WO2006087238A9

WO2006087238A9 - Method for the production of macrolides

Info

Publication number: WO2006087238A9
Application number: PCT/EP2006/001673
Authority: WO
Inventors: Audun Heggelund
Original assignee: Alpharma Aps; Audun Heggelund
Priority date: 2005-02-21
Filing date: 2006-02-21
Publication date: 2006-10-05
Also published as: AU2006215709A1; CN101124236A; WO2006087238B1; EP1856136A1; WO2006087238A1; JP2008530169A; CA2598139A1

Abstract

A process for the conversion of 6-11 bridged bicyclic ketolide or erythromycin oximes to 6-11 bridged bicyclic ketolides or erythromycins comprises reacting a 6-11 bridged macrolide with a deoximating agent, preferably an oxidative deoximating agent such as Dess-Martin periodinane. The procedure may comprise deoximation of certain erythromycin A C-9 oxime derivatives with regeneration of the C-9 keto function.

Description

METHOD FOR THE PRODUCTION OF MACROLIDES

FIELD OF INVENTION

The invention provides a process for the conversion of 6-11 bridged macrolide (e.g. erythromycin or derivatives thereof) oximes to a corresponding macrolide having corresponding keto functionality.

BACKGROUND OF INVENTION

Ketolides and erythromycin derivatives are useful in treatment and prevention of bacterial infections. 6-11 Bridged bicyclic ketolides and erythromycins have been described in several publications by Enanta Pharmaceuticals Inc. The 6-11 bridge structure has been Introduced into erythromycin structures (WO 03/095466 A1, US 2004/005861 A1), ketolides with a C₃ ketone substituted for the cladinose sugar (WO 03/097659 A1, US 2004/0157787 A1, US 2004/0171818 A1, Org. Lett. 2004, 6, 4455- 4458), as well as the ring-enlarged azalides (US 6,645,941 B1, US 6,764,998 B1).

Common for the 6-11 bridged bicyclic erythromycins/ketolides/azalides is that they show good antibacterial activities against macrolide susceptible bacteria, as well as efflux-resistant strains.

In particular, compounds of the formula (V), with a keto function at C₉, and methods of preparing them, were described in WO 03/097659 A1 and US 2004/0157787 Al However, the synthetic routes were unnecessarily long and complicated. A ten step synthesis from erythromycin 9-oxime was needed to prepare the parent compound (1- 2). The product was isolated in 43% overall yield from erythromycin 9-oxime. US 2004/266998 discloses a method for the generation of a 6-11 bridged erythromycin analogue via a deoximation step. However, the 6-11 bridge structure must be established after the deoximation step which ensures that ten synthetic steps are required to obtain a 6-11 bridged structure with keto functionality at the C₉ position.

A general review of deoximation reactions has been previously presented by Corsaro et al. (Synthesis 2001, 13 1903-1931 ). Also, the use of Dess-Martin periodinane as a deoximation agent in general has been disclosed by Chaudhari and Akamanchi (Synthesis 1999, 5 760-764).

SUMMARY OF INVENTION

As macrolides are expensive compounds, it is very important that the conversion of macrolides is performed as efficiently as possible. There exists a need for a process that improves the efficacy of the conversion of the oxime group to a keto group, e.g. in the process for introduction of the 6-11 bridge, thereby reducing the cost.

It has now been surprisingly found that it is possible to produce 6-11 bridged bicyclic ketolide or erythromycin derivatives of general formula (I) with a keto function in the 9- position,

(I)

in a simple way, by treating 6-11 bridged bicyclic erythromycin or ketolide oximes with a deoximation reagent. Thereby removal of the oxime with regeneration of the parent keto function occurs. This does not follow the teachings in WO 03/097659 A1 and US 2004/0157787.

Furthermore, it has surprisingly been found out that when a 3-hydroxy-9-oxime 6-11 bridged bicyclic derivative (R₆ = OH, R₇ = H) is treated with a reagent for oxidative deoximation, regeneration of the C₉ keto function is accompanied by concurrent oxidation of the C₃ alcohol to the corresponding keto function (R₆ and R₇ taken together are =0).

DETAILED DISCLOSURE

In accordance with the above findings, the present invention relates to a method for the (selective) conversion of an oxime group in a macrolide to an oxo group, said method comprising treatment of the macrolide with a deoximating agent. The macrolide is preferably a derivative of erythromycin, such as a ketolide or an azalide, especially a macrolide wherein the oxime group is placed at the 9 position of the macrolide. It is presently preferred that the macrolide comprises a bridge between 6-0 and 11-0, such as a hydrocarbon group, an alkylidene group or a bridge having the formula: - alkyl— C(=alkylidene)— alkyl-.

Thus, in an interesting embodiment, the invention relates to a method for converting a macrolide of Formula Il to a macrolide of Formula III.

