[go: up one dir, main page]

WO2001077135A1 - Process for preparing 6-methyl erythromycin a - Google Patents

Process for preparing 6-methyl erythromycin a Download PDF

Info

Publication number
WO2001077135A1
WO2001077135A1 PCT/KR2001/000255 KR0100255W WO0177135A1 WO 2001077135 A1 WO2001077135 A1 WO 2001077135A1 KR 0100255 W KR0100255 W KR 0100255W WO 0177135 A1 WO0177135 A1 WO 0177135A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
ethanol
compound
process according
sodium
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.)
Ceased
Application number
PCT/KR2001/000255
Other languages
French (fr)
Inventor
Kyoung Hoon Kim
Hyeung Geun Baek
Sung Bo Shim
Tae Won Kang
Kyung Hwan Kim
Jung Woo Kim
Chung Il Hong
Yong Kyu Park
Jae Wook Shin
Kyung Yong Jin
Hyun Nam Song
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.)
Chong Kun Dang Corp
Original Assignee
Chong Kun Dang Corp
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 Chong Kun Dang Corp filed Critical Chong Kun Dang Corp
Priority to AU2001236163A priority Critical patent/AU2001236163A1/en
Publication of WO2001077135A1 publication Critical patent/WO2001077135A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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

Definitions

  • the present invention relates to a novel process for preparing 6-methyl erythromycin A of the following formula 1, which has a broad antibacterial efficacy as a macrolide antibiotic.
  • 6-methyl erythromycin A of the above formula 1 which has a broad antibacterial effect as a macrolide antibiotic is generally prepared by methylating 6- hydroxyl group of erythromycin A, due to low regioselectivity toward position of 6- hydroxyl group in the methylation, the methylation is conducted after protection of 2'- hydroxyl and 3'-dimethylamino groups.
  • the inventor of the present invention has conducted research for a long period of time to cope with necessity for a new method which can not only resolve the problems of the conventional process but also provide safety and higher yield, and as the result, developed a novel manufacturing method by which 6-methyl erythromycin A can be synthesized by a higher yield relative to the prior art
  • the object of the present invention is to provide a novel process for easily synthesizing 6-methyl erythromycin A by carrying out methylation on 6-hydroxyl group of erythromycin A with a higher regioselectivity and yield as compared to the prior art
  • the present invention relates to a manufacturing process for 6-methyl erythromycin A of formula 1, which is characterized in that erythromycin A of formula 2 is oxidized to form 3'-N-ox ⁇ de erythromycin A of formula 3, this compound of formula 3 is methylated to form 3'-N-ox ⁇ de-6-methyl erythromycin of formula 4,and the compound 4 is then subjected to reduction SCHEME 2
  • Oxidizing agents used in the oxidation of 3'-d ⁇ methylam ⁇ no group of erythromycin A include m-chloroperoxybenzoic acid in the presence of methylene chloride, peroxybenzoic acid in benzene, hydrogen peroxide in methanol, t-butyl hydroperoxide in the presence of vanadium pentoxide and ozone in the presence of calcium carbonate
  • the amount of oxidizing agent can be varied between 1 0-10 0 equivalents against the amount of erythromycin A, most preferably 1 2-5 0 equivalents Reaction temperature is between -20°C and distillation temperature of solvent, and preferably -5 to 15°C Reaction time is 1 minute to 24 hours, preferably 1 minute to 1 hour
  • the methylation of 3'-N-ox ⁇ de erythromycin A derivative of formula 3 is carried out in a) polar aprotic solvent or mixed solvent thereof, or b) a mixture of any one of tetrahydrofuran or 1
  • Methylating agent includes lodomethane, bromomethane, chloromethane, dimethylsulfate, methyl p-toluenesulfonate or methyl methanesulfonate, and the amount is 1 0-10 0 equivalents against that of 3'-N-ox ⁇ de erythromycin A and preferably 1 0-3 0 equivalents
  • the strong alkali metal base is various as defined above, most preferably sodium or potassium hydroxide. The amount varies between 1.0-10.0 equivalents against 3'-N-oxide erythromycin A, most preferably 1.0-2.0 equivalents.
  • the reduction of 3 '-N-oxide erythromycin A of formula 3 is carried out at 0 ⁇ 60°C for 1-48 hours, most preferably at room temperatures for 1 hour.
  • a reducing agent hydrogen and Raney nickel in ethanol, hydrogen and palladium in ethanol, hydrogen and platinum oxide in ethanol, sodium tellurium hydride in ethanol, alloy of sodium and nickel in methanol, tributyltin in tetrahydrofuran, samarium iodide in the presence of dioxane, hydroxylamine hydrochloride in tetrahydrofuran, sodium iodide in acetonitrile, ferric nitrate in acetonitrile, stannic chloride in acetonitrile, ferrous sulfate in methanol, palladium in mixed solvent of ethanol and cyclohexane, carbon disulfide in chloroform, sodium bisulfide in ethanol, or zinc in the presence of acetic acid and
  • the present invention for the methylation reaction, forms nitrogen oxide only at 3'-dimethylamino group by a suitable oxidizing agent thereby resulting in protection of the 3'-dimethylamino group and at the same time, the 2'- hydroxyl group, and can quantitatively conduct the deprotection without further reaction

