EP1727824A1 - Process for the preparation of clarithromycin - Google Patents

Process for the preparation of clarithromycin

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Publication number
EP1727824A1
EP1727824A1 EP05716204A EP05716204A EP1727824A1 EP 1727824 A1 EP1727824 A1 EP 1727824A1 EP 05716204 A EP05716204 A EP 05716204A EP 05716204 A EP05716204 A EP 05716204A EP 1727824 A1 EP1727824 A1 EP 1727824A1
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EP
European Patent Office
Prior art keywords
acetate
group
formula
methyl
solvent
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.)
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Application number
EP05716204A
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German (de)
French (fr)
Inventor
Immaculada Bosch
Victor Centellas
Sandra Romero
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.)
Sandoz AG
Original Assignee
Sandoz AG
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Classifications

    • 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 clarithromycin (see Merck Index, 12 edition (1996) page 2404) of formula I, a well known and useful antibacterial agent:
  • a compound of formula I may be prepared by known methods, starting e.g. from a compound of formula II:
  • Erythromycin A oxime Erythromycin A oxime is described in US 3,478,014 and may be produced from erythromycin A. Erythromycin A oxime has been described as useful for the production of antibacterial macrolides.
  • Clarithromycin produced using toxic solvents may potentially contain residual toxic solvents. It is desirable to limit the presence of such residual solvents because of their inherent toxicity, in order to protect patients from potential adverse effects.
  • Benzene is classed as a Class 1 solvent, under the accepted European Pharmacopoeia classification system.
  • the class 1 solvents are those solvents which should not be employed in the manufacture of pharmaceuticals because of their unacceptable toxicity and deleterious environmental effect.
  • the other solvents mentioned above are classed as Class 2 solvents under accepted European Pharmacopoeia classification system.
  • the class 2 solvents are those solvents which should be limited in pharmaceutical products because of their inherent toxicity. Class 1 and 2 solvents are considered toxic solvents within the definitions of the European Pharmacopoeia. (For the standard classification of solvents see for example - European Pharmacopoeia, Supplement 1999, page 295: RESIDUAL SOLVENTS.)
  • the present invention provides a process for the production of clarithromycin of formula I from erythromycin A oxime of formula II, comprising the steps of:
  • each step is carried out in the presence of a solvent with a low toxic potential or water.
  • Small amounts of one or more toxic solvents may be used together with low toxic potential solvents in the process according to the present invention.
  • no more than 20% v/v, more preferably no more than 10 % v/v, most preferably no more than 5% v/v, e.g. no more than 1 % v/v of the solvent used in any one step should be a toxic solvent.
  • no more than 10 % v/v, preferably no more than 5% v/v, e.g. no more than 0.5% v/v of the total solvent used in the described process according to the present invention should be a toxic solvent.
  • the process according to the present invention uses only solvents with a low toxic potential.
  • the present invention provides a process for the production of clarithromycin of formula I from erythromycin A oxime of formula II, comprising the steps of: - protecting the hydroxyl groups in position 2' and 4" of the compound of formula II by reacting with a silylating agent, and protecting the hydroxyl group of the oxime group in position 9 of the ring structure of the compound of formula II with an acetal-type protecting agent.
  • Suitable solvents with low toxic potential for use in the process according to the present invention include less toxic solvents, of lower risk to human health, classified according to European Pharmacopoeia as Class 3 solvents.
  • Class 3 includes no solvent known as a human health hazard at levels normally accepted in pharmaceutical products.
  • Suitable solvents include ketones, for instance acetone, methylethylketone and methylisobutylketone; alcohols, for instance butanols such as 1-butanol ,2-butanol and 3-methyl-l-butanol, propanols such as 1-propanol, 2-propanol and 2-methyl-1-propanol, ethanol and 1-pentanol; formates, for instance ethyl formate; acetates, for instance methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate; ethers, for instance anisole, t-butylmethyl ether and ethyl ether; acids, for instance acetic acid and formic acid; sulphoxides, for instance dimethylsulphoxide; hydrocarbons, for instance cumene, heptane and pentane; or a mixture
  • Preferred solvents include acetone, methylethylketone, methylisobutylketone, 1-butanol ,2- butanol, 3-methyl-1-butanol, 1-propanol, 2-propanol, 2-methyl-1-propanol, ethanol, 1- pentanol, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, anisole, ethyl ether, dimethylsulphoxide, cumene, heptane and pentane; or a mixture of two or more thereof in any proportion.
  • the erythromycin A oxime of formula II may be used in any suitable form, including as free base in any form, such as any crystalline form, anhydrous form, or in the form of a solvate such as, for instance, a hydrate, e.g. a dihydrate or a hemihydrate; or a solvate with a non- halogenated solvent.
  • a salt including a salt formed with the dimethylamino group, such as a salt of an inorganic acid e.g. a hydrochloride or a salt of an organic acid e.g.
  • a formate, acetate or propionate or a salt formed with the oxime group, for instance an oximate such as 1 ,8-diazabicyclo(5,4,0)undec-7-ene ( DBU) oximate, 1 ,5- diazabicyclo(4,3,0)non-5-ene (DBN) oximate or tetramethylguanidine oximate. Salts formed with the dimethylamino group, such as hydrochloride, formate, acetate or propionate are particularly mentioned. Also, for instance, as different isomers in the oxime group of the ring structure, e.g. the E isomer and the Z isomer, either in isolation or a mixture thereof in any proportion
  • the protection of the hydroxyl groups in position 2' and 4" of the compound of formula II the protection of the hydroxyl group of the oxime group in position 9 of the ring structure of the compound of formula II in the first step of the reaction can be carried out in any desired order.
  • silyating agents for use in protecting the hydroxyl groups in position 2' and 4 " of the compound of formula II include chlorosilanes, such as trimethylchlorosilane and tert-butyldimethylchlorosilane; silylamines such as 1 ,1 ,1 ,3,3,3,-hexamethyldisilazane and trimethylsilylimidazole, silylamides such as bis(trimethylsilyl) acetamide and bis(trimethylsilyl)urea, or a mixture thereof.
  • chlorosilanes such as trimethylchlorosilane and tert-butyldimethylchlorosilane
  • silylamines such as 1 ,1 ,1 ,3,3,3,-hexamethyldisilazane and trimethylsilylimidazole
  • silylamides such as bis(trimethylsilyl) acetamide and bis(trimethylsilyl)urea
  • Suitable solvents for use in the protection of the hydroxyl groups in position 2' and 4 " of the compound of formula II include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate, or a mixture thereof.
  • Preferred acetal-type protecting agents for use in protecting the hydroxyl of the oxime group in position 9 of the ring structure of erythromycin A oxime of formula II include 2- methoxypropene, 2,2-dimethoxy propane, 1 ,1-diisopropoxy cyclohexene and 1-isopropoxy-1- cyclohexene.
  • Preferred solvents for use in the protection of hydroxyl of the oxime group in position 9 of the ring structure include acetone, methyl ethylketone or methylisobutylketone, or a mixture thereof.
  • the methylation of the hydroxyl group in step (ii) may suitably be carried out by reaction with a methylating agent and a base.
  • Suitable methylating agents include methyl halides , such as methyl bromide and methyl iodide; methyl sulphates, such as methyl sulphate and dimethyl sulphate; and sulphonates such as methyl p-toluenesulphonate, methyl methanesulphonate and methyl trifluoromethanesulphonate.
  • Suitable bases for use in the methylation include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride; and organic bases such as alcoxides, e.g.
  • tetraalkyl ammonium hydroxides e.g. tetramethylammonium hydroxide.
  • organic bases such as amines, e.g. alkyl amines such as trimethylamine, triethylamine and tripropylamine; or e.g. arylamines such as pyridine, methyl pyridines or dimetrhylpyridines; may be mixed with the above mentioned bases in the methylation reaction.
  • Suitable solvents for use in the methylation of the hydroxyl group in position 6 of the ring structure include ketones, e.g. acetone, methylethylketone and methylisobutylketone; formates, e.g. ethyl formate; acetates, e.g. methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate; ethers, e.g. anisole, t-butylmethyl ether and ethyl ether; sulphoxides, e.g. dimethylsulphoxide and hydrocarbons, e.g.
  • ketones e.g. acetone, methylethylketone and methylisobutylketone
  • formates e.g. ethyl formate
  • acetates e.g. methyl acetate, e
  • the present invention provides clarithromycin of formula I obtained according to the process described herein.
  • the present invention provides clarithromycin of formula I which is practically free or free from toxic solvents which are a risk for human health, e.g. class 1 or class 2 solvents as defined according to the accepted European Pharmacopoeia classification of organic solvents.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, clarithromycin obtained according to the process described herein and which is free of toxic solvents, in association with at least one pharmaceutical carrier or diluent.
  • the process for the production of clarithromycin according to the present invention allows for the reduction or elimination of the use of toxic solvents which can pose a risk to human health and to the environment, e.g. class 1 and 2 solvents.
  • the process of the present invention provides effective production of clarithromycin and may be carried out on a industrial scale.
  • the process according to the present invention allows for the production of clarithromycin which is practically free or free from toxic solvents which can pose a risk to human health.
  • clarithromycin used herein includes clarithromycin in any form, including crystalline forms such as Form 0, Form I, Form II , Form III and Form IV ; salts such as salts with organic and inorganic acids, pharmaceutical salts, solvates, e.g. hydrates; and mixtures thereof, as well as amorphous solids, syrups or semisolids comprising clarithromycin in any state of purity.
  • free from toxic solvents includes traces of toxic solvents, i.e. solvents which are a risk for human health, e.g. solvents defined as class 1 or class 2 solvents according to the accepted European Pharmacopoeia classification of organic solvents, in clarithromycin according to the present invention, such as amounts of 50ppm and below, e.g. 2 to 50ppm, or even less.
  • the protection of the hydroxyl groups in position 2' and 4 " may be performed by, e.g. conventional silylating procedures, for instance according to the silylation methods described in T.W. Greene and P.G.M. Wuts, Protective Groups in Organics Synthesis, 2 nd Edition, John Wiley and Sons, (1991); e.g. by reacting erythromycin A oxime of formula II with a silylating agent, e.g. with a trimethylsilylating agent in a solvent and, optionally in the presence of a catalyst.
  • silylating agent e.g. with a trimethylsilylating agent in a solvent and, optionally in the presence of a catalyst.
  • silylating agents may include chlorosilanes, such as trimethylchlorosilane and tert-butyldimethylchlorosilane; silylamines such as 1 ,1 ,1,3,3,3,- hexamethyldisilazane and trimethylsilylimidazole, silylamides such as bis(trimethylsilyl) acetamide and bis(trimethylsilyl)urea and a mixture thereof.
  • the amount of silylating agent is not critical, conveniently at least 1 equivalents and more, e.g. up to 10 equivalents silylation reagent per equivalent of erythromycin A oxime of formula II may be used.
  • catalysts may include, for instance sulfonic acids, such as p-toluenesulponic acid; acids such as trifluoroacetic acid; silylating agents, such as chlorotrimethylsilane, bromotrimethylsilane and trimethylsilyltrifluoroacetic acid; amines and ammonium salts, such as ammonium chloride or triethylammonium chloride; amides and imides, such as succinimide, 3,3- dimethylglutarimide, 1 ,8-naphtalimide; 1 ,2-benzisothiazol-3(2H)-one, 1 ,2-benzisothiazol- 3(2H)-one 1 ,1-dioxide; and phtalimides, sulfamides, such as N,N-dimethyIsulfamide and p- toluenesulfonamides, phosphoroamides and their derivatives, such as phosphoro
  • Class 3 solvents that may be used for the protection of the hydroxyl groups in position 2' and 4 " include ketones, e.g. acetone, methylethylketone and methylisobutylketone; formates, e.g. ethyl formate; acetates, e.g. methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate; ethers, e.g. anisole, t-butylmethyl ether and ethyl ether; sulphoxides, e.g. dimethylsulphoxide and hydrocarbons, e.g.
  • ketones e.g. acetone, methylethylketone and methylisobutylketone
  • formates e.g. ethyl formate
  • acetates e.g. methyl acetate, eth
  • the reaction with the silylating agent is carried out at a temperature between 0 °C and the refluxing temperature of the solvent.
  • the amount of solvent employed is not critical, and may range from less than 1 mL, e.g. less than 0.5 mL, e.g. 0.3 mL of solvent per g of starting product to more than 10 mL, or more than 50 mL of solvent per g of starting product.
  • the silylation reaction may be also carried out in different conditions of pressure, for instance at atmospheric pressure or at a pressure higher or lower than atmospheric pressure.
  • the protection of the hydroxyl of the oxime group in position 9 of the ring structure may be performed by reacting erythromycin A oxime of formula II with an acetal-type protecting agent in a solvent.
  • acetal-type protecting agents may include compound of formula III:
  • Ri is lower alkyl, e.g. (C ) alkyl, cycloalkyl, e.g. (C 3 - ⁇ ) such as (C 3 -e) cycloalkyl, aryl, e.g. phenyl, e.g. unsubstituted or susbstituted, e.g. by groups which are inert under alkylation conditions;
  • R 2 is hydrogen, lower alkyl, e.g. (C ) alkyl, aryl, e.g. phenyl, e.g. unsubstituted or susbstituted, e.g. by groups which are inert under alkylation conditions;
  • R 3 is hydrogen, lower alkyl, e.g. (C M ) alkyl, aryl, e.g. phenyl, e.g. unsubstituted or susbstituted, e.g. by groups which are inert under alkylation conditions;
  • R 4 is a group of formula -OR 5 , wherein R 5 is a hydrogen or lower alkyl
  • Ri and R 2 ; or Ri and R 3 form together a ring, e.g. a 5- to 7- membered ring, e.g. interrupted by an hetero atom, e.g. oxygen;
  • R 2 and R 3 form together a ring, e.g. a 5- to 7- membered ring such as cycloalkyl or a 5- to 7- membered ring interrumped by an hetero atom, e.g. oxygen;
  • Preferred acetal-type protecting agents include 2-methoxypropene, 2,2-dimethoxy propane, 1 ,1-diisopropoxy cyclohexene and 1-isopropoxy-1-cyclohexene.
  • the amount of acetal-type protecting agent is not critical, conveniently at least 1 equivalent and more, e.g. up to 8 equivalents acetal-type protecting agent are used, in the conditions that are usually employed for the introduction of an acetal-type protecting group to a hydroxyl group.
  • Erythromycin A oxime of formula II may be reacted with a compound of formula III in a solvent in the presence of a catalyst.
  • Suitable catalysts for the reaction are e.g. acids, e.g. organic acids such as formic acid, acetic acid or p-toluenesulphonic acid and e.g. salts of amine, e.g. triethylamine or pyridine, with inorganic acids, e.g. hydrochloric and hydrobromic acids, or with organic acids, e.g. sulphonic acids, e.g. p-toluenesulphonic acid, e.g. pyridine hydrochloride, hydrobromide or pyridinium p-toluenesulphonate; and mixtures of these catalysts.
  • acids e.g. organic acids such as formic acid, acetic acid or p-toluenesulphonic acid and e.g. salts of amine,
  • Class 3 solvents that may be used for the protection of the hydroxyl of the oxime group in position 9 of the ring structure include ketones, e.g. acetone, methylethylketone and methylisobutylketone, alcohols, e.g. butanols, e.g. 1-butanol ,2- butanol and 3-methyl-1-butanol; e.g. propanols, e.g. 1-propanol, 2-propanol and 2-methyl-1- propanol; e.g. ethanol and 1-pentanol; formates, e.g. ethyl formate; acetates, e.g.
  • the reaction with the acetal-type protecting agent is carried out at a temperature between 0 °C and the refluxing temperature of the solvent.
  • the amount of solvent employed is not critical, and may range from less than 1 mL, e.g. less than 0.5 mL, e.g. 0.3 mLI of solvent per g of starting product to more than 10 mL, e,g, more than 50 mL of solvent per g of starting product.
  • the acetalization reaction may be also carried out in different conditions of pressure, for instance, at atmospheric pressure or e.g. at a pressure higher or lower than atmospheric pressure.
  • erythromycin A oxime of formula II may be first reacted with a silylating agent to protect the 2' and 4" hydroxyl groups in the silylating conditions described above, and the resulting compound may then be protected in the hydroxyl of the oxime group by reacting with an acetal-type protecting group in the acetalization conditions described above.
  • erythromycin A oxime of formula II may first be reacted with an acetal-type protecting group in the acetalization conditions described above, and the product obtained may then be reacted with a silylating agent to protect the 2' and 4" hydroxyl groups in the silylating conditions described previously.
  • the product obtained after the protection of the 2' and 4" hydroxyl groups and the hydroxyl of the oxime group of the ring structure may be methylated in the hydroxyl group in position 6 of the ring structure, e.g by reacting with a methylating agent and a base in a solvent.
  • methylating agents may include, e.g. methyl halides , such as methyl bromide and methyl iodide; methyl sulphates, such as methyl sulphate and dimethyl sulphate and sulphonates, such as methyl p-toluenesulphonate, methyl methanesulphonate and methyl trifluoromethanesulphonate.
  • the amount of methylating agent used is not critical, conveniently at least 1 equivalent and more, e.g. up to 8 equivalents of methylating agent may be used in the conditions that are usually employed for the methylating of a hydroxyl group, e.g. in the presence of a base.
  • bases used in the methylation may include, e.g. inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride; and organic bases, e.g. alcoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide and potassium tert- butoxide, e.g. tetraalkyl ammonium hydroxides, such as tetramethylammonium hydroxide.
  • Other organic bases such as amines, e.g. alkyl amines such as trimethylamine, triethylamine and tripropylamine; or e.g. arylamines such as pyridine, methyl pyridines or dimetrhylpyridines; may be mixed with the above mentioned bases in the methylation reaction.
  • Class 3 solvents that may be used for the methylation of the hydroxyl group in position 6 of the ring structure include ketones, e.g. acetone, methylethylketone and methylisobutylketone; formates, e.g. ethyl formate; acetates, e.g. methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate; ethers, e.g. anisole, t-butylmethyl ether and ethyl ether; sulphoxides, e.g. dimethylsulphoxide and hydrocarbons, e.g.
  • ketones e.g. acetone, methylethylketone and methylisobutylketone
  • formates e.g. ethyl formate
  • acetates e.g. methyl acetate,
  • the reaction with the methylating agent is carried out at a temperature between 20 °C and the refluxing temperature of the solvent.
  • the amount of solvent employed is not critical, and may range from less than 1 mL, e.g. less than 0.5 mL, e.g. 0.3 mL of solvent per g of starting product to more than 10 mL, e,g, more than 50 mL of solvent per g of starting product.
  • the methylation reaction may be also carried out in different conditions of pressure, e,g, at atmospheric pressure or e.g. at a pressure higher or lower than atmospheric pressure.
  • the product obtained after the methylation in the hydroxyl group in the position 6 of the ring structure may be deprotected, e.g. the protected hydroxyl groups in position 2' and 4" of the ring structure may be eliminated to obtain hydroxyl groups and the oxime protected group of the ring structure may be deprotected and deoximated to obtain a carbonyl group.
  • the deprotection steps may be carried out using conventional methods, e.g. by hydrolysis under acidic conditions in a solvent.
  • Class 3 solvents that may be used for the hydrolysis under acidic conditions include ketones, e.g. acetone, methylethylketone and methylisobutylketone, alcohols, such as butanols, e.g. 1-butanol ,2-butanol and 3-methyl-1- butanol; propanols, e.g.
  • formates such as ethyl formate
  • acetates such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate
  • Acids used for achieving the acidic conditions may include Class 3 solvent acids, such as acetic acid, and formic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid and sulphuric acid.
  • the hydrolysis of the protecting groups may be carried out at a temperature between 0 °C and the refluxing temperature of the solvent.
  • the amount of solvent employed is not critical, and may range from less than 1 mL, e.g. less than 0.5 mL, e.g. 0.3 mLI of solvent per g of starting product to more than 10 mL, e,g, more than 50 mL of solvent per g of starting product.
  • the deprotection may be also carried out in different conditions of pressure, e,g, at atmospheric pressure or at a pressure higher or lower than atmospheric pressure.
  • the deoximation reaction may be performed by conventional methods, e.g. by reacting with a deoximation agent in a solvent.
  • deoximation agents include, e.g. inorganic sulfur oxide compounds, e.g. sodium hydrogen sulfite, sodium sulfite, sodium hydrosulfite, sodium metabisultife, potassium hydrogen sulfite and potassium metabisultife and their aqueous solutions.
  • the amount of deoximating agent used agent is not critical, conveniently at least 1 equivalent and more, e.g. up to 8 equivalents of the deoximating agent may be used in the conditions that are usually employed for the deoximation reactions, e.g.
  • Class 3 solvents that may be used for the deoximation are the same that used for the hydrolysis of the 2' and 4" groups, and include ketones, e.g. acetone, methylethylketone and methylisobutylketone, alcohols, e.g. butanols, e.g. 1-butanol ,2- butanol and 3-methyl-1-butanol; e.g. propanols, e.g. 1-propanol, 2-propanol and 2-methyl-1- propanol; e.g.
  • ketones e.g. acetone, methylethylketone and methylisobutylketone
  • alcohols e.g. butanols, e.g. 1-butanol ,2- butanol and 3-methyl-1-butanol
  • propanols e.g. 1-propanol, 2-propanol and 2-methyl-1- propanol;
  • ethanol and 1-pentanol formates, e.g. ethyl formate; acetates, e.g. methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate; ethers, e.g. anisole.t-butylmethyl etherand ethyl ether; acids, e.g. acetic acid and formic acid, sulphoxides, e.g. dimethylsulphoxide and hydrocarbons, e.g. cumene, heptane and pentane; and mixtures of these solvents in any proportion.
  • formates e.g. ethyl formate
  • acetates e.g. methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate
  • Water may also be present in the medium used for the deoximation.
  • the deoximation may be carried out at a temperature between 0 °C and the refluxing temperature of the solvent.
  • the amount of solvent employed is not critical, and may range from less than 1 mL, e.g. less than 0.5 mL, e.g. 0.3 mLI of solvent per g of starting product to more than 10 mL, e,g, more than 50 mL of solvent per g of starting product.
  • the deoximation may be also carried out in different conditions of pressure, e,g, at atmospheric pressure or at a pressure higher or lower than atmospheric pressure.
  • the hydrolysis of the protected hydroxyl groups and the deoximation reaction may be carried out in separated steps or at the same time.
  • clarithromycin may be isolated from the reaction medium by conventional methods, e.g. by precipitating by adding a base.
  • the product obtained may be transformed to any known form, e.g. crystalline form, by recrystallizing in a medium formed by a class 3 solvent or a mixture of Class 3 solvents, according to European Pharmacopoeia classification, optionally in the presence of water, e.g. by recrystallization in ethanol or in a mixture of ethanol and water; and drying conventional methods, e.g. by drying under vacuum.
  • a pharmaceutical composition comprising clarithromycin free of toxic solvents as an active ingredient according to the present invention may contain the same concentrations of clarithromycin and may be used for the same indications in the same dosages as a known pharmaceutical composition containing clarithromycin as an active ingredient as is presently on the market.

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Abstract

The present invention relates to a process for the production of clarithromycin using solvents with a low toxic potential and water.

Description

Process for the Preparation of Clarithromycin
The present invention relates to clarithromycin (see Merck Index, 12 edition (1996) page 2404) of formula I, a well known and useful antibacterial agent:
19
A compound of formula I may be prepared by known methods, starting e.g. from a compound of formula II:
19
known as "erythromycin A oxime". Erythromycin A oxime is described in US 3,478,014 and may be produced from erythromycin A. Erythromycin A oxime has been described as useful for the production of antibacterial macrolides.
Known methods of preparing clarithromycin of formula I from erythromycin A oxime of formula II, feasible to be done on industrial scale, often involve the use of toxic solvents in several steps, with a risk to human health and environment. Clarithromycin produced using toxic solvents may potentially contain residual toxic solvents. It is desirable to limit the presence of such residual solvents because of their inherent toxicity, in order to protect patients from potential adverse effects.
One known process for preparation of clarithromycin of formula I from erythromycin A oxime of formula II, described in US 4,990, 602, discloses the use of solvents including dichloromethane, tetrahydrofuran, benzene, chloroform, N,N-dimethylformamide,hexane and acetonitrile in the examples of clarithromycin preparation disclosed therein.
Another process for the preparation of clarithromycin of formula I from erythromycin A oxime of formula II, disclosed in WO 01/87807, describes the use of toluene as the solvent in the methylating step.
Benzene is classed as a Class 1 solvent, under the accepted European Pharmacopoeia classification system. According to the European Pharmacopoeia classification, the class 1 solvents are those solvents which should not be employed in the manufacture of pharmaceuticals because of their unacceptable toxicity and deleterious environmental effect. The other solvents mentioned above are classed as Class 2 solvents under accepted European Pharmacopoeia classification system. According to the European Pharmacopoeia classification, the class 2 solvents are those solvents which should be limited in pharmaceutical products because of their inherent toxicity. Class 1 and 2 solvents are considered toxic solvents within the definitions of the European Pharmacopoeia. (For the standard classification of solvents see for example - European Pharmacopoeia, Supplement 1999, page 295: RESIDUAL SOLVENTS.)
Accordingly, there remains a need for an industrial process for the production of clarithromycin of formula I, which allow the use of toxic solvents to be reduced or avoided. ln one embodiment the present invention provides a process for the production of clarithromycin of formula I from erythromycin A oxime of formula II, comprising the steps of:
- protecting the hydroxyl groups in position 2' and 4" of the compound of formula I I by reacting with a silylating agent, and protecting the hydroxyl group of the oxime group in position 9 of the ring structure of the compound of formula II with an acetal-type protecting agent.
- methylating the hydroxyl group in position 9 of the ring structure of the protected compound of step (i); and
- deprotecting the hydroxyl groups in position 2' and 4" of the ring structure to obtain hydroxyl groups and deprotecting and deoximating the oxime group of the ring structure to obtain a carbonyl group,
wherein each step is carried out in the presence of a solvent with a low toxic potential or water.
Small amounts of one or more toxic solvents may be used together with low toxic potential solvents in the process according to the present invention. Preferably no more than 20% v/v, more preferably no more than 10 % v/v, most preferably no more than 5% v/v, e.g. no more than 1 % v/v of the solvent used in any one step should be a toxic solvent. Preferably no more than 10 % v/v, preferably no more than 5% v/v, e.g. no more than 0.5% v/v of the total solvent used in the described process according to the present invention should be a toxic solvent.
Preferably the process according to the present invention uses only solvents with a low toxic potential.
Accordingly, in another embodiment the present invention provides a process for the production of clarithromycin of formula I from erythromycin A oxime of formula II, comprising the steps of: - protecting the hydroxyl groups in position 2' and 4" of the compound of formula II by reacting with a silylating agent, and protecting the hydroxyl group of the oxime group in position 9 of the ring structure of the compound of formula II with an acetal-type protecting agent.
- methylating the hydroxyl group in position 9 of the ring structure of the protected compound of step (i); and
- deprotecting the hydroxyl groups in position 2' and 4" of the ring structure to obtain hydroxyl groups and deprotecting and deoximating the oxime group of the ring structure to obtain a carbonyl group,
using only solvents with a low toxic potential or water.
Suitable solvents with low toxic potential for use in the process according to the present invention include less toxic solvents, of lower risk to human health, classified according to European Pharmacopoeia as Class 3 solvents. Class 3 includes no solvent known as a human health hazard at levels normally accepted in pharmaceutical products. Suitable solvents include ketones, for instance acetone, methylethylketone and methylisobutylketone; alcohols, for instance butanols such as 1-butanol ,2-butanol and 3-methyl-l-butanol, propanols such as 1-propanol, 2-propanol and 2-methyl-1-propanol, ethanol and 1-pentanol; formates, for instance ethyl formate; acetates, for instance methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate; ethers, for instance anisole, t-butylmethyl ether and ethyl ether; acids, for instance acetic acid and formic acid; sulphoxides, for instance dimethylsulphoxide; hydrocarbons, for instance cumene, heptane and pentane; or a mixture of two or more thereof in any proportion.
Preferred solvents include acetone, methylethylketone, methylisobutylketone, 1-butanol ,2- butanol, 3-methyl-1-butanol, 1-propanol, 2-propanol, 2-methyl-1-propanol, ethanol, 1- pentanol, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, anisole, ethyl ether, dimethylsulphoxide, cumene, heptane and pentane; or a mixture of two or more thereof in any proportion. The erythromycin A oxime of formula II may be used in any suitable form, including as free base in any form, such as any crystalline form, anhydrous form, or in the form of a solvate such as, for instance, a hydrate, e.g. a dihydrate or a hemihydrate; or a solvate with a non- halogenated solvent. Also in the form of a salt, including a salt formed with the dimethylamino group, such as a salt of an inorganic acid e.g. a hydrochloride or a salt of an organic acid e.g. a formate, acetate or propionate; or a salt formed with the oxime group, for instance an oximate such as 1 ,8-diazabicyclo(5,4,0)undec-7-ene ( DBU) oximate, 1 ,5- diazabicyclo(4,3,0)non-5-ene (DBN) oximate or tetramethylguanidine oximate. Salts formed with the dimethylamino group, such as hydrochloride, formate, acetate or propionate are particularly mentioned. Also, for instance, as different isomers in the oxime group of the ring structure, e.g. the E isomer and the Z isomer, either in isolation or a mixture thereof in any proportion
The protection of the hydroxyl groups in position 2' and 4" of the compound of formula II the protection of the hydroxyl group of the oxime group in position 9 of the ring structure of the compound of formula II in the first step of the reaction can be carried out in any desired order.
The protection of the hydroxyl groups in position 2' and 4 " of the compound of formula II can be carried out using conventional silylating agents. Preferred silyating agents for use in protecting the hydroxyl groups in position 2' and 4 " of the compound of formula II include chlorosilanes, such as trimethylchlorosilane and tert-butyldimethylchlorosilane; silylamines such as 1 ,1 ,1 ,3,3,3,-hexamethyldisilazane and trimethylsilylimidazole, silylamides such as bis(trimethylsilyl) acetamide and bis(trimethylsilyl)urea, or a mixture thereof. Suitable solvents for use in the protection of the hydroxyl groups in position 2' and 4 " of the compound of formula II include methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate, or a mixture thereof.
Preferred acetal-type protecting agents for use in protecting the hydroxyl of the oxime group in position 9 of the ring structure of erythromycin A oxime of formula II include 2- methoxypropene, 2,2-dimethoxy propane, 1 ,1-diisopropoxy cyclohexene and 1-isopropoxy-1- cyclohexene. Preferred solvents for use in the protection of hydroxyl of the oxime group in position 9 of the ring structure include acetone, methyl ethylketone or methylisobutylketone, or a mixture thereof. The methylation of the hydroxyl group in step (ii) may suitably be carried out by reaction with a methylating agent and a base. Suitable methylating agents include methyl halides , such as methyl bromide and methyl iodide; methyl sulphates, such as methyl sulphate and dimethyl sulphate; and sulphonates such as methyl p-toluenesulphonate, methyl methanesulphonate and methyl trifluoromethanesulphonate. Suitable bases for use in the methylation include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride; and organic bases such as alcoxides, e.g. sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide and potassium tert- butoxide; tetraalkyl ammonium hydroxides, e.g. tetramethylammonium hydroxide. Optionally other organic bases such as amines, e.g. alkyl amines such as trimethylamine, triethylamine and tripropylamine; or e.g. arylamines such as pyridine, methyl pyridines or dimetrhylpyridines; may be mixed with the above mentioned bases in the methylation reaction.
Suitable solvents for use in the methylation of the hydroxyl group in position 6 of the ring structure include ketones, e.g. acetone, methylethylketone and methylisobutylketone; formates, e.g. ethyl formate; acetates, e.g. methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate; ethers, e.g. anisole, t-butylmethyl ether and ethyl ether; sulphoxides, e.g. dimethylsulphoxide and hydrocarbons, e.g. cumene, heptane and pentane; and mixtures of two or more thereof in any proportion. Propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate and dimethylsulphoxide, or a mixture of two or more thereof in any proportion, are particularly mentioned.
According to another aspect the present invention provides clarithromycin of formula I obtained according to the process described herein.
According to one preferred embodiment the present invention provides clarithromycin of formula I which is practically free or free from toxic solvents which are a risk for human health, e.g. class 1 or class 2 solvents as defined according to the accepted European Pharmacopoeia classification of organic solvents.
In another aspect the present invention provides a pharmaceutical composition comprising, as an active ingredient, clarithromycin obtained according to the process described herein and which is free of toxic solvents, in association with at least one pharmaceutical carrier or diluent.
The process for the production of clarithromycin according to the present invention allows for the reduction or elimination of the use of toxic solvents which can pose a risk to human health and to the environment, e.g. class 1 and 2 solvents. The process of the present invention provides effective production of clarithromycin and may be carried out on a industrial scale.
The process according to the present invention allows for the production of clarithromycin which is practically free or free from toxic solvents which can pose a risk to human health.
The term "clarithromycin" used herein includes clarithromycin in any form, including crystalline forms such as Form 0, Form I, Form II , Form III and Form IV ; salts such as salts with organic and inorganic acids, pharmaceutical salts, solvates, e.g. hydrates; and mixtures thereof, as well as amorphous solids, syrups or semisolids comprising clarithromycin in any state of purity.
The term "free from toxic solvents" used herein includes traces of toxic solvents, i.e. solvents which are a risk for human health, e.g. solvents defined as class 1 or class 2 solvents according to the accepted European Pharmacopoeia classification of organic solvents, in clarithromycin according to the present invention, such as amounts of 50ppm and below, e.g. 2 to 50ppm, or even less.
The process according to one embodiment of the present invention may be carried out as follows:
The protection of the hydroxyl groups in position 2' and 4 " may be performed by, e.g. conventional silylating procedures, for instance according to the silylation methods described in T.W. Greene and P.G.M. Wuts, Protective Groups in Organics Synthesis, 2nd Edition, John Wiley and Sons, (1991); e.g. by reacting erythromycin A oxime of formula II with a silylating agent, e.g. with a trimethylsilylating agent in a solvent and, optionally in the presence of a catalyst. Examples of silylating agents may include chlorosilanes, such as trimethylchlorosilane and tert-butyldimethylchlorosilane; silylamines such as 1 ,1 ,1,3,3,3,- hexamethyldisilazane and trimethylsilylimidazole, silylamides such as bis(trimethylsilyl) acetamide and bis(trimethylsilyl)urea and a mixture thereof. The amount of silylating agent is not critical, conveniently at least 1 equivalents and more, e.g. up to 10 equivalents silylation reagent per equivalent of erythromycin A oxime of formula II may be used. Examples of catalysts may include, for instance sulfonic acids, such as p-toluenesulponic acid; acids such as trifluoroacetic acid; silylating agents, such as chlorotrimethylsilane, bromotrimethylsilane and trimethylsilyltrifluoroacetic acid; amines and ammonium salts, such as ammonium chloride or triethylammonium chloride; amides and imides, such as succinimide, 3,3- dimethylglutarimide, 1 ,8-naphtalimide; 1 ,2-benzisothiazol-3(2H)-one, 1 ,2-benzisothiazol- 3(2H)-one 1 ,1-dioxide; and phtalimides, sulfamides, such as N,N-dimethyIsulfamide and p- toluenesulfonamides, phosphoroamides and their derivatives, such as phosphoroamidates; and imidazole and imidazole derivatives, such as trimethylsilylimidazole.
Examples of Class 3 solvents that may be used for the protection of the hydroxyl groups in position 2' and 4 " include ketones, e.g. acetone, methylethylketone and methylisobutylketone; formates, e.g. ethyl formate; acetates, e.g. methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate; ethers, e.g. anisole, t-butylmethyl ether and ethyl ether; sulphoxides, e.g. dimethylsulphoxide and hydrocarbons, e.g. cumene, heptane and pentane; and mixtures of these solvents in any proportion. Particularly noted are propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate, or a mixture thereof. The reaction with the silylating agent is carried out at a temperature between 0 °C and the refluxing temperature of the solvent. The amount of solvent employed is not critical, and may range from less than 1 mL, e.g. less than 0.5 mL, e.g. 0.3 mL of solvent per g of starting product to more than 10 mL, or more than 50 mL of solvent per g of starting product. The silylation reaction may be also carried out in different conditions of pressure, for instance at atmospheric pressure or at a pressure higher or lower than atmospheric pressure.
The protection of the hydroxyl of the oxime group in position 9 of the ring structure may be performed by reacting erythromycin A oxime of formula II with an acetal-type protecting agent in a solvent. Examples of acetal-type protecting agents may include compound of formula III:
wherein
Ri is lower alkyl, e.g. (C ) alkyl, cycloalkyl, e.g. (C3-β) such as (C3-e) cycloalkyl, aryl, e.g. phenyl, e.g. unsubstituted or susbstituted, e.g. by groups which are inert under alkylation conditions;
R2is hydrogen, lower alkyl, e.g. (C ) alkyl, aryl, e.g. phenyl, e.g. unsubstituted or susbstituted, e.g. by groups which are inert under alkylation conditions;
R3 is hydrogen, lower alkyl, e.g. (CM) alkyl, aryl, e.g. phenyl, e.g. unsubstituted or susbstituted, e.g. by groups which are inert under alkylation conditions;
R4 is a group of formula -OR5, wherein R5 is a hydrogen or lower alkyl
or
Ri and R2; or Ri and R3 form together a ring, e.g. a 5- to 7- membered ring, e.g. interrupted by an hetero atom, e.g. oxygen;
or
R2 and R3 form together a ring, e.g. a 5- to 7- membered ring such as cycloalkyl or a 5- to 7- membered ring interrumped by an hetero atom, e.g. oxygen;
or
R2 and R4 form together a R6CH= group, wherein Re is a hydrogen atom or lower alkyl Preferred acetal-type protecting agents include 2-methoxypropene, 2,2-dimethoxy propane, 1 ,1-diisopropoxy cyclohexene and 1-isopropoxy-1-cyclohexene. The amount of acetal-type protecting agent is not critical, conveniently at least 1 equivalent and more, e.g. up to 8 equivalents acetal-type protecting agent are used, in the conditions that are usually employed for the introduction of an acetal-type protecting group to a hydroxyl group. For example, Erythromycin A oxime of formula II , or the derivative obtained after protecting the hydroxyl groups in position 2' and 4 " may be reacted with a compound of formula III in a solvent in the presence of a catalyst. Suitable catalysts for the reaction are e.g. acids, e.g. organic acids such as formic acid, acetic acid or p-toluenesulphonic acid and e.g. salts of amine, e.g. triethylamine or pyridine, with inorganic acids, e.g. hydrochloric and hydrobromic acids, or with organic acids, e.g. sulphonic acids, e.g. p-toluenesulphonic acid, e.g. pyridine hydrochloride, hydrobromide or pyridinium p-toluenesulphonate; and mixtures of these catalysts.
Examples of Class 3 solvents that may be used for the protection of the hydroxyl of the oxime group in position 9 of the ring structure include ketones, e.g. acetone, methylethylketone and methylisobutylketone, alcohols, e.g. butanols, e.g. 1-butanol ,2- butanol and 3-methyl-1-butanol; e.g. propanols, e.g. 1-propanol, 2-propanol and 2-methyl-1- propanol; e.g. ethanol and 1-pentanol; formates, e.g. ethyl formate; acetates, e.g. methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate; ethers, e.g. anisole, t-butylmethyl ether and ethyl ether; acids, e.g. acetic acid and formic acid, sulphoxides, e.g. dimethylsulphoxide and hydrocarbons, e.g. cumene, heptane and pentane; and mixtures of these solvents in any proportion. The reaction with the acetal-type protecting agent is carried out at a temperature between 0 °C and the refluxing temperature of the solvent. The amount of solvent employed is not critical, and may range from less than 1 mL, e.g. less than 0.5 mL, e.g. 0.3 mLI of solvent per g of starting product to more than 10 mL, e,g, more than 50 mL of solvent per g of starting product. The acetalization reaction may be also carried out in different conditions of pressure, for instance, at atmospheric pressure or e.g. at a pressure higher or lower than atmospheric pressure.
The protection of the 2' and 4" hydroxyl groups and the protection of the hydroxyl of the oxime group in the ring structure can be done in any desired sequence. Specifically, in one option erythromycin A oxime of formula II may be first reacted with a silylating agent to protect the 2' and 4" hydroxyl groups in the silylating conditions described above, and the resulting compound may then be protected in the hydroxyl of the oxime group by reacting with an acetal-type protecting group in the acetalization conditions described above. In another option, erythromycin A oxime of formula II may first be reacted with an acetal-type protecting group in the acetalization conditions described above, and the product obtained may then be reacted with a silylating agent to protect the 2' and 4" hydroxyl groups in the silylating conditions described previously.
The product obtained after the protection of the 2' and 4" hydroxyl groups and the hydroxyl of the oxime group of the ring structure may be methylated in the hydroxyl group in position 6 of the ring structure, e.g by reacting with a methylating agent and a base in a solvent.
Examples of methylating agents may include, e.g. methyl halides , such as methyl bromide and methyl iodide; methyl sulphates, such as methyl sulphate and dimethyl sulphate and sulphonates, such as methyl p-toluenesulphonate, methyl methanesulphonate and methyl trifluoromethanesulphonate. The amount of methylating agent used is not critical, conveniently at least 1 equivalent and more, e.g. up to 8 equivalents of methylating agent may be used in the conditions that are usually employed for the methylating of a hydroxyl group, e.g. in the presence of a base. Examples of bases used in the methylation may include, e.g. inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydride, and potassium hydride; and organic bases, e.g. alcoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide and potassium tert- butoxide, e.g. tetraalkyl ammonium hydroxides, such as tetramethylammonium hydroxide. Other organic bases such as amines, e.g. alkyl amines such as trimethylamine, triethylamine and tripropylamine; or e.g. arylamines such as pyridine, methyl pyridines or dimetrhylpyridines; may be mixed with the above mentioned bases in the methylation reaction.
Examples of Class 3 solvents that may be used for the methylation of the hydroxyl group in position 6 of the ring structure include ketones, e.g. acetone, methylethylketone and methylisobutylketone; formates, e.g. ethyl formate; acetates, e.g. methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate; ethers, e.g. anisole, t-butylmethyl ether and ethyl ether; sulphoxides, e.g. dimethylsulphoxide and hydrocarbons, e.g. cumene, heptane and pentane; and mixture of these solvents in any proportion. The reaction with the methylating agent is carried out at a temperature between 20 °C and the refluxing temperature of the solvent. The amount of solvent employed is not critical, and may range from less than 1 mL, e.g. less than 0.5 mL, e.g. 0.3 mL of solvent per g of starting product to more than 10 mL, e,g, more than 50 mL of solvent per g of starting product. The methylation reaction may be also carried out in different conditions of pressure, e,g, at atmospheric pressure or e.g. at a pressure higher or lower than atmospheric pressure.
The product obtained after the methylation in the hydroxyl group in the position 6 of the ring structure may be deprotected, e.g. the protected hydroxyl groups in position 2' and 4" of the ring structure may be eliminated to obtain hydroxyl groups and the oxime protected group of the ring structure may be deprotected and deoximated to obtain a carbonyl group.
The deprotection steps may be carried out using conventional methods, e.g. by hydrolysis under acidic conditions in a solvent. Examples of Class 3 solvents that may be used for the hydrolysis under acidic conditions include ketones, e.g. acetone, methylethylketone and methylisobutylketone, alcohols, such as butanols, e.g. 1-butanol ,2-butanol and 3-methyl-1- butanol; propanols, e.g. 1-propanol, 2-propanol and 2-methyl-1-propanol; ethanol and 1- pentanol; formates, such as ethyl formate; acetates, such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate; ethers, such as. anisole, t-butylmethyl ether and ethyl ether; acids, such as acetic acid and formic acid, sulphoxides, such as dimethylsulphoxide and hydrocarbons, such as cumene, heptane and pentane; and mixtures of these solvents in any proportion. Water may also be used in the medium for the deprotection. Acids used for achieving the acidic conditions may include Class 3 solvent acids, such as acetic acid, and formic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid and sulphuric acid.The hydrolysis of the protecting groups may be carried out at a temperature between 0 °C and the refluxing temperature of the solvent. The amount of solvent employed is not critical, and may range from less than 1 mL, e.g. less than 0.5 mL, e.g. 0.3 mLI of solvent per g of starting product to more than 10 mL, e,g, more than 50 mL of solvent per g of starting product. The deprotection may be also carried out in different conditions of pressure, e,g, at atmospheric pressure or at a pressure higher or lower than atmospheric pressure.
The deoximation reaction may be performed by conventional methods, e.g. by reacting with a deoximation agent in a solvent. Examples of deoximation agents include, e.g. inorganic sulfur oxide compounds, e.g. sodium hydrogen sulfite, sodium sulfite, sodium hydrosulfite, sodium metabisultife, potassium hydrogen sulfite and potassium metabisultife and their aqueous solutions. The amount of deoximating agent used agent is not critical, conveniently at least 1 equivalent and more, e.g. up to 8 equivalents of the deoximating agent may be used in the conditions that are usually employed for the deoximation reactions, e.g. by reacting with the deoximating agent in a solvent, e.g. in an acidic of neutral medium. Examples of Class 3 solvents that may be used for the deoximation are the same that used for the hydrolysis of the 2' and 4" groups, and include ketones, e.g. acetone, methylethylketone and methylisobutylketone, alcohols, e.g. butanols, e.g. 1-butanol ,2- butanol and 3-methyl-1-butanol; e.g. propanols, e.g. 1-propanol, 2-propanol and 2-methyl-1- propanol; e.g. ethanol and 1-pentanol; formates, e.g. ethyl formate; acetates, e.g. methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate and isobutyl acetate; ethers, e.g. anisole.t-butylmethyl etherand ethyl ether; acids, e.g. acetic acid and formic acid, sulphoxides, e.g. dimethylsulphoxide and hydrocarbons, e.g. cumene, heptane and pentane; and mixtures of these solvents in any proportion. Water may also be present in the medium used for the deoximation. The deoximation may be carried out at a temperature between 0 °C and the refluxing temperature of the solvent. The amount of solvent employed is not critical, and may range from less than 1 mL, e.g. less than 0.5 mL, e.g. 0.3 mLI of solvent per g of starting product to more than 10 mL, e,g, more than 50 mL of solvent per g of starting product. The deoximation may be also carried out in different conditions of pressure, e,g, at atmospheric pressure or at a pressure higher or lower than atmospheric pressure.
The hydrolysis of the protected hydroxyl groups and the deoximation reaction may be carried out in separated steps or at the same time.
After the deprotection of the hydroxyl groups in position 2' and 4" of the ring structure and the deoximation of the oxime protected group of the ring structure, clarithromycin may be isolated from the reaction medium by conventional methods, e.g. by precipitating by adding a base. The product obtained may be transformed to any known form, e.g. crystalline form, by recrystallizing in a medium formed by a class 3 solvent or a mixture of Class 3 solvents, according to European Pharmacopoeia classification, optionally in the presence of water, e.g. by recrystallization in ethanol or in a mixture of ethanol and water; and drying conventional methods, e.g. by drying under vacuum. A pharmaceutical composition comprising clarithromycin free of toxic solvents as an active ingredient according to the present invention may contain the same concentrations of clarithromycin and may be used for the same indications in the same dosages as a known pharmaceutical composition containing clarithromycin as an active ingredient as is presently on the market.
The following non-limitative examples illustrate the invention.
All temperatures are in degree Celsius and are uncorrected.
Examples
Example 1
(1 ) 100.0 g of erythromycin A oxime was mixed with 300 mL of isopropyl acetate, 66,3 mL of 1 ,1 ,1 ,,3,3,3,hexamethyldisilazane and 1.2 g of saccharin. The mixture was heated to reflux and stirred for two hours. The reaction mixture was then cooled and 125 mL of water was added to the mixture. The aqueous phase was separated off and the organic phase was subsequently concentrated by distilling under vacuum.
176.8 g of a mixture of 2',4"-O- bis(trimethylsilyl)erythromycin A 9-oxime and isopropyl acetate was obtained.
(2) The product from (1 ) was dissolved in 310 mL of acetone. 127,5 g of 1 ,1- diisopropoxycyclohexane and 31.0 g of pyridine hydrobromide were added. The mixture was stirred at 40-45 °C for 3 hours. Then 300 mL of isopropyl acetate, 250 mL of 5% aqueous sodium carbonate and 9 mL of 20% aqueous sodium hydroxide were added. After stirring the aqueous phase was seperated off, and the organic phase was concentrated by distilling under vacuum. 246 g of a mixture 2',4"-O- bis(trimethylsilyl)erythromycin A 9-{O-[1-(1- methylethoxy)-cyclohexyl]oxime} and isopropyl acetate was obtained.
(3) 123 g of the mixture obtained in (2) was mixed with 190 mL isopropyl acetate and 300 mL of dimethylsulfoxide. The mixture was cooled to 5-10 °C and 11.2 mL of methyl iodide and 11.75 g of potassium hydroxide were added. The mixture was stirred at 5-10 °C for 90 minutes and then 9 mL of 40 % aqueous methylamine and 200 mL of water were added. This mixture was then stirred for 15 minutes and the aqueous phase was separated off. The organic phase was concentrated under vacuum. 161.9 g of a mixture crude 2',4"-O- bis(trimethylsilyl)-6-O-methyl erythromycin A 9-{O-[1-(1-methylethoxy)-cyclohexyl]oxime} and isopropyl acetate was obtained.
(4) The product obtained in (3) was suspended in 90 mL of ethanol and 180 mL of water. The pH of the mixture was adjusted to pH 2.5 -3.5 by adding formic acid and the mixture was then heated to 40-45 °C for 3 hours. When the deprotection reaction was completed, 110 mL of 40 % aqueous sodium hydrogen sulphite solution and 200 mL of ethanol were added. The mixture was heated to reflux and stirred for 1 hour. Then the mixture was cooled to 60 °C, and 100 mL of water were added. The product was precipitated by adding 20 % aqueous sodium hydroxide to adjust the pH of the mixture to 10.5-11. The solid precipitate was filtered, washed with water and ethanol and dried. 27.4 g of crude clarithromycin was obtained, which was further recrystallized in ethanol to obtain the pure product.
Example 2
(1) 120.0 g of erythromycin A oxime hydrochloride, with an assay of about 80 % in erythromycin A oxime was mixed with 300 mL of isopropyl acetate, 104 mL of
1 ,1 ,1 ,,3,3,3,hexamethyldisilazane and 1.2 g of saccharin. The mixture was heated to reflux and stirred for two hours. Then the reaction mixture was cooled and 125 mL of water are added. The aqueous phase was separated off and the organic phase was concentrated by distilling under vacuum. 207 g of a mixture of 2',4"-O- bis(trimethylsilyl)erythromycin A 9- oxime and isopropyl acetate was obtained.
(2) The product obtained above in (1 ) was dissolved in 310 mL of acetone. 127,5 g of 1 ,1- diisopropoxycyclohexane and 31.0 g of pyridine hydrobromide were then added. The mixture was stirred at 40- 45 °C for 3 hours. Then 300 L of isopropyl acetate, 250 mL of 5% aqueous sodium carbonate and 9 mL of 20% aqueous sodium hydroxide were added. After stirring and the aqueous phase was seperated off, and the organic phase was concentrated by distilling under vacuum. 236 g of a mixture 2',4"-O- bis(trimethylsilyl)erythromycin A 9-{O- [1-(1-methylethoxy)-cyclohexyl]oxime} and isopropyl acetate was obtained.
(3) 118 g of the mixture obtained in (2) was mixed with 185 mL isopropyl acetate and 200 mL of dimethylsulfoxide. The mixture was cooled to 5-10 °C and 11.2 mL of methyl iodide and
11.75 g of potassium hydroxide were added. The mixture was stirred at 5-10 °C for 90 minutes and then 9 mL of 40 % aqueous methylamine and 200 mL of water were added. This mixture was stirred for 15 minutes, and the aqueous phase was separated off. The organic phase was concentrated to dryness under vacuum. 84.96 g of crude 2',4"-O- bis(trimethylsilyl)-6-O-methyl erythromycin A 9-{O-[1-(1-methylethoxy)-cyclohexyl]oxime} was obtained.
(4) The product obtained in (3) was suspended in 90 mL of ethanol and 180 mL of water. The pH of the mixture was adjusted to pH 2.5 -3.5 by adding formic acid and the mixture was then heated to 40-45 °C for 90 minutes. When the deprotection reaction was completed, 110 mL of 40 % aqueous sodium hydrogen sulphite solution and 200 mL of ethanol were added. The mixture was heated to reflux and stirred for 1 hour. Then the mixture was cooled to 60 °C, and 100 mL of water was added. The product was precipitated by adding 20 % aqueous sodium hydroxide to adjust the pH of the mixture to 10.5-11. The solid precipitate was filtered, washed with water and ethanol and dried. 24.7 g of crude clarithromycin was obtained. Recrystallization of the crude product in ethanol yielded pure clarithromycin.

Claims

Claims
1. A process for the production of clarithromycin of formula I from erythromycin A oxime of formula II, comprising the steps of:
(i) protecting the hydroxyl groups in position 2' and 4" of the compound of formula II by reacting with a silylating agent, and protecting the hydroxyl group of the oxime group in position 9 of the ring structure of the compound of formula II with an acetal-type protecting agent, (ii) methylating the hydroxyl group in position 6 of the ring structure of the protected compound of step (i); and (iii) deprotecting the hydroxyl groups in position 2' and 4" of the ring structure to obtain hydroxyl groups and deprotecting and deoximating the oxime group of the ring structure to obtain a carbonyl group, wherein each step is carried out in the presence of a solvent with a low toxic potential.
2. A process according to claim 1 wherein the low toxic potential solvent is selected from the group consisting of acetone, methylethylketone, methylisobutylketone, 1-butanol , 2- butanol, 3-methyl-1-butanol, 1-propanol, 2-propanol, 2-methyl-1-propanol, ethanol, 1- pentanol, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate; anisole, t-butylmethyl ether and ethyl ether, acetic acid, formic acid, dimethylsulphoxide, cumene, heptane and pentane; or a mixture thereof in any proportion.
3. A process according to claim 1 wherein the low toxic potential solvent is selected from the group consisting of acetone, methylethylketone, methylisobutylketone, 1-butanol ,2-butanol, 3-methyl-1-butanol, 1-propanol, 2-propanol, 2-methyl-1-propanol, ethanol, 1-pentanol, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, anisole, ethyl ether, dimethylsulphoxide, cumene, heptane and pentane; or a mixture thereof in any proportion.
4. A process according to any one of the preceding claims wherein protection of the hydroxyl groups in position 2' and 4" of the compound of formula II in step (i) is carried out by reaction with a trimethylsilylating agent in the presence of a solvent from the group comprising propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate, or a mixture thereof.
5. A process according to any one of the preceding claims wherein protection of the hydroxyl group in position 9 of the ring structure of the compound of formula II in step (i) is carried out by reaction with 2-methoxypropene, 2,2-dimethoxy propane, 1 ,1-diisopropoxy cyclohexene or 1-isopropoxy-1-cyclohexene, in the presence of a solvent chosen from the group comprising acetone, methyl ethylketone or methylisobutylketone, or a mixture thereof.
6. A process according to any one of the preceding claims wherein the methylation of the hydroxyl group in position 6 of the ring in step (ii) is carried out by reaction with a methylating agent and a base in the presence of a solvent selected from the group comprising propyl acetate, isopropyl acetate, butyl acetate or isobutyl acetate, dimethylsulfoxide or a mixture thereof.
7. A process according to any one of the preceding claims wherein said process uses only solvent with a low toxic potential or water.
8. Clarithromycin of formula I obtained by a process according to any one of the preceding claims.
EP05716204A 2004-03-19 2005-03-18 Process for the preparation of clarithromycin Withdrawn EP1727824A1 (en)

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