EP1036084A1 - Synthese chimique de 6-o-alkyle erythromycine c - Google Patents

Synthese chimique de 6-o-alkyle erythromycine c

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Publication number
EP1036084A1
EP1036084A1 EP98959495A EP98959495A EP1036084A1 EP 1036084 A1 EP1036084 A1 EP 1036084A1 EP 98959495 A EP98959495 A EP 98959495A EP 98959495 A EP98959495 A EP 98959495A EP 1036084 A1 EP1036084 A1 EP 1036084A1
Authority
EP
European Patent Office
Prior art keywords
erythromycin
group
oxime
alkyl
oximeketal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98959495A
Other languages
German (de)
English (en)
Inventor
Stephen H. Montgomery
Michael D. Ives
Jih-Hua Liu
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP1036084A1 publication Critical patent/EP1036084A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to erythromycin derivatives. More particularly, the present invention pertains to a process for the chemical synthesis of 6-O-alkyl derivatives of erythromycin C.
  • 6-O-alkyl derivatives of erythromycin C have use as antibacterial agents.
  • 6-O-methyl erythromycin C (clarithromycin C), shown below, is a potent macrolide antibiotic.
  • 6-O-methyi erythromycin C is a minor fermentation product of the microbial transformation of 6-O-methyl erythromycin A by Mucor circinelloides (McAlpine et al., 27 th International Conference of Antimicrobial Agents and Chemotherapy, New York, October, 1987). There are, however, no reported methods for the chemical synthesis of 6-O-methyl erythromycin C. There is a need in the art, therefore, to provide a rapid, efficient method of chemically synthesizing 6-0- alkyl derivatives of erythromycin C and, in particular, 6-O-methyl erythromycin C.
  • the present invention provides an efficient and practical method of synthesizing a 6-O-alkyl erythromycin C derivative and, particularly 6-O-methyl erythromycin C.
  • the synthetic process starts with the conversion of erythromycin C to 9-oxime erythromycin C.
  • the oxime hydroxyl group (N-OH) of 9-oxime erthromycin C is protected.
  • the 9-oxime protected derivative is O-protected at the 2'- and 4"- hydroxyl groups and the 6-hydroxyl group is alkylated.
  • the 6-O-alkyl erythromycin C derivative is then obtained by deprotecting the 9-oxime hydroxyl group, deprotecting the 2'- and 4"- hydroxyl groups and deoximating the 9-oxime.
  • protection of the oxime hydroxyl group is accomplished by reacting 9-oxime erythromycin C with a ketalizing reagent such as a loweralkyl cycloalkyl ketal.
  • O- Protection of the 2'- and 4"-hydroxyl groups is accomplished using an acyl protecting group.
  • Acetyl is a most preferred acyl protecting group.
  • the 9-oxime derivative (oxime protected or unprotected) can be unsubstituted at the 3'-dimethylamino position or can contain a conventional N-protecting group at that position.
  • exemplary and preferred N-protecting groups are alkoxycarbonyl groups, alkoxyalkoxycarbonyl groups, haloalkoxycarbonyl groups, unsaturated alkoxycarbonyl groups, substituted benzyloxycarbonyl groups, substituted phenoxycarbonyl groups, and the like.
  • the present invention also relates to novel intermediates useful in the preparation of a 6-O-alkyl erythromycin C.
  • Those intermediates are 9-oxime derivatives that are alkylated at the 6- position and unsubstituted or substituted at the 2'-, 3'- and/or 4"- positions.
  • alkyl refers to saturated, straight or branched-chain hydrocarbon radicals containing between one and ten carbon atoms including, but not limited to, methyl, ethyl, propyl, isopropyl, ⁇ -butyl, tert- butyl and neopentyl. More preferably, the alkyl is limited to lower aikyls having 1-6 carbons.
  • alkylating agent refers to a reagent capable of placing an alkyl group onto a nucleophilic site, including, but not limited to, alkyl halides such as methyl bromide, ethyl bromide, n-propyl bromide, methyl iodide, ethyl iodide; and n-propyl bromide; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate; and di-n-propyl sulfate; and alkyl or aryl sulfonates such as methyl-p-toluenesulfonate, ethyl methanesulfonate, n-propyl methanesuifonate, and the like.