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Saccharide Compounds (AREA)

Abstract

The present invention relates to a process for preparing 6-methyl erythromycin A. The present invention, for the methylation reaction, forms nitrogen oxide only at 3'-dimethylamino group by a suitable oxidizing agent thereby resulting in protection of the 3'-dimethylamino group and at the same time, the 2'-hydroxyl group, and can quantitatively conduct the deprotection without further reaction. The present invention can directly proceed to deprotection step after methylation without extra purification process.

Description

PROCESS FOR PREPARING 6-METHYL ERYTHROMYCIN A
Technical Field
The present invention relates to a novel process for preparing 6-methyl erythromycin A of the following formula 1, which has a broad antibacterial efficacy as a macrolide antibiotic.
Figure imgf000002_0001
Formula 1 Background Art
Though 6-methyl erythromycin A of the above formula 1 which has a broad antibacterial effect as a macrolide antibiotic is generally prepared by methylating 6- hydroxyl group of erythromycin A, due to low regioselectivity toward position of 6- hydroxyl group in the methylation, the methylation is conducted after protection of 2'- hydroxyl and 3'-dimethylamino groups.
A prior art can be briefly illustrated by scheme 1.
It is a method of methylating erythromycin A after protecting 2'-hydroxyl and 3'-dimethylamino groups of desoamine by treating with an excessive amount of Cbz-Cl, and it is as follows ((J. Antibiotics 37, 187, 1984: 43, 286, 1990), EP 0041355). SCHEME 1
Figure imgf000003_0001
Figure imgf000003_0002
The above prior art is a four-step process where erythromycin is reacted with an excessive amount of, relatively expensive, Cbz-Cl(10 equivalents or more, Cbz = benzyloxycarbonyl) to protect 2'-hydroxyl and 3'-dimethylamino groups by a relative low yield of 60%, 6-hydroxyl group is methylated, each Cbz group is deprotected, and 3'-amino group is then subjected to additional reductive methylation with formaldehyde thereby to produce the final product of formula 1 Further, this method was defective in that silica gel column chromatography, by which industrial mass production is difficult, should be employed for the purification of product after the methylation
The inventor of the present invention has conducted research for a long period of time to cope with necessity for a new method which can not only resolve the problems of the conventional process but also provide safety and higher yield, and as the result, developed a novel manufacturing method by which 6-methyl erythromycin A can be synthesized by a higher yield relative to the prior art
Therefore, the object of the present invention is to provide a novel process for easily synthesizing 6-methyl erythromycin A by carrying out methylation on 6-hydroxyl group of erythromycin A with a higher regioselectivity and yield as compared to the prior art
Disclosure of the Invention The present invention relates to a manufacturing process for 6-methyl erythromycin A of formula 1, which is characterized in that erythromycin A of formula 2 is oxidized to form 3'-N-oxιde erythromycin A of formula 3, this compound of formula 3 is methylated to form 3'-N-oxιde-6-methyl erythromycin of formula 4,and the compound 4 is then subjected to reduction SCHEME 2
Figure imgf000004_0001
Figure imgf000004_0002
