EP2753637A1 - Process for the synthesis of telavancin, its pharmaceutically acceptable salts as well as an n-protected imine-derivative of telavancin - Google Patents

Process for the synthesis of telavancin, its pharmaceutically acceptable salts as well as an n-protected imine-derivative of telavancin

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Publication number
EP2753637A1
EP2753637A1 EP12755879.9A EP12755879A EP2753637A1 EP 2753637 A1 EP2753637 A1 EP 2753637A1 EP 12755879 A EP12755879 A EP 12755879A EP 2753637 A1 EP2753637 A1 EP 2753637A1
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EP
European Patent Office
Prior art keywords
telavancin
protected
imine
iii
formaldehyde
Prior art date
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EP12755879.9A
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German (de)
French (fr)
Inventor
David BENITO-GARAGORRI
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Sandoz AG
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Sandoz AG
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Application filed by Sandoz AG filed Critical Sandoz AG
Priority to EP12755879.9A priority Critical patent/EP2753637A1/en
Publication of EP2753637A1 publication Critical patent/EP2753637A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/006—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure
    • C07K9/008—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence being part of a ring structure directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin

Definitions

  • telavancin Process for the synthesis of telavancin, its pharmaceutically acceptable salts as well as an N-protected f mine-derivative of telavancin
  • the invention relates to a process for the preparation of telavancin, or a pharmaceutically acceptable salt thereof, wherein said process comprises an alkylation of vancomycin which provides N-protected-decylaminoethylvancomycin-imine, followed by an aminomethylation to obtain N-protected-telavancin-imine, which is then reduced and deprotected to provide telavancin, or a pharmaceutically acceptable salt thereof.
  • Another embodiment refers to N- protected-telavancin-imine which is formed during the process of the invention.
  • Telavancin is a derivative of vancomycin, and represents a bactericidal lipoglycopeptide which can e.g. be used for treating methicillin-resistant Staphylococcus aureus (MRS A) or other gram- positive infections.
  • MRS A methicillin-resistant Staphylococcus aureus
  • telavancin requires several process steps as e.g. described in WO 03/029270 A2.
  • This publication discloses a process for reductive alkylation of glycopeptide antibiotics, wherein the glycopeptide and the aldehyde are reacted in the presence of a base to form an imine and/or hemiaminal, which is then reduced in the presence of a reducing agent under acidic conditions.
  • the product of the reductive alkylation is not isolated but directly contacted with an amine to remove the protecting group from the intermediate product.
  • the deprotected intermediate product is isolated and then subjected to an aminomethylation reaction to provide telavancin.
  • US 6,887,976 B2 also describes a process for the preparation of phosphonate derivatives of glycopeptide antibiotics.
  • the process comprises a reductive alkylation of a glycopeptide such as vancomycin to provide a first side chain to said glycopeptide.
  • the deprotected and isolated derivative of vancomycin having said first side chain is then subjected to an aminomethylation reaction to provide the desired phosphonate derivatives such as telavancin.
  • WO 01/83521 A2 describes a process for reductive alkylation of a saccharide-amine of a glycopeptide antibiotic such as vancomycin. According to the process described in this publication, as improvement over formerly applied processes, the reaction mixture is acidified to improve selectivity of the reductive alkylation.
  • WO 03/018607 A2 describes a process for preparing derivatives of glycopeptide antibiotics having an amino-containing side chain by carrying out a reductive alkylation process. The process is carried out in a single reaction vessel without isolation of intermediate reaction products.
  • telavancin or its pharmaceutical acceptable salts are available, it is an object of the present invention to provide an alternative process, in particular an enhanced process that overcomes at least one of the problems of the prior art processes.
  • telavancin and its pharmaceutically acceptable salts can be prepared from vancomycin by conducting an alkylation to obtain N-protected-decylaminoethylvancomycin-imine (i.e. providing a first side chain to vancomycin) followed by an aminomethylation (providing a second side chain to vancomycin), wherein the N-protected-decylaminoethylvancomycin-imine is subjected to aminomethylation without firstly reducing said imine to the N-protected- decylaminoethylvancomycin.
  • the present invention provides for a new synthesis route for telavancin and its pharmaceutically acceptable salts.
  • N- protected-decylaminoethylvancomycin-imine can be subjected to an aminomethylation reaction without having to conduct a reduction step prior to the aminomethylation reaction. Furthermore, it is not necessary to carry out a deprotection step prior to the aminomethylation reaction.
  • telavancin As mentioned above, the known processes for preparing telavancin apply multiple process steps, i.e. forming an imine via addition of an aldehyde to vancomycin (introduction of a first side chain), reduction and deprotection of said imine, followed by the introduction of a phosphonate side chain (second side chain).
  • intermediate products such as the product resulting from the introduction of the first side chain are isolated and used as starting material for further reaction. It would represent an enhancement to be able to carry out the preparation of telavancin starting from vancomycin while only having to isolate the N-protected-telavancin-imine.
  • N-protected-decylaminoethylvancomycin-imine can be subjected to the aminomethylation reaction without firstly having to isolate said imine which is formed by alkylation of vancomycin.
  • N-protected-telavancin-imine can be reduced and deprotected in a so-cal!ed "one pot synthesis", i.e. without having to isolate any intermediate products such as e.g. the N-protected-decylaminoethylvancomycin-imine or N-protected-telavancin.
  • telavancin or pharmaceutically acceptable salts thereof is simple and effective.
  • a further unexpected result which was made within the context of the invention is that the aminomethylation of the N-protected-decylaminoethylvancomycin can be conducted by using an oligomer resulting from the reaction of aminomethylphosphonic acid and formaldehyde. By doing so, the direct use of the toxic agent formaldehyde can be avoided.
