WO1999032500A2

WO1999032500A2 - Intermediates in macrolide production

Info

Publication number: WO1999032500A2
Application number: PCT/EP1998/008320
Authority: WO
Inventors: Immaculada Bosch; Victor Centellas; José Diago
Original assignee: Biochemie S.A.
Priority date: 1997-12-22
Filing date: 1998-12-18
Publication date: 1999-07-01
Also published as: AU2274799A; ES2177448B1; ES2177448A1; WO1999032500A3

Abstract

Erythromycin A oxime wherein the hydroxyl group of the oxime group is in reacted form resulting from reaction with a strong organic base or with a silylation agent; a process for its production and its use as an intermediate in the production of macrolides of the erythromycin type, such as roxithromycin, clarithromycin, azithromycin and similar compounds.

Description

Intermediates in macrolide production

The present invention relates to intermediates useful in the synthesis of antibacterial macrolides, such as of the erythromycin type, for example erythromycin A type, e.g. roxithromvcin, claπthromycin, azithromvcin and similar compounds.

In US 3,478,014 there is described a compound of formula

OH

hereinafter designated as "erythromycin A oxime", which may be produced from erythomycin A which is a well known, e.g. antibacterial agent. Erythromycin A oxime may be useful in the production of antibacterial macrolides.

According to the present invention, novel intermediates, e.g. useful in the production of antibacterial macrolides have surprisingly been found, which may improve e.g. the production process of antibacterial macrolides, e.g. roxithromycin, azithromycin and claπthromycin.

In one aspect the present invention provides erythromycin A oxime, e.g. of formula I, wherein the hydroxyl group of the oxime group is in reacted form resulting from reaction with a strong organic base or with a silylation agent. In another aspect the present invention provides a compound of formula

wherein R_A denotes a silyl group; or a group of formula

(H) n ^■ B wherein (i) n = 1 and B is a compound of formula

R R«

wherein R,, R_.', R₂ and R₂' independently of each other denote hydrogen or an aliphatic or aromatic group; or Ri and Ri' independently of each other denote an aliphatic or aromatic group and R₂ and R₂' together with the nitrogen atom denote a ring or ring system, (ii) n = 1 and B is a compound of formula

wherein R and R' independently of each other denote hydrogen or an aliphatic or aromatic group; x denotes 3, 4, or 5 and y denotes 2, 3 or 4; (iii) n = 1 and B is a compound of formula

wherein R₃, R₄,R₅, Re and R7 denote independently of each other hydrogen or an aliphatic or aromatic group; or R₃ is as defined above; and either R₄ and R5 denote together (C_.-₄)alkylidene and R₆ and R₇ independently of each other denote hydrogen or an aliphatic or aromatic group; or R₄ and R₅ denote together (Cι-₄)alkylidene and R_<s and R₇ denote together (Cι-₄)alkylidene; or R* and R₇ denote together (Cι-₄)alkylidene and R₄ and R₅ independently of each other denote hydrogen or an aliphatic or aromatic group; (iv) n = 1 and B is a compound of formula

wherein R_8. R<_>_ Rio, Rn and R₁₂ independently of each other denote hydrogen or an aliphatic or aromatic group, and X denotes CH_2} NH, O or S; (v) n = 0 and B is a group of formula. Z⁺R,₃Ri4RιsRi6 VH

wherein Z denotes nitrogen and R_] , R_H, R15, and R_l6 independently of each other denote an aliphatic or aromatic group.

Erythromycin A, e.g. a compound of formula I, wherein the hydroxyl group of the oxime group is in reacted form resulting from reaction with a strong organic base is designated hereinafter as "Erythromycin A oxime in the form of an oximate with a strong organic base" or "An oximate according to the present invention" and includes a compound of formula II wherein R_A denotes a a group of formula (H) _n B wherein n and B are as defined above. The formation of erythromycin A oxime in the form of an oximate with a strong organic base may be determined, e.g. by mass spectroscopy, e.g. with electrosprav as ionizing technique. The presence of the molecular peak of an oximate of erythromycin A oxime under such conditions may be evidence for oximate formation of erythrymycin A oxime with a strong organic base.

In another aspect, the present invention provides an oximate according to the present invention, e.g. a compound of formula II, wherein R, R', Ri, Rj', R₂, R₂', R₃, R , Rj, R₆, R₇, R₈, Ro, Rio, Rn, Rn, Rι₃, ι , i₅ and R₁₆ are as defined above, which shows a molecular peak of an oximate of erythromycin A oxime of formula I with a strong organic base in mass spectroscopy determination.

Amidine-type strong organic bases, e.g. compounds of formulae III and IV are e.g. commercially available, such as l,5-diazabicyclo(4,3,0)non-5-ene (DBN) and 1 ,8- diazabιcyclo(5,4,0)undec-7-ene (DBU); or may be easily produced, e.g. as appropriate, e.g. as conventional, for example by known, e.g. analogous methods, e.g. as described in Synthesis, 591 (1972) which is introduced herein by reference. Preferred compounds include DBN and DBU, e.g. DBU.

Guanidine-type strong organic bases, e.g. compounds of formula V, may be linear, e.g. R ., R₄ R₅, R_ft and R7 denote independently of each other hydrogen or an aliphatic or aromatic group; or cyclic, such as bicyclic, e.g. R is as defined above; and either R₄ and R . denote together (CXalkyhdene and R₆ and R₇ independently of each other denote hydrogen or an aliphatic or aromatic group; or R₄ and R₅ denote together (C₁-₄)alkvhdene and R₆ and R₇ denote together (Cι-₄)alkylιdene; or R„ and R₇ denote together (C₁-₄)alkvlιdene and R₄ and R₅ independently of each other denote hydrogen or an aliphatic or aromatic group. Linear guanidines include e.g. tetramethvlguanidine, pentamethylguanidine, tetraethylguanidine, tetramethylethylguanidine and tetramethylbenzylguanidine. Suitable cvchc and bicyclic guanidines include e.g. l,5,7-tπazabιcvclo-(4,4,0)-dec-5-ene, and 7-methyl, 7-ethyl, 7-benzyl and 7-phenyl derivatives thereof. Preferred compounds of formula V include e.g. 1,1,3,3- tetramethylguanidine. Compounds of formula V are e.g. commercially available or may be easily produced, e.g. as appropriate, e.g. as conventional, for example bv known, e.g. analogous methods described in prior art, e.g. in Synthetic Communications, 13, 67, (1983) which is introduced herein by reference.