Oxidizing agents used in the oxidation of 3'-dιmethylamιno group of erythromycin A include m-chloroperoxybenzoic acid in the presence of methylene chloride, peroxybenzoic acid in benzene, hydrogen peroxide in methanol, t-butyl hydroperoxide in the presence of vanadium pentoxide and ozone in the presence of calcium carbonate The amount of oxidizing agent can be varied between 1 0-10 0 equivalents against the amount of erythromycin A, most preferably 1 2-5 0 equivalents Reaction temperature is between -20°C and distillation temperature of solvent, and preferably -5 to 15°C Reaction time is 1 minute to 24 hours, preferably 1 minute to 1 hour The methylation of 3'-N-oxιde erythromycin A derivative of formula 3 is carried out in a) polar aprotic solvent or mixed solvent thereof, or b) a mixture of any one of tetrahydrofuran or 1 ,2-dιmethoxy ethane with any one of polar aprotic solvents, in the presence of alkaline strong base Polar aprotic solvents include dimethyl sulfoxide, N,N-dιmethyl formamide, and hexamethylphosphotπamide The preferred mixing ratio is 1 1 by volume Alkaline strong bases include potassium hydroxide, sodium hydroxide, sodium hydride or potassium hydride, and the most preferable methylation condition is using sodium or potassium hydroxide in the presence of tetrahydrofuran, dimethyl sulfoxide or a mixture of these Temperature is between -20°C and room temperature, preferably 0~5°C and reaction time, 10 minutes to 48 hours, preferably 30 minutes to 4 hours
Methylating agent includes lodomethane, bromomethane, chloromethane, dimethylsulfate, methyl p-toluenesulfonate or methyl methanesulfonate, and the amount is 1 0-10 0 equivalents against that of 3'-N-oxιde erythromycin A and preferably 1 0-3 0 equivalents The strong alkali metal base is various as defined above, most preferably sodium or potassium hydroxide. The amount varies between 1.0-10.0 equivalents against 3'-N-oxide erythromycin A, most preferably 1.0-2.0 equivalents.
The reduction of 3 '-N-oxide erythromycin A of formula 3 is carried out at 0~60°C for 1-48 hours, most preferably at room temperatures for 1 hour. As a reducing agent, hydrogen and Raney nickel in ethanol, hydrogen and palladium in ethanol, hydrogen and platinum oxide in ethanol, sodium tellurium hydride in ethanol, alloy of sodium and nickel in methanol, tributyltin in tetrahydrofuran, samarium iodide in the presence of dioxane, hydroxylamine hydrochloride in tetrahydrofuran, sodium iodide in acetonitrile, ferric nitrate in acetonitrile, stannic chloride in acetonitrile, ferrous sulfate in methanol, palladium in mixed solvent of ethanol and cyclohexane, carbon disulfide in chloroform, sodium bisulfide in ethanol, or zinc in the presence of acetic acid and water, can be used.
The present invention is explained in detail by the following Examples, but the scope of the present invention is not limited thereby.
Examples
Examples 1. Preparation of 3'-N-oxide erythromycin A: compound (2) — » compound (3) lOg (13.5mmol) of Erythromycin A was dissolved in 50 ml of methylene chloride, 7g (20.2mmol) of m-chloroperbenzoic acid was added thereto at room temperature and stirred for 10 minutes. The reaction solution was washed with 20ml of saturated NaHCO3 three times, and then with saturated brine. The reaction solution was dehydrated with anhydrous MgSO4, and the solvent was evaporated under reduced pressure thereby to obtain lOg of the compound of formula 2 (yield 99%).
Η NMR (CDC13) δ 3.35(s, 3H, OCH3), 3.23 (s, 3H, ONCH3), 3.21(s, 3H, ONCH3)
13C NMR (CDCL3) δ 222.7, 176.2, 58.9, 52.6
[M+H]+ m/z=750
Example 2. Preparation of 3'-N-oxide-6-methyl erythromycin A: compound (3) — » compound (4)
