EP2753638A1

EP2753638A1 - Process for the synthesis of telavancin and its pharmaceutically acceptable salts as well as n-protected derivatives thereof

Info

Publication number: EP2753638A1
Application number: EP12759086.7A
Authority: EP
Inventors: David BENITO-GARAGORRI
Original assignee: Sandoz AG
Current assignee: Sandoz AG
Priority date: 2011-09-09
Filing date: 2012-09-07
Publication date: 2014-07-16
Also published as: WO2013034675A1

Abstract

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

Description

Process for the synthesis of telavancin and its pharmaceutically acceptable salts as well as N-protected derivatives thereof

The invention relates to a process for the preparation of telavancin, or a pharmaceutically acceptable salt thereof, wherein said process comprises a reductive alkylation of vancomycin which provides N-protected-decylaminoethylvancomycin, followed by an aminomethylation to obtain N-protected-telavancin, which is then deprotected to provide telavancin, or a pharmaceutically acceptable salt thereof. Another embodiment refers to N-protected-telavancin and pharmaceutically acceptable salts thereof, which are 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 a reductive alkylation reaction to obtain N-protected-decylaminoethylvancomycin (i.e. providing a first side chain to vancomycin) followed by an aminomethylation reaction (providing a second side chain to vancomycin), wherein the N-protected-decylaminoethylvancomycin is subjected to the aminomethylation reaction without carrying out a deprotection step first. Thus, the present invention provides for a new synthesis route for telavancin and its pharmaceutically acceptable salts. It was also unexpectedly observed that the presence of the N-protection group at the decylaminoethyl side chain of vancomycin influences the aminomethylation reaction when combined with the imine reduction step, although the decylaminoethyl side chain is far removed from that part of the vancomycin-structure where aminomethylation takes place. It was found that when carrying out the known processes for the preparation of telavancin from vancomycin in the form of a one-pot synthesis, the reaction rate of the aminomethylation reaction is very slow.

As mentioned above, the known processes for preparing telavancin apply multiple process steps, in particular 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) by aminomethylation. 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 materials for further reaction. It would represent an enhancement to be able to carry out the preparation of telavancin starting from vancomycin while performing a so-called "one pot synthesis" method that is e.g. more economic, since it does not require isolating any intermediate products. Unexpectedly, it was found that by using the process as described herein, the reaction rate of the aminomethylation reaction may be increased to allow carrying out the process as a one-pot synthesis.

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

 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 or hemiaminal,

iii) acidifying the reaction mixture obtained in step (ii) by adding an acid,

iv) adding a reducing agent to the reaction mixture obtained in step (iii) in order to produce N-protected-decylaminoethylvancomycin,

v) bringing the N-protected-decylaminoethylvancomycin of step (iv) 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,

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

or pharmaceutically acceptable salts thereof, preferably the HCI salt.

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).

In 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) or hemiaminal. 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,i]fluorenylmethyl carbamate, 3- indenylmethyl carbamate, 2-chloro-3-indenylmethyl carbamate, benz[ jinden-3-ylmethyl carbamate, 1 , 1 -dioxobenzo[b]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- 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. 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. be between 1 and 2 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 N.N-dimethylformamide (DMF), Ν,Ν-Dimethylacetamide, N- methylpyrrolidone, dimethylsulfoxide (DMSO) 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 (iv).

Step (ii) is furthermore carried out in the presence of a 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). In step (iii), the reaction mixture obtained in step (ii) is acidified by adding acid(s). Optionally, the imine or hemiaminal of step (ii) is isolated prior to step (iii). In this case, the isolated imine or hemiaminal can then be redissolved/resuspended in a solvent or mixture of solvents which can then be acidified. Preferably, the imine or hemiaminal of step (ii) is not isolated prior to step (iii). Acidifying the reaction mixture in step (iii) 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 (iii) can e.g. be between 3 and 6

equivalents based on vancomycin. Additionally preferred, in step (iii) a polar protic solvent, such as for example an alcohol selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, and mixtures thereof, preferably methanol is added to the reaction mixture. For step (iii), the polar protic solvent preferably is not water. In general, it is preferred not to use any water in steps (i)-(iii).

