WO2000027856A1 - Macrolide intermediates - Google Patents

Macrolide intermediates Download PDF

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Publication number
WO2000027856A1
WO2000027856A1 PCT/EP1999/008578 EP9908578W WO0027856A1 WO 2000027856 A1 WO2000027856 A1 WO 2000027856A1 EP 9908578 W EP9908578 W EP 9908578W WO 0027856 A1 WO0027856 A1 WO 0027856A1
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compound
formula
water
erythromycin
oxime
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PCT/EP1999/008578
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French (fr)
Inventor
Immaculada Bosch
Victor Centellas
José Diago
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Biochemie S.A.
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Priority to AU11615/00A priority Critical patent/AU1161500A/en
Publication of WO2000027856A1 publication Critical patent/WO2000027856A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • 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

Definitions

  • the present invention relates to the synthesis of antibacterial macrolides, such as erythromycins, for example erythromycin A type, e.g. roxithromycin, dirithromycin, clarithromycin, azithromycin and similar compounds.
  • erythromycins for example erythromycin A type, e.g. roxithromycin, dirithromycin, clarithromycin, azithromycin and similar compounds.
  • Azithromycin (9-deoxo-9a-aza-9a-methyl-9a-homoerithromycin A) is a well-known antibacterial agent described e.g. in The Merck Index, 12 ,h edition (1996), page 157 (946).
  • a compound useful in the preparation of azithromycin is a compound of the following formula I
  • This compound may be prepared by known methods comprising (i) in situ preparation of a compound of formula I from an erythromycin A O-arylsulphonyl oxime, e.g. by a Beckmann rearrangement, and (ii) isolation of a compound of formula I which involves a large number of extractions using chlorinated solvents. It was now surprisingly found that a compound of formula I may be isolated in a much simpler method with significant advantages, e.g. useful on industrial scale, e.g. avoiding extraction steps and e.g. avoiding the use of halogenated solvents.
  • the invention provides a compound of formula I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%.
  • the present invention provides a process for the production of a compound of formula I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, which comprises isolating a compound of formula I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, from an aqueous solvent system by adding a base and adjusting the pH, e.g and preparing a compound of formula I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, from an erythromycin A oxime by a Beckmann rearrangement.
  • An erythromycin A oxime derivative susceptible for Beckmann rearrangement may be prepared, e.g. by reacting an erythromycin A oxime with an arene sulphonyl halide, optionally in the presence of a base.
  • the term "erythromycin A oxime” includes erythromycin A oxime in the form of a free base and erythromycin A oxime in the form of a salt.
  • Erythromycin A oxime in the form of a salt includes an erythromycin A oxime in the form of an acid addition salt, e.g. with the dimethylamino group in position 3' of the sugar residue in position 5 of the ring system, e.g. with organic or inorganic acids, e.g. a salt with an organic acid such as a formate or acetate, or with an inorganic acid, such as a hydrochloride or thiocyanate.
  • arene sulphonyl halide includes a compound of formula:
  • a base in step ii) includes e.g. a base suitable to act as an acid scavenger including organic bases, such as amines and inorganic bases such as an alkali, e.g. sodium, potassium; earth alkali, e.g. calcium, magnesium; and ammonium hydroxide, carbonate or hydrogencarbonate, preferably sodium hydrogencarbonate.
  • any carbon containing group may contain up to 22 carbon atoms; e.g. alkyl includes (Ci-z alkyl, e.g. (C ⁇ -8 )alkyl, such as lower alky!, e.g. (d. 6 )alkyl, for example particularly
  • the reaction between an erythromycin A oxime and an arene sulphonyl halide may be carried out preferably under conditions as conventional for a Beckmann rearrangement, including in situ preparation of an erythromycin A O-arylsulphonyl oxime in aqueous medium where immediate rearrangement may occur to give a compound of formula I.
  • aqueous medium includes a mixture of water with one or more water-miscible solvents, such as alcohols, e.g. methanol, ethanol or isopropanol; lower ketones such as acetone; and amides such as dimethylformamide and dimethylacetamide, preferably a mixture of water and acetone.
  • One or more equivalents of an arene sulphonyl chloride may be used per equivalent erythromycin A oxime, e.g. preferably 1 to 2, and more, preferably 1 to 1.5 equivalents.
  • Appropriate reaction conditions for the preparation of a compound of formula I according to the present invention may include, e.g.
  • - a temperature range of about -15°C up to the reflux temperature of the solvent system used, such as from -10°C to 50°C , e.g. from -5°C to 30°C.
  • an appropriate pressure e.g. atmospheric pressure, and a pressure which is above or below atmospheric pressure
  • a dilution range between 1 g and 1000 g of the erythromycin A oxime starting compound per litre of aqueous medium.
