WO2002096917A1 - Purification process and intermediates - Google Patents

Purification process and intermediates Download PDF

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Publication number
WO2002096917A1
WO2002096917A1 PCT/GB2002/002532 GB0202532W WO02096917A1 WO 2002096917 A1 WO2002096917 A1 WO 2002096917A1 GB 0202532 W GB0202532 W GB 0202532W WO 02096917 A1 WO02096917 A1 WO 02096917A1
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formula
compound
atom
salt
process according
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PCT/GB2002/002532
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French (fr)
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David Gordon Acton
Brian Roger Meyrick
Stanley Lee
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Astrazeneca Ab
Astrazeneca Uk Limited
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02Phosphorus compounds
    • C07F9/025Purification; Separation; Stabilisation; Desodorisation of organo-phosphorus compounds
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02Phosphorus compounds
    • C07F9/547Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom

Definitions

  • the present invention relates to a process for purification of certain oxazolidinone derivatives, and in particular oxazolidinone derivatives which are useful as anti-Gram positive bacterial agents, as well as to intermediates useful in this process.
  • HET is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (1- 4C)alkoxy and halogen, and or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl;
  • R 2 and R 3 are independently hydrogen or fluoro;
  • Rep is of the formula R 13 CO- (wherein R 13 is (l-lOC)alkyl substituted by two or more hydroxy groups; 2 of which are in a 1,2-diol orientation, ie. there is a terminal primary alcohol with an adjacent secondary alcohol), or pharmaceutically-acceptable salts, or in-vivo- hydrolysable esters thereof.
  • HET is (unsubstituted) isoxazol-3-yl, 1,2,4- oxadiazol-3-yl, isothiazol-3-yl or l,2,5-thiadiazol-3-yl are preferred.
  • those of formula (1-1) are the pharmaceutically active anti-bacterial enantiomer.
  • the pure enantiomer depicted in (1-1), or mixtures of the 5R and 5S enantiomers, for example a racemic mixture are included in WO 99/64417. If a mixture of enantiomers is used, a larger amount (depending upon the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer.
  • the enantiomer depicted below is the 5R enantiomer.
  • some compounds of the formula (I) and (1-1) may have other chiral centres, and such optical and diastereo-isomers, and racemic mixtures may possess antibacterial activity. It is well known in the art how to prepare optically-active forms (for example by resolution of the racemic form by recrystallisation techniques, by chiral synthesis, by enzymatic resolution, by biotransformation or by chromatographic separation) and how to determine antibacterial activity.
  • In-vivo hydrolysable esters include compounds of formula (I) and (1-1) in which any free hydroxy group independently forms a phosphoryl ester of the formula (PD3) :
  • a pharmaceutically acceptable cation such as an alkaline metal ion such as sodium or potassium
  • Suitable pharmaceutically-acceptable salts include base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N- methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine, tris-(2-hydroxyethyl)amine, N-methyl deglucamine, piperazine, and amino acids such as lysine and arginine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions.
  • a preferred pharmaceutically- acceptable salt is the sodium salt.
  • Another preferred pharmaceutically acceptable salt is the potassium salt.
  • salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
  • R 8 is -OR 9 , -SR 9 , -NHR 10 or -NR n R 12 , wherein
  • R 9 is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl; or
  • R 9 is a C-linked 6-membered heteroaryl ring containing 1 or 2 nitrogen heteroatoms, which ring is optionally substituted on any available C atom (provided that when the N atom is adjacent to the link, there is no substitution on any C atom that is adjacent to this N atom) by 1, 2 or 3 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy, (l-4C)alkoxycarbonyl and halogen;
  • R 10 is is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (1- 4C)alkoxy, (l-4C)alkoxycarbonyl and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl; or R 10 is a C-linked 6-membered heteroaryl ring containing 2 or 3 nitrogen heteroatoms, which ring is optionally substituted on any available C atom by 1, 2 or 3 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy, (l-4C)alkoxycarbonyl and halogen;
  • R 11 and R 12 together with the nitrogen atom to which they are attached form a 5-membered heteroaryl ring, containing either (i) 1 to 3 further nitrogen heteroatoms or (ii) a further, heteroatom selected from O and S together with an optional further nitrogen heteroatom; which ring is optionally substituted on a C atom by an oxo or thioxo group; and/or the ring is optionally substituted on a C atom by 1 or 2 (l-4C)alkyl groups; and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl; or R 11 and R 12 together with the nitrogen atom to which they are attached form a 6-membered heteroaryl ring containing up to three nitrogen heteroatoms in total (including the linking heteroatom), which ring is substituted on a suitable C atom by oxo or thioxo and optionally substituted on any available C atom by 1 or 2 (l-4C)al
  • R 14 is a bond or a (l-8C)alkyl group which is optionally substituted by one or more hydroxy groups; which process comprises carrying out one or both of the following steps: a) contacting the compound of formula (II) or salt thereof with an expanded brominated polystyrene resin, washing to remove inorganic contamination, and desorbing the product from the resin; and/or b) converting the compound of formula (II) to an ammonium salt thereof, removing impurities therefrom, and if desired, reconverting ammonium salt to a compound of formula (U) or to a pharmaceutically acceptable salt.
  • Suitable pharmaceutically acceptable salts of compounds of formula (II) are alkali metal salts such as sodium or potassium and in particular are the disodium phosphate salts. These will be of formula (UA)
  • R 2 , R 3 , R 8 and R 14 are as defined above in relation to formula (U) and R 17 and R 18 are a pharmaceutically acceptable cation, such as an alkaline metal ion such as sodium or potassium.
  • the polystyrene resin is suitably pre-swollen with water.
  • a particularly suitable polystyrene resin is SP207 available from Mitsubishi, Japan. This resin maybe mixed with water, which is absorbed and so swells the resin. Preferably also an alcohol such as ethanol or methanol, is mixed with the water used to swell the resin.
  • the compound of formula (I) is first adsorbed onto the resin, preferably at a loading of about 40 to 70 mg/lg resin. Once adsorbed, it may be subject to procedures such as water or acid such as HC1 washes, to remove contaminants. After washing, the product is suitably desorbed from the resin by eluting it with an appropriate organic solvent such as a (l-6C)alcohol, for example methanol or ethanol.
  • an appropriate organic solvent such as a (l-6C)alcohol, for example methanol or ethanol.
  • R 2 , R 3 , R 14 and R 8 are as defined in relation to formula (II); have a good crystallinity. They can be prepared for example by addition of ammonia or ammonia solutions to the free acid, and are amenable to washing with organic solvents such as (1-6C) alcohols such as methanol, to remove contaminants. This can be done using conventional methods.
  • Ammonium salts of compounds of formula (U) and in particular compounds of formula (III) are novel and form a further aspect of the invention.
  • purification is carried out using a combination of steps (a) and (b) above.
  • the compound is subjected to a preliminary purification using the method of step (a), then subjected to step (b), and finally, to a further step (a) purification.
  • Preferred compounds of formula (U) and methods for preparing them are as described in WO 99/64417.
  • -R 8 is -OR 9 .
  • R 8 is a group -NHR 10 and methods of preparation are shown in WO00/21960.
  • Particular examples of R 10 are isoxazol-3-yl, isoxazol-5-yl, l,2,4-oxadiazol-3-yl, isothiazol-3-yl, l,2,4-thiadiazol-3-yl or l,2,5-thiadiazol-3- yi.
  • R 9 is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl.
  • the compound of formula (II) is obtained in the form of a pharmaceutically acceptable salt as hereinbefore described, such as an alkali metal salt such as sodium or potassium and in particular the disodium phosphate salts, or is converted to such a salt after recovery using conventional methods.
  • a pharmaceutically acceptable salt such as an alkali metal salt such as sodium or potassium and in particular the disodium phosphate salts, or is converted to such a salt after recovery using conventional methods.
  • R 2 , R 3 , R 9 and R 14 are as defined in relation to formula (II).
  • R 1 is a direct bond.
  • R 2 and R 3 are fluorine.
  • R 9 or R ° where these are present are isoxazolyl, and particularly isoxazol-3-yl.