In step (iv), a reducing agent is added to the reaction mixture obtained in step (iii) in order to produce N-protected-decylaminoethylvancomycin.

Additionally preferred, the reducing agent that is used in step (iv) 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 (iv) can e.g. be carried out by adding the reducing agent to the reaction mixture obtained in step (iii) 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 (iv) can e.g. be between 1 and 3 equivalents, preferably between 1 and 2 equivalents, based on the amount of vancomycin.

In step (v) the N-protected-decylaminoethylvancomycin of step (iv) is brought into contact with either (a) formaldehyde and aminomethylphosphonic acid, or (b) the oligomer resulting from the reaction of aminomethylphosphonic acid and formaldehyde in the presence of an excess base, thereby obtaining N-protected-telavancin (see Formula (IV) as depicted below). As explained above, using said oligomeric reagent allows avoiding the direct use of the toxic formaldehyde. Optionally, the N-protected-decylaminoethylvancomycin of step (iv) is isolated prior to step (v). In this case, the isolated N-protected-decylaminoethylvancomycin can then be

redissolved/resuspended in a solvent or mixture of solvents for further processing in step (v). Preferably, the N-protected-decylaminoethylvancomycin of step (iv) is not isolated prior to step (v).

Additionally preferred, step (v) is carried out in the presence of a polar protic solvent, particularly preferred water. Thus, in a preferred embodiment, the reaction mixture in step (v) includes the following solvents: the inert solvent(s) of step (ii) such as DMF, water and optionally an alcohol such as methanol.

Additionally preferred, the oligomer employed in step (v) 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 (v) 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 (v) can e.g. be carried out by adding acetonitrile and base, preferably DIPEA, to the reaction mixture of step (iv) or to N-protected-decylaminoethylvancomycin

redissolved/resuspended in a solvent, 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 be further stirred at a temperature of between 15 and 30°C for e.g. 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 (v) can e.g. be between 2 and 10 equivalents, preferably between 4 and 5, based on vancomycin. The amount of formaldehyde can e.g. be between 1 and 5 equivalents, preferably between 1 and 3

equivalents, based on vancomycin.

Formaldehyde used in step (v) can 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 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, or until the reaction is substantially complete. The pH value of the reaction mixture after adding excess base in step (v) can e.g. be between 10 and 11.

In an alternative embodiment, the oligomer employed in step (v) 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 (iv) 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. In step (vi), the N-protected-telavancin of step (v) is brought into contact with a deprotecting agent to provide telavancin. Optionally, the N-protected-telavancin of step (v) is isolated prior to step (vi). In this case, the isolated N-protected-telavancin can then be redissolved/suspended in a solvent or mixture of solvents for further processing in step (vi). Preferably, N-protected- telavancin of step (v) is not isolated prior to step (vi). 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- diazabicyclo[2.2.2]octane (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 from the reaction mixture of step (vi). 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 2.5 and then warming up the reaction mixture to a temperature of 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, preferably its pharmaceutically acceptable salt. The precipitated telavancin or its pharmaceutically acceptable salt can e.g. be filtered off, washed with cold acetonitrile and dried.

In the process according to the invention, steps (iv) and (v) are preferably carried out without isolating any intermediate products formed in step (iv), in particular without isolating N- protected-decylaminoethylvancomycin. Also preferred, steps (i)-(vi) are carried out without isolating any intermediate products.

Additionally preferred, steps (ii)-(vi) are carried out in one reaction vessel.

Additionally preferred, steps (ii)-(vi) are carried out without any steps of solvent removal and filtration and/or removal of intermediates. 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) according to Formula IV:

or pharmaceutically acceptable salts thereof, preferably the HCI salt. The derivative of telavancin and its pharmaceutically acceptable salts can be prepared as described above. Isolation of said N-protected-telavancin can be conducted after step (v). N- protected-telavancin can e.g. be prepared by carrying out the above process while not applying the deprotection step (vi). Preferred R-substituents are also described above.