5g (6.7mmol) of 3'-N-oxide erythromycin A was dissolved with 50ml of 1 : 1 mixture of anhydrous THF and anhydrous DMSO and kept at 0°C, and 560mg(10.0 mmol) of KOH was added. The reaction solution was stirred for 30 minutes and iodomethane 1.04ml (16.7mmol) was added. After stirring at room temperature for 2 hours, it was diluted with ethyl acetate (50ml) and washed with water and saturated saline solution. This was dehydrated with anhydrous MgSO and the solvent was evaporated under reduced pressure thereby to obtain 5.2g of residue. This is used directly to the next reaction without further purification.
1H NMR (CDCL3) δ 3.34(s, 3H, OCH3), 3.18(s, 6H, ONCH3). 3.01(s, 3H, OCH3) 13C NMR (CDCL3) δ 221.4, 176.2, 102.8, 96.4, 59.2, 52.5, 50.9, 50.0 [M+H]+ m/z=764
Example 3. Preparation of 6-methyl erythromycin A: compound (4)— ^compound
(1)
The compound (1.82g, 2.4mmol) obtained in said Example 2 was dissolved in
20ml of methanol, and 10% Pd/C 200mg was added and stirred under hydrogen at room temperature for 1 hour. Pd/C was removed from the reaction solution and the residue obtained by evaporating of solvent under reduced pressure The residue obtained was recrystallized with methanol thereby to obtain 0 81g of the compound of formula 1 (45%)
1H NMR (CDC13) δ 3 30(s, 3H, OCH3), 3 00 (s, 6H, ONCH3), 3 00(s, 3H, OCH3), 2 25(s, 6H, N(CH3)2),
13C NMR (CDCL3) δ 221 3, 176 2, 103 1, 96 4, 50 9, 49 8, 40 6 [M+H]"1 m/z=748
Example 4. Preparation of 6-methyl erythromycin A: compound (4)— »compound (1)
The compound (5g, 6 54mmol) obtained in said Example 2 was dissolved in 100ml of 3 1 mixture of ethanol and cyclohexene 10% Pd/C 35mg was added and heated at 67°C The reaction mixture was stirred 5 hours and allowed from cool to room temperature The mixture was filtered with a celite/Al O3, washed with 20ml of ethanol, and then 10ml of methylene chloride The solvent was evaporated under reduced pressure The residue was recrystallized with ethanol thereby to obtain 3 25g of the compound of formula 1 (66 4%) 1H NMR (CDCb) δ 3 30(s, 3H, OCH3), 3 00 (s, 6H, ONCH3), 3 00(s, 3H, OCH3), 2 25(s, 6H, N(CH3)2),
1 C NMR (CDCL ) δ 221 3, 176 2, 103 1, 96 4, 50 9, 49 8, 40 6 [M+H]" m/z=748
Example 5. Preparation of 6-methyl erythromycin A: compound (4)— >compound (1)
The compound (0 15g) obtained in said Example 2 was dissolved in 5ml of chloroform Carbon disulfide (0 5g, 3 Oeq) was added and refluxed for 4hours The solvent was evaporated under reduced pressure The residue was recrystallized with ethanol thereby to obtain 0 09g of the compound of formula 1 (60%)
1H NMR (CDC13) δ 3 30(s, 3H, OCH3), 3 00 (s, 6H, ONCH3), 3 00(s, 3H, OCH3),
2 25(s, 6H, N(CH3)2),
1 C NMR (CDCL3) δ 221 3, 176 2, 103 1, 96 4, 50 9, 49 8, 40 6
[M+H] ' m/z=748
First, in case of the prior art, for regioselectivity in the methylation reaction, simultaneous protection of both 2'-hydroxyl and 3'-dimethylamino groups should be conducted, and then additional reductive methylation should be carried out at the time of deprotection In contrast, the present invention, for the methylation reaction, forms nitrogen oxide only at 3'-dimethylamino group by a suitable oxidizing agent thereby resulting in protection of the 3'-dimethylamino group and at the same time, the 2'- hydroxyl group, and can quantitatively conduct the deprotection without further reaction
Second, the prior art had to use silica gel column chromatography, by which industrial mass production is difficult, for the purification of methylation product, while the present invention can directly proceed to deprotection (i e , reduction) step after methylation without extra purification process