Substituted pipeπdines, piperazines, morphohnes and thiomorpholines, e.g. compounds of formula VI are known as strong organic alkyl bases. Compounds of formula VI are e.g. commercially available or may be easily produced, e.g. as appropriate, e.g. as conventional, for example by known, e.g. analogous, methods. Preferred compounds of formula VI include e.g. 2,2,6,6- tetramethylpipeπdine and 1,2,2,6,6-pentamethylpιpeπdιne. Ammonium group type strong organic bases, e.g. of formula VII include beside the cation as defined in formula VTI an appropriate anion, e.g. an hydroxide or halogenide, such as chloride, bromide. Compounds of formula VII including an appropriate anion are e.g. commercially available or may be easily produced, e.g. as appropriate, e.g. as conventional, for example by known, e.g. analogous, methods. Preferred compounds of formula VII include e.g. tetramethylammonium, tetraethylammonium, tetrabutylammonium and cetyltπ methyl- ammonium hydroxide and halogenide, e.g. chloride, bromide.

An oximate according to the present invention, e.g. of formula II, may have the following advantages compared with erythromycin A oxime:

- the oximate group may represent an "activated form" in an oximate according to the present invention, e.g. in the oximino group in position 9 of the ring system; and may have increased reactivity in comparison with erythromycin A oxime; e.g. in O-substitution of the oximino group in position 9 of the ring system; which ma^y thus be performed under mild conditions and may avoid, e.g. degrading, side reactions;

- an oximate according to the present invention may show increased regioselectivity in comparison with erythromycin A oxime; e.g. in O-substitution of the oximino group in position 9 of the ring system; e.g. side reactions of free hvdroxv groups in erythromycin A oxime during O-substitution of the oximino group in position 9 of the ring system may be avoided; increased reactivity and regioselectivity of the oximate according to the present invention may result in higher yields in subsequent reactions in comparison with erythromycin A oxime; an oximate according to the present invention produced from erythromycin A oxime may have the same E- or Z-configuration as ervthromvcin A oxime used as starting material; e.g. the production of an oximate according to the present invention from ervthromvcin A oxime may be carried out without isomerisation reactions.

An oximate according to the present invention may be produced as follows: A strong organic base, e.g. as described in the meaning of B in a compound of formula II above, and, in case that B means a cation of formula VH, a cation of formula VII with an appropriate anion, e.g. a hydroxide or halogenide, may be reacted with ervthromvcin A oxime;

- at appropriate reaction temperatures, including e.g. a range of ca. -50° C and the reflux temperature of a solvent (system) used, such as from -10° C to 40° C, and e.g. more than 40°C; and

- under appropriate pressure, e.g. under atmospheric pressure, and under a pressure which is above or below atmospheric pressure; and

- e.g. in a solvent or in a solvent system, e.g. in a mixture of solvents.

Appropiate solvents include halogenated solvents, such as halogenated aliphatic and aromatic, hydrocarbons, e.g. halogenated alkanes, e.g. dichloromethane; ketones such as dialkvlketones, e.g. acetone; alkyl esters such as acetic acid esters, e.g. ethyl acetate and isopropyl acetate; hydrocarbons, such as aliphatic (alkyl) and aromatic (aryl) solvents, e.g. toluene; ethers such as cyclic, e.g. alkyl, ethers, having e.g. 4 to 8, e.g. 5 to 6 ring members, such as tetrahydrofurane; amides, e.g. alkyl amides, such as formic and acetic acid amides, e.g. formamide, N,N-dιmethvlformamιde, N,N-dιmethvlacetamιde and N-methvlacetamide; preferably halogenated hydrocarbons, ketones and cyclic ethers, and mixtures of solvents e.g. comprising indiv idual solvents as described abo\ e. The solvent system may include water, e.g. a small amount of water.

The amount of a strong organic base is not critical; if per equivalent ervthromvcin A oxime an amount of a strong organic base which is below one equivalent is used, a mixture of an oximate according to the present invention and of erythromycin A oxime mav be obtained; if per equivalent erythromycin A oxime an amount of a strong organic base which is one equivalent and more is used, an oximate according to the present invention may be obtained. An appropriate amount includes e.g. 1 to 20, such as 1 to 5, e.g. 1 to 3 equivalents of a strong organic base per equivalent erythromycin A oxime. An oximate according to the present invention may be obained, e.g. in the form of an e.g. stable, solid, e.g. crystalline, precipitate, e.g. if appropriate, after removal of at least part of the solvent (system), e.g. by distillation or evaporation, e.g. in the presence of an anti-solvent. Precipitation and isolation of an oximate according to the present invention may be carried out as appropriate, e.g. as conventional in the precipitation and isolation of a compound from a reaction mixture, for example by known, e.g. analogous methods, such as solvent (system) evaporation, filtration, centrifugation.

Characterisation of an oximate according to the present invention may be carried out by IR, NMR and mass spectroscopy determination. An oximate according to the present invention, such as of formua II, may exist as E-isomer, Z-isomer and mixtures of an E-isomer and an Z-isomer. An oximate according to the present invention produced according to the present invention may have the same E- or Z-configuration as erythromycin A oxime used as starting material; and undesired isomerisation reactions may be avoided.

In another aspect the present invention provides a process for the production of erythromycin A oxime, e.g. of formula I, in the form of an oximate with a strong organic base, such as of formua II, comprising reacting erythromycin A oxime with a strong organic base, e.g. of formulae EH, IVN and VI; and VH in the form of a cation of formula VII with an appropriate anion, such as a hydroxide or halogenide; and, if desired, isolating erythromycin A oxime, e.g. of formula I, in the form of an oximate, such as of formua H.

If not otherwise defined herein alkyl includes (Cι.₂₂)alkyl, e.g. (Cι.g)alkyl, such as (d^alkyl, for example (C_].₄)alkyl; aryl includes (C₅-i₈)aryl, such as C(₀-ι₂)aryl, preferably phenyl, napthyl. An aliphatic group includes e.g. alkyl, cycloylkyl, alkenyl and alkinyl; preferably alkyl. Alkenyl and alkinyl include e.g. (C₂.₂₂)alkenyl and alkinyl, e.g. (C₂.g)alkenyl and alkinyl, such as (C₂-₆)alkenyl and alkinyl, for example (C₂.₄)alkenyl and alkinyl. Cycloalkyl includes ( .g)cycloalkyl, such as (C₄.₇)cycloalkyl, e.g. (C₅.6_.cycloalkyl. An aromatic group includes aryl. A silyl group includes a silyl protecting group, e.g. a conventional silyl protecting group, such as a trialkylsilyl group, for example the trimethylsilyl group. A ring includes e.g. an aliphatic and an aromatic ring having 4 to 8, e.g. 5 to 6 ring members; ring members include carbon atom based ring members and heteroatoms; e.g. up to 3 heteroatoms; e.g. selected from N, O, S; a ring system includes more than one ring, e.g. bicyclic or tπcvchc rings. Any group defined herein may be unsubstituted or substituted, e.g. bv groups which are inert under relevant reaction conditions.