Examples

The following examples describe the present invention in detail, but they are 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 - Stepwise synthesis of telavancin

Step A - Preparation of Fmoc-decylaminoethylvancomycin-imine Under nitrogen, Fmoc-decylaminoacetaldehyde (6.80 g) and vancomycin hydrochloride

(20.00 g) were suspended in 60 mL DMF. DIPEA (5 mL) and DMF (3x20mL) were added, and the mixture was stirred at room temperature for 5.5 hours. The product was precipitated with 10% NaCI (700 mL), and the mixture was stirred for one hour at room temperature, filtered and washed with 10% NaCI and acetontrile. The solid was slurried in acetonitrile (50 mL), stirred at room temperature for 16 hours, filtered, and washed with acetonitrile. Yield: 7.7 g (dried under vacuum for 16 hours) and 5.0 g (dried under vacuum for one hour and used directly in step B below). Step B - Preparation of Fmoc-telavancin

Under nitrogen, Fmoc-decylaminoethylvancomycin-lmine (5.0 g) was dissolved in 45 mL DMF. Methanol (18 mL), TFA (830 μΙ_) and 'BuNH₂ BH₃ (260 mg) were added, and the mixture was stirred at room temperature for 2 hours. Acetonitrile (60 mL) and DIPEA (9.5 mL) were added, and the mixture was stirred at room temperature for 30 minutes. After the addition of aminomethylphosphonic acid (1.38 g) suspended in 20 mL acetonitrile, the mixture was stirred at room temperature for 30 minutes, followed by the addition of water (80 mL) and further stirring for 20 minutes. The mixture was then cooled down to -10°C, formaldehyde (36% in water, 440 μί) was added and the reaction was stirred at -10°C for 16 hours. The mixture was acidified with 3N HCI to pH = 2.3, allowed to warm to room temperature and poured over 500 mL acetonitrile, whereupon a white precipitate was formed. The precipitate was stirred for one hour at room temperature, filtered and dried under vacuum at room temperature to yield 3.40 g of crude Fmoc-telavancin.

Step C - Preparation of telavancin

Under nitrogen, Fmoc-telavancin (150 mg) was suspended in 2 mL DMF, piperidine (339 L) was added and the mixture was stirred at room temperature for 2 hours. The mixture was then acidified with 3N HCI to pH = 2-3 and acetonitrile (8 mL) was added to precipitate the product. This was filtered off, washed with acetonitrile and dried to yield 130 mg of crude telavancin hydrochloride.

Example 2 - One-pot synthesis of telavancin

Under nitrogen, a solution of Fmoc-decylaminoacetaldehyde (0.36 g) in DMF (10 mL) was added to a suspension of vancomycin (1.0 g) in 10 mL DMF. DIPEA (0.27 mL) was added, and the mixture was stirred at room temperature for 5.5 hours. Methanol (3 mL) and TFA (235 μί) were added, and the mixture was stirred at room temperature for 15 minutes. 'BuNH₂ BH₃ (67.5 mg) was added, and the mixture was stirred at room temperature for 1.5 hours. Acetonitrile (22 mL) and DIPEA (2.4 mL) were added, and the mixture was stirred at room temperature for 20 minutes. Aminomethylphosphonic acid (0.36 g suspended in 2 mL acetonitrile) was added, and the mixture was stirred for 20 minutes at room temperature. Water (25 mL) was added, and the mixture was stirred for 20 minutes at room temperature and then cooled down to -10°C. Formaldehyde (36% in water, 1 13 pL) was added, and the mixture was stirred at -10°C for 18 hours. The reaction mixture was warmed up to 5°C, and piperidine (1.10 mL) was added. After slowly warming up to 15°C and the addition of more piperidine (0.6 mL), the cleavage of the Fmoc protecting group was complete. The mixture was cooled down to -10°C, acidified with 3N HCI to pH = 2.54 and warmed to room temperature. Upon addition of acetonitrile (250 mL), a white solid precipitated. The mixture was stirred for one hour and the solid was filtered off, washed with cold acetonitrile and dried to yield 1.39 g of crude telavancin hydrochloride.

