clarithromycin 9-Hydrazone Clarithromycin 9-hydrazone (2 g, 2.6 mmoles) dissolved in 40 mL of methylene chloride and tetrabutylammonium bromide (1 g, 3.1 mmoles) was added thereto and the heterogeneous solution was cooled to 0-5 °C. Sodium hypochlorite solution (9%-60 mL) was added and the mixture was stirred for 90 minutes. The phases were separated and the organic phase was washed with water (40 mL) and the solvent was removed under vacuum to yield 2.4 g of the crude product. The crude product was chromatographed on a silica gel column (250 g, 4x25 cm) with isopropyl alcohol: hexane mixture (5: 95) which contains 2% diethylamine. The appropriate fractions were collected (1.2 g) and the product was crystallized from ethanol to afford 0.9 g of the product (clarithromycin).'H-NMR (CDCL, 500 MHZ)-8H-2.33 (6H, s, =NMe2), 3.02 (3H, s, 6-OCH3), 3. 32 (3H, s, 3"-OCH3).

'3C-NMR (CDCl3,90 MHZ)-6c-45.1 (C8), 49.4 (3"-OCH3), 50.5 (6-OH3), 175.7 (C,), 221.0 (C=O). Mass spectra (FAB)-748.5 (MH+).

Example 8: Preparation of Clarithromycin From Clarithromycin 9-Hydrazone 0.2g (1.5 mmoles) cupric chloride dissolved in 8 mL of water was added to a solution of 0.2 g (0.6 mmoles) clarithromycin 9-hydrazone in 4 mL methylene chloride. 0.1 g tetrabutylammonium bromide was added to the heterogeneous mixture. The pH of the solution was adjusted to 5.1 by addition of a 10% solution of diethylamine in water. The heterogeneous mixture was heated to 40°C and stirred for 3 hours. An additional 60 mg (0.5 mmoles) of cupric chloride was added, and the heterogeneous mixture was stirred for 3 more

hours. The reaction was allowed to stir overnight, the phases were separated, and the aqueous phase was extracted with 20 mL methylene chloride. The combined organic phases were washed with 10 mL of 10% aqueous NaHCO3 solution, and the solvent evaporated to give 288 mg of crude product, which was triturated with water then dried to yield 195 mg of clarithromycin, 60% pure by chromatography.

Example 9: Synthesis of Clarithromycin from Clarithromycin 9- Methylsulfonylhydrazone Clarithromycin 9-methylsulfonylhydrazone (0.2g, 0.23 mmol) was dissolved in 10 ml of methylene chloride. Tetrabutylammonium bromide (0.08g, 0.21 mmol) was added thereto and the mixture was cooled to 0-5°C. A mixture of sodium hypochlorite solution (9%, 0.4ml, 0.48 mmol) and 5 ml water was added, stirred for about 1 hour, additional sodium hypochlorite solution (9%, 3.8 ml, 4.56 mmol) was added in 6 portions with stirring time about 1 hour after each portion. After phase separation, the organic phase was washed with water, dried with magnesium sulfate and evaporated to dryness to give 0.22 g of material containing (HPLC) clarithromycin with impurities-the yield of clarithromycin was about 13%.

Example 10: Synthesis of Clarithromycin from Clarithromycin 9-Tosylhydrazone A solution of 0.6 ml 9% sodium hypochlorite (0.72 mmol) in 7.5 ml of water was added to a solution of clarithromycin 9-tosylhydrazone (0.5 g, 0.56 mmol) and tetrabutylammonium bromide (0.25 g, 0.78 mmol) in 25 ml methylene chloride. The reaction mixture was stirred for 1.5 hour at ambient temperature, the organic layer was separated and evaporated to dryness to give 0.6 g of material containing about 10% clarithromycin (HPLC)- the yield of clarithromycin was about 14%.

Example 11: Synthesis of Erythromycin A 9-N, N-Dimethylhydrazone 1,1-dimethylhydrazine (19.5 g, 325 mmol) was added to a solution of erythromycin A (20g, 27.3 mmol) in 100 ml of methanol followed by addition of 2 ml concentrated HCI. The solution was refluxed for more than 48 hours. After evaporation to dryness the rest was triturated a few times with methylene chloride and water. Combined

organic extracts were washed with sodium sulphate and evaporated to dryness giving 16.5 g of the titled substance. MS: M+ 775.

Example 12: Preparation of Clarithromycin from Clarithromycin 9- Isopropylidenehydrazone To a solution of clarithromycin 9-isopropylidenehydrazone (3g, 3.74 mmol) dissolved in a 1: 1 mixture of methylene chloride: water (50 ml), cupric chloride dihydrate (3.2g, 18.8 mmol) and tetrabutylammonium bromide (1.5g, 4.65 mmol) were added in four equal portions of 30 °C. The pH of the solution was adjusted to 3.5 by the addition of 10% NaHCO3 solution. The reaction was then stirred until starting material was no longer visible.

The aqueous and organic phases were separated and the aqueous phase was extracted with methylene chloride (50ml). The combined organic phases were extracted with a solution of NH40H/NH4C1 mixture (2 x 40 ml) and water (40 ml). The solvent was then evaporated to yield 2.9 g of crude product.

Example 13: Preparation of Clarithromycin from Clarithromycin 9- Isopropylidenehydrazone To a solution of clarithromycin 9-isopropylidenehydrazone (0.2g, 0.26 mmol) dissolved in THF (1.5 ml), cupric acetate (104 mg, 0.52 mmol) dissolved in water (5 ml) was added drop-wise over 15 minutes and the mixture was heated to 50 °C. The reaction was then stirred until starting material was no longer visible. The aqueous and organic phases were separated and the aqueous phase was extracted with methylene chloride (10 ml). The combined organic phases were evaporated and dried at high vacuum to yield 158 mg of the crude product.

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.