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Title:
PROCESS FOR PREPARING 6-METHYL ERYTHROMYCIN A
Document Type and Number:
WIPO Patent Application WO/2001/077135
Kind Code:
A1
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.

Inventors:
KIM KYOUNG HOON (KR)
BAEK HYEUNG GEUN (KR)
SHIM SUNG BO (KR)
KANG TAE WON (KR)
KIM KYUNG HWAN (KR)
KIM JUNG WOO (KR)
HONG CHUNG IL (US)
PARK YONG KYU (KR)
SHIN JAE WOOK (KR)
JIN KYUNG YONG (KR)
SONG HYUN NAM (KR)
Application Number:
PCT/KR2001/000255
Publication Date:
October 18, 2001
Filing Date:
February 21, 2001
Export Citation:
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Assignee:
CHONG KUN DANG PHARM CORP (KR)
KIM KYOUNG HOON (KR)
BAEK HYEUNG GEUN (KR)
SHIM SUNG BO (KR)
KANG TAE WON (KR)
KIM KYUNG HWAN (KR)
KIM JUNG WOO (KR)
HONG CHUNG IL (US)
PARK YONG KYU (KR)
SHIN JAE WOOK (KR)
JIN KYUNG YONG (KR)
SONG HYUN NAM (KR)
International Classes:
C07H1/00; C07H17/08; (IPC1-7): C07H17/08; C07H1/00
Domestic Patent References:
WO1998035976A11998-08-20
WO1998004573A11998-02-05
Foreign References:
US5919916A1999-07-06
US5872229A1999-02-16
Attorney, Agent or Firm:
Suh, Jong Wan (New-Seoul Building 828-8, Yeoksam-dong Kangnam-ku Seoul 135-080, KR)
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Claims:
CLAIMS
1. I. A process for preparing 6methyl 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 6methyl erythromycin A of the formula I by reduction of the compound of formula 4.
2. Formula 3 Formula 4 Formula 1.
3. 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 ptoluenesulfonate and methyl methanesulfonate.
4. 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.
5. The process according to Claim 3, which is characterized in that the polar aprotic solvent is a) dimethyl sulfoxide, N, Ndimethyl formamide, hexamethylphosphotriamide or mixed solvent thereof, or b) a mixture of any one of tetrahydrofuran or 1,2dimethoxyethanol with any one of dimethyl sulfoxide, N, N dimethyl formamide or hexamethylphosphotriamide.
6. The process according to Claim 3, which is characterized in that the base is potassium hydroxide, sodium hydroxide, sodium hydride or potassium hydride.
7. 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.
8. 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.
9. Formula 2.
10. The process according to Claim 7, where the oxidation reaction is carried out in mchloroperoxybenzoic acid in the presence of methylene chloride, peroxybenzoic acid in benzene, hydrogen peroxide in methanol, tbutylhydroperoxide in the presence of vanadium pentoxide or ozone in the presence of calcium carbonate.
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.

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 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; = 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-oxide erythromycin A of formula 3, this compound of formula 3 is methylated to form 3'-N-oxide-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'-dimethylamino 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-oxide 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-dimethoxyethane with any one of polar aprotic solvents, in the presence of alkaline strong base. Polar aprotic solvents include dimethyl sulfoxide, N, N-dimethyl formamide, and hexamethylphosphotriamide. 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 iodomethane, bromomethane, chloromethane, dimethylsulfate, methyl p-toluenesulfonate or methyl methanesulfonate, and the amount is 1. 0-10. 0 equivalents against that of 3'-N-oxide 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 I 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 (1-'). 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 NaHC03 three times, and then with saturated brine. The reaction solution was dehydrated with anhydrous MgS04, and the solvent was evaporated under reduced

pressure thereby to obtain lOg of the compound of formula 2 (yield 99%). lH NMR (CDCl3) 6 3 35 (s, 3H, OCH3), 3. 23 (s, 3H, ONCH3), 3. 21 (s, 3H, ONCH3) 3C NMR (CDCL3) 5 222. 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) o 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 (50mi) and washed with water and saturated saline solution. This was dehydrated with anhydrous MgSO4 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.

'H NMR (CDCL3) 6 3. 34 (s, 3H, OCH3), 3. 18 (s, 6H, ONCH3). 3.01 (s, 3H, OCH3) 13C NMR (CDCL3) 8221. 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) ocompound (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%).

'H NMR (CDC13) 5 3. 30 (s, 3H, OCH3), 3 00 (s, 6H, ONCH3), 3. 00 (s, 3H, OCH3), 2. 25 (s, 6H, N (CH3) 2), '3C NMR (CDCL3) 8 221. 3,176.2,103.1,96.4,50.9,49.8,40.6 [M+H]'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/Al203, 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%).

'H NMR (CDCl3) 6 3 30 (s, 3H, OCH3), 3. 00 (s, 6H, ONCH3), 3. 00 (s, 3H, OCH3), 2. 25 (s, 6H, N (CH3) 2), '3C NMR (CDCL3) 6 221. 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. 0eq) 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%).

'H NMR (CDCl3) 8 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) 6 221. 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.