  • a particularly preferred compound of formula (II) is 5(R)-Isoxazol-3-yloxymethyl-3-(4-(l-(2(S)-hydroxy-3-phoshoryl-propanoyl)-l,2,5,6- -tetrahydropyridy-4-yl)-3,5-difluorophenyl)oxazolidin-2-one and a preferred salt is the disodium salt. It follows that a preferred compound of formula (IH) is of formula (V)
  • Polystyrene resin sold as Resin SP207B by Misubishi (500g) was placed in a reaction vessel and ethanol in the form of Industrial Methylated Spirit 74op (IMS) (400ml) added, followed by water (600ml) . The mixture was stirred and then allowed to stand for 2 hours. This process swelled the resin and removed any bromine trapped within the pores of the resin. The swollen resin was placed in a filter column and the liquor allowed to run off. It was then washed with water (4x 1000ml).
  • IMS Industrial Methylated Spirit 74op
  • the product was then desorbed from the resin by eluting with aqueous IMS.
  • the elution was carried out three times, first with a mixture of 200ml IMS and 800ml water, twice more with a mixture of 400ml IMS and 600ml water.
  • the combined eluates were concentrated by evaporation under reduced pressure, keeping the temperatures at less than 50°C, to give an aqueous concentrate (105ml) of the product.
  • the pH may be adjusted to pH 8.0 by addition of 1M sodium hydroxide.
  • the desired disodium salt product product may then be precipitated from the concentrate by adding the concentrate to ethanol, as described for Example 2. (Yield 82.5 %).
  • Example 2
  • Polystyrene resin sold as Resin SP207B (200g) was pre-swollen as described in Example 1.
  • the product was desorbed from the resin by eluting with aqueous IMS as described in Example 1.
  • the combined eluents were evaporated under reduced pressure, maintaining the temperature at less than 50°C, to give a sticky gum.
  • the gum was dissolved into methanol (120ml), cooled to 20 °C and ammonia (20.36ml 2M in methanol) added dropwise, whilst maintaining the temperature at 20°C.
  • a crystalline precipitate formed (the di-ammonium phosphate salt) which was isolated by filtration and washed with chilled methanol (2 x 12ml). The structure was confirmed by X ray powder diffraction.
  • the diammonium phosphate salt was dissolved in water (480ml), added to fresh pre- swollen resin SP207B (200g before swelling) on a column, washed with aqueous 1M hydrochloric acid (120ml), and then with water (3 x 120ml) to remove inorganic salts.
  • the product was again desorbed from the resin by eluting with aqueous IMS as described above, concentrated by evaporation as described above (to 24ml). The temperature was adjusted to 20°C, and the pH was adjusted to pH 8.0 with 2M sodium hydroxide.
  • the solution was diluted by addition of an equal volume of water, then added dropwise to a mixture of IMS (200ml) and water (20ml) over at least one hour, with vigorous stirring, maintaining the temperature at approximately 40°C. The resulting mixture was stirred for at least 30 minutes at 40°C. The precipitated solid was filtered, washed with IMS and sucked dry, then dried in vacuum oven below 40°C to give desired di-sodium salt

Abstract

Purification Process and IntermediatesA process for purification of a compound of formula (II) or a salt thereof, wherein R8 is -OR9, -SR9, -NHR10 or -NR11R12, where R9, R10, R11 and R12 are various specified heteraryl groups, R2 and R3 are independently hydrogen or fluoro; R14 is a bond or a (1-8C)alkyl group which is optionally substituted by one or more hydroxy groups;which process comprises carrying out one or both of the following steps: a) contacting said compound with an expanded brominated polystyrene resin, washing to remove inorganic contamination, and desorbing the product from the resin; and/orb) converting the compound of formula (II) to an ammonium salt thereof, removing impurities therefrom, and if desired, reconverting ammonium salt to a compound of formula (II) or to a pharmaceutically acceptable salt.

Description

Purification Process And Intermediates
The present invention relates to a process for purification of certain oxazolidinone derivatives, and in particular oxazolidinone derivatives which are useful as anti-Gram positive bacterial agents, as well as to intermediates useful in this process.