Comparative Example 1 - One-pot synthesis of telavancin according to prior art process

Under nitrogen, a solution of Fmoc-decylaminoacetaldehyde (0.36 g) in DMF (6 mL) was added to a suspension of vancomycin (1.0 g) in 6 mL DMF. DIPEA (0.27 mL) was added, and the mixture was stirred at room temperature for 5.5 hours. Methanol (3 mL) and TFA (235 pL) were added, and the mixture was stirred at room temperature for 17 minutes. 'BuNH₂ BH₃ (67.5 mg) was added, and the mixture was stirred at room temperature for 1.5 hours. Piperidine (1.10 mL) was added, and the mixture was stirred for 45 minutes. Acetonitrile (15 mL) and DIPEA (2.4 mL) were added, and the mixture was stirred at room temperature for 15 minutes. Aminomethylphosphonic acid (0.36 g suspended in 2 mL acetonitrile) was added, and the mixture was stirred for 15 minutes at room temperature. Water (17 mL) was added, and the mixture was stirred for 20 minutes at room temperature and then cooled down to -10°C. Formaldehyde (36% in water, 113 pL) was added, and the mixture was stirred at -10°C. After 97.5 hours, only very small amounts of telavancin had formed, and the reaction was discarded.

The invention also refers to the following numbered embodiments:

Item (1 ) Process for the preparation of telavancin according to Formula I



or a salt thereof,

bringing the vancomycin of step (i) into contact with a compound of Formula III

acidifying the reaction mixture obtained in step (ii) by adding an acid,

adding a reducing agent to the reaction mixture obtained in step (iii) in order to produce N-protected-decylaminoethylvancomycin,

bringing the N-protected-decylaminoethylvancomycin of step (iv) 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,

bringing the N-protected-telavancin of step (v) into contact with a deprotecting agent to provide telavancin,

isolating telavancin or a pharmaceutically acceptable salt thereof. Item (2) The process of item (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[r]inden-3- ylmethyl carbamate, 1 , 1 -dioxobenzo[6]thiophene-2 -yimethyl carbamate, 2-methylsulfonyl-3- phenyl-1 -prop-2-enyloxy carbamate and 2,7-di-iert-butyl[9-( 10,10-dioxo10,10,10,10- 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. Item (3) The process of item (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.

Item (4) The process of any of items (1 )-(3), wherein the oligomer employed in step (v) 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.

Item (5) The process of any of items (1 )-(4), wherein steps (iv) and (v) are carried out without isolating any intermediate products formed in step (iv), in particular without isolating N- protected-decylaminoethylvancomycin, preferably steps (i)-(vi) are carried out without isolating any intermediate products.

Item (6) The process of any of the preceding items, wherein in step (iii) an alcohol selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, and mixtures thereof, preferably methanol is added to the reaction mixture. Item (7) The process of any of the preceding items, wherein the reducing agent that is used in step (iv) 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. Item (8) The process of any of the preceding items, wherein formaldehyde used in step (v) 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.

Item (9) The process of item (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.

Item (10) The process of any of the preceding items, wherein steps (ii)-(vi) are carried out in one reaction vessel.

Item (11 ) The process of any of the preceding items, wherein steps (ii)-(vi) are carried out without any steps of solvent removal and filtration. Item (12) The process of any of the preceding items, wherein the process provides telavancin HCI.

Item (13) The process of any of the preceding items, wherein no step of removing protecting groups is carried out prior to step (vi).