  • alkyl halides such as methyl bromide, ethyl bromide, n-propyl bromide, methyl iodide, ethy
  • aryl(lower alkyl) refers to a lower alkyl radical having appended thereto 1 -3 aromatic hydrocarbon groups, as for example benzyl, diphenylbenzyl, trityl and phenylethyl.
  • aryloxy refers to an aromatic hydrocarbon radical which is joined to the rest of the molecule via an ether linkage ⁇ i.e., through an oxygen atom), as for example phenoxy.
  • cycloalkyl refers to a saturated monocyclic hydrocarbon radical having from three to eight carbon atoms in the ring and optionally substituted with between one and three additional radicals selected from among lower alkyl, halo(lower alkyl), lower alkoxy, and halogen.
  • cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1 -fluoro-cyclopropyl, and 2-fluorocyclopropyl.
  • ketal refers to a compound in which the carbonyl oxygen of a ketone has been replaced by two alkoxy groups.
  • lower alkenyl refers to a straight or branched-chain hydrocarbon radical containing between two and six carbon atoms and possessing at least one carbon-carbon double bond. Examples of lower alkenyl radicals include vinyl, allyl, 2- or 3-butenyl, 2-, 3- or 4-pentenyl, 2-, 3-, 4- or 5-hexenyl and isomeric forms thereof.
  • lower alkoxy refers to a lower alkyl radical which is joined to the rest of the molecule via an ether linkage ⁇ i.e., through an oxygen atom).
  • lower alkoxy radicals include, but are not limited to, methoxy and ethoxy.
  • lower alkyl refers to an alkyl radical containing one to six carbon atoms including, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl and neopentyl.
  • polar aprotic solvent refers to polar organic solvents lacking an easily removable proton , including, but not limited to, N,N- dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, acetonitrile, and the like.
  • sil refers to a radical of the formula Si (R 1 )(R 2 )(R 3 ) where each of R 1 , R 2 and R 3 are independently hydrogen, lower alkyl, aryl, phenyl, phenylsubstituted lower alkyl, cycloalkyl or alkenyl.
  • strong alkali metal base refers to an alkali metal base having a weak conjugate acid, including, but not limited to, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, potassium t-butoxide, and the like.
  • substituted aryl(lower alkyl) refers to an aryl(lower alkyl) residue as defined above having between one and three non- hydrogen ring substituents, each independently selected from among halogen, lower alkoxy, lower alkyl, hydroxy-substituted lower alkyl, and (lower alkyl)amino.
  • substituted aryl(lower alkyl) radicals include 2-fluorophenylmethyl, 4-fluorophenylethyl and 2,4- difluorophenylpropyl.
  • weak organic amine base refers to an organic amine base having a strong conjugate acid, including, but not limited to trimethylamine, triethylamine, tripropylamine, pyridine, 2- methoxypyridine, 1-methylpyrrolidine, 1-methylpiperidine, and 1- ethylpiperidine, and the like.
  • the present invention provides a process of preparing a 6-O-alkyl derivative of erythromycin C. That process includes the steps of converting erythromycin C to 9-oxime erythromycin C, protecting the oxime hydroxyl group (N-OH) and reacting the 9-oxime protected erythromycin C with an alkylating agent.
  • a process of the present invention begins with erythromycin
  • erythromycin C typically produced using fermentation. Conversion to 9-oxime erythromycin C is accomplished using standard procedures well known in the art. Briefly, erythromycin C is reacted with either hydroxylamine hydrochloride and a base, free hydroxylamine in methanol or hydroxylamine and an organic acid (See, e.g.. U.S.
  • oximation of erythromycin C is accomplished using hydroxylamine and formic acid.
  • the 9-oxime hydroxyl group (N-OH) of 9-oxime erythromycin C is then protected.
  • Suitable protecting groups for the 9-oxime hydroxyl group are silyl and ketal groups.
  • the 9-oxime erythromycin C can be silylated by reacting the compound with a silylating reagent.