Deoximation

in which formulas R₁ and R₂ independently are alkyl, or taken together are alkylidene; R₃ is OH or alkoxy; R₄ is H or alkyl; R₅ is H or alkyl; R₈ is OH or alkoxy; and Z is an acyl group (such as alkanoyl).

In a preferred embodiment, R₁ and R₂ taken together are =CH₂, R₃ is OH, R₄ Is CH₂CH₃, R₅ is H₁ R₈ is OH and Z is Acetyl.

In another interesting embodiment of the method of the invention, the macrolide of Formula IV is converted to a macrolide of Formula V One or two steps Deoximation/oxidation

in which Formulas Ri and R₂ independently are H or alkyl, or taken together are alkyliden; R₃ is OH or alkoxy;

R₄ is H or alkyl,

R₅ is H or alkyl,

and Z is an acyl group (such as alkanoyl).

Preferably, Ri and R₂ taken together are =CH₂, R₃ is OH, R₄ is CH₂CH₃, Rs is H, and Z is Acetyl.

As deoximating agent, an agent suitable for ketone-regeneration from oximes can be used, such as an oxidative deoximating agent, in particular a derivative of 2- lodoxybenzoic acid, such as IBX or Dess-Martin periodinane.

Such a deoximating agent can be used alone, or together with an oxidizing agent, thus the method of the invention can be carried out be treatment of the macrolide with a deoximating agent, followed by treatment with an oxidizing agent

In an interesting embodiment, a C₉ oxime, C₃ hydroxyl macrolide can, in a one-step procedure, be converted to the corresponding C₉, C₃ di-ketone macrolide by treatment with both a deoximating and an oxidizing agent, or a single agent which is oxidizing deoximating agent, such as a derivative of 2-lodoxybenzoic acid, e.g. Dess-Martin periodinane (two equivalents).

The invention also relates to novel compounds of the Formula I,

(l)

in which Formula

Z represents H, acyl, alkanoyl or acetyl;

R₁ and R₂ independently represent H, C₁-C₆ alkyl, or together they represent =CH₂ or C₁-C₆ alkyliden;

R3, R₄, R₅. R7 independently represent H, or Ci-C₆ alkyl;

R₆ represents OH, or together with the adjacent R₇, an =0 group.

Thus, the present invention provides an efficient method for converting 6-11 bridged bicyclic erythromycin 9-oximes of general formula (II) to 6-11 bridged bicyclic erythromycins of general Formula (III). Deoximation

The transformation is mediated by treating a compound of the general Formula (II) with a suitable reagent for ketone-regeneration from oximes.

Furthermore, a 3-0-desciadinosyl 6-1 1 bridged bicyclic erythromycin 9-oxime of Formula (IV) can be converted to the corresponding 6-11 bridged bicyclic ketolide of general Formula (V) in either one or optionally two sequential steps upon treatment with suitable reagents. In this particular case, deoximation of the C₉ oxime is accompanied by oxidation of the C₃ alcohol to a keto function.

One or two steps Deoximation/oxidation

In the one step procedure the substrate is treated with two equivalents of a reagent for oxidative deoximation. In the two step procedure any deoximation reagent can be used for regeneration of the C₉ ketone. Subsequently, any oxidising agent can be used for the oxidation of the C₃ alcohol. With the present methodology the parent 6-11 bridged bicyclic ketolide compound (1-2) is available in only five chemical steps from erythromycin 9-oxιme.

In particular, the present invention can be used to transform the compound (1-1 ) in one chemical step to the parent 6-11 bridged bicyclic ketolide (1-2) in a process with deoximation/oxidation followed by removal of the C-2' protecting group. Hence, the present methodology provides an efficient synthesis of 6-11 bridged bicyclic ketolides. In particular, the parent compound (1-2) can be prepared in no more than five synthetic steps from erythromycin 9-oxime.

Scheme 1

1 Dess-Martin periodinane

2 Methanol

Treatment of the 6-11 bridged bicyclic erythromycin 9-oxιme (2-1 ) with Dess-Martin periodinane provides the corresponding C₉ keto analogue (2-2).

Scheme 2

DEFINITIONS

The term ketolide refers to derivatives of erythromycin A wherein the cladinose sugar has been removed and replaced by a C₃ keto function.

The term azalide refers to derivatives of erythromycin A wherein the macrolactone ring has been extended to a 15-membered ring with a nitrogen atom included.

The term "alkyl" includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. Preferably, the alkyl group has 1-10 carbon atoms, and most preferred 1 , 2, 3, 4, 5, or 6 carbon atoms. The alkyl groups may be Interrupted by one or more heteroatoms, and may be substituted, such as with halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. The term "alkoxy" stands for an -0-alkyl group. The term "alkylidene" refers to optionally unsaturated divalent alkyl radicals.

The term "acyl" encompasses carboxylic acyl groups having the formula A-C(=O)-, in which formula A represents a substituent, such as an alkyl, alkenyl, aryl, heteroaryl or aralkyl group, the chain in said groups being optionally interrupted by one or more heteroatoms and the groups being optionally substituted. Examples on acyl groups are formyl, C₁-C₆ alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-C_rC₆ alk(en/yn)ylcarbonyl, cycloalkylcarbonyl, or cycloalkyl- C₁-C₆ alk(en/yn)ylcarbonyl group.