Our International Patent Application No. WO 99/64417 describes a new class of antibacterial oxazolidinone compounds which are effective as anti-Gram positive bacterial agents, and certain processes for their preparation. These include compounds of formula (T):
Figure imgf000002_0001
(I) wherein
HET is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (1- 4C)alkoxy and halogen, and or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl; R2 and R3 are independently hydrogen or fluoro;
Rep is of the formula R13CO- (wherein R13 is (l-lOC)alkyl substituted by two or more hydroxy groups; 2 of which are in a 1,2-diol orientation, ie. there is a terminal primary alcohol with an adjacent secondary alcohol), or pharmaceutically-acceptable salts, or in-vivo- hydrolysable esters thereof.
It is to be understood that all terms used in the definition of formula (I) above are as defined in WO 99/64417.
Of the above compounds, those in which HET is (unsubstituted) isoxazol-3-yl, 1,2,4- oxadiazol-3-yl, isothiazol-3-yl or l,2,5-thiadiazol-3-yl are preferred.
Of the compounds of formula (I), those of formula (1-1) are the pharmaceutically active anti-bacterial enantiomer. The pure enantiomer depicted in (1-1), or mixtures of the 5R and 5S enantiomers, for example a racemic mixture are included in WO 99/64417. If a mixture of enantiomers is used, a larger amount (depending upon the ratio of the enantiomers) will be required to achieve the same effect as the same weight of the pharmaceutically active enantiomer. For the avoidance of doubt the enantiomer depicted below is the 5R enantiomer.
Figure imgf000003_0001
(1-1)
Furthermore, some compounds of the formula (I) and (1-1) may have other chiral centres, and such optical and diastereo-isomers, and racemic mixtures may possess antibacterial activity. It is well known in the art how to prepare optically-active forms (for example by resolution of the racemic form by recrystallisation techniques, by chiral synthesis, by enzymatic resolution, by biotransformation or by chromatographic separation) and how to determine antibacterial activity.
In-vivo hydrolysable esters include compounds of formula (I) and (1-1) in which any free hydroxy group independently forms a phosphoryl ester of the formula (PD3) :
O
II
R19CT / ^ O R20O (PD3) where R19 and R20 are independently selected from hydrogen or a pharmaceutically acceptable cation, as described hereinafter, such as an alkaline metal ion such as sodium or potassium, to give a pharmaceutically acceptable salt.
Suitable pharmaceutically-acceptable salts include base salts such as an alkali metal salt for example sodium or potassium, an alkaline earth metal salt for example calcium or magnesium, an organic amine salt for example triethylamine, morpholine, N- methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N,N-dibenzylethylamine, tris-(2-hydroxyethyl)amine, N-methyl deglucamine, piperazine, and amino acids such as lysine and arginine. There may be more than one cation or anion depending on the number of charged functions and the valency of the cations or anions. A preferred pharmaceutically- acceptable salt is the sodium salt. Another preferred pharmaceutically acceptable salt is the potassium salt.
However, to facilitate isolation of the salt during preparation, salts which are less soluble in the chosen solvent may be preferred whether pharmaceutically-acceptable or not.
Of the above compounds of formula (I) and (1-1), 5(R)-isoxazol-3-yloxymethyl-3-(4- (l-(2(S)-hydroxy-3-phosphoryl -propanoyl)-l,2,5,6-tetrahydropyrid-4-yl)-3,5- difluorophenyl)oxazolidin-2-one is especially preferred.
Various methods for preparing compounds of formula (I) and (1-1) are described in WO 99/64417. Yet further methods are described in copending International Patent Application No. PCT/GBOO/04527 (WO 01/40236) which specifically describes and claims a modified route to phosphate prodrugs of the compounds of formula (I) and the like.
The routes used in the preparation of these compounds and particularly the phosphate prodrugs are relatively long and complex. Although the product obtained is generally acceptable, there is a possibility that impurities will be generated at some stage during the production process. As the compounds are intended for pharmaceutical use, extremely high levels of purity are required.
The applicants have found that certain novel techniques for effecting purification effectively.