  • one embodiment provides a process for the preparation of telavancin according to Formula I
  • R is a protecting group, and an excess base in an inert solvent or mixture of inert solvents, to form an imine (N-protected-decylaminoethylvancomycin-imine),
  • step (iii) bringing the imine (N-protected-decylaminoethylvancomycin-imine) of step (ii) into contact with (a) formaldehyde and aminomethylphosphonic acid or (b) the oligomer resulting from the reaction of aminomethylphosphonic acid and formaldehyde, in the presence of a base, preferably excess of base, thereby obtaining N-protected-telavancin-imine, which is then isolated,
  • step (iii) providing a mixture comprising N-protected-telavancin-imine of step (iii), an acid and an inert solvent (i.e. in a solvent which does not hydrolyze the imine-compound),
  • step (iv) adding a reducing agent to the mixture obtained in step (iv) in order to produce N- protected-telavancin,
  • telavancin a derivative of telavancin according to Formula IV
  • the invention relates to a process for the preparation of telavancin or pharmaceutical salts thereof from vancomycin or a salt thereof comprising process steps (i) to (vii). n step (i), vancomycin according to Formula II
  • vancomycin or salt thereof is provided.
  • Said vancomycin or salt thereof can be prepared according to any known method.
  • step (ii) the vancomycin (or salt thereof) of step (i) is brought into contact with a compound of Formula III
  • R is a protecting group, to provide an imine (N-protected-decylaminoethylvancomycin- imine).
  • the N-protected-decylaminoethylvancomycin-imine obtained in step (ii) has the following Formula V:
  • R is an amine-labile protecting group selected from the group consisting of 9-fluorenylmethyl carbamate, 17-tetrabenzo[a,c,g,/]fluorenylmethyl carbamate, 3- indenylmethyl carbamate, 2-chloro-3-indenylmethyl carbamate, benz[f]inden-3-yimethyl carbamate, 1 , 1 -dioxobenzo[j ]thiophene-2-ylmethyl carbamate, 2-methylsulfonyl-3-phenyl-1 - prop-2-enyloxy carbamate and 2,7-di-t-butyl[9-( 10, 10-dioxo10,10,10,10- tetra hyd roth i oxa n thy I )] m ethyl carbamate, wherein the 9-fluorenylmethyl group in 9- fluorenylmethyl carbamate is optionally substituted with 1 to
  • the amount of the compound according to Formula III that is used in step (ii) can e.g. (for example) be between 1 and 3 equivalents based on vancomycin.
  • Step (ii) is carried out in the presence of an inert solvent or a mixture of inert solvents.
  • inert solvent refers to any solvents that do not react with vancomycin, i.e. do not react with functional groups of vancomycin.
  • inert solvents suitable in this respect are commonly known.
  • Example of inert solvents are ⁇ , ⁇ -dimethylformamide (DMF), ⁇ , ⁇ -Dimethylacetamide, dimethyl sulfoxide (DMSO), N-methylpyrrolidone and acetonitrile and the like and mixtures thereof, with DMF being preferred.
  • water is not used as solvent prior to step (v) or water is not present during the reduction in step (v).
  • Step (ii) is furthermore carried out in the presence of base, preferably excess of base.
  • Suitable bases are e.g. organic bases, such as amines, or alkali metal carboxylate salts, and inorganic bases, such as alkali metal carbonates. Specific examples of suitable bases are
  • DIPEA diisopropylethylamine
  • N-methylmorpholine N-methylmorpholine
  • triethylamine triethylamine
  • diisopropylethylamine being preferred. It is also possible to use a mixture of different types of bases.
  • step (ii) is carried out by combining a solution of the compound according to Formula III, preferably dissolved in DMF, with a suspension of vancomycin, preferably suspended in DMF, thereby forming a reaction mixture, then adding excess base to said reaction mixture.
  • the reaction mixture comprising or consisting of vancomycin or a salt thereof, the compound of Formula III, the inert solvent(s) and the base(s) can e.g. be stirred for a time of between 1 and 24 hours, preferably for a time of between 5 and 12 hours.
  • Step (ii) can e.g. be carried at a temperature of between 0°C and 100°C, further preferred of between 0°C and 50°C, even further preferred of between 15°C and 25°C.
  • Step (ii) can additionally be carried out under inert atmosphere, preferably under nitrogen gas.
  • the only materials added to, i.e. contained in, the reaction mixture in step (ii) are vancomycin or a salt thereof, the compound according to Formula III, the base(s) and the inert solvent(s).
  • N-protected-decylaminoethylvancomycin-imine After N-protected-decylaminoethylvancomycin-imine has been formed in step (ii), said N- protected-decylaminoethylvancomycin-imine is optionally isolated. Isolation techniques are well known in the art and further described in respect to step (vii) below. For example, isolating N- protected-decylaminoeihy!vancomycin-imine can comprise precipitation and filtration steps. Preferably, N-protected-decylaminoethylvancomycin-imine is not isolated.
  • step (iii) the N-protected-decylaminoethylvancomycin-imine of step (ii) is brought into contact with either (a) formaldehyde and aminomethylphosphonic acid in the presence of a base or (b) a base and then the oligomer resulting from the reaction of aminomethylphosphonic acid and formaldehyde, preferably in the presence of a base, is added, thereby obtaining N-protected- telavancin-imine.
  • using said oligomeric reagent allows avoiding the direct use of the toxic formaldehyde.
  • step (ii) can be carried out without isolating N-protected- decylaminoethylvancomycin-imine.
  • step (iii) is carried out starting from the reaction mixture obtained in step (ii).
  • step (iii) can include redissolving or resuspending said isolated N-protected- decylaminoethylvancomycin-imine in a solvent prior to contacting it with excess base and (a) formaldehyde and aminomethylphosphonic acid or (b) the oligomer resulting from the reaction of aminomethylphosphonic acid and formaldehyde.
  • step (iii) is carried out in the presence of a polar protic solvent, particularly preferred water.
  • the reaction mixture in step (iii) includes the following solvents: the inert solvent(s) of step (ii) such as DMF, optionally acetonitrile and water. If N-protected-decylaminoethylvancomycin-imine is isolated in step (ii), said reaction mixture in step (iii) may not include the inert solvents(s) of step (ii).
  • the oligomer employed in step (iii) is the product resulting from the reaction of aminomethylphosphonic acid with formaldehyde.
  • Said oligomer can be prepared separately by reacting aminomethylphosphonic acid with formaldehyde, preferably in the presence of a base.
  • the base in step (iii) can e.g. be a tertiary amine, preferably triethylamine, or DIPEA.
  • the amount of added base can e.g. be between 15 and 25 equivalents, preferably 20 equivalents, based on the amount of vancomycin.