  • the ratio water-organic solvent or solvents in the aqueous medium used is not critical; e.g. a ratio ranging from 50 to 0.02 parts (volume) of water per part or organic solvent (volume), such as between 5 and 0.2; e.g. 1.5 to 0.67 parts of water per part of organic solvent (volume).
  • a compound of formula I obtained may be isolated from an aqueous solvent system by adding a base and adjusting the pH, e.g. to an appropriate value.
  • aqueous solvent system includes e.g. the same aqueous medium, e.g. in the same water-organic solvent ranges, used for the Beckmann rearrangement, or a more diluted medium, preferably, more water may be added to the aqueous medium used for the Beckmann reaction, e.g. the water-organic solvent or solvents ratio may be in the range from 50 to 0.67, such as from 5 to 0.67, e.g. more than 1 part of water per part of organic solvent may be used.
  • the pH of the aqueous solvent system may be adjusted to an appropriate pH, e.g. by addition of a base. Suitable bases include, for example, an inorganic base, such as, for example, an alkali, e.g.
  • a base may be preferably a hydroxide, e.g. sodium and ammonia; preferably in aqueous solution.
  • the term "appropiate pH” includes a pH range wherein the compound of formula I is present in the solution or suspension in free base form.
  • An appropriate pH includes e.g. about, 8.5 to 12, such as 9.0 to 11.0; for example 10.0 to 11.5.
  • a compound of formula I may be isolated as conventional, e.g. by centrifugation or filtration, and dried, e.g.
  • a compound of formula I in form of a hydrate according to the present invention may be dried to give a water content below 2%, for example by drying at temperatures higher than 70°C.
  • erythromycin A oxime in the form of a free base or in the form of a salt may be suspended or dissolved in a mixture of water and acetone, in the presence of a base such as sodium hydrogencarbonate.
  • a base such as sodium hydrogencarbonate.
  • p-Toluene sulphonyl chloride may be added, and the mixture may be allowed to stir at about room temperature, e.g. until Beckmann rearrangement of a compound has occurred.
  • the aqueous medium may be diluted by addition of more water, and the pH may be adjusted to e.g. about, 10 to 11.5.
  • a compound of formula I in the form of a hydrate may precipitate and may be isolated by filtration.
  • An isolated compound of formula I according to the present invention may have a water content of about 4.0 to 10.0%, e.g. 8.0 to about 10.0%, such as about 8.5 to about 9.5%, e.g. 8.8 to 9.2%.
  • the differential scanning calorimetry of a compound of formula I in the form of a hydrate may show at a heating rate of 10°C/minute an endotherm between 50 and 105°C (loss of water) and a decomposition peak starting at 250°C with a maximum about 270°C.
  • the thermal gravimetric analysis at a heating rate of 5°C/minute may show a 8.92% weight loss between room temperature and 95°C.
  • the stoechiometric amount of water is 8.97%, and a compound of formula I may be, e.g. in the form of a tetrahydrate.
  • a compound of formula I in the form of a stable hydrate e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, may be crystalline.
  • X-ray powder diffraction patterns of a compound of formula I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, are given in Tablel and more detailed in Table 2.
  • the present invention provides a compound of formula I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, in crystalline form, e.g. having a X-ray diffraction pattern of Table 1.
  • the process according to the present invention is economic and ecological and may be used on industrial scale.
  • Advantages of the process of the present invention may include:
  • the yields may be higher than 85%, e.g. even higher than 90%
  • a compound of formula I in the form of a stable hydrate e.g. having a water content of 8.0 to 10.0%, may be useful in the production of azithromycin.
  • the present invention provides a process for the production of erythromycins, e.g. azithromycin, e.g. in the form of a solvate, comprising
  • the present invention provides the use of compound I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, in the production of erythromycins, e.g. azithromycin.
  • erythromycins e.g. azithromycin or azithromycin in the form of a solvate
  • the starting material may be stable
  • the starting material may be pure, e.g. may have an assay higher than 97 % on anhydrous basis
  • the starting material may contain no halogenated solvents - the starting material may be produced on industrial scale.
  • 9-Deoxo-6-deoxy-6, 9-epoxy-9,9a-didehydro-9a- aza-9a-homoerythromycin A may precipitate, the crystals are filtered off and washed with water. The solid obtained is dried at 60°C. 6.05 g (92% of theory) of 9-deoxo-6-deoxy-6, 9- epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A in the form of a stable hydrate is obtained. Water content: 9.0 %. Assay on anhydrous basis: 97.2 %.
  • IR (KBr): 3489,3447,3290, 1717,1697,1456, 1383, 1197, 1165, 1126, 1112, 1095, 1017, 959 cm-1 ; DSC (heating rate of 10°C/min): endotherm between 50 and 105°C (loss of water), decomposition peak starting at 250°C with a maximum about 270°C; Thermal gravimetric analysis (heating rate of 5°C/min): 8.92% weight loss between room temperature and 95°C. The stoechiometric amount of water of the hydrate is 8.97%.
  • X-ray powder diffraction pattern as described in Tables 1 and 2.