An oximate according to the present invention may be useful e.g. in the production of intermediates, which may e.g. be useful in the production of macrolides, such as of the erythromycin type, for example erythromycin A type, e.g. such as described in EP 33255, which is introduced herein bv reference, e.g. in the production of roxithromycin; and e.g. such as described in US 4,328,334, which is introduced herein by reference, e.g. in the production of azithromycin; and e.g. such as described in EP 158467 and EP 272110 , which is introduced herein by reference, e.g. in the production of claπthromycin.

Reactions of erythromycin A oxime e.g. as described in the above cited references EP 33255, US 4,328,334, EP 158467 and EP 272110, and e.g. similar reactions of erythromycin A oxime, which e.g. may result in a compound described in the above cited references, may be carried out with an oximate according to the present invention, such as of formua II; including e.g. O-alkylation, O-silylation, O-sulphonylation and O-acylation of the oximino group in position 9 of the ring system. An oximate according to the present invention may be used in isolated form; or an oximate according to the present invention may be formed "in situ" and used in subsequent reactions; e.g. without isolation of an oximate according to the present invention. Subsequent reaction of an oximate according to the present invention may be carried out as appropriate, e.g. as conventional, e.g. by reaction of an oximate according to the present invention with an appropriate alkylating, silylating, sulphonylating or acylating agent; e.g. in an appropriate, e.g. conventional solvent (system), at appropriate, e.g. conventional temperatures.

E.g. an O-alkylated erythromycin A oxime, such as roxythromvcin mav be produced bv alkylation of an oximate according to the present invention, with an, e.g. conventional, alkvlation agent; e.g. a compound of formula

Alk-L wherein Alk denote an alkyl group and L denotes a leaving group, e.g. halogen, such as chloride, bromide, iodide, preferably chloride. Alk includes alkyl which is interrupted by heteroatoms, e.g. oxygen, e.g. one or more, e.g. 2, such as alkoxyalkoxyalkyl, e.g. methoxyethoxymethyl; the oximate being e.g. produced in situ in the reaction mixture, or being an isolated oximate; e.g. in the presence of a solvent (system), e.g. as described above for the production of an oximate of the present invention.

In another aspect the present invention provides a process for the production of an O- alkylated erythromycin A oxime, e.g. roxythromycin, comprising reacting a compound of formula II, wherein R_A denotes a group of formula (H) _n B

wherein n an B are as defined above with a compound of formula

Alk-L wherein Alk denote an alkyl group, e.g. methoxyethoxymethyl, and L denotes a leaving group, e.g. halogen, such as chloride, bromide, iodide, preferably chloride.

E.g. an O-sulphonylated erythromycin A oxime, such as (E)-9-[0-(p(toluenesulphonyl)oxιme of erythromycin A may be produced by sulphonylation of an oximate according to the present invention; the oximate being e.g. produced in situ in the reaction mixture, or being an isolated oximate; with an, e.g. conventional, sulphonylating agent, e.g. p-toluenesulphonyl chloride; in the presence of a solvent (system) , e.g. as described above for the production of an oximate of the present invention, e.g. acetone.

E.g. an O-acylated erythromycin A oxime, such as (E)-9-[0-(phenylacetyl)oxιme of erythromycin A may be produced by acylation of an oximate according to the present invention; the oximate being e.g. produced in situ in the reaction mixture, or being an isolated oximate; with an, e.g. conventional, acylation agent, e.g. phenacetyl chloride; in the presence of a solvent (system) , e.g. as described above for the production of an oximate of the present invention, e.g. acetone.

E.g. an O-silylated erythromycin A oxime includes a compound of formula H wherein R_A denotes a silyl group, e.g. of formula

wherein R' , R'₅ and R'„ independently of each other denote hydrogen, alkyl, alkenyl, cycloalkyl, aryl; preferably alkyl, e.g. (C, _s)alkyl, such as (Cj ₆)alkvl, e.g. (C,.₄)alkyl, such as methyl, ethyl, iso-propyl, butyl. Erythromycin A oxime wherein the hydroxy group in the hydroxyimino group is silylated is new. In another aspect the present invention provides erythromycin A oxime wherein the hydroxy group in the hydroxyimmo group is silvlated.

A process for the production of a compound of formula H wherein R_A denotes a silyl group mav be carried out as follows:

As a starting material erythromycin A oxime in the form of an oximate with a strong organic base according to the present invention, preferably an DBU or TMG oximate, e g in a solvent or solvent system, e.g. chlorinated solvents such as dichloromethane; ketones such as acetone; alkvl esters such as ethyl acetate, isopropyl acetate or n-butyl acetate; hydrocarbons; ethers; polar aprotic solvents such as N,N-dιmethylformamιde, N,N-dιmethylacetamιde, dimethylsulfoxide; and a mixture of one or more solvents, e.g. as described above may be reacted with a silylating agent, e.g. which is conventional for the silvlation of hydroxyl groups, including silanes such as tπalkylmonochlorosilanes, e.g. tπmethvlchlorosilane, dialkyldichlorosilanes, silylated amides, such as bisilylacetamides, e.g. N-O- bιs(tπmethylsιlyl)acetamιde, silylated ureas such as bisilylurea, e.g. N,N- bιs(tπmethylsιlyl)urea, silylated amines, e.g. hexamethyldisilazane, silylated organic bases, such as silylated lmidazoles, e.g. tπmethylsilylimidazole; and mixtures of silylated agents, e.g. as described above, preferably monochlorosilanes, e.g. tπmethylchlorosilane, t- butyldimethylchlorosilane and tπisopropylchlorosilane; at an appropriate reaction temperature, e.g. between -50°C, e.g. -10°C and the refluxing temperature of the solvent svstem used. Per equivalent of an oximate according to the present invention, e.g. ca., one to, e.g. ca., 1.5, such as 1 to 1.1 equivalents of a silvlation agent mav conveniently be used. A compound of formula II wherein R_A denotes a silyl group may be obtained and may precipitate; e.g. after removal of solvent; and if desired, may be isolated, e.g. as conventional.

In another aspect the present invention provides a process for the production of erythromycin A oxime wherein the hydroxy group in the hydroxyimmo group is silylated comprising silylating a compound of formula II wherein R_A denotes a group of formula (H) _n B wherein n and B are as defined above.

Ervthromvcin A oxime wherein the hydroxy group in the hvdroxvimino group is silylated, e.g. protected bv silyl, may be useful as an intermediate in the production of macrolides, e.g. in reactions in other positions of the ring system than in position 9 of the ring system, e.g. in reactions which require the hydroxy group of the oxime in protected form.

Erythromycin A oxime wherein the hydroxy group in the hydroxyimino group is silylated may be further silylated in position 2' and 4" of the ring system.

Thus, in another aspect the present invention provides a process for the production of a compound of formula H wherein R_A denotes silyl and wherein the hydroxy groups in position 2' and 4" of the ring system are silylated, e.g. by a group SiR'₄R'₅R'₆ wherein R'₄, R' _. and R'₆ are as defined above, comprising reacting a compound of formula II, wherein R-, denotes a a silyl group with a silylating agent.