  • Step (iii) can e.g. be carried out by adding acetonitrile and base, preferably DIPEA, to the reaction mixture of step (ii) or to the solution/suspension containing previously isolated N- protected-decylaminoethylvancomycin-imine, followed by stirring at a temperature of between 15°C and 30°C for 5 minutes to 1 hour, preferably 5 minutes to 30 minutes.
  • acetonitrile and base preferably DIPEA
  • aminomethylphosphonic acid can e.g. be added to the reaction mixture, followed by stirring at a temperature of e.g. between 15 and 30°C for 5 minutes to 1 hour, preferably 5 minutes to 30 minutes.
  • reaction mixture comprising aminomethylphosphonic acid
  • water can be added and the mixture can e.g. be further stirred at a temperature of between 15 and 30°C for 5 minutes to 1 hour, preferably 5 minutes to 30 minutes, followed by cooling of the reaction mixture to a temperature of between -15°C and -5°C and then adding formaldehyde, preferably in an amount of between 1 and 5 equivalents based on vancomycin.
  • the amount of aminomethylphosphonic acid which is used in step (iii) can e.g. be between 2 and 10 equivalents, preferably between 4 and 5, based on vancomycin.
  • Formaldehyde used in step (iii) can e.g. be added in the form of a solution of formaldehyde in water, preferably a 30-40 wt.-% solution of formaldehyde in water, optionally containing 5 to 15 wt.-% methanol.
  • the reaction mixture comprising formaldehyde or said oligomer can e.g. be stirred at a temperature of between -15°C and -5°C, preferably -10°C, for 6 to 48 hours, preferably 12 to 20 hours.
  • the pH value of the reaction mixture after adding excess base in step (iii) can e.g. be between 10 and 11 .
  • the oligomer employed in step (iii) is the product resulting from the reaction of aminomethylphosphonic acid with formaldehyde. Said oligomer is added at a temperature between -15°C and -5°C, preferably -10°C, to a reaction mixture of step (ii) or to redissolved/resuspended N-protected-decylaminoethylvancomycin containing a base, wherein the reaction mixture contains an inert solvent or mixture of solvents and a polar protic solvent such as water.
  • N-protected-telavancin-imine After N-protected-telavancin-imine has been formed in step (iii), said N-protected-telavancin- imine is isolated from the reaction mixture. This allows carrying out a change of the solvent system, in particular, it allows removing water from the reaction mixture prior to the reduction step.
  • the isolation of N-protected-telavancin-imine can be carried out according to well known methods, e.g. by carrying out precipitation, filtration and drying steps.
  • step (iv) an acidified mixture of N-protected-telavancin-imine of step (iii) and a solvent is provided. Said acidified mixture can e.g. be obtained by suspending/dissolving N-protected- telavancin-imine of step (iii) in a solvent, e.g. in DMF, and then adding one or more acids.
  • Acidifying the mixture in step (iv) can e.g. be carried out by adding one or more acids selected from the group consisting of trifluoroacetic acid (TFA), trichloroacetic acid, citric acid, formic acid, hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, phosphoric acid and acetic acid, preferably TFA, to the reaction mixture.
  • TFA trifluoroacetic acid
  • the resulting pH of the reaction mixture can e.g. be adjusted to be within a range of e.g. between 3 and 6.
  • the reaction mixture comprising said one or more acids can then e.g.
  • step (iv) be stirred at a temperature of between 0°C and 50°C, preferably of between 15°C and 25°C, for 5 minutes to 2 hours, preferably for 5 to 40 minutes.
  • the amount of acid(s) added in step (iv) can e.g. be between 3 and 6 equivalents based on vancomycin.
  • the acid used in step (iv) does not contain water.
  • the reaction mixture in step (iv) does not contain water in order not to hydrolyze the imine.
  • a polar protic solvent such as for example an alcohol e.g. selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, and mixtures thereof, preferably methanol is added to the reaction mixture.
  • an alcohol e.g. selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, and mixtures thereof, preferably methanol is added to the reaction mixture.
  • step (v) a reducing agent is added to the mixture obtained in step (iv) in order to produce N- protected-telavancin.
  • the reducing agent that is used in step (v) is selected from the group consisting of tert.-butylamine borane, sodiumcyanoborohydride, sodium triacetoxyborohydride, pyridine/borane, sodium borohydride, zinc borohydride, N-methylmorpholino borane, and triethylamine borane, preferably tert.-butylamine borane.
  • Step (v) can e.g. be carried out by adding the reducing agent to the mixture obtained in step (iv) and then stirring the thereby formed reaction mixture at a temperature of between 0°C and
  • the amount of reducing agent that is used in step (v) can e.g. be between 1 and 3 equivalents, preferably between 1 and 2 equivalents, based on the amount of vancomycin.
  • the N-protected-telavancin of step (v) is brought into contact with a deprotecting agent to provide telavancin.
  • the deprotecting agent can be chosen according to common knowledge depending on the protecting group that is used (see e.g. Greene's Protective Groups in Organic Synthesis, Peter G.M. Wuts, Theodora W. Greene, 2007 John Wiley & Sons, Inc., Hoboken, New Jersey, Fourth Edition).
  • the deprotecting agent is an amine base and preferably, the protecting group is a carbamate group.
  • amine bases are methylamine, ethylamine, tert-butylamine, triethylamine, piperidine, morpholine, ammonium hydroxide, 1 , 4-d iaza b i cyclo [2.2.2]octa ne (DABCO), dicyclohexylamine, pyridine, p- dimethylaminopyridine, diisopropylethylamine, 1 ,8-diazabyciclo[5.4.0]undec-7-ene (DBU), piperazine and ethanolamine.
  • DBUCO 4-d iaza b i cyclo [2.2.2]octa ne
  • Step (vi) can further e.g. comprise warming up the reaction mixture of step (v) to a temperature of between 0°C and 15°C, preferably 0°C and 10°C, followed by addition of said deprotecting agent, for instance a deprotecting agent selected from the group consisting of methylamine, ethylamine, tert.-butylamine, triethylamine, morpholine, ammonium hydroxide, 1 ,4- diazabicyclo[2.2.2]octane (DABCO) and piperidine, preferably piperidine, e.g. followed by warming the reaction mixture to a temperature of between 10 and 20°C, optionally followed by addition of a further amount of said base, and stirring the thereby obtained reaction mixture for a time of e.g. 5 minutes to 1 hour at said temperature
  • a deprotecting agent selected from the group consisting of methylamine, ethylamine, tert.-butylamine, triethylamine,
  • step (vi) said deprotecting agent can e.g. be used in an amount of 15 to 50 equivalents based on vancomycin
  • step (vii) telavancin or a pharmaceutically acceptable salt thereof is isolated. Additionally preferred, isolating telavancin or its pharmaceutically acceptable salt is carried out by precipitation and filtration methods.