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Abstract

The present invention relates to the preparation of 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A, of Formula (I) in the form of a stable hydrate and its use as an intermediate in the production of azithromycin.

Description

Macrolide Intermediates
The present invention relates to the synthesis of antibacterial macrolides, such as erythromycins, for example erythromycin A type, e.g. roxithromycin, dirithromycin, clarithromycin, azithromycin and similar compounds.
Azithromycin (9-deoxo-9a-aza-9a-methyl-9a-homoerithromycin A) is a well-known antibacterial agent described e.g. in The Merck Index, 12,h edition (1996), page 157 (946). A compound useful in the preparation of azithromycin is a compound of the following formula I
Figure imgf000003_0001
i.e. 9-deoxo-6-deoxy-6,9-epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A. This compound may be prepared by known methods comprising (i) in situ preparation of a compound of formula I from an erythromycin A O-arylsulphonyl oxime, e.g. by a Beckmann rearrangement, and (ii) isolation of a compound of formula I which involves a large number of extractions using chlorinated solvents. It was now surprisingly found that a compound of formula I may be isolated in a much simpler method with significant advantages, e.g. useful on industrial scale, e.g. avoiding extraction steps and e.g. avoiding the use of halogenated solvents.
Thus, in one aspect the invention provides a compound of formula I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%.
In another aspect the present invention provides a process for the production of a compound of formula I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, which comprises isolating a compound of formula I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, from an aqueous solvent system by adding a base and adjusting the pH, e.g and preparing a compound of formula I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, from an erythromycin A oxime by a Beckmann rearrangement.
A process according to the present invention may be carried out as follows: An erythromycin A oxime derivative susceptible for Beckmann rearrangement may be prepared, e.g. by reacting an erythromycin A oxime with an arene sulphonyl halide, optionally in the presence of a base. The term "erythromycin A oxime" includes erythromycin A oxime in the form of a free base and erythromycin A oxime in the form of a salt. Erythromycin A oxime in the form of a salt includes an erythromycin A oxime in the form of an acid addition salt, e.g. with the dimethylamino group in position 3' of the sugar residue in position 5 of the ring system, e.g. with organic or inorganic acids, e.g. a salt with an organic acid such as a formate or acetate, or with an inorganic acid, such as a hydrochloride or thiocyanate.
The term arene sulphonyl halide includes a compound of formula:
R-C6H4-SO2-X wherein R is hydrogen, alkyl, halogen or acylamino and X is halogen, preferably a p-toluene sulphonyl halide, e.g. p-toluenesulphonyl chloride. A base in step ii) includes e.g. a base suitable to act as an acid scavenger including organic bases, such as amines and inorganic bases such as an alkali, e.g. sodium, potassium; earth alkali, e.g. calcium, magnesium; and ammonium hydroxide, carbonate or hydrogencarbonate, preferably sodium hydrogencarbonate. If not otherwise defined herein any carbon containing group may contain up to 22 carbon atoms; e.g. alkyl includes (Ci-z alkyl, e.g. (Cι-8)alkyl, such as lower alky!, e.g. (d.6)alkyl, for example
Figure imgf000005_0001
particularly
Figure imgf000005_0002
The reaction between an erythromycin A oxime and an arene sulphonyl halide may be carried out preferably under conditions as conventional for a Beckmann rearrangement, including in situ preparation of an erythromycin A O-arylsulphonyl oxime in aqueous medium where immediate rearrangement may occur to give a compound of formula I. The term aqueous medium includes a mixture of water with one or more water-miscible solvents, such as alcohols, e.g. methanol, ethanol or isopropanol; lower ketones such as acetone; and amides such as dimethylformamide and dimethylacetamide, preferably a mixture of water and acetone. One or more equivalents of an arene sulphonyl chloride may be used per equivalent erythromycin A oxime, e.g. preferably 1 to 2, and more, preferably 1 to 1.5 equivalents. Appropriate reaction conditions for the preparation of a compound of formula I according to the present invention may include, e.g.