According to the present invention, there is provided a process for purification of a compound of formula (H)
Figure imgf000004_0001
or a salt thereof, wherein R8 is -OR9, -SR9, -NHR10 or -NRnR12, where
R9 is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl; or
R9 is a C-linked 6-membered heteroaryl ring containing 1 or 2 nitrogen heteroatoms, which ring is optionally substituted on any available C atom (provided that when the N atom is adjacent to the link, there is no substitution on any C atom that is adjacent to this N atom) by 1, 2 or 3 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy, (l-4C)alkoxycarbonyl and halogen;
R10 is is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (1- 4C)alkoxy, (l-4C)alkoxycarbonyl and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl; or R10 is a C-linked 6-membered heteroaryl ring containing 2 or 3 nitrogen heteroatoms, which ring is optionally substituted on any available C atom by 1, 2 or 3 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy, (l-4C)alkoxycarbonyl and halogen;
R11 and R12 together with the nitrogen atom to which they are attached form a 5-membered heteroaryl ring, containing either (i) 1 to 3 further nitrogen heteroatoms or (ii) a further, heteroatom selected from O and S together with an optional further nitrogen heteroatom; which ring is optionally substituted on a C atom by an oxo or thioxo group; and/or the ring is optionally substituted on a C atom by 1 or 2 (l-4C)alkyl groups; and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl; or R11 and R12 together with the nitrogen atom to which they are attached form a 6-membered heteroaryl ring containing up to three nitrogen heteroatoms in total (including the linking heteroatom), which ring is substituted on a suitable C atom by oxo or thioxo and optionally substituted on any available C atom by 1 or 2 (l-4C)alkyl substituents; R2 and R3 are independently hydrogen or fluoro;
R14 is a bond or a (l-8C)alkyl group which is optionally substituted by one or more hydroxy groups; which process comprises carrying out one or both of the following steps: a) contacting the compound of formula (II) or salt thereof with an expanded brominated polystyrene resin, washing to remove inorganic contamination, and desorbing the product from the resin; and/or b) converting the compound of formula (II) to an ammonium salt thereof, removing impurities therefrom, and if desired, reconverting ammonium salt to a compound of formula (U) or to a pharmaceutically acceptable salt.
For the avoidance of doubt, it is to be understood that the current invention comprises carrying out only step a), only step b), step a) followed by step b), or step b) followed by step a). Suitable pharmaceutically acceptable salts of compounds of formula (II) are alkali metal salts such as sodium or potassium and in particular are the disodium phosphate salts. These will be of formula (UA)
Figure imgf000006_0001
where R2, R3, R8 and R14 are as defined above in relation to formula (U) and R17 and R18 are a pharmaceutically acceptable cation, such as an alkaline metal ion such as sodium or potassium.
When the purification is carried out using step (a) above, the polystyrene resin is suitably pre-swollen with water. A particularly suitable polystyrene resin is SP207 available from Mitsubishi, Japan. This resin maybe mixed with water, which is absorbed and so swells the resin. Preferably also an alcohol such as ethanol or methanol, is mixed with the water used to swell the resin.
Thus in the process of step (b), the compound of formula (I) is first adsorbed onto the resin, preferably at a loading of about 40 to 70 mg/lg resin. Once adsorbed, it may be subject to procedures such as water or acid such as HC1 washes, to remove contaminants. After washing, the product is suitably desorbed from the resin by eluting it with an appropriate organic solvent such as a (l-6C)alcohol, for example methanol or ethanol. When purification is effected using step (b) above, the applicants have found that the ammonium salts of compounds of formula (U) and in particular the diammonium phosphate salts of formula (IH)
Figure imgf000007_0001
where R2, R3, R14 and R8 are as defined in relation to formula (II); have a good crystallinity. They can be prepared for example by addition of ammonia or ammonia solutions to the free acid, and are amenable to washing with organic solvents such as (1-6C) alcohols such as methanol, to remove contaminants. This can be done using conventional methods.
Ammonium salts of compounds of formula (U) and in particular compounds of formula (III) are novel and form a further aspect of the invention.
In particular, purification is carried out using a combination of steps (a) and (b) above. In one embodiment, the compound is subjected to a preliminary purification using the method of step (a), then subjected to step (b), and finally, to a further step (a) purification.