  • Step (vii) can e.g. comprise cooling the reaction mixture of step (vi) to a temperature of between -15°C and -5°C, acidifying the reaction mixture with acid, e.g. 3N HCI, to a pH of between 2 and 3, preferably to a pH of about 2.9 and then warming up the reaction mixture to a temperature of e.g. between 15°C and 30°C.
  • acid e.g. 3N HCI
  • Step (vii) can e.g. additionally comprise adding acetonitrile to the reaction mixture to promote precipitation of telavancin or its pharmaceutically acceptable salt.
  • the precipitated telavancin or its pharmaceutically acceptable salt, preferably its pharmaceutically acceptable salt can e.g. be filtered off, washed with cold acetonitrile and dried.
  • steps (ii) and/or (v) are preferably carried out without isolating any intermediate products, in particular without isolating N-protected- decylaminoethylvancomycin-imine and/or N-protected-telavancin. Also preferred, steps (i)-(ii) and (iv)-(v) are carried out without isolating any intermediate products and/or removal of solvents. Additionally preferred, steps (ii) and (iii) are carried out in one reaction vessel. Additionally preferred, steps (iv)-(vii) are (also) carried out in one reaction vessel.
  • step (ii) is carried out without any steps of solvent removal and filtration. Additionally preferred, steps (iv)-(vi) are (also) carried out without any steps of solvent removal and filtration. Additionally preferred, no step of removing protection groups is carried out prior to step (vi). Additionally preferred, the process provides telavancin HCI.
  • the present invention also relates to a derivative of telavancin (N-protected-telavancin-imine) and pharmaceutically acceptable salts thereof, preferably the HCI salt, according to Formula IV:
  • telavancin and its pharmaceutically acceptable salts can be prepared as described above. Isolation of said N-protected-telavancin-imine can be conducted after step (iii), e.g. by carrying out the above process while not applying steps (iv)-(vii). Preferred R- substituents are also described above.
  • DIPEA diisopropylethylamine

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Abstract

The invention relates to a process for the preparation of telavancin, or a pharmaceutically acceptable salt thereof, wherein said process comprises an alkylation of vancomycin which provides N-protected-decylaminoethylvancomycin-imine, followed by an aminomethylation to obtain N-protected-telavancin-imine, which is then reduced and deprotected to provide telavancin, or a pharmaceutically acceptable salt thereof. Another embodiment refers to N-protected-telavancin-imine which is formed during the process of the invention.

Description

Process for the synthesis of telavancin, its pharmaceutically acceptable salts as well as an N-protected f mine-derivative of telavancin
The invention relates to a process for the preparation of telavancin, or a pharmaceutically acceptable salt thereof, wherein said process comprises an alkylation of vancomycin which provides N-protected-decylaminoethylvancomycin-imine, followed by an aminomethylation to obtain N-protected-telavancin-imine, which is then reduced and deprotected to provide telavancin, or a pharmaceutically acceptable salt thereof. Another embodiment refers to N- protected-telavancin-imine which is formed during the process of the invention.
Background prior art
Telavancin is a derivative of vancomycin, and represents a bactericidal lipoglycopeptide which can e.g. be used for treating methicillin-resistant Staphylococcus aureus (MRS A) or other gram- positive infections.
The process for preparation of telavancin requires several process steps as e.g. described in WO 03/029270 A2. This publication discloses a process for reductive alkylation of glycopeptide antibiotics, wherein the glycopeptide and the aldehyde are reacted in the presence of a base to form an imine and/or hemiaminal, which is then reduced in the presence of a reducing agent under acidic conditions. In contrast to prior art processes, the product of the reductive alkylation is not isolated but directly contacted with an amine to remove the protecting group from the intermediate product. The deprotected intermediate product is isolated and then subjected to an aminomethylation reaction to provide telavancin. US 6,887,976 B2 also describes a process for the preparation of phosphonate derivatives of glycopeptide antibiotics. The process comprises a reductive alkylation of a glycopeptide such as vancomycin to provide a first side chain to said glycopeptide. The deprotected and isolated derivative of vancomycin having said first side chain is then subjected to an aminomethylation reaction to provide the desired phosphonate derivatives such as telavancin.
WO 01/83521 A2 describes a process for reductive alkylation of a saccharide-amine of a glycopeptide antibiotic such as vancomycin. According to the process described in this publication, as improvement over formerly applied processes, the reaction mixture is acidified to improve selectivity of the reductive alkylation.
WO 03/018607 A2 describes a process for preparing derivatives of glycopeptide antibiotics having an amino-containing side chain by carrying out a reductive alkylation process. The process is carried out in a single reaction vessel without isolation of intermediate reaction products.
Although some efficient processes for the synthesis of telavancin or its pharmaceutical acceptable salts are available, it is an object of the present invention to provide an alternative process, in particular an enhanced process that overcomes at least one of the problems of the prior art processes.
Summary of the invention
It was surprisingly found within the context of the present invention that telavancin and its pharmaceutically acceptable salts can be prepared from vancomycin by conducting an alkylation to obtain N-protected-decylaminoethylvancomycin-imine (i.e. providing a first side chain to vancomycin) followed by an aminomethylation (providing a second side chain to vancomycin), wherein the N-protected-decylaminoethylvancomycin-imine is subjected to aminomethylation without firstly reducing said imine to the N-protected- decylaminoethylvancomycin. Thus, the present invention provides for a new synthesis route for telavancin and its pharmaceutically acceptable salts. It was unexpectedly observed that N- protected-decylaminoethylvancomycin-imine can be subjected to an aminomethylation reaction without having to conduct a reduction step prior to the aminomethylation reaction. Furthermore, it is not necessary to carry out a deprotection step prior to the aminomethylation reaction.