- a temperature range of about -15°C up to the reflux temperature of the solvent system used, such as from -10°C to 50°C , e.g. from -5°C to 30°C.
- an appropriate pressure, e.g. atmospheric pressure, and a pressure which is above or below atmospheric pressure; and
- appropriate dilution, e.g. a dilution range between 1 g and 1000 g of the erythromycin A oxime starting compound per litre of aqueous medium. The ratio water-organic solvent or solvents in the aqueous medium used is not critical; e.g. a ratio ranging from 50 to 0.02 parts (volume) of water per part or organic solvent (volume), such as between 5 and 0.2; e.g. 1.5 to 0.67 parts of water per part of organic solvent (volume).
A compound of formula I obtained may be isolated from an aqueous solvent system by adding a base and adjusting the pH, e.g. to an appropriate value.
The term "aqueous solvent system" includes e.g. the same aqueous medium, e.g. in the same water-organic solvent ranges, used for the Beckmann rearrangement, or a more diluted medium, preferably, more water may be added to the aqueous medium used for the Beckmann reaction, e.g. the water-organic solvent or solvents ratio may be in the range from 50 to 0.67, such as from 5 to 0.67, e.g. more than 1 part of water per part of organic solvent may be used. The pH of the aqueous solvent system may be adjusted to an appropriate pH, e.g. by addition of a base. Suitable bases include, for example, an inorganic base, such as, for example, an alkali, e.g. sodium, potassium; earth alkali, e.g. calcium, magnesium; and ammonium; hydroxide, carbonate, bicarbonate; and an organic base, such as ammonia and an amine, an alkyl amine. A base may be preferably a hydroxide, e.g. sodium and ammonia; preferably in aqueous solution. The term "appropiate pH" includes a pH range wherein the compound of formula I is present in the solution or suspension in free base form. An appropriate pH includes e.g. about, 8.5 to 12, such as 9.0 to 11.0; for example 10.0 to 11.5. A compound of formula I may be isolated as conventional, e.g. by centrifugation or filtration, and dried, e.g. to provide a compound of formula I in the form of a stable hydrate, e.g. having a water content of 8.0 to 10.0%. The yields may be very high, even higher than 85%, e.g even higher than 90% . The assay of the product obtained according to the present invention may also be very high, even higher than 95% , even higher than 97 % on anhydrous basis. A compound of formula I in form of a hydrate according to the present invention may be dried to give a water content below 2%, for example by drying at temperatures higher than 70°C.
In a preferred process of the present invention erythromycin A oxime in the form of a free base or in the form of a salt may be suspended or dissolved in a mixture of water and acetone, in the presence of a base such as sodium hydrogencarbonate. p-Toluene sulphonyl chloride may be added, and the mixture may be allowed to stir at about room temperature, e.g. until Beckmann rearrangement of a compound has occurred. The aqueous medium may be diluted by addition of more water, and the pH may be adjusted to e.g. about, 10 to 11.5. A compound of formula I in the form of a hydrate may precipitate and may be isolated by filtration.
An isolated compound of formula I according to the present invention may have a water content of about 4.0 to 10.0%, e.g. 8.0 to about 10.0%, such as about 8.5 to about 9.5%, e.g. 8.8 to 9.2%. The differential scanning calorimetry of a compound of formula I in the form of a hydrate may show at a heating rate of 10°C/minute an endotherm between 50 and 105°C (loss of water) and a decomposition peak starting at 250°C with a maximum about 270°C. The thermal gravimetric analysis at a heating rate of 5°C/minute may show a 8.92% weight loss between room temperature and 95°C. The stoechiometric amount of water is 8.97%, and a compound of formula I may be, e.g. in the form of a tetrahydrate.
A compound of formula I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, may be crystalline. X-ray powder diffraction patterns of a compound of formula I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, are given in Tablel and more detailed in Table 2.
Table 1
Figure imgf000007_0001
Table 2
Figure imgf000007_0002
Figure imgf000008_0001
In Tables 1 and 2 "d" denotes the interplanar spacing; I l0 denotes the relative intensity and A denotes Angstrom.
In another aspect the present invention provides a compound of formula I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, in crystalline form, e.g. having a X-ray diffraction pattern of Table 1.
The process according to the present invention is economic and ecological and may be used on industrial scale. Advantages of the process of the present invention may include:
- halogenated solvents may be eliminated
- the yields may be higher than 85%, e.g. even higher than 90%
- the assay on the anhydrous basis of the compound of formula I obtained is higher than 95%, e.g. higher than 97%.
A compound of formula I in the form of a stable hydrate, e.g. having a water content of 8.0 to 10.0%, may be useful in the production of azithromycin.
In a further aspect the present invention provides a process for the production of erythromycins, e.g. azithromycin, e.g. in the form of a solvate, comprising
(i) reducing a compound of formula I in the form of a stable hydrate, e.g. in the presence of hydrogen and a catalyst or a metal hydride, e.g. sodium borohydride, to form 9-deoxo-9a-aza-9a-homoerythromycin A, (ii) methylating 9-deoxo-9a-aza-9a-homoerythromycin A obtained in step i) in the 9a-aza position to form 9-deoxo-9a-aza-9a-methyl-9a-homoerithromycin A, and
(iii) isolating erythromycins, e.g. in the form of a solvate. Production and isolation may e.g. be carried out but as conventional but using a compound of formula I in the form of a stable hydrate as starting material.
In a further aspect the present invention provides the use of compound I in the form of a stable hydrate, e.g. having a water content of 4.0 to 10.0%, e.g. 8.0 to 10.0%, in the production of erythromycins, e.g. azithromycin.
The use of a compound of formula I in form of a stable hydrate as starting material for the production of erythromycins, e.g. azithromycin or azithromycin in the form of a solvate, according to the present invention may have the following advantages:
- the starting material may be stable
- the starting material may be pure, e.g. may have an assay higher than 97 % on anhydrous basis
- the starting material may contain no halogenated solvents - the starting material may be produced on industrial scale.
The following example may illustrate the invention wihout limiting its scope. All temperatures are given in degree Celsius and are uncorrected. Preferably liquid chromatography, e.g. HPLC, may be used to assay for the erythromycin A oxime used as starting material and the obtained compound of formula I.
Example
To a suspension of 6.27 g of erythromycin A oxime (assay 95.5%) in 25 ml of acetone at ca. 5°C, a solution of 1.68 g of sodium hydrogencarbonate in 30 ml of water is added. To the mixture obtained a solution of 1.90 g p-toluensulphonyl chloride in 8 ml of acetone is added dropwise, keeping the temperature at about 5°C. The reaction mixture is allowed to stir at ca. 5°C for ca. an additional hour, and for ca. a further hour at room temperature. The reaction mixture is diluted with 50 ml of water and the pH is adjusted to 10 to 11 by addition of 20% w/w aqueous sodium hydroxide. 9-Deoxo-6-deoxy-6, 9-epoxy-9,9a-didehydro-9a- aza-9a-homoerythromycin A may precipitate, the crystals are filtered off and washed with water. The solid obtained is dried at 60°C. 6.05 g (92% of theory) of 9-deoxo-6-deoxy-6, 9- epoxy-9,9a-didehydro-9a-aza-9a-homoerythromycin A in the form of a stable hydrate is obtained. Water content: 9.0 %. Assay on anhydrous basis: 97.2 %.
IR (KBr): 3489,3447,3290, 1717,1697,1456, 1383, 1197, 1165, 1126, 1112, 1095, 1017, 959 cm-1 ; DSC (heating rate of 10°C/min): endotherm between 50 and 105°C (loss of water), decomposition peak starting at 250°C with a maximum about 270°C; Thermal gravimetric analysis (heating rate of 5°C/min): 8.92% weight loss between room temperature and 95°C. The stoechiometric amount of water of the hydrate is 8.97%. X-ray powder diffraction pattern as described in Tables 1 and 2.

Claims

What we claim is:
1. A compound of formula
Figure imgf000011_0001
in the form of a stable hydrate.
A compound according to claim 1 having a X-ray powder diffraction pattern of Table 1 :
Figure imgf000011_0002
Table 1
A compound according to any one of claims 1 or 2 in crystalline form.
4. A compound according to anyone of claims 1 to 3 having a water content of 4 to 10%.
5. A compound according to anyone of claims 1 to 4 having a water content of 8 to 10%.
6. A process for the production of a compound of formula I according to any one of claims 1 to 4 which comprises isolating a compound of formula I from an aqueous solvent system by adding a base and adjusting the pH.
7. Use of a compound according to any one of claims 1 to 5 in the production of erythromycins.
8. Use of a compound according to any one of claims 1 to 5 in the production of azithromycin.
PCT/EP1999/008578 1998-11-10 1999-11-09 Macrolide intermediates WO2000027856A1 (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001000640A1 (en) * 1999-06-29 2001-01-04 Biochemie S.A. Macrolides
EP1304326A1 (en) * 2000-07-25 2003-04-23 Laboratorio Silanes, S.A. de C.V. Single-step process for preparing 7,16-deoxy-2-aza-10-o-cladinosil-12-o-desosaminil-4,5-dihydroxi-6-ethyl-3,5,9,11,13,15-hexamethylbicycle (11.2.1)hexadeca-1(2)-en-8-ona and obtaining a new form of 9-desoxo-9a-methyl-9a-aza-9a-homoerythromycin a
US7683162B2 (en) 2004-08-30 2010-03-23 Taro Pharmaceutical Industries Limited Process of preparing a crystalline azithromycin monohydrate
CN104892697A (en) * 2015-05-05 2015-09-09 黄石世星药业有限责任公司 Azithromycin production technology
CN105481913A (en) * 2014-09-19 2016-04-13 宁夏启元药业有限公司 Method for synthesizing azithromycin
CN106432370A (en) * 2016-09-12 2017-02-22 上海现代制药海门有限公司 Preparation method of high-purity erythromycin 6,9-imino ether

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001000640A1 (en) * 1999-06-29 2001-01-04 Biochemie S.A. Macrolides
US6703372B1 (en) 1999-06-29 2004-03-09 Biochemie S.A. Macrolides
EP1712556A1 (en) * 1999-06-29 2006-10-18 Sandoz AG Azithromycin monohydrate
HRP20010956B1 (en) * 1999-06-29 2010-09-30 Biochemie S.A. Macrolides
EP1304326A1 (en) * 2000-07-25 2003-04-23 Laboratorio Silanes, S.A. de C.V. Single-step process for preparing 7,16-deoxy-2-aza-10-o-cladinosil-12-o-desosaminil-4,5-dihydroxi-6-ethyl-3,5,9,11,13,15-hexamethylbicycle (11.2.1)hexadeca-1(2)-en-8-ona and obtaining a new form of 9-desoxo-9a-methyl-9a-aza-9a-homoerythromycin a
EP1304326A4 (en) * 2000-07-25 2004-06-16 Silanes Sa De Cv Lab Single-step process for preparing 7,16-deoxy-2-aza-10-o-cladinosil-12-o-desosaminil-4,5-dihydroxi-6-ethyl-3,5,9,11,13,15-hexamethylbicycle (11.2.1)hexadeca-1(2)-en-8-ona and obtaining a new form of 9-desoxo-9a-methyl-9a-aza-9a-homoerythromycin a
US7683162B2 (en) 2004-08-30 2010-03-23 Taro Pharmaceutical Industries Limited Process of preparing a crystalline azithromycin monohydrate
CN105481913A (en) * 2014-09-19 2016-04-13 宁夏启元药业有限公司 Method for synthesizing azithromycin
CN104892697A (en) * 2015-05-05 2015-09-09 黄石世星药业有限责任公司 Azithromycin production technology
CN106432370A (en) * 2016-09-12 2017-02-22 上海现代制药海门有限公司 Preparation method of high-purity erythromycin 6,9-imino ether

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