  • a preferred silylating reagent has the formula
  • R', R", and R' are independently hydrogen, lower alkyl, aryl, phenyl, phenyl substituted lower alkyl, cycloalkyl or alkenyl and X is a halogen or a sulfonate (e.g., mesylate, tosylate).
  • a suitable organic base such as triethylamine (Et 3 N), pyridine, imidazole or di-trimethylsilyl amine [HN(TMS) 2 ].
  • the silylating reaction can also be carried out in the presence of a suitable acid such as HC0 2 H.
  • silylating reagent has the formula: HN[Si(R')(R")(R'")] 2
  • R', R", and R' are defined above.
  • Protection of the oxime hydroxyl group can also be accomplished by reacting 9-oxime erythromycin C with a suitable ketalizing reagent.
  • a suitable ketalizing reagent is a lower alkyl cycloalkyl ketal.
  • An especially preferred ketalizing reagent is isopropyl cyclohexyl ketal.
  • O-protecting groups are acyl groups or lower alkyl monocarbonyl groups such as acetyl, propionyl, butyryl, isobutyryl and the like.
  • O-protecting groups in the preparation of erythromycin derivatives has been described (See, e.g.. U.S. Patent No. 4,672,109, and European Patent Application 0260938A2, the disclosures of which are incorporated herein by reference).
  • O-protecting groups are positioned using standard procedures well known in the art.
  • an acetyl group can be positioned at the 2'- and 4"- positions by reacting erythromycin C (9-oxime or 9-oximketal) with an acetylating agent in an aprotic solvent.
  • Suitable acetylating agents that can be used include anhydride and acid halide compounds of the formula (R 4 CO) 2 0 or R 4 COCI, where R 4 is hydrogen or a substituent group such as lower alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl and the like) or aryl (e.g., phenyl, p-methoxyphenyl, p-chlorophenyl, m-chlorophenyl, o-chlorophenyl, 2,4,-dichlorophenyl, p-bromophenyl, m-nitrophenyl, p-nitrophenyl, benzhydryl, 1 -naphthyl and the like).
  • R 4 is hydrogen or a substituent group such as lower alkyl (e.g., methyl, ethyl,
  • aprotic solvents examples include dichloromethane, chloroform, DMF, tetrahydrofuran, dimethyl sulfoxide, ethyl acetate, N-methyl-2- pyrrolidone, hexamethylphosphoric triamide, 1 ,2-dimethoxyethane, acetonitrile, and the like.
  • N-protecting groups are alkoxycarbonyl groups (e.g., a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, an n-propoxycarbonyl group, an n- butoxycarbonyl group, an isobutyloxycarbonyl group, a sec- butyloxycarbonyl group, a t-butyloxycarbonyl group, a 2- ethylhexyloxycarbonyl group, a cyclohexyloxycarbonyl group, a methyloxycarbonyl group and the like); alkoxyalkoxycarbonyl groups (e.g., a methoxymethoxycarbonyl group, an ethoxymethoxycarbonyl group,
  • the dimethylamino moiety at the 3'-position may also be protected as a quaternary salt by reacting with a 3'-dimethyiamino derivative A-X, wherein A is a 2-alkenyl group, a benzyl group or a substituted benzyl group; and X is a halogen atom (See, e.g.. U.S. Patent No. 4,670,549).
  • A is a 2-alkenyl group, a benzyl group or a substituted benzyl group
  • X is a halogen atom
  • the 6-hydroxyl group is selectively alkylated.
  • the hydroxyl-protected compound is reacted with a suitable alkylating agent in the presence of a base.
  • suitable alkylating agents are alkyl halides such as methyl bromide, ethyl bromide, n-propyl bromide, methyl iodide, ethyl iodide, n-propyl iodide, dimethyl sulfate, diethyl sulfate, di-n-propyl sulfate, methyl-p- toluenesulfonate, ethyl methanesulfonate, and n-propyl methanesulfonate.
  • Exemplary and preferred bases are a strong alkali metal base, preferably selected from the group consisting of an alkali metal hydride, alkali metal hydroxide or alkali metal alkoxide, and a weak organic amine base, preferably selected from the group consisting of trimethylamine, triethylamine, tripropylamine, pyridine, 2- methoxypyridine, 1-methylpyrrolidine, 1-methylpiperidine, and 1- ethylpiperidine.
  • a strong alkali metal base preferably selected from the group consisting of an alkali metal hydride, alkali metal hydroxide or alkali metal alkoxide