As mentioned above, the known processes for preparing telavancin apply multiple process steps, i.e. forming an imine via addition of an aldehyde to vancomycin (introduction of a first side chain), reduction and deprotection of said imine, followed by the introduction of a phosphonate side chain (second side chain). In said prior art processes, intermediate products such as the product resulting from the introduction of the first side chain are isolated and used as starting material for further reaction. It would represent an enhancement to be able to carry out the preparation of telavancin starting from vancomycin while only having to isolate the N-protected-telavancin-imine.
Unexpectedly, it was found that N-protected-decylaminoethylvancomycin-imine can be subjected to the aminomethylation reaction without firstly having to isolate said imine which is formed by alkylation of vancomycin. Thus, it is possible to carry out the aminomethylation without previous workup of the reaction mixture such as by removal of solvents. Furthermore, it was unexpectedly found that N-protected-telavancin-imine can be reduced and deprotected in a so-cal!ed "one pot synthesis", i.e. without having to isolate any intermediate products such as e.g. the N-protected-decylaminoethylvancomycin-imine or N-protected-telavancin.
The process for preparing telavancin or pharmaceutically acceptable salts thereof according to the invention is simple and effective. A further unexpected result which was made within the context of the invention is that the aminomethylation of the N-protected-decylaminoethylvancomycin can be conducted by using an oligomer resulting from the reaction of aminomethylphosphonic acid and formaldehyde. By doing so, the direct use of the toxic agent formaldehyde can be avoided. Thus, one embodiment provides a process for the preparation of telavancin according to Formula I
a pharmaceutically acceptable salt thereof, wherein the process comprises the steps of: providing vancomycin according to Formula II
or a salt thereof,
ii) bringing the vancomycin of step (i) into contact with a compound of Formula III
wherein R is a protecting group, and an excess base in an inert solvent or mixture of inert solvents, to form an imine (N-protected-decylaminoethylvancomycin-imine),
iii) bringing the imine (N-protected-decylaminoethylvancomycin-imine) of step (ii) into contact with (a) formaldehyde and aminomethylphosphonic acid or (b) the oligomer resulting from the reaction of aminomethylphosphonic acid and formaldehyde, in the presence of a base, preferably excess of base, thereby obtaining N-protected-telavancin-imine, which is then isolated,
iv) providing a mixture comprising N-protected-telavancin-imine of step (iii), an acid and an inert solvent (i.e. in a solvent which does not hydrolyze the imine-compound),
v) adding a reducing agent to the mixture obtained in step (iv) in order to produce N- protected-telavancin,
vi) bringing the N-protected-telavancin of step (v) into contact with a deprotecting agent to provide telavancin, vii) isolating telavancin or a pharmaceutically acceptable salt thereof. Another embodiment refers to a derivative of telavancin according to Formula IV
Detailed description
The invention relates to a process for the preparation of telavancin or pharmaceutical salts thereof from vancomycin or a salt thereof comprising process steps (i) to (vii). n step (i), vancomycin according to Formula II
or a salt thereof is provided. Said vancomycin or salt thereof can be prepared according to any known method.
In step (ii), the vancomycin (or salt thereof) of step (i) is brought into contact with a compound of Formula III
wherein R is a protecting group, to provide an imine (N-protected-decylaminoethylvancomycin- imine).
The N-protected-decylaminoethylvancomycin-imine obtained in step (ii) has the following Formula V:
Additionally preferred, R is an amine-labile protecting group selected from the group consisting of 9-fluorenylmethyl carbamate, 17-tetrabenzo[a,c,g,/]fluorenylmethyl carbamate, 3- indenylmethyl carbamate, 2-chloro-3-indenylmethyl carbamate, benz[f]inden-3-yimethyl carbamate, 1 , 1 -dioxobenzo[j ]thiophene-2-ylmethyl carbamate, 2-methylsulfonyl-3-phenyl-1 - prop-2-enyloxy carbamate and 2,7-di-t-butyl[9-( 10, 10-dioxo10,10,10,10- tetra hyd roth i oxa n thy I )] m ethyl carbamate, wherein the 9-fluorenylmethyl group in 9- fluorenylmethyl carbamate is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-6 alkyl, trialkylsilyl, halo, nitro and sulfo. In a particularly preferred embodiment, the compound of Formula III is N-(9-fluorenylmethyloxycarbonyl)- decylaminoacetaldehyde.
The amount of the compound according to Formula III that is used in step (ii) can e.g. (for example) be between 1 and 3 equivalents based on vancomycin.
Step (ii) is carried out in the presence of an inert solvent or a mixture of inert solvents. The term "inert solvent" refers to any solvents that do not react with vancomycin, i.e. do not react with functional groups of vancomycin. Inert solvents suitable in this respect are commonly known. Example of inert solvents are Ν,Ν-dimethylformamide (DMF), Ν,Ν-Dimethylacetamide, dimethyl sulfoxide (DMSO), N-methylpyrrolidone and acetonitrile and the like and mixtures thereof, with DMF being preferred. Preferably, water is not used as solvent prior to step (v) or water is not present during the reduction in step (v).
Step (ii) is furthermore carried out in the presence of base, preferably excess of base. Suitable bases are e.g. organic bases, such as amines, or alkali metal carboxylate salts, and inorganic bases, such as alkali metal carbonates. Specific examples of suitable bases are
diisopropylethylamine (DIPEA), N-methylmorpholine, and triethylamine, with
diisopropylethylamine being preferred. It is also possible to use a mixture of different types of bases.
The base can e.g. be used in an amount of 1.5 to 3 equivalents based on the amount of vancomycin. In one embodiment, step (ii) is carried out by combining a solution of the compound according to Formula III, preferably dissolved in DMF, with a suspension of vancomycin, preferably suspended in DMF, thereby forming a reaction mixture, then adding excess base to said reaction mixture. The reaction mixture comprising or consisting of vancomycin or a salt thereof, the compound of Formula III, the inert solvent(s) and the base(s) can e.g. be stirred for a time of between 1 and 24 hours, preferably for a time of between 5 and 12 hours.