Preferred compounds of formula (U) and methods for preparing them are as described in WO 99/64417.
Suitably, in the compound of formula (II), -R8 is -OR9.
Examples of compounds of formula (II) where R8 is a group ~NRπR12, and methods ' for preparing them, are described in copending International Patent Application no.
PCT/GBOl/01815 (WO 01/81350). Particular examples of group R8 in this case is N-linked tetrazole or triazole.
Examples of compounds of formula (It) where R8 is a group -NHR10 and methods of preparation are shown in WO00/21960. Particular examples of R10 are isoxazol-3-yl, isoxazol-5-yl, l,2,4-oxadiazol-3-yl, isothiazol-3-yl, l,2,4-thiadiazol-3-yl or l,2,5-thiadiazol-3- yi. In addition, it may be preferred that in the compound of formula (U), R9 is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl.
Suitably the compound of formula (II) is obtained in the form of a pharmaceutically acceptable salt as hereinbefore described, such as an alkali metal salt such as sodium or potassium and in particular the disodium phosphate salts, or is converted to such a salt after recovery using conventional methods.
Particular examples of compounds of formula (II) are compounds of formula (TV)
Figure imgf000008_0001
(IV) where
R2, R3, R9 and R14 are as defined in relation to formula (II).
Most preferably, in the above compounds R1 is a direct bond. Suitably R2 and R3 are fluorine.
A particular example of the R9 or R ° where these are present are isoxazolyl, and particularly isoxazol-3-yl.
Thus a particularly preferred compound of formula (II) is 5(R)-Isoxazol-3-yloxymethyl-3-(4-(l-(2(S)-hydroxy-3-phoshoryl-propanoyl)-l,2,5,6- -tetrahydropyridy-4-yl)-3,5-difluorophenyl)oxazolidin-2-one and a preferred salt is the disodium salt. It follows that a preferred compound of formula (IH) is of formula (V)
Figure imgf000009_0001
(V) The invention will now be illustrated but not limited by the following Examples. Example 1 Purification using polystyrene resin
Polystyrene resin, sold as Resin SP207B by Misubishi (500g) was placed in a reaction vessel and ethanol in the form of Industrial Methylated Spirit 74op (IMS) (400ml) added, followed by water (600ml) . The mixture was stirred and then allowed to stand for 2 hours. This process swelled the resin and removed any bromine trapped within the pores of the resin. The swollen resin was placed in a filter column and the liquor allowed to run off. It was then washed with water (4x 1000ml).
A disodium salt of 5(R)-isoxazol-3-yloxymethyl-3-(4-(l-(2(S)-hydroxy-3-phosphoryl - propanoyl)-l ,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one, prepared as described for example in WO 99/64417 (50g) was dissolved in water (1000ml) and added to the pre-swollen resin. The aqueous liquor was allowed to run off slowly with minimal disruption of the resin cake, which was then washed with water (3x 500ml) to remove inorganic contamination. The product was then desorbed from the resin by eluting with aqueous IMS. The elution was carried out three times, first with a mixture of 200ml IMS and 800ml water, twice more with a mixture of 400ml IMS and 600ml water. The combined eluates were concentrated by evaporation under reduced pressure, keeping the temperatures at less than 50°C, to give an aqueous concentrate (105ml) of the product. The pH may be adjusted to pH 8.0 by addition of 1M sodium hydroxide.
The desired disodium salt product product may then be precipitated from the concentrate by adding the concentrate to ethanol, as described for Example 2. (Yield 82.5 %). Example 2
Purification using polystyrene resin by way of ammonium salt
Polystyrene resin sold as Resin SP207B (200g) was pre-swollen as described in Example 1.