  • a weak organic amine base preferably selected from the group consisting of trimethylamine, triethylamine, tripropylamine, pyridine, 2- methoxypyridine, 1-methylpyrrolidine, 1-methylpiperidine, and 1- ethylpiperidine.
  • the alkylation step is carried out in a suitable solvent that includes methyl-t-butyl ether.
  • suitable solvent that includes methyl-t-butyl ether.
  • exemplary and preferred solvents are polar aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, hexamethylphosphoric triamide, tetrahydrofuran, 1 ,2-dimethoxyethane, acetonitrile or ethyl acetate, or a mixture of such polar aprotic solvents maintained at a reaction temperature and for a period of time sufficient to effect alkylation, preferably from -15°C to room temperature for a period of 1 to 8 hours.
  • 6-O-alkyl erythromycin C proceeds by removing the O-protecting groups from the 2'- and 4"-positions and the ketal group from the 9-oximeketal and then deoximating the 9- oxime.
  • Means for removing the O-protecting groups at the 2'- and 4"-positions are well known in the art and depend upon the nature of the protecting group.
  • the acetyl group can be removed by reacting the acetylated derivative with a compound of the formula R 5 OH, where R 5 is alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl and the like).
  • R 5 is alkyl (e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl and the like).
  • the reaction can take place in the absence or presence of an acid (e.g., formic acid, acetic acid) or water, or can take place in the absence or presence of a base (e.g., KC0 3 , NaC0 3 , KHC0 3 , NaHC0 3 ).
  • ketal group from the 9-oximeketal is accomplished using acidification.
  • a final step in the preparation of a 6-O-alkyl erythromycin C is deoximation.
  • Deoximation is carried out in accordance with standard procedures well known in the art (See e.g., U.S. Patent No. 4,672,109). Briefly, 9-oxime erythromycin C is reacted with sodium hydrogen sulfite in alcohol (e.g., ethanol) and refluxed. The solution is cooled, alkalinized and precipitated with aqueous alkali metal bicarbonate. The precipitate formed in the above reaction is collected by filtration, washed and recrystallized with alcohol.
  • alcohol e.g., ethanol
  • erythromycin C (Compound 1) is reacted with hydroxylamine in the presence of formic acid and methanol to form 9-oxime erythromycin C (Compound 2).
  • Compound 2 is then reacted with a ketalizing reagent followed by reaction with pyridine hydrochloride and acetic anhydride in acetonitrile to form 2', 4"-diacetyl-9-oximeketal erythromycin C (Compound 3).
  • Methylation of the 6-OH group is then carried out by reacting Compound 3 with a methylating agent (methyl bromide) and potassium hydroxide in an appropriate solvent [dimethylsulfoxide
  • DMSO methyl-9-oximeketal erythromycin C
  • THF tetrahydrofuran
  • the ketal group at the 9-position is removed by reacting Compound 4 with formic acid.
  • the resulting 9-oxime is deoximated with sodium metabisulfide.
  • the acetyl groups at the 2'- and 4"-positions are removed by reaction with ethyl alcohol, water, methanol (MeOH) and potassium carbonate (K 2 C0 3 ) to yield 6-O-methyl erythromycin C (Compound 5).
  • the present invention also provides 9-oxime derivatives of erythromycin C, which derivatives are intermediates in the synthesis of a 6-O-alkyl erythromycin C.
  • a 9-oxime derivative of the present invention is alkylated at the 6-position and unsubstituted (i.e., 2'-OH, 4"-OH, 3'-dimethyl) or substituted at the 2', 4" or 3'-positions with a conventional protecting group as set forth above.
  • a 9-oxime erythromycin C derivative of the present invention corresponds to the structure I below:
  • R is hydrogen, ketal or silyl
  • R 6 is hydrogen or alkyl
  • R 7 and R 8 are each independently hydrogen or a conventional O-protecting group
  • R 9 is -NR 10 CH 3 , where R 10 is methyl (CH 3 ) or a conventional N-protecting group or -N + (CH 3 ) 2 R 11 X, where R 11 is 2- alkenyl, benzyl or substituted benzyl, and X is a halogen such as Br, Cl or I.