Step (ii) can e.g. be carried at a temperature of between 0°C and 100°C, further preferred of between 0°C and 50°C, even further preferred of between 15°C and 25°C. Step (ii) can additionally be carried out under inert atmosphere, preferably under nitrogen gas.
In one embodiment, the only materials added to, i.e. contained in, the reaction mixture in step (ii) are vancomycin or a salt thereof, the compound according to Formula III, the base(s) and the inert solvent(s).
After N-protected-decylaminoethylvancomycin-imine has been formed in step (ii), said N- protected-decylaminoethylvancomycin-imine is optionally isolated. Isolation techniques are well known in the art and further described in respect to step (vii) below. For example, isolating N- protected-decylaminoeihy!vancomycin-imine can comprise precipitation and filtration steps. Preferably, N-protected-decylaminoethylvancomycin-imine is not isolated.
In step (iii) the N-protected-decylaminoethylvancomycin-imine of step (ii) is brought into contact with either (a) formaldehyde and aminomethylphosphonic acid in the presence of a base or (b) a base and then the oligomer resulting from the reaction of aminomethylphosphonic acid and formaldehyde, preferably in the presence of a base, is added, thereby obtaining N-protected- telavancin-imine. As explained above, using said oligomeric reagent allows avoiding the direct use of the toxic formaldehyde.
As explained above, step (ii) can be carried out without isolating N-protected- decylaminoethylvancomycin-imine. In this case, step (iii) is carried out starting from the reaction mixture obtained in step (ii). In the case were N-protected-decylaminoethylvancomycin-imine is isolated in step (ii), step (iii) can include redissolving or resuspending said isolated N-protected- decylaminoethylvancomycin-imine in a solvent prior to contacting it with excess base and (a) formaldehyde and aminomethylphosphonic acid or (b) the oligomer resulting from the reaction of aminomethylphosphonic acid and formaldehyde.
Additionally preferred, step (iii) is carried out in the presence of a polar protic solvent, particularly preferred water. Thus, in a preferred embodiment, the reaction mixture in step (iii) includes the following solvents: the inert solvent(s) of step (ii) such as DMF, optionally acetonitrile and water. If N-protected-decylaminoethylvancomycin-imine is isolated in step (ii), said reaction mixture in step (iii) may not include the inert solvents(s) of step (ii). Additionally preferred, the oligomer employed in step (iii) is the product resulting from the reaction of aminomethylphosphonic acid with formaldehyde. Said oligomer can be prepared separately by reacting aminomethylphosphonic acid with formaldehyde, preferably in the presence of a base. The base in step (iii) can e.g. be a tertiary amine, preferably triethylamine, or DIPEA. The amount of added base can e.g. be between 15 and 25 equivalents, preferably 20 equivalents, based on the amount of vancomycin.
Step (iii) can e.g. be carried out by adding acetonitrile and base, preferably DIPEA, to the reaction mixture of step (ii) or to the solution/suspension containing previously isolated N- protected-decylaminoethylvancomycin-imine, followed by stirring at a temperature of between 15°C and 30°C for 5 minutes to 1 hour, preferably 5 minutes to 30 minutes. After stirring the reaction mixture comprising acetonitrile and base, aminomethylphosphonic acid can e.g. be added to the reaction mixture, followed by stirring at a temperature of e.g. between 15 and 30°C for 5 minutes to 1 hour, preferably 5 minutes to 30 minutes. After stirring the reaction mixture comprising aminomethylphosphonic acid, water can be added and the mixture can e.g. be further stirred at a temperature of between 15 and 30°C for 5 minutes to 1 hour, preferably 5 minutes to 30 minutes, followed by cooling of the reaction mixture to a temperature of between -15°C and -5°C and then adding formaldehyde, preferably in an amount of between 1 and 5 equivalents based on vancomycin.
The amount of aminomethylphosphonic acid which is used in step (iii) can e.g. be between 2 and 10 equivalents, preferably between 4 and 5, based on vancomycin. Formaldehyde used in step (iii) can e.g. be added in the form of a solution of formaldehyde in water, preferably a 30-40 wt.-% solution of formaldehyde in water, optionally containing 5 to 15 wt.-% methanol. The reaction mixture comprising formaldehyde or said oligomer can e.g. be stirred at a temperature of between -15°C and -5°C, preferably -10°C, for 6 to 48 hours, preferably 12 to 20 hours.
The pH value of the reaction mixture after adding excess base in step (iii) can e.g. be between 10 and 11 .
In an alternative embodiment, the oligomer employed in step (iii) is the product resulting from the reaction of aminomethylphosphonic acid with formaldehyde. Said oligomer is added at a temperature between -15°C and -5°C, preferably -10°C, to a reaction mixture of step (ii) or to redissolved/resuspended N-protected-decylaminoethylvancomycin containing a base, wherein the reaction mixture contains an inert solvent or mixture of solvents and a polar protic solvent such as water.
After N-protected-telavancin-imine has been formed in step (iii), said N-protected-telavancin- imine is isolated from the reaction mixture. This allows carrying out a change of the solvent system, in particular, it allows removing water from the reaction mixture prior to the reduction step. The isolation of N-protected-telavancin-imine can be carried out according to well known methods, e.g. by carrying out precipitation, filtration and drying steps. In step (iv), an acidified mixture of N-protected-telavancin-imine of step (iii) and a solvent is provided. Said acidified mixture can e.g. be obtained by suspending/dissolving N-protected- telavancin-imine of step (iii) in a solvent, e.g. in DMF, and then adding one or more acids.
Acidifying the mixture in step (iv) can e.g. be carried out by adding one or more acids selected from the group consisting of trifluoroacetic acid (TFA), trichloroacetic acid, citric acid, formic acid, hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, phosphoric acid and acetic acid, preferably TFA, to the reaction mixture. The resulting pH of the reaction mixture can e.g. be adjusted to be within a range of e.g. between 3 and 6. The reaction mixture comprising said one or more acids can then e.g. be stirred at a temperature of between 0°C and 50°C, preferably of between 15°C and 25°C, for 5 minutes to 2 hours, preferably for 5 to 40 minutes. The amount of acid(s) added in step (iv) can e.g. be between 3 and 6 equivalents based on vancomycin. Preferably, the acid used in step (iv) does not contain water. Preferably, the reaction mixture in step (iv) does not contain water in order not to hydrolyze the imine.