Item (14) The process of any of the preceding items, wherein the compound of Formula III is N-(9-fluorenylmethyloxycarbonyl)-decylaminoacetaldehyde and is used in an amount of between 1 and 2 equivalents, preferably about 1.25 equivalents, wherein diisopropylethylamine is used in step (ii) in an amount of 1.5 to 3 equivalents, preferably about 2.2 equivalents, wherein in step (iii) the reaction mixture is acidified by adding trifiuoroacetic acid in an amount of between 3 and 6 equivalents, preferably 3.1 equivalents, wherein the reducing agent that is used in step (iv) is tert.-butylamine borane and is used in an amount of between 1 and 3 equivalents, preferably about 1.1 equivalents, wherein diisopropylethylamine is used in step (v) in an amount of between 15 and 25 equivalents, preferably about 20 equivalents, wherein the amount of aminomethylphosphonic acid which is used in step (v) is between 2 and 10 equivalents, preferably about 4.6 equivalents, and wherein the amount of formaldehyde is between 1.5 and 5 equivalents, preferably about 2.1 equivalents, wherein piperidine is used as deprotecting agent in a total amount of 20 to 30 equivalents, preferably about 22.5 equivalents, wherein the solvent in step (ii) is Ν,Ν-dimethylformamide, wherein in step (iii) methanol is added, and wherein in step (v) water and acetonitrile are added, wherein all amounts are based on the amount of vancomycin.

Item (15) Derivative of telavancin according to Formula IV

or pharmaceutically acceptable salts thereof, preferably the HCI salt.

Cited literature

WO 03/029270 A2, US 6,887,976 B2, WO 01/83521 A2, and WO 03/018607 A2.

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

acidifying the reaction mixture obtained in step (ii) by adding an acid,

isolating telavancin or a pharmaceutically acceptable salt thereof; and wherein steps (iv) and (v) are carried out without isolating any intermediate products formed in step (iv).

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[b]thiophene-2-ylmethyl carbamate, 2- methylsulfonyl-3-phenyl-1-prop-2-enyloxy carbamate and 2 , 7-d i-iert-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 (v) 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 steps (i)-(vi) are carried out without isolating any intermediate products.

The process of any of the preceding claims, wherein in step (iii) an alcohol selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol, and mixtures thereof, preferably methanol is added to the reaction mixture.

The process of any of the preceding claims, wherein the reducing agent that is used in step (iv) 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.

The process of any of the preceding claims, wherein formaldehyde used in step (v) 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.

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.

The process of any of the preceding claims, wherein steps (ii)-(vi) are carried out in one reaction vessel.

11. The process of any of the preceding claims, wherein steps (ii)-(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. The process of any of the preceding claims, wherein the compound of Formula III is N-(9- fiuorenylmethyloxycarbonyl)-decyiaminoacetaldehyde and is used in an amount of between 1 and 2 equivalents, preferably about 1.25 equivalents, wherein diisopropylethylamine is used in step (ii) in an amount of 1.5 to 3 equivalents, preferably about 2.2 equivalents, wherein in step (iii) the reaction mixture is acidified by adding trifluoroacetic acid in an amount of between 3 and 6 equivalents, preferably 3.1 equivalents, wherein the reducing agent that is used in step (iv) is tert.-butylamine borane and is used in an amount of between 1 and 3 equivalents, preferably about 1.1 equivalents, wherein diisopropylethylamine is used in step (v) in an amount of between 15 and 25 equivalents, preferably about 20 equivalents, wherein the amount of aminomethylphosphonic acid which is used in step (v) is between 2 and 10 equivalents, preferably about 4.6 equivalents, and wherein the amount of formaldehyde is between 1.5 and 5 equivalents, preferably about 2.1 equivalents, wherein piperidine is used as deprotecting agent in a total amount of 20 to 30 equivalents, preferably about 22.5 equivalents, wherein the solvent in step (ii) is Ν,Ν-dimethylformamide, wherein in step (iii) methanol is added, and wherein in step (v) water and acetonitrile are added, wherein all amounts are based on the amount of vancomycin.

N-protected-te!avancin according to Formula IV, wherein R is a protection group,

or pharmaceutically acceptable salts thereof, preferably the HCI salt, wherein said N-protected- telavancin is obtainable or obtained by isolation of N-protected-telavancin after step (v) of the process as defined in any of claims 1 , 2, 4, 6-9 and 14.