  • the compound of structure I is shown without spatial bond orientation. Structure I, thus, defines all combinations of bond orientation and is intended to cover all possible stereo- configurations (e.g., epimers).
  • the bond orientations of Structure I are the same as shown above for 6-0- methyl erythromycin C.
  • 9-oxime erythromycin C is unsubstituted (unprotected) at the 2'-, 3' and 4"-positions. Ketalation of such a derivative results in formation of a 9-oximeketal derivative of structure I, where R 7 and R 8 are both hydrogen and R 6 is methyl.
  • 9-oxime erythromycin C used in the synthetic process has conventional O-protecting groups at the 2'- and/or 4"- positions.
  • Conventional O-protecting groups for protecting hydroxyls from alkylation are well known in the art and include silyl, acyl, lower alkenyl monocarbonyl, alkoxycarbonyl, alkylcarbonyl, lower alkoxycarbonylalkylcarbonyl, and arylcarbonyl groups.
  • Erthromycin C 15.38 g (21.4 m mole) was dissolved in 150 mL methanol, and 46.6 g 50% w/w hydroxylamine and 14.5 g formic acid (88%) were added at room temperature; the temperature rose to 36 5 C and external heating was started. The solution was refluxed for 16 hours and then cooled to ambient temperature. The volume of the solution was reduced to half under vacuum distillation and 200 mL ethyl acetate was added to extract the product. After the layers were separated, the lower aqueous layer was re-extracted once more with 200 mL ethyl acetate. The two ethyl acetate layers were combined and washed with 50 mL water. The organic layer was dried with magnesium sulfate, and the solids were removed by filtration, providing a clear solution, which was stripped on Rotavap to give 15.06 g of the title compound.
  • Example 2 The product from Example 2 was dissolved in 20 mL pyridine into which 2 mL acetic anhyride was added. The mixture was stirred for 26 hours and quenched with 100 mL ether and 50 g ice. Then, 20 mL of 2N sodium hydroxide and 10 g of sodium chloride were added. The layers were separated and the upper organic layer was washed with 15 mL saturated salt solution. The organic layer was dried with magnesium sulfate and the solids were removed by filtration. The solvent was distilled under vacuum and the residual oil chased three ties with 15 mL toluene each time; 2.0 g of the title product was obtained.
  • Example 4 was accomplished by acid hydrolysis of the ketal functionality followed by sodium bisulfite treatment.
  • 1.2 g of the product from Example 4 was dissolved in 60 mL 3A alcohol and 60 mL water with 0.31 g formic acid (88%).
  • the solution was heated to 60- 65°C for two hours. 3.0 grams of sodium bisulfite was added and the mixture stirred for 2 hours.
  • the solution was cooled to room temperature and the volume reduced to half under vacuum distillation. Methylene chloride (100 mL) was used to extract the product. After removal of the solvent, 0. 82 g of 2'-acetyl erythromycin C was obtained.
  • 6-O-Methyl erythromycin C prepared in accordance with Examples 1 -5 was assayed in vitro for antibacterial activity as follows: Twelve petri dishes containing successive aqueous dilutions of the test compound mixed with 10mL of sterilized Brain Heart Infusion (BHI) agar (Difco 0418-01-5) were prepared. Each plate was inoculated with 1 :100 (or 1 :10 for slow-growing strains, such as Micrococcus and Streptococcus) dilutions of up to 32 different micoorganisms, using a Steers replicatore block. The inoculated plates were incubated at 35- 37° for 20 to 24 hours. In addition, a control plate, using BHI agar containing no test compound, was prepared and incubated at the beginning and end of each test.
  • BHI Brain Heart Infusion
  • An additional plate containing a compound having known susceptibility patterns for the organisms being tested and belonging to the same antibiotic clas as the test compound was also prepared and incubated as further control, as well as to provide test-to-test comparability.
  • MIC minimum inhibitory concentration