Additionally preferred, in step (iv) a polar protic solvent, such as for example an alcohol e.g. selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, and mixtures thereof, preferably methanol is added to the reaction mixture.
In step (v), a reducing agent is added to the mixture obtained in step (iv) in order to produce N- protected-telavancin.
Additionally preferred, the reducing agent that is used in step (v) is selected from the group consisting of tert.-butylamine borane, sodiumcyanoborohydride, sodium triacetoxyborohydride, pyridine/borane, sodium borohydride, zinc borohydride, N-methylmorpholino borane, and triethylamine borane, preferably tert.-butylamine borane.
Step (v) can e.g. be carried out by adding the reducing agent to the mixture obtained in step (iv) and then stirring the thereby formed reaction mixture at a temperature of between 0°C and
50°C, even further preferred of between 15°C and 25°C for 0.5 to 5 hours, preferably for 1 to 3 hours.
The amount of reducing agent that is used in step (v) can e.g. be between 1 and 3 equivalents, preferably between 1 and 2 equivalents, based on the amount of vancomycin. In step (vi), the N-protected-telavancin of step (v) is brought into contact with a deprotecting agent to provide telavancin. The deprotecting agent can be chosen according to common knowledge depending on the protecting group that is used (see e.g. Greene's Protective Groups in Organic Synthesis, Peter G.M. Wuts, Theodora W. Greene, 2007 John Wiley & Sons, Inc., Hoboken, New Jersey, Fourth Edition). Preferably, the deprotecting agent is an amine base and preferably, the protecting group is a carbamate group. Examples of amine bases are methylamine, ethylamine, tert-butylamine, triethylamine, piperidine, morpholine, ammonium hydroxide, 1 , 4-d iaza b i cyclo [2.2.2]octa ne (DABCO), dicyclohexylamine, pyridine, p- dimethylaminopyridine, diisopropylethylamine, 1 ,8-diazabyciclo[5.4.0]undec-7-ene (DBU), piperazine and ethanolamine.
Step (vi) can further e.g. comprise warming up the reaction mixture of step (v) to a temperature of between 0°C and 15°C, preferably 0°C and 10°C, followed by addition of said deprotecting agent, for instance a deprotecting agent selected from the group consisting of methylamine, ethylamine, tert.-butylamine, triethylamine, morpholine, ammonium hydroxide, 1 ,4- diazabicyclo[2.2.2]octane (DABCO) and piperidine, preferably piperidine, e.g. followed by warming the reaction mixture to a temperature of between 10 and 20°C, optionally followed by addition of a further amount of said base, and stirring the thereby obtained reaction mixture for a time of e.g. 5 minutes to 1 hour at said temperature
In step (vi) said deprotecting agent can e.g. be used in an amount of 15 to 50 equivalents based on vancomycin In step (vii), telavancin or a pharmaceutically acceptable salt thereof is isolated. Additionally preferred, isolating telavancin or its pharmaceutically acceptable salt is carried out by precipitation and filtration methods.
Step (vii) can e.g. comprise cooling the reaction mixture of step (vi) to a temperature of between -15°C and -5°C, acidifying the reaction mixture with acid, e.g. 3N HCI, to a pH of between 2 and 3, preferably to a pH of about 2.9 and then warming up the reaction mixture to a temperature of e.g. between 15°C and 30°C.
Step (vii) can e.g. additionally comprise adding acetonitrile to the reaction mixture to promote precipitation of telavancin or its pharmaceutically acceptable salt. The precipitated telavancin or its pharmaceutically acceptable salt, preferably its pharmaceutically acceptable salt, can e.g. be filtered off, washed with cold acetonitrile and dried.
In the process according to the invention, steps (ii) and/or (v) are preferably carried out without isolating any intermediate products, in particular without isolating N-protected- decylaminoethylvancomycin-imine and/or N-protected-telavancin. Also preferred, steps (i)-(ii) and (iv)-(v) are carried out without isolating any intermediate products and/or removal of solvents. Additionally preferred, steps (ii) and (iii) are carried out in one reaction vessel. Additionally preferred, steps (iv)-(vii) are (also) carried out in one reaction vessel.
Additionally preferred, step (ii) is carried out without any steps of solvent removal and filtration. Additionally preferred, steps (iv)-(vi) are (also) carried out without any steps of solvent removal and filtration. Additionally preferred, no step of removing protection groups is carried out prior to step (vi). Additionally preferred, the process provides telavancin HCI.
The present invention also relates to a derivative of telavancin (N-protected-telavancin-imine) and pharmaceutically acceptable salts thereof, preferably the HCI salt, according to Formula IV:
The derivative of telavancin and its pharmaceutically acceptable salts can be prepared as described above. Isolation of said N-protected-telavancin-imine can be conducted after step (iii), e.g. by carrying out the above process while not applying steps (iv)-(vii). Preferred R- substituents are also described above.
Example
The following example describes the present invention in detail, but it is not to be construed to be in any way limiting for the present invention.
In the examples below, the following abbreviations have the following meanings. Any abbreviations not defined have their generally accepted meaning. Unless otherwise stated, all temperatures are in degrees Celsius (°C).
ACNL: acetonitrile
DIPEA: diisopropylethylamine
DMF: dimethylformamide Fmoc: 9-fluorenylmethoxycarbonyl
TFA: trifluoroacetic acid
Example 1 - Synthesis of telavancin hydrochloride
Step A - Synthesis of Fmoc-decylaminoethylvancomycin-lmine
Under nitrogen, a solution of Fmoc-decylaminoacetaldehyde (1.56 g) in 20 mL DMF was added to a suspension of vancomycin hydrochloride (5.00 g) in 20 mL DMF. DIPEA (1.20 mL) was added, and the mixture was stirred at room temperature for 21 hours. The product was precipitated with 10% NaCI (230 mL), and the solid was slurried in acetonitrile (50 mL), stirred at room temperature for 2 hours, filtered, washed with acetonitrile and dried to yield 3.08 g of Fmoc-decylaminoethylvancomycin-imine. Step B - Synthesis of Fmoc-telavancin-imine
Under nitrogen, a suspension of aminomethylphosphonic acid (93.7 mg) in acetonitrile/water (80:20, 5 mL) was added to to a suspension of Fmoc- decylaminoethylvancomicin-imine (0.25 g) in acetonitrile/water (80:20, 8 mL) and the mixture was stirred at room temperature for 29 minutes. DIPEA (0.46 mL) was added, and the mixture was stirred at room temperature for 25 minutes. After cooling to -10°C, formaldehyde (36% in water, 24 pL) was added, and the mixture was stirred at -10°C for 17.5 hours. Acetonitrile (25 mL) was added while cold, whereupon a white solid precipitated. This was filtered off and dried to yield 0.22 g of crude Fmoc-telavancin-imine.
Step C - Synthesis of telavancin hydrochloride
Under nitrogen, NaCNBH3 (10.2 mg) was added to a suspension of Fmoc-telavancin-imine (101.6 mg) in DMF (5 mL). TFA (12 pL) and methanol (1 mL) were added, and the mixture was stirred at room temperature. Further NaCNBH3 (10.2) was added to drive the reaction to completion, after which piperidine (0.2 mL) was added, and the mixture was stirred at room temperature for two hours. The mixture was then acidified with 3N HCI to pH = 2.86, and crude telavancin hydrochloride was precipitated with acetonitrile (35 mL), filtered off and dried under vacuum. Cited literature
WO 03/029270 A2, US 6,887,976 B2, WO 01/83521 A2, and WO 03/018607 A2.

Claims

Claims
1. Process for the preparation of telavancin according to Formula I
or a pharmaceutically acceptable salt thereof, wherein the process comprises the steps of:
i) providing vancomycin according to Formula II
or a salt thereof,
bringing the vancomycin of step (i) into contact with a compound of Formula III
wherein R is a protecting group, and an excess base in an inert solvent or mixture of inert solvents, to form N-protected-decylaminoethylvancomycin-imine, optionally isolating said N-protected-decylaminoethylvancomycin-imine,
bringing the N-protected-decylaminoethylvancomycin-imine of step (ii) into contact with (a) formaldehyde and aminomethylphosphonic acid or (b) the oligomer resulting from the reaction of aminomethylphosphonic acid and formaldehyde, in the presence of a base, thereby obtaining N-protected-telavancin-imine, which is then isolated,
providing a mixture comprising the isolated N-protected-telavancin-imine of step (iii), an acid and a solvent,
adding a reducing agent to the mixture obtained in step (iv) in order to produce N- protected-telavancin, optionally isolating said N-protected-telavancin, vi) bringing the N-protected-telavancin of step (v) into contact with a deprotecting agent to provide telavancin,
vii) isolating telavancin or a pharmaceutically acceptable salt thereof.
The process of claim 1 , wherein R is an amine-labile protecting group selected from the group consisting of 9-fluorenylmethyl carbamate, 17-tetrabenzo[a,c,g,/]fluorenylmethyl carbamate, 3-indenylmethyl carbamate, 2-chloro-3-indenylmethyl carbamate, benz[/]inden-3-ylmethyl carbamate, 1 , 1 -dioxobenzo[t»]thiophene-2-ylmethyl carbamate, 2- methylsulfonyl-3-phenyl-1-prop-2-enyloxy carbamate and 2,7-di-t-butyl[9-(10,10- dioxol 0,10,10,10-tetrahydrothioxanthyl)]methyl carbamate, wherein the 9-fluorenylmethyl group in 9-fluorenylmethyl carbamate is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-6 alkyl, trialkylsilyl, halo, nitro and sulfo.
The process of claim 1 or 2, wherein the deprotecting agent is an amine base, preferably selected from the group of methylamine, ethylamine, tert-butylamine, triethylamine, piperidine, morpholine, ammonium hydroxide, 1 ,4-diazabicyclo[2.2.2]octane (DABCO), dicyclohexylamine, pyridine, p-dimethylaminopyridine, diisopropylethylamine, 1 ,8- diazabyciclo[5.4.0]undec-7-ene (DBU), piperazine and ethanolamine.
The process of any of claims 1-3, wherein the oligomer employed in step (iii) is the product resulting from the reaction of aminomethylphosphonic acid with formaldehyde in the presence of a base, preferably a tertiary amine, preferably triethylamine, or diisopropylethylamine.
The process of any of claims 1-4, wherein step (iii) is carried out without isolating any intermediate products formed in step (ii), in particular without isolating N-protected- decylaminoethylvancomycin-imine of step (ii).
The process of any of the preceding claims, wherein in step (iv) an alcohol selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, and mixtures thereof, preferably methanol is added to the mixture.
The process of any of the preceding claims, wherein the reducing agent that is used in step (v) is selected from the group consisting of tert.-butylamine borane, sodiumcyanoborohydride, sodium triacetoxyborohydride, pyridine/borane, sodium borohydride, zinc borohydride, N-methylmorpholino borane, and triethylamine borane, preferably tert.-butylamine borane 8. The process of any of the preceding claims, wherein formaldehyde used in step (iii) is added in the form of a solution of formaldehyde in water, preferably a 30-40 wt.-% solution of formaldehyde in water, optionally containing 5 to 15 wt.-% methanol.
9. The process of claim 8, wherein the reaction mixture comprising formaldehyde is stirred at a temperature of between -15°C and -5°C for 6 to 48 hours, preferably 12 to 20 hours.
10. The process of any of the preceding claims, wherein steps (ii) and (iii) are carried out in one reaction vessel. 11. The process of any of the preceding claims, wherein steps (ii) and (iv)-(vi) are carried out without any steps of solvent removal and filtration.
12. The process of any of the preceding claims, wherein the process provides telavancin HCI. 13. The process of any of the preceding claims, wherein no step of removing protecting groups is carried out prior to step (vi).
14. N-protected-telavancin-imine according to Formula IV, wherein R is a protecting group,
or pharmaceutically acceptable salts thereof; wherein said N-protected-telavancin-imine is obtainable or obtained by isolation of N-protected-telavancin-imine after step (iii) of the process as defined in any of claims 1 , 2, 4, 5, 8, 9, and 10.
EP12755879.9A 2011-09-09 2012-09-07 Process for the synthesis of telavancin, its pharmaceutically acceptable salts as well as an n-protected imine-derivative of telavancin Withdrawn EP2753637A1 (en)

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