A disodium salt of 5(R)-isoxazol-3-yloxymethyl-3-(4-(l-(2(S)-hydroxy-3-phosphoryl - propanoyl)-l,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)oxazolidin-2-one, prepared as described for example in WO 99/64417 (12g) was dissolved in water (480ml) and added to the pre-swollen resin on a column. This was washed with chilled aqueous 1M hydrochloric acid (120ml) and then with water (3 x 120ml) to remove inorganic salts. The product was desorbed from the resin by eluting with aqueous IMS as described in Example 1. The combined eluents were evaporated under reduced pressure, maintaining the temperature at less than 50°C, to give a sticky gum. The gum was dissolved into methanol (120ml), cooled to 20 °C and ammonia (20.36ml 2M in methanol) added dropwise, whilst maintaining the temperature at 20°C.
A crystalline precipitate formed (the di-ammonium phosphate salt) which was isolated by filtration and washed with chilled methanol (2 x 12ml). The structure was confirmed by X ray powder diffraction.
The diammonium phosphate salt was dissolved in water (480ml), added to fresh pre- swollen resin SP207B (200g before swelling) on a column, washed with aqueous 1M hydrochloric acid (120ml), and then with water (3 x 120ml) to remove inorganic salts. The product was again desorbed from the resin by eluting with aqueous IMS as described above, concentrated by evaporation as described above (to 24ml). The temperature was adjusted to 20°C, and the pH was adjusted to pH 8.0 with 2M sodium hydroxide.
The solution was diluted by addition of an equal volume of water, then added dropwise to a mixture of IMS (200ml) and water (20ml) over at least one hour, with vigorous stirring, maintaining the temperature at approximately 40°C. The resulting mixture was stirred for at least 30 minutes at 40°C. The precipitated solid was filtered, washed with IMS and sucked dry, then dried in vacuum oven below 40°C to give desired di-sodium salt
(71.6%). i.r. (cm4) 1,744 (C=O)carbamate, 1637 (C=O) tertiary amide. 13C n.m.r. (125MHz) ppm. 172.2, 172.1, 162.3, 160.4(2C), 156.3, 138.4, 127.1, 125.8, 114.3, 102.6 (2C), 96.6, 72.3, 70.4, 69.6, 66.1, 47, 45.5, 40.3, 29.5.

Claims

Claims
1. A process for purification of a compound of formula (U)
Figure imgf000011_0001
or a salt thereof, wherein
R8 is -OR9, -SR9, -NHR10 or -NRnR12, where
R9 is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl; or
R9 is a C-linked 6-membered heteroaryl ring containing 1 or 2 nitrogen heteroatoms, which ring is optionally substituted on any available C atom (provided that when the N atom is adjacent to the link, there is no substitution on any C atom that is adjacent to this N atom) by 1, 2 or 3 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy, (l-4C)alkoxycarbonyl and halogen;
R10 is is a C-linked 5-membered heteroaryl ring containing 2 to 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted on an available carbon atom by 1 or 2 substituents independently selected from (l-4C)alkyl, amino, (l-4C)alkylamino, (1- 4C)alkoxy, (l-4C)alkoxycarbonyl and halogen, and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl; or
R10 is a C-linked 6-membered heteroaryl ring containing 2 or 3 nitrogen heteroatoms, which ring is optionally substituted on any available C atom by 1, 2 or 3 substituents independently selected from (l-4C)aIkyl, amino, (l-4C)alkylamino, (l-4C)alkoxy, (l-4C)alkoxycarbonyl and halogen; Rπ and R12 together with the nitrogen atom to which they are attached form a 5-membered heteroaryl ring, containing either (i) 1 to 3 further nitrogen heteroatoms or (ii) a further heteroatom selected from O and S together with an optional further nitrogen heteroatom; which ring is optionally substituted on a C atom by an oxo or thioxo group; and/or the ring is optionally substituted on a C atom by 1 or 2 (l-4C)alkyl groups; and/or on an available nitrogen atom (provided that the ring is not thereby quaternised) by (l-4C)alkyl; or
1 1 1
R and R together with the nitrogen atom to which they are attached form a 6-membered heteroaryl ring containing up to three nitrogen heteroatoms in total (including the linking heteroatom), which ring is substituted on a suitable C atom by oxo or thioxo and optionally substituted on any available C atom by 1 or 2 (l-4C)alkyl substituents; R2 and R3 are independently hydrogen or fluoro;
R14 is a bond or a (l-8C)alkyl group which is optionally substituted by one or more hydroxy groups; which process comprises carrying out one or both of the following steps:
a) contacting the compound of formula (II) or salt thereof, with an expanded brominated polystyrene resin, washing to remove inorganic contamination, and desorbing the product from the resin; and/or b) converting the compound of formula (II) to an ammonium salt thereof, removing impurities therefrom, and if desired, reconverting ammonium salt to a compound of formula (U) or to a pharmaceutically acceptable salt.