Claims

A process for preparing 6-methyl erythromycin A shown by formula 1, characterized by comprising a step for preparing a compound of formula 4 by methylating a compound of formula 3 with a methylating agent and a step for preparing 6-methyl erythromycin A of the formula 1 by reduction of the compound of formula 4.
Figure imgf000010_0001
Formula 3
Figure imgf000010_0002
Formula 4
Figure imgf000010_0003
Formula 1
2. The process according to Claim 1, which is characterized in that said methylating agent comprises one or more things selected from iodomethane, bromomethane, chloromethane, dimethylsulfate, methyl p-toluenesulfonate and methyl methanesulfonate.
3. The process according to Claim 2, which is characterized in that said methylation reaction is conducted in polar aprotic solvent in the presence of a base.
4. The process according to Claim 3, which is characterized in that the polar aprotic solvent is a) dimethyl sulfoxide, N,N-dimefhyl formamide, hexamethylphosphotriamide or mixed solvent thereof, or b) a mixture of any one of tetrahydrofuran or 1,2-dimethoxyethanol with any one of dimethyl sulfoxide, N,N- dimethyl formamide or hexamethylphosphotriamide.
5. The process according to Claim 3, which is characterized in that the base is potassium hydroxide, sodium hydroxide, sodium hydride or potassium hydride.
6. The process according to Claim 3, which is characterized in that the said reduction is conducted with hydrogen and Raney nickel in ethanol, hydrogen and palladium in ethanol, hydrogen and platinum oxide in ethanol, sodium tellurium hydride in ethanol, alloy of sodium and nickel in methanol, tributyltin in tetrahydrofuran, samarium iodide in the presence of dioxane, hydroxylamine hydrochloride in tetrahydrofuran, sodium iodide in acetonitrile, ferric nitrate in acetonitrile, stannic chloride in acetonitrile, ferrous sulfate in methanol, palladium in mixed solvent of ethanol and cyclohexane, carbon disulfide in chloroform, sodium bisulfide in ethanol, or zinc in the presence of acetic acid and water, as a reducing agent. 7 The process according to Claim 1, which is characterized in that the compound of formula 3 is prepared by oxidation of the compound of formula 2
Figure imgf000012_0001
Formula 2
8 The process according to Claim 7, where the oxidation reaction is carried out in m-chloroperoxybenzoic acid in the presence of methylene chloride, peroxybenzoic acid in benzene, hydrogen peroxide in methanol, t-butylhydroperoxide in the presence of vanadium pentoxide or ozone in the presence of calcium carbonate
PCT/KR2001/000255 2000-04-08 2001-02-21 Process for preparing 6-methyl erythromycin a Ceased WO2001077135A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001236163A AU2001236163A1 (en) 2000-04-08 2001-02-21 Process for preparing 6-methyl erythromycin a

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR2000/18441 2000-04-08
KR1020000018441A KR20000037126A (en) 2000-04-08 2000-04-08 Process for preparing 6-methyl erythromycin A

Publications (1)

Publication Number Publication Date
WO2001077135A1 true WO2001077135A1 (en) 2001-10-18

Family

ID=19662799

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2001/000255 Ceased WO2001077135A1 (en) 2000-04-08 2001-02-21 Process for preparing 6-methyl erythromycin a

Country Status (3)

Country Link
KR (1) KR20000037126A (en)
AU (1) AU2001236163A1 (en)
WO (1) WO2001077135A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1232171A4 (en) * 1999-11-24 2002-10-31 Hanmi Pharm Ind Co Ltd ELABORATION OF CLARITHROMYCIN
US6875619B2 (en) 1999-11-12 2005-04-05 Motorola, Inc. Microfluidic devices comprising biochannels