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Abstract

L'invention concerne un procédé de préparation d'un dérivé 6-O-alkyle de l'érythromycine C. Ce procédé consiste à protéger les 2'-,4''- et 9-oxime hydroxyles avec des groupes protecteurs acétyle et cétal, en alkylant les groupes 6-hydroxyle, en éliminant les groupes protecteurs et en désoximant. L'invention concerne également des intermédiaires utilisés dans le procédé.
EP98959495A 1997-12-01 1998-11-17 Synthese chimique de 6-o-alkyle erythromycine c Withdrawn EP1036084A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US982214 1992-11-25
US98221497A 1997-12-01 1997-12-01
PCT/US1998/024601 WO1999028333A1 (fr) 1997-12-01 1998-11-17 Synthese chimique de 6-o-alkyle erythromycine c

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EP1036084A1 true EP1036084A1 (fr) 2000-09-20

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EP (1) EP1036084A1 (fr)
JP (1) JP2001525332A (fr)
KR (1) KR20010032613A (fr)
AU (1) AU1528299A (fr)
CA (1) CA2310003A1 (fr)
IL (1) IL136089A0 (fr)
WO (1) WO1999028333A1 (fr)

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KR100317907B1 (ko) * 1998-11-24 2001-12-24 김 완 주 신규한 중간체, 이를 이용한 마크로라이드계 항생제의제조방법
ES2195727B1 (es) * 2001-07-05 2005-03-01 Ercros Industrial, S.A. Un procedimiento para la obtencion de claritromicina.

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YU43658B (en) * 1983-07-18 1989-10-31 Pliva Pharm & Chem Works Process for preparing 7,16-dioxa-2-aza-10-0-cladinosyl-12,0-desosaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15-hexamethyl-bicyclo(11.2.1)hexadeca-1(2)-ene-8
GB8506380D0 (en) * 1985-03-12 1985-04-11 Beecham Group Plc Chemical compounds
KR960000434B1 (ko) * 1986-12-17 1996-01-06 다이쇼 세이야꾸 가부시끼가이샤 에리스로마이신 a유도체 및 그의 제조 방법
JP2000509712A (ja) * 1996-05-07 2000-08-02 アボツト・ラボラトリーズ ６―ｏ―置換エリスロマイシン及びその製造方法

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Title
See references of WO9928333A1 *

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AU1528299A (en) 1999-06-16
KR20010032613A (ko) 2001-04-25
CA2310003A1 (fr) 1999-06-10
IL136089A0 (en) 2001-05-20
WO1999028333A1 (fr) 1999-06-10
JP2001525332A (ja) 2001-12-11

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