2. A process according to claim 1 wherein the compound of formula (II) is a pharmaceutically acceptable salt of formula (II).
3. A process according to claim 2 wherein the pharmaceutically acceptable salt is a disodium phosphate salt.
4. A process according to any one of claims 1 to 3 wherein the purification is carried out using step (a) above.
5. A process according to claim 1 wherein the polystyrene resin used is preswollen with water and an alcohol.
6. A process according to any one of claims 4 or claim 5 wherein the compound of formula (U) is adsorbed onto the said polystyrene resin, subjected to one or more aqueous or acid washes, and the product is desorbed from the resin by eluting it with an organic solvent.
7. A process according to any one of claims 1 to 3 wherein purification is effected using step (b) above.
8. A process according to claim 7 wherein the ammonium salt is a diammonium phosphate salt of formula (HI)
Figure imgf000013_0001
where R2, R3, R14 and R8 are as defined in claim 1.
9. A process according to claim 7 or claim 8 wherein the ammonia salt is washed with organic solvent before conversion back to the compound of formula (II) or pharmaceutically acceptable salt thereof.
10. A process according to any one of the preceding claims which comprises a combination of steps (a) and (b).
11. A process according to any one of the preceding claims wherein R is a group OR .
12. A process according to any one of the preceding claims wherein the compound of formula (II) is a compound of formula (IV)
Figure imgf000014_0001
(IV)
or a salt thereof, where R2, R3, R9 and R14 are as defined in claim 1.
13. A process according to any one of the preceding claims wherein R14 is a direct bond.
14. An ammonium salt of a compound of formula (II) as defined in claim 1.
15. An ammonium salt according to claim 14 which is a compound of formula (IU) as defined in claim 8.
16. An ammonium salt of formula (V)
Figure imgf000014_0002
PCT/GB2002/002532 2001-06-01 2002-05-29 Purification process and intermediates WO2002096917A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7022705B2 (en) 2001-10-25 2006-04-04 Astrazeneca Ab Isoxazoline derivatives useful as antimicrobials
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
US7473699B2 (en) 2002-02-28 2009-01-06 Astrazeneca Ab 3-cyclyl-5-(nitrogen-containing 5-membered ring)methyl-oxazolidinone derivatives and their use as antibacterial agents

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064417A2 (en) * 1998-06-05 1999-12-16 Astrazeneca Ab Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them
WO2000021960A1 (en) * 1998-10-09 2000-04-20 Astrazeneca Ab Heterocyclyl amino methyloxa zolidinones as antibacterials
WO2002017732A2 (en) * 2000-08-31 2002-03-07 Tempesta, Michael, S. Efficient method for producing compositions enriched in anthocyanins

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999064417A2 (en) * 1998-06-05 1999-12-16 Astrazeneca Ab Oxazolidinone derivatives, process for their preparation and pharmaceutical compositions containing them
WO2000021960A1 (en) * 1998-10-09 2000-04-20 Astrazeneca Ab Heterocyclyl amino methyloxa zolidinones as antibacterials
WO2002017732A2 (en) * 2000-08-31 2002-03-07 Tempesta, Michael, S. Efficient method for producing compositions enriched in anthocyanins

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7396847B2 (en) 2001-09-11 2008-07-08 Astrazeneca Ab Oxazolidinone and/or isoxazoline as antibacterial agents
US7022705B2 (en) 2001-10-25 2006-04-04 Astrazeneca Ab Isoxazoline derivatives useful as antimicrobials
US7473699B2 (en) 2002-02-28 2009-01-06 Astrazeneca Ab 3-cyclyl-5-(nitrogen-containing 5-membered ring)methyl-oxazolidinone derivatives and their use as antibacterial agents

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