Silylation may be carried out as appropriate, e.g. as conventional, e.g. as described above for the silylation of the 9-hydroxyιmino group; preferably in the presence of a silylated lmidazole, e.g. a tri(C₁. )alkylsilylimidazole, such as l-(tnmethylsilyl)ιmidazole, and e.g. in the presence of a silane, e.g. a trialkylmonochlorosilane, such as tπmethylchlorosilane as a silylation agent. The amount of silylation agent is not critical; conveniently at least 2 equivalents and more, e.g. up to 5 equivalents silylation agent per equivalent of a compound of formula II, wherein R_A denotes a silyl group may be used. In a preferred embodiment silylation of the hydroxyl groups in position 9, 2' and 4" of the ring system may be carried out in an one pot reaction starting from an erythromycin A oximate according to the present invention.

In still another aspect the present invention provides a process for the production of 6-0- alkyl erythromycms A comprising the steps i) producing a compound of formula II wherein R_A denotes a silyl group; ii) reacting a compound obtained in step i) with a silylating agent to obtain a compound of formula II wherein R_A denotes a silyl group and wherein the hydroxyl groups in position

2' and 4" are silylated; iii) treating a compound obtained in step ii) with an alkylating agent to obtain a compound of formula II wherein R_A denotes a silyl group and wherein the hydroxyl groups in position

2' and 4" are silylated and wherein the hydroxyl group in position 6 is alkylated; and IV) removing the silyl groups from and deoximating a compound obtained in step in) to obtain erythromycin A wherein the hydroxy group in position 6 of the ring system is alkvlated; e.g. claπthromycin. Step in) may be earned out as in conventional alkylation, e.g.in the presence of a base and an alkylating reagent; e.g. for methylation analogously as described in T.W. Greene et alt.: "Protective Groups in Organic Synthesis", second edition, 1991, pages 14-16, John Wiley & Sons Inc.. Preferred alkylating agents include methyl bromide, -iodide, dimethyl sulphate, methyl p-toluenesulphonate, methyl methanesulphonate, ethyl bromide, ethyl iodide , diethyl sulphate, n-propyl bromides and -iodides. Preferred solvents include polar solvents, such as tetrahydrofuran, ethyl acetate or acetone; polar aprotic solvents such as N,N-dιmethyl- formamide, dtmethylsulfoxide, N-methyl-2-pyrrohdone and a mixture of two or more solvents as described. A preferred base includes sodium and potassium hydroxide, sodium and potassium hydride, lithium dusopropylamide, alkaline alkoxides, such as sodium methoxide and amines such as triethylamine or dnsopropylethvlamine; or a mixture of two or more bases as described. Preferably alkylation may be carried out at temperatures between -40 and 40°C, preferably between -10 and 30°C. Silyl groups from the hydroxy groups in 2', 4" and 9 of the ring system may e.g. be removed under acidic conditions or in the presence of fluoride ions, e.g. by a method as conventional, e.g. analogously as described in T.W. Greene et alt.: "Protective Groups in Organic Synthesis", second edition, 1991, pages 68-87, John Wiley & Sons Inc.. Deoximation of the oxime group to obtain a carbonyl group may be carried out as conventional, e.g. as described in T.W. Greene et al., "Protective Groups in Organic Synthesis", second edition, 1991, pages 68-87, John Wiley δ Sons Inc or in J. March: "Advanced Organic Chemistry", fourth edition, 1992, pages 884-885. Removal of the silyl groups and deoximation under acidic conditions may be carried out simultanously.

E.g. erythromycin A oximes wherein the hydroxy group of the oxime is alkylated, e.g. roxythromycin, and wherein the hydroxy group of the oxime is acylated, silylated or sulphonylated, e.g. obtained according to the present invention, is a useful intermediate e.g. in the production of claπthromycin. Conversation of an erythromycin wherein the hydroxy group of the oxime is alkylated, e.g. roxythromycin, into clanthromvcin is new.

In another aspect the present invention provides a process for the production of clanthromvcin comprising the steps 1) silylating the hydroxy groups in position 2' and 4" in the ring system of an erythromycin A oxime wherein the hydroxy group of the oxime is alkylated, e.g. roxythromycin, e.g. which is obtained by reacting a compound of formula II, wherein R_A denotes a group of formula (H) _n B wherein n an B are as defined above with a compound of formula

Alk-L e.g. a compound of formula

CH₃OC₂H₅OCH₂-L wherein Alk denotes an alkyl group and L denotes a leaving group, u ) methvlating the hydroxy group in position 6 of the ring system in a compound obtained in step l) to obtain erythromycin A oxime wherein the hydroxy group of the oxime is alkylated, e.g. roxythromycin and wherein the hydroxyl groups in position 2' and 4" are silylated and wherein the hydroxyl group in position 6 is methylated; and iii) removing the silyl groups from and deoximating a compound obtained in step n) to obtain claπthromycin; e.g. and isolating clarthromyαn, e.g. in the form of a salt and/or in the form of a solvate from a reacction mixture.

A process according to the present invention may be carried out as follows:

Erythromycin A oximes wherein the hydroxy group of the oxime is alkylated, e.g. roxythromycin may be produced e.g. according to an appropπate process, e.g. as conventional, or, preferably, according to the present invention, e.g. as described above. Silylation of the hydroxy groups in positions 2' and 4" of the ring system may be carried out e.g. analogously as described above in the production of a compound of formula π, wherein R_A denotes silyl and wherein the hydroxy groups in position 2' and 4" of the ring system are silylated and using an erythromycin A oxime wherein the hydroxy group of the oxime is alkylated, e.g. roxythromycin instead of a compound of formula II, wherein R_A denotes silyl as a starting material. Methylation of the hydroxy group in position 6 of the ring system in an erythromycin A oxime wherein the hydroxy group of the oxime is alkylated, e.g. roxythromycin, and wherein the hydroxy groups in positions 2' and 4" of the ring system are silylated may be carried out analogously as described above in the production of clanthromvcin but using an erythromycin A oxime wherein the hydroxy group of the oxime is alkylated, e.g. roxythromycin and wherein the hydroxy groups in position 2' and 4" of the ring system are silvlated instead of a compound of formula II, wherein R_A denotes a silvl group and wherein the hvdroxy groups in position 2' and 4" of the ring system are silylated, as a starting material. Removal of the silyl groups and deoximation of erythromycin A oximes wherein the hydroxy group of the oxime is alkylated, e.g. roxythromycin, and wherein the hydroxy groups in position 2' and 4" of the ring system are silylated and wherein the hydroxyl group in position 6 of the ring system is methylated may be carried out e.g. analogously as described above in the production of clanthromvcin but using an erythromycin A oxime wherein the hydroxy group of the oxime is alkylated, e.g. roxythromycin, and wherein the hydroxy groups in position 2' and 4" of the ring system are silylated and wherein the hydroxyl group in position 6 of the ring system is methylated instead of a compound of formula II, wherein R_A denotes a silyl group and wherein the hvdroxy groups in position 2' and 4" of the ring system are silylated and wherein the hydroxyl group in position 6 is methylated, as a starting material.