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100452026B1 (en) * 2002-11-15 2004-10-08 종근당바이오 주식회사 Method for producing 6-methyl erythromycin A

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004573A1 (en) * 1996-07-29 1998-02-05 Abbott Laboratories Crystal form i of clarithromycin
WO1998035976A1 (en) * 1997-02-13 1998-08-20 Abbott Laboratories 3'-n-oxide, 3'-n-dimethylamine, 9-oxime erythromycin a derivatives
US5872229A (en) * 1995-11-21 1999-02-16 Abbott Laboratories Process for 6-O-alkylation of erythromycin derivatives
US5919916A (en) * 1997-12-01 1999-07-06 Abbott Laboratories 6-O-alkyl derivatives of erythronolide B

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5872229A (en) * 1995-11-21 1999-02-16 Abbott Laboratories Process for 6-O-alkylation of erythromycin derivatives
WO1998004573A1 (en) * 1996-07-29 1998-02-05 Abbott Laboratories Crystal form i of clarithromycin
WO1998035976A1 (en) * 1997-02-13 1998-08-20 Abbott Laboratories 3'-n-oxide, 3'-n-dimethylamine, 9-oxime erythromycin a derivatives
US5919916A (en) * 1997-12-01 1999-07-06 Abbott Laboratories 6-O-alkyl derivatives of erythronolide B

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6875619B2 (en) 1999-11-12 2005-04-05 Motorola, Inc. Microfluidic devices comprising biochannels
EP1232171A4 (en) * 1999-11-24 2002-10-31 Hanmi Pharm Ind Co Ltd ELABORATION OF CLARITHROMYCIN

Also Published As

Publication number Publication date
AU2001236163A1 (en) 2001-10-23
KR20000037126A (en) 2000-07-05

Similar Documents

Publication Publication Date Title
CA1239639A (en) Epimeric azahomoerythromycin a derivative and intermediates therefor
EP0195960B1 (en) Method for selective methylation of erythromycin a derivatives
KR100561326B1 (en) 3'-N-oxide, 3'-N-dimethylamine, 9-oxime erythromycin A derivative
JP4040877B2 (en) Method for producing clarithromycin
US4526889A (en) Epimeric azahomoerythromycin A derivative, intermediates and method of use
WATANABE et al. CHEMICAL MODIFICATION OF ERYTHROMYCINS. IX. 1) SELECTIVE METHYLATION AT THE C-6 HYDROXYL GROUP OF ERYTHROMYCIN A OXIME DERIVATIVES AND PREPARATION OF CLARITHROMYCIN
KR100491183B1 (en) Process of preparing azithromycin and crystalline 9-deoxo-9a-aza-9a-homoerythromycin a hydrate used therein
CA1209987A (en) Chemical process for the synthesis of macrolide antibiotics
PL155812B1 (en) Method of obtaining novel derivatives of thylosine and 10,11,12,13-tetrahydrothylosine
WO2001077135A1 (en) Process for preparing 6-methyl erythromycin a
AU2002357482B2 (en) Method for the production of desclarithromycin, and intermediate products
KR100850408B1 (en) A process for preparing Eiprubicin and Pharmaceutically acceptable salt thereof
CA1289949C (en) Method for the preparation of 4'-0- tetrahydropyranyladriamycin b
SK284841B6 (en) 12,13-Dihydroxy derivatives of tylosin and method of their preparation
PL182429B1 (en) Derivatives of 12, 13-epoxytholosine and method of obtaining them
KR20000037127A (en) Process for preparing erythromycin A 6-methyl derivatives
JPH07224067A (en) Production of 7-alkoxy or hydroxystaurosporine substance
JPH07224068A (en) Production of 6-deaza-6-oxostaurosporine substance
KR20010008496A (en) Process for the preparation of 6-O-methyl erythromycin
JPH0366315B2 (en)
KR19990085779A (en) Method for preparing 6-0-methyl erythromycin

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP