EP1490382A1 - Process of preparing azithromycin and crystalline 9-deoxo-9a-aza-9a-homoerythromycin a hydrate used therein - Google Patents
Process of preparing azithromycin and crystalline 9-deoxo-9a-aza-9a-homoerythromycin a hydrate used thereinInfo
- Publication number
- EP1490382A1 EP1490382A1 EP02717187A EP02717187A EP1490382A1 EP 1490382 A1 EP1490382 A1 EP 1490382A1 EP 02717187 A EP02717187 A EP 02717187A EP 02717187 A EP02717187 A EP 02717187A EP 1490382 A1 EP1490382 A1 EP 1490382A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- deoxo
- aza
- homoerythromycin
- solution
- 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- Withdrawn
Links
Definitions
- the present invention relates to a method of preparing azithromycin using a crystalline 9-deoxo-9a-aza-9a-homoerythromycin A hydrate as an intermediate, and a novel precursor thereof, crystalline 9-deoxo-9a-aza-9a- homoerythromycin A hydrate, and a process for the preparation thereof.
- Azithromycin 9-deoxo-9a-aza-9a-memyl-9a-homoerythromycin A (IUPAC name: N-me1i ⁇ yl-ll-aza-10-deoxo-10-dihydroerythromycin A), is an azalide-based semisynthetic macrolide antibiotic of formula (I) which is very effective in treating respiratory organ diseases, sexual contact infection, skin infection diseases and the like, as disclosed in US Patent Nos. 4,517,359 and 4,474,768 (Kirst and Sides, Antimicrob. Agents Chemother., 33, 1419(1989)):
- azithromycin is prepared by conducting conventional Eschweiler-Clarke reductive N-methylation (Eschweiler and Clarke, Org. React, 5, 290(1945)) of the 9a-positon of 9-deoxo-9a-aza-9a-homoerythromycin A of formula (II), as described in US Patent No. 4,517,359, or by protecting the 3'- nitrogen of 9-deoxo-9a-aza-9a-homoerythromycin A of formula (II) with N- oxide, conducting N-methylation of the 9a-position thereof and then removing the N-oxide protecting group, as described in US Patent No. 4,474,768.
- the compound of formula (II) is thus a very important precursor in the preparation of azithromycin.
- 9-Deoxo-9a-aza-9a-homoerythromycin A of formula (II) may be prepared by reducing 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza- homoerythromycin A (simply, 6,9-imino ether) of formula (III) which is prepared from erythromycin A 9-oxime in accordance with a conventional method (Djokic et al., J. Chem. Soc. Perkin Trans. I, 1881(1986)).
- US Patent Nos. 4,328,334 and 6,013,778 disclose a method of preparing the compound of formula (II) from the compound of formula (III) by way of conducting hydrogenation under a high hydrogen pressure in the presence of a rhodium(Rh), platinum(Pt), palladium(Pd) or ruthenium(Ru) metal or metal oxide catalyst; and Austrian Patent No. 8,600,536, by way of conducting electrical reduction.
- these methods have the problem that they require the use of an expensive precious metal catalyst and a high hydrogen pressure of 65 psi or higher, or that electrical reduction is not suitable for mass-production.
- US Patent No. 4,328,334 discloses a method of preparing the compound of formula (II) by reducing the compound of formula (III) in a methanol solution maintained at 4 ° C with a reducing agent such as NaBH.
- a reducing agent such as NaBH.
- this method requires a large excess amount of NaBBU (16 mole equivalents or more) and the reduction product existing in the form of a borate complex must be subjected to further hydrolysis using an inorganic acid such as hydrochloric acid, the hydrolysis reaction inducing a side reaction to produce a large quantity of impurities (Djokic et al., J. Chem. Soc. Perkin Trans. I, 1881(1986)).
- 9-deoxo- 9a-aza-9a-homoerythromycin A of formula (II) may be prepared by hydrogenating erythromycin A 9-oxime or 9-deoxo-l l-deoxy-9,l l-epoxy-9,9a- didehydro-9a-aza-homoerythromycin (simply, 9,11-imino ether) of formula (IV) prepared from 6,9-imino ether of formula (III) under a high pressure in the presence of Pt0 2 .
- this method suffers from a high manufacturing cost.
- a method of preparing azithromycin of formula (I) comprising the steps of: (a) reducing 6,9-imino ether of formula (III) dissolved in methanol with 5 to 7 mole equivalents of NaBIL, at -20 to -10°C, treating the reaction mixture with an acidic aqueous acetone solution of citric acid, and adjusting the solution pH to 10.5 to 12.0 to obtain a crystalline hydrate of 9-deoxo-9a-aza-9a- homoerythromycin A of formula (II); and
- step (b) N-methylating the compound of formula (II) prepared in step (a) with an aqueous formaldehyde-formic acid mixture in an organic solvent:
- FIG. 1 a powder X-ray diffraction scan of the crystalline 9-deoxo-9a- aza-9a-homoerythromycin A hydrate prepared in accordance with the inventive method;
- FIG. 2 a powder X-ray diffraction scan of 9-deoxo-9a-aza-9a- homoerythromycin A prepared in accordance with a conventional method.
- an organic solvent such as dichloromethane, chloroform and 1,2- dichloroethane are added to the resulting residue, and then the organic layer is separated and concentrated.
- citric acid in an amount ranging from 1 to 20 mole equivalents based on the amount of the 6,9-imino ether.
- the pH of the mixture is adjusted to 2.0 to 3.0 with HC1 at a temperature of 0 ° C to room temperature, and stirred for at least 30 min.
- citric acid hydrolyzes the borate complex of the reduction product efficiently without inducing undesirable side reaction.
- the solution pH is adjusted to 10.5 to 12.0 at a temperature of 0 ° C to room temperature to induce precipitation of crystals.
- the precipitated crystals are filtered and dried at 40 ° C to give a pure monohydrate form of crystalline hydrate of 9-deoxo-9a-aza-9a- homoerythromycin A of formula (II) having a melting point of 126 to 130 ° C and a moisture content of 2.0 to 3.5% (determined by Kaal-Fisher moisture measurement) in a high yield of 85% or higher.
- the amount of acetone used is preferably in the range of 1 to 5 ml per 1 g of the compound of formula (III), and water, in a volume ranging from 1 to 4 folds of the acetone volume.
- the crystalline hydrate of formula (II) thus obtained may be further recrystallized from a mixed solvent of water and an organic solvent such as acetone, methanol and acetonitrile to improve the purity thereof.
- an organic solvent such as acetone, methanol and acetonitrile
- the pH of the recrystallized solution is adjusted to 10.5 or higher, and the amount of the organic solvent used is in the range of 1 to 2 ml per 1 g of the crystalline hydrate, the water to organic solvent volume ratio being in the range of 1 to 4.
- the crystalline hydrate of 9-deoxo-9a-aza-9a-homoerythromycin A of formula (II) obtained in accordance with the present invention is completely free of boron-containing impurities and it is a novel compound which is characteristically different from the well-known, amorphous anhydrous 9-deoxo- 9a-aza-9a-homoerythromycin A prepared by prior methods (US Patent Nos. 4,328,334 and 6,013,778, and International Publication Patent No. 94/26758) as judged by its melting point, moisture content and powder X-ray diffraction pattern, as shown in Table.
- the crystalline hydrate of 9- deoxo-9a-aza-9a-homoerythromycin A of formula (II) obtained in step (a) is subjected to conventional Eschweiler-Clarke reductive N-methylation (Eschweiler and Clarke, Org.
- React 5, 290(1945)
- a formic acid-aqueous formaldehyde mixture in an organic solvent which may be a halogenized solvent such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; an alcohol such as methanol, ethanol and isopropanol; a ketone such as acetone, ethylmethylketone and isobutylmethylketone; and an ester such as methyl acetate, ethyl acetate and isopropyl acetate, to give azithromycin of formula (I) in a high yield of at least 90%.
- a halogenized solvent such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane
- an alcohol such as methanol, ethanol and isopropanol
- a ketone such as acetone, ethylmethylketone and isobutylmethyl
- the amounts of formic acid and formaldehyde used are each independently in the range of 1 to 3 mole equivalents based on the amount of the crystalline hydrate of 9-deoxo- 9a-aza-9a-homoerythromycin A of formula (II), and the reaction may be performed at a temperature ranging from room temperature to the boiling point of the solvent.
- Example 1 Preparation of crystalline 9-deoxo-9a-aza-9a-homoerythromycin A hydrate
- Example 2 Purification of crystalline 9-deoxo-9a-aza-9a-homoerythromycin A hydrate
- Example 2 20 g of the crystalline 9-deoxo-9a-aza-9a-homoerythromycin A hydrate obtained in Example 1 was dissolved in 30 ml of acetone, and 90 ml of water was added thereto at room temperature. The solution pH was adjusted to above 10.5 with a dilute sodium hydroxide solution, cooled to below 10°C and stirred for 1 hr. The precipitated crystals was filtered, washed with cold water and dried at 40 ° C overnight to obtain 18.8 g of a purified form of the title compound (recovery: 94%).
- Example 3 Purification of crystalline 9-deoxo-9a-aza-9a-homoerythromycin A hydrate
- Example 2 The procedure of Example 2 was repeated except that methanol was used instead of acetone, to obtain a purified form of the title compound (recovery: 90%).
- Example 4 Purification of crystalline 9-deoxo-9a-aza-9a-homoerythromycin A hydrate
- Example 2 The procedure of Example 2 was repeated except that acetonitrile was used instead of acetone, to obtain a purified form of the title compound (recovery: 92%).
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- Saccharide Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/KR2002/000588 WO2003082889A1 (en) | 2001-03-21 | 2002-04-03 | Process of preparing azithromycin and crystalline 9-deoxo-9a-aza-9a-homoerythromycin a hydrate used therein |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1490382A1 true EP1490382A1 (en) | 2004-12-29 |
EP1490382A4 EP1490382A4 (en) | 2007-09-12 |
Family
ID=33411531
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP02717187A Withdrawn EP1490382A4 (en) | 2002-04-03 | 2002-04-03 | Process of preparing azithromycin and crystalline 9-deoxo-9a-aza-9a-homoerythromycin a hydrate used therein |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP1490382A4 (en) |
JP (1) | JP2005522470A (en) |
CN (1) | CN1276919C (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101624412B (en) | 2008-07-10 | 2012-07-04 | 刘力 | Derivative of macrolides, method for preparing same and application thereof |
CN101724000B (en) * | 2008-10-29 | 2012-05-30 | 广东东阳光药业有限公司 | Crystallization method of erythrocin |
CN103159811A (en) * | 2011-12-10 | 2013-06-19 | 山东方明药业集团股份有限公司 | Preparation method for azithromycin intermediate 9a-deoxo-9a-aza-9a-homoerythromycin A |
CN102417531B (en) * | 2011-12-20 | 2014-06-11 | 浙江国邦药业有限公司 | Method for preparing azithromycin monohydrate |
CN105315316A (en) * | 2014-07-21 | 2016-02-10 | 常州制药厂有限公司 | Preparation method for azithromycin intermediate |
CN106632543A (en) * | 2016-12-20 | 2017-05-10 | 宁夏启元药业有限公司 | Synthesis method of azithromycin |
CN109293719A (en) * | 2018-10-12 | 2019-02-01 | 浙江国邦药业有限公司 | A kind of dihydro homoerythromycin crystal compound and preparation method thereof |
CN114516895A (en) * | 2020-11-19 | 2022-05-20 | 江苏威奇达药业有限公司 | Azithromycin amine crystallization method |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0827965A2 (en) * | 1996-07-11 | 1998-03-11 | Astur-Pharma, S.A. | Synthesis of 9-deoxo- 9a-aza 11,12-deoxy- 9a-methyl-9a-homoerythromycin A 11,12- hydrogenorthoborate dihydrate |
EP0941999A2 (en) * | 1998-03-13 | 1999-09-15 | Hovione Inter Ltd. | Preparation of azithromycin dihydrate |
WO2001000640A1 (en) * | 1999-06-29 | 2001-01-04 | Biochemie S.A. | Macrolides |
WO2002015842A2 (en) * | 2000-08-23 | 2002-02-28 | Wockhardt Limited | Process for preparation of anhydrous azithromycin |
-
2002
- 2002-04-03 JP JP2003580353A patent/JP2005522470A/en active Pending
- 2002-04-03 CN CN02828700.2A patent/CN1276919C/en not_active Expired - Fee Related
- 2002-04-03 EP EP02717187A patent/EP1490382A4/en not_active Withdrawn
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0827965A2 (en) * | 1996-07-11 | 1998-03-11 | Astur-Pharma, S.A. | Synthesis of 9-deoxo- 9a-aza 11,12-deoxy- 9a-methyl-9a-homoerythromycin A 11,12- hydrogenorthoborate dihydrate |
EP0941999A2 (en) * | 1998-03-13 | 1999-09-15 | Hovione Inter Ltd. | Preparation of azithromycin dihydrate |
WO2001000640A1 (en) * | 1999-06-29 | 2001-01-04 | Biochemie S.A. | Macrolides |
WO2002015842A2 (en) * | 2000-08-23 | 2002-02-28 | Wockhardt Limited | Process for preparation of anhydrous azithromycin |
Non-Patent Citations (1)
Title |
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See also references of WO03082889A1 * |
Also Published As
Publication number | Publication date |
---|---|
JP2005522470A (en) | 2005-07-28 |
EP1490382A4 (en) | 2007-09-12 |
CN1625560A (en) | 2005-06-08 |
CN1276919C (en) | 2006-09-27 |
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Inventor name: SEONG, MI RA Inventor name: KIM, GI JEONG Inventor name: SUH, KWEE HYUN Inventor name: YUN, SANG MIN |
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Inventor name: KIM, GI JEONG Inventor name: YUN, SANG MIN Inventor name: SUH, KWEE HYUN Inventor name: SEONG, MI RA |
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