In another aspect the invention provides the use of erythromycin A oxime wherein the hydroxyl group of the oxime group is in reacted form resulting from reaction with a strong organic base or with a silylation agent, such as of formua El, as an intermediate, e.g. in reactions of the hydroxyl group of the oxime group, such as e.g. O-alkylation, O-silylation, O-sulphonylation, O-acylation; useful e.g. in the production of macrolides of the erythromycin type, for example erythromycin A type, e.g. in the production of e.g. roxithromyαn, e.g. claπthromycin, e.g. azithromycin and e.g. similar compounds.

The following non limitative examples illustrate the present invention.Temperatures are given in degree Celsius and are uncorrected. Erythromycin A oxime is a compound of formula I.

Characterization of erythromycin A oxime in the form of an oximate with a strong organic base is carried out by IR (data given describe the most characteristic absorption bands), Η-

NMR and mass spectroscopy (MS).

Mass spectroscopy data (MS) are determined by use of electrospray as ionizing technique (ESP + ), which allows determination of the molecular peak of an ervthromvcin A oxime in the form of an oximate.

Η-NMR determination, shown in Table 1, shows a molar ratio of about 1 :1 between the strong organic base and ervthromvcin A oxime in an ervthromvcin A oxime in the form of an oximate. DBU: 1 ,8-diazabicyclo (5,4,0) undec-7-ene

TMG: 1,1,3,3,-tetramethylguanidine

PMP: 1 ,2,2,6,6-pentamethylpiperidine

TMA: tetramethylammonium DBU oximate: Erythromycin A oxime in the form of an oximate with DBU

TMG oximate: Erythromycin A oxime in the form of an oximate with TMG

PMP oximate: Erythromycin A oxime in the form of an oximate with PMP

TMA oximate: Erythromycin A oxime in the form of an oximate with TMA

MEM-C1: Methoxyethoxymethyl chloride C (I) in Table 1: Number of C-atom shown in the ring system of formula 1(C)

OXIME (in Table 1): Erythromycin A oxime of formula I

MS-FAB: Mass spectra

TΗF: tetrahydrofurane

DMF: dimethylformamide DMSO: dimethylsulphoxide

Example 1 DBU oximate

1.5 g of erythromycin A oxime are suspended in 8 ml of methylenechloride at 20°. 0.3 ml of DBU are added and the mixture is stirred for ca. 1 hour at room temperature. The reaction mixture is concentrated under vacuum. DBU oximate precipates as a white, crystalline solid and is filtrated off.

Yield: 1.8 g (100 % of theory); MS (ESP + ; F = 50): m/z = 902 (MH⁺); IR ( KBr, cm^"1 ): 3600-3450, 1736, 1640, 1615; 'HNMR data shown in TABLE 1 below.

Example 2

According to the method of example 1, but using 8 ml of acetone instead of methylene chloride, 1.7 g (94 % of theory) of solid DBU oximate are obtained. Characterisation as in Example 1.

Example 3

TMG oximate

0.25 ml of TMG are added to a solution of 1.50 g of erythromycin A oxime in 10 ml of methylene chloride. The mixture is stirred at room temperature. After ca. 1 hour, the solvent is evaporated off. Solid TMG oximate is obtained. Yield: 1.62 g (94 % of theory); MS (ESP + ; F = 50): m/z = 865 (MH⁺); IR ( KBr, cm^"1 ):

3600-3460, 1738, 1594, 1462; ¹HNMR data shown in TABLE 1 below.

Example 4 PMP oximate 1.5 g of erythromycin A oxime are suspended in 8 ml of methylenechloride at ca. 20°C. 0.36 ml of PMP are added and the mixture is stirred for ca. 1 hour at room temperature and concentrated under vacuum. Solid PMP oximate is obtained. Yield: 1.81 g ( 100% of theory); MS (ESP + ; F = 50): m/z = 905 (MH⁺); IR ( KBr, cm^{" 1} ):

3600-3000, 1739, 1709, 1641, 1463; 'HNMR data shown in TABLE 1 below.

Example 5

TMA oximate

To a solution of 3.1 g of erythromycin A oxime in 15 ml of THF, cooled to ca. 0°, 747 mg of tetramethylammonium hydroxide in 15 ml of TΗF are added and the mixture is stirred for ca. 30 min at ca. 0°-5 °, dried over MgS0₄ and concentrated under vacuum. Solid TMA oximate is obtained.

Yield: 2.96 g (90% of theory); MS (ESP + ; F = 50): m/z = 823 (MH⁺); IR ( KBr, cm^"1 ): 3600-3075, 1727, 1645,1566, 1489, 1378; 'HNMR data shown in TABLE 1 below.

OH

TABLE 1

In TABLE 1 C(I) corresponds to the position of the carbon atoms in the ring system of a compound of formula 1(C). The numerical values are the 'HNMR data values.

Example 6

Roxythromycin via alkylation of TMG oximate 0.86 g of TMG oximate, obtained as described in example 2 are dissolved in 5 ml of TΗF under nitrogen atmosphere. 0.23 ml of MEM-CI and 0.13 ml of TMG are added. The reaction mixture is heated to ca. 40°C and is kept at this temperature for ca. 4 hours. HPLC determination shows a conversion of TMG oximate into roxithromvcin of 80%.

Example 7

Roxythromycin via alkylation of TMG oximate

To a solution of 0.86 g of TMG oximate in 2 ml of toluene are added 0.05 g of tetrabutylammonium bromide, 2 ml of 10 % aqueous NaOH solution and 0.23 ml of MEM- Cl are added to the mixture and the reaction mixture is heated to 40° for ca. 2 hours. 0.11 ml of MEM-CI and 1 ml of 10% aqueous NaOH solution are added and the mixture is heated to 40°c for ca. 1 hour. HPLC determination shows a conversion of TMG oximate into roxithromvcin of 87%.

Example 8

Roxythromycin via alkylation of DBU oximate

To a suspension of 9.0 g of erythromycin A oxime in 24 ml of toluene, 1.8 mL of DBU are added and the mixture is stirred for ca. 1 hour at room temperature. DBU oximate is formed in situ. The reaction mixture is stirred for ca. 1 hour and 0.58 mg of tetrabutylammonium bromide, 24 ml of a 2N aqueous NaOH solution and 2.75 ml of MEM-CI are added. The reaction mixture is heated to 40°, stirred for ca. 2 hours at this temperature and treated with 12 ml of a 2N aqueous NaOH solution and 1.4 ml of MEM-CI. Stirring is continued for ca. 2 hours. HPLC determination shows a conversion of DBU oximate into roxythromycin of 76 %.

Example 9

Roxythromycin via alkylation of TMA oximate

To a suspension of 6.3 g of erythromycin A oxime in 30 ml acetone 5.7 ml of a 25 % w/w aqueous solution of tetramethyl ammonium hydroxide are added at ca. 0°-5°. The mixture is stirred for ca. 15 minutes at ca. 0°-5 °. Erythromycin A oxime in the form of an oximate with TMA is obtained in situ. 1.3 ml of MEM-CI are added to the reaction mixture and the mixture is stirred for ca. 30 minutes at ca. 0°-5°. HPLC determination shows a conversion of TMA oximate into roxithromycin of 83%. Example 10

(E)-9-[Q-(phenylacetyl)oxιme of ervthromvcin A via acylation of DBU oximate

A mixture of 3.15 g of erythromycin A oxime and 0.66 mL of DBU in 70 ml of acetone is stirred for ca. 1 hour at room temperature. DBU oximate is obtained in situ. The reaction mixture is cooled to ca. 0°-5 °, a solution of 0.6 ml of phenvlacetvl chloride in 5 ml of acetone is added dropwise within ca. 10 minutes and the mixture obtained is stirred for ca. 1 hour at ca. 0°-5°. HPLC determination shows a conversion of DBU oximate into (E)-9-[0-(phenvlacetyl)oxιme of erythromycin A of 83 %. (E)-9-[0-(phenylacetyl)oxιme of ervthromvcin A is isolated as a solid. MS (FAB): 867 (M⁺); IR ( KBr, cm^'1): 3600-3300, 1735, 1648, 1588, 1496, 1458, 1379; ¹³C NMR: d 168.6 (PhCH₂COON=C9), 166.2 (PhCH2COON=C9), 133.1 (PhCH₂COON=C9), 129.3 (PhCH₂COON=C9), 128.6 (PhCH₂COON=C9), 127.2 (PhCH₂COON=C9), 54.3 (PhCH₂COON=C9)

Example 11

(E)-9-[0-(phenylacetyl)oxιme of ervthromvcin A via acylation of PMP oximate 1.0 g of PMP oximate, obtained as described in example 4, is dissolved in 25 ml of acetone. The mixture obtained is cooled to ca. 0°-5°, 0.18 ml of phenylacetyl chloride, dissolved in 3 ml of acetone, are added and the mixture is stirred at ca. 0°-5° for ca. 1 hour. HPLC determination shows a conversion of PMP oximate into (E)-9-[0-(phenylacetyl)oxιme of erythromycin A of 87 %. Isolation and characterisation as described in Example 10.

Example 12

(E)-9-[Q-(phenylacetyl)oxιme of ervthromvcin A via acylation of TMA oximate 2.41 g of TMA oximate, obtained as described in example 5, are dissolved in 50 ml of acetone, coooled to ca. 0°-5° and treated dropwise with a solution of 0.42 ml of phenvlacetyl chloride in 5 ml of acetone. The reaction mixture is stirred at ca. 0°-5° for ca. 1 hour. HPLC determination shows a conversion of TMA oximate into (E)-9-[0-(phenylacetyl)oxιme of erythromycin A of 92.1 %. Isolation and characterisation as described in Example 10.

Example 13

(E)-9-[0-(p-toluensulphonyl)θxιme of ervthromvcin A via sulphonylation of TMG oximate To a solution of 3.1 1 g of erythromycin A oxime in 60 ml of acetone, 0.55 ml of TMG are added, the mixture is stirred at room temperature for ca. 1 hour and cooled to ca. 0°-5°. 0.55 ml of TMG and a solution of 1.68 g of p-toluensulfonyl chloride in 30 ml of acetone are added within ca. 30 minutes and the mixture is stirred at ca. 0°-5 ° for ca. 4 hours.

HPLC determination shows a conversion of TMG oximate into

(E)-9-[0-(p-toluensulphonyl)oxime of erythromycin A of 90%.

Example 14

E)-9-[Q-(p-toluensulphonyl)oxime of ervthromvcin A via sulphonylation of DBU oximate

A mixture of 3.11 g of erythromycin A oxime in 60 ml of acetone and 0.65 ml of DBU is stirred at room temperature for ca. 1 hour and cooled to ca. 0°-5°. 0.65 ml of DBU and a solution of 1.68 g of p-toluensulfonyl chloride in 30 ml of acetone are added to the reaction mixture within ca. 30 minutes, the mixture obtained is stirred at ca. 0°-5° for ca. 4 hours.

HPLC determination shows a conversion of DBU oximate into

(E)-9-[0-(p-toluensulphonyl)oxime of erythromycin A of 73.8%.

Example 15

9-O-trimethylsilyl-erythromvcin A-9-oxime

To a solution of 1.5 g of the TMG oximate of erythromycin A in 15 ml of methylenechloride, cooled at 0 °C, 0.22 ml of trimethylchlorosilane are added. The mixture is stirred for ca. 20 hours at room temperature and poured over water. The layers are separated and the aqueous layer is extracted with methylenechloride. The organic layer is washed with a saturated solution of NaHCO3, dried over anhydrous sodium sulphate and concentrated to dryness under vacuum. 1.28 g of 9-O-trimethylsilyl-erythromycin A-9-oxime are obtained. Yield: 91.6%of theory; MS (FAB +): m/z= 822 (M⁺); IR (KBr, cm^"1): 3600-3350, 1738, 1613, 1462, 1380; ¹³C-NMR (CDCI3, 75.4 MHz): d 174.8 (C=N), -0.04 (Me3SiON=)

Example 16

9-O-tert-butyldimethylsilyl-erythromycin A-9-oxime

Is carried out analogously as described in example 15 but using 283 mg of tert- butyldimethylchlorosilane instead of 0.22 ml of trimethylchlorosilane. 1.32 g of 9-O-tert- butyldimethylsilyl-erythromycin A-9-oxιme are obtained.

Yield: 89.9% of theory; MS (FAB +): m/z= 864 (M⁺); IR (KBr, cm^"1 ): 3600-3400, 1738, 1464, 1380; ^,3C-NMR (CDCI3, 75.4 MHz): d 174.9 (C=N), 25.8 (Me.3CSiMe2), -5.3 (Me^CSiMe?) Example 17

9-O-trιιsopropylsιlyl-ervtrhomycιn A-9-oxιme

Is carried out analogously as described in example 15 but using 0.37 ml of trnsopropvlchlorosilane instead of 0.22 ml of trimethylchlorosilane and stirring the mixture for ca. 60 hours instead of ca. 20 hours, at room temperature 1.43 g of 9-O-tnιsopropylsιlyl- erytrhomvαn A-9-oxιme are obtained. Yield: 91.2% of theory

MS (FAB +): m/z= 906 (M⁺); IR (KBr, cm^"1):3600-3400, 1740, 1464, 1381 ¹³C-NMR (CDCI3, 75.4 MHz): d 174.5 (C=N), 17.8 (Me2CHSι), 11.7 (Me2CHSι)

Example 18

2'.4".9-0-trιs(tπmethylsιlyl)-erythromycιn A-9-oxιme

To a solution obtained after ca. 20 hours of stirring as described in example 15, 0.35 ml of trimethylchlorosilane and 0.65 ml of l-(tπmethylsιlyl)ιmιdazole are added and the mixture is stirred at room temperature for ca. 1 hour. A precipitate formed is filtrated off. The filtrated solution is washed with a saturated solution of NaHCθ3, dried over anhydrous sodium sulphate and concentrated to dryness under vacuum. 1.42 g of 2',4",9-0-tπs(tπmethylsιlyl)- erythromvcin A-9-oxιme are obtained

Yield: 85.0% of theory; MS (FAB +): m/z= 966 (M⁺); ¹³C-NMR (CDCI3, 75.4 MHz): d 175.3 (C=N), 80.9 (4"), 74.3 (2'), 1.0 (Me3Sι), 0.9 (Me3Sι), -0.8 (Me3SιON=)

Analogously as described in example 18 but using the corresponding silylation agent the following compounds are prepared:

2'.4"-0-bιs(trιmethylsιlyl)-9-0-tert-butyldιmethylsιlyl-ervthromvcιn A-9-oxιme Yield: 85.0%of theory; MS (FAB +): m/z= 1008 (M⁺);

^UC-NMR (CDCI3, 75.4 MHz): d 174.8 (C=N), 80.9 (4"), 74.3 (2'), 25.8 (Me.3CSιMe2), 1.0 (Me3Sι), 0.9 (Me3Sι), -5.3 (Me3CSιMe2)

2'.4"-0-bιs(trιmethylsιlyl)-9-0-trιιsopropylsιlyl-ervtrhomvcιn A-9-oxιme Yield: 84.2%of theory; MS (FAB +): m/z= 1050 (M⁺):

^,3C-NMR (CDCI3, 75.4 MHz): d 175.2 (C=N), 80.7 (4"), 74.2 (2'), 17.9 (Me2CHSι), 11.7 (Me2CHSι), 1.0 (Me3Sι), 0.9 (Me3Sι) Example 19 a. Methylation of 2\4".9-0-tris(trimethylsilyl)-ervthromycin A-9-oxime

To a solution of 3.9 g of 2',4",9-0-tris(trimethylsilyl)-erythromycin A-9-oxime in 50 ml of THF, cooled at 0 °C, 3.5 ml of sodium methoxide (30% in methanol) are added. The mixture obtained is kept under stirring at ca. 0 °C for ca. 30 minutes and 1.05 ml of methyl iodide are added. After ca. 2 hours at ca. 0 °C, 25 ml of water and 50 ml of methylenechloride are added. The phases are separated and the organic phase is washed with a saturated solution of NaHCθ3, dried over anhydrous magnesium sulphate and concentrated to dryness under vacuum. 4.02 g of 2',4",9-0-tris(trimethylsilyl)-erythromycin A-9-oxime wherein the hydroxy group in position 6 of the ring system is methylated in the form of a white solid is obtained, confirmed by MS and NMR spectra characerization data. b. Methylation of 2'.4"-0-bis(trimethylsilyl⁾-9-0-tert-butyldimethylsilyl-erythromvcin A-9- oxime

Analogously as described in example 19 a., but starting from 2',4"-0-bis(trimethylsilyl)-9-0- tert-butyldimethylsilyl-erythromycin A-9-oxime and using as a solvent DMF instead of THF and as a base sodium hydride (80%) instead of sodium methoxide and ethyl acetate instead of methylenechloride 2',4",9-0-tris(trimethylsilyl)-erythromycin A-9-oxime wherein the hydroxy group in position 6 of the ring system is methylated in the form of a white solid is obtained, confirmed by MS and NMR spectra characerization data. c. Methylation of 2'.4"-0-bis(trimethylsilyl)-9-0-triisopropylsilyl-erythromycin A-9-oxime Analogously as described in example 19 a., but starting from 2',4"-0-bis(trimethylsilyl)-9-0- triisopropylsilyl-erythromycin A-9-oxime and using as a solvent DMSO/THF (1:1) instead of THF and as a base powdered KOH and triethylamine instead of sodium methoxide and ethyl acetate instead of methylenechloride 2',4"-0-bis(trimethylsilyl)-9-0-triisoproρylsilyl- erythromycin A-9-oxime wherein the hydroxy group in position 6 of the ring system is methylated in the form of a white solid is obtained, confirmed by MS and NMR spectra characerization data.

Example 20 6-O-methyl-ervthromvcin A-9-oxime

A crude solid obtained according to example 19 is dissolved in a mixture of ethanol and water (1:1). The solution is acidified by addition of formic acid and the mixture is kept at room temperature. After stirring for ca. 3-5 hours, 6-O-methyl-erythromycin A-9-oxime is obtained. MS (FAB +): m/z= 763 (M⁺); IR (KBr, cm^"1): 3600-3350, 1738, 1613, 1462, 1380 ¹³C-NMR (CDCI3, 75.4 MHz): d 170.4 (C=N), 51.1 (6-O-Me)

Example 21 6-O-Methyl-ervthromycιn A (clanthromvcin)

To a solution of 264 mg of 6-O-methyl-erythromycιn A-9-oxιme obtained according to example 20, in 4 ml of ethanol/water (1:1), 146 mg of sodium hydrogen sulfite and 33 ml of formic acid are added and the mixture is stirred for ca. 2 hours at ca. 80°C. 4 ml of water are added to the mixture obtained and the resulting mixture is cooled to ca. 5 °C. The pH of the solution is adjusted to ca. 10 by addition of 2 N aqueous sodium hydroxide solution and the resulting mixture is stirred for ca. 1 hour. A solid is formed, filtrated off, washed with water and dried. 6-O-methyl-erythromycιn A (claπthromycin) is obtained.

Example 22 a) 2'-4 "-Q-bιs(trιmethylsιlyl)-9-O-(2-methoχyethoxymethyl)-eryhtomycιn A-9-oxιme 8.81 g of roxithromycin are dissolved in 50 ml of ethyl acetate and 4.45 ml of hexamethyldisilazane and 44 mg of saccharin are added. The mixture is heated under reflux for ca. 150 minutes and cooled to room temperature. The ethyl acetate solution obtained is washed with 100 ml of a 5% aqueous sodium hydrogen carbonate solution and with 100 ml of water, dried over anhydrous magnesium sulphate, filtered and evaporated to dryness.

8.07 g of 2'-4 "-0-bιs(tπmethylsιlyl)-9-O-(2-methoxyethoxymethyl)-eryhtomycιn A-9-oxιme are obtained.

IR (KBr, cm : 3470, 2970, 2938, 2827, 1738, 1458, 1380, 1287, 1251

13C-NMR (CDCl₃,_754MHz) : 1-04 (Me₃Sι), 1.15 (Me₃Sι) b) 2'-4"-O-bιs(tπmethylsιlyl)-9-O-(2-methoxyethoxymethyl)-6-O-methyl ervhtomvcin A-9- oxime To a solution of 3.96 g of 2'-4 "-O-bιs(tπmethyIsιlyl)-9-O-(2-methoxyethoxymethyl)- eryhtomvcin A-9-oxιme in 50 ml of DMSO/TΗF (1:1) cooled at ca. 0/5°, 1.05 g of powdered potassium hydroxide and 1.0 ml of methyl iodide are added. The mixture obtained is stirred for ca. 45 minutes at 0/5 °. 6 ml of methylamine (40 % in water), 100 ml of water and 60 ml of ethyl acetate are added. A two-phase svstem is obtained. The organic phase is decanted and the aqueous phase is extracted with 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and evaporated to dryness. 4.4 g of 2'-4"-0-bis(trimethylsilyl)-9-O-(2-methoxyethoxymethyl)-6-O-methyl eryhtomycin A- 9-oxime in the form of a foam are obtained.

6-O-methyl erithromycin A oxime may be obtained from 2'-4"-O-bis(trimethylsilyl)-9-0-(2- methoxyethoxymethyl)-6-0-methyl eryhtomycin A-9-oxime as conventional, e.g. as described in the description above.

Claims

1. Erythromycin A oxime wherein the hydroxyl group of the oxime group is in reacted form resulting from reaction with a strong organic base or with a silylation agent.

2. A compound of formula

.OR

wherein R_A denotes a silyl group; or a group of formula

(H) n - B wherein

(i) n = 1 and B is a compound of formula

R; ΓÇö C=N ΓÇö R,

.N.

R, RJ

wherein Ri, Ri', R₂ and R₂' independently of each other denote hydrogen or an aliphatic or aromatic group; or Rj and R,' independently of each other denote an aliphatic or aromatic group and R₂ and R₂' together with the nitrogen atom denote a ring or ring system, (ii) n = 1 and B is a compound of formula

wherein R₃, R ,Rs, R-s and R₇ denote independently of each other hydrogen or an aliphatic or aromatic group; or R is as defined above; and either R₄ and R₅ together denote (C]-₄)alkylidene and R₆ and R₇ independently of each other denote hydrogen; or an aliphatic or aromatic group; or R₄ and R₅ together denote (C 4)alkylidene and R₆ and R₇ together denote (C╬╣-₄)alkylidene; or R┬½ and R together denote (C╬╣-₄)alkylidene and R₄ and R₅ independently of each other denote hydrogen or an aliphatic or aromatic group; (iv) n = 1 and B is a compound of formula

wherein R₈, R9, Rio, Rn and R independently of each other denote hydrogen or an aliphatic or aromatic group, and X denotes CH₂, NH, O or S; (v) n = 0 and B is a group of formula

wherein Z denotes nitrogen, and R╬╣₃, R╬╣₄, R₁5, and R₁₆ independently of each other denote an aliphatic or aromatic group.

3. Erythromycin A oxime wherein the hydroxyl group of the oxime group is in reacted form resulting from reaction with a strong organic base which shows a molecular peak of an oximate of erythromycin A oxime of formula I with a strong organic base in mass spectroscopy determination.

4. A process for the production of erythromycin A oxime in the form of an oximate with a strong organic base, comprising reacting erythromycin A oxime with a strong organic base, and, if desired isolating erythromycin A oxime in the form of an oximate.

5. Erythromycin A oxime wherein the hydroxy group in the hydroxyimino group is silylated.

6. A process for the production of erythromycin A oxime wherein the hydroxy group in the hydroxyimino group is silylated comprising silylating a compound of formula II wherein R_A denotes a group of formula (H) _n- B wherein n and B are as defined in claim 2.

7. A process for the production of a compound of formula II of claim 2, wherein R_A denotes silyl and wherein the hydroxy groups in position 2' and 4" of the ring system are silylated, comprising reacting a compound of formula II, wherein R_A denotes a a silyl group with a silylating agent.

8. Use of Erythromycin A oxime wherein the hydroxyl group of the oxime group is in reacted form resulting from reaction with a strong organic base or with a silylation agent. as an intermediate in the production of macrolides of the erythromycin type.

9. Use according to claim 8 in the production of roxithromycin, clarithromycin, or azithromycin.

10. A process for the production of an O-alkylated erythromycin A oxime comprising reacting a compound of formula II according to claim ╧Ç, wherein R_A denotes a group of formula (H) _n- B wherein n an B are as defined in claim 2 with a compound of formula

Alk-L wherein Alk denotes an alkyl group and L denotes a leaving group.

11. A process according to claim 10 for the production of roxythromycin wherein Alk denotes the group CH₃OC₂H₅OCH₂-.

12. A process for the production of clarithromycin comprising the steps i) silylating the hydroxy groups in position 2' and 4" in the ring system of an erythromycin A oxime wherein the hydroxy group of the oxime is alkylated, ii) methylating the hydroxy group in position 6 of the ring system in a compound obtained in step i) to obtain erythromycin A oxime wherein the hydroxy group of the oxime is alkylated and wherein the hydroxyl groups in position 2' and 4" are silylated and wherein the hydroxyl group in position 6 is methylated; and iii) removing the silyl groups from and deoximating a compound obtained in step ii) to obtain clarithromycin.

13. A process for the production of clarithromycin comprising the steps i) silylating the hydroxy groups in position 2' and 4" in the ring system of roxythromycin, ii) methylating the hydroxy group in position 6 of the ring system in a compound obtained in step i) to obtain roxythromycin wherein the hydroxyl groups in position 2' and 4" are silylated and wherein the hydroxyl group in position 6 is methylated; and iii) removing the silyl groups from and deoximating a compound obtained in step ii) to obtain clarithromycin; e.g. and isolating clarthromycin.

14. A process for the production of clarithromycin comprising the steps i) producing roxythromycin by reacting a compound of formula H, wherein R_A denotes a group of formula (H) _n- B wherein n an B are as defined above with a compound of formula

wherein Alk denotes an alkyl group and L denotes a leaving group, ii) silylating the hydroxy groups in position 2' and 4" in the ring system of roxythromycin, iii) methylating the hydroxy group in position 6 of the ring system in a compound obtained in step i) to obtain roxythromycin wherein the hydroxyl groups in position 2' and 4" are silylated and wherein the hydroxyl group in position 6 is methylated; and iv) removing the silyl groups from and deoximating a compound obtained in step ii) to obtain clarithromycin.