The term "derivative of 2-lodoxybenzoic acid" refers to 2-lodoxybenzoic acid (IBX) and derivatives thereof able to deoximate an oxime group, and includes Dess-Martin periodinane. The term Dess-Martin periodinane refers to the compound with the systematic name 1 ,1 ,1-triacetoxy-1 ,1-dihydro-1 ,2-benziodoxol-3-(1 H)-one. The term deoximation refers to the process where a carbonyl compound is regenerated from the corresponding oxime. In the case of deoximation of erythromycin 9-oxime derivatives, the carbonyl group is a ketone.

The use of the terms "a" and "an" and "the" and similar referents In the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to,") unless otherwise noted. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.

Preferred embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventors expect skilled artisans to employ such variations as appropriate, and the inventors intend for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above- described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

EXAMPLES

Example 1

To produce a compound of general Formula (V): R₁ and R₂ taken together are =CH₂, R₃ is OH, R₄ is CH₂CH₃, R₅ is H and Z is Ac.

The compound of structure (1-1) (500 mg, 0.73 mmol) is dissolved in dichloromethane saturated with water (12.5 ml), and Dess-Martin periodinane (629 mg, 1.46 mmol) is added slowly. The reaction mixture is stirred at room temperature in inert atmosphere until TLC indicates full conversion of the starting material. Aqueous sodium hydroxide is added, and the product is extracted with dichloromethane. The combined organic layers are washed with water and brine, and dried (MgSO₄). Removal of the solvents provides the compound of general Formula (V) (with Ri and R₂ taken together are =CH₂, R₃ is OH, R₄ is CH₂CH₃, R₅ is H and Z is Ac) as a white solid.

Example 2

To produce a compound of general Formula (V): Ri and R₂ taken together are =CH₂, R₃ is OH, R₄ is CH₂CH₃, R₅ is H and Z Is Ac. The compound of structure (1-1) (500 mg, 0.73 mmol) is dissolved in dichloromethane saturated with water (12.5 ml), and Dess-Martin periodinane (315 mg, 0.73 mmol) is added slowly. The reaction mixture is stirred at room temperature in inert atmosphere until TLC indicates full conversion of the starting material. Aqueous sodium hydroxide is added, and the product is extracted with dichloromethane. The combined organic layers are washed with water and brine, and dried (MgSO₄). Removal of the solvents provides the C₃ alcohol as a white solid.

The alcohol is dissolved in dichloromethane (12.5 ml), and Dess-Martin periodinane (315 mg, 0.73 mmol) is added. The reaction mixture is stirred until TLC indicates full conversion of the starting material. Aqueous sodium hydroxide is added, and the product is extracted with dichloromethane. The combined organic layers are washed with water and brine, and dried (MgSO₄). Removal of the solvents provides the corresponding de-oximated oxidized analogue of the starting material (of general Formula (V) with R₁ and R₂ taken together are =CH₂, R₃ is OH, R₄ is CH₂CH₃, R₅ is H and Z Is Ac) as a white solid.

Example 3

To produce a compound of general Formula (III): Ri and R₂ taken together are =CH₂, R₃ is OH, R₄ is CH₂CH₃, R₅ is H, R₈ is OH and Z Is Ac.

The compound of structure (2-1 ) (500 mg, 0.59 mmol) is dissolved in dichloromethane saturated with water (12.5 ml), and Dess-Martin periodinane (254 mg, 0.59 mmcl) is added slowly. The reaction mixture is stirred at room temperature in inert atmosphere until TLC indicates full conversion of the starting material. Aqueous sodium hydroxide is added, and the product is extracted with dichloromethane. The combined organic layers are washed with water and brine, and dried (MgSO₄). Removal of the solvents provides the compound of general Formula (III) (Ri and R₂ taken together are =CH₂, R3 is OH, R₄ is CH₂CH₃, R₅ is H, R₈ is OH and Z Is Ac) as a white solid.

Whilst the above-identified erythromycin analogues having the listed 6-11 bridge structures can be converted directly it is also possible to convert the erythromycin analogues having the bridge structures detailed in US 2004/0266998 (the entire disclosure of which is incorporated by reference herein). Also, the invention extends to the conversion of ketolides and azides having an oxime group to the corresponding ketolide and azide having a keto group, for example at the C₉ position.

Claims

1. A method of converting an oxime group in a 6,11 bridged macrolide to an oxo group, said method comprising reacting a 6,11 bridged macrolide with a deoximating agent.

2. A method according to Claim 1 , wherein the macrolide is a derivative of erythromycin, such as a ketolide or an azalide.

3. A method according to Claim 1 or 2, wherein the oxime group is placed at the 9 position of the macrolide.

4. A method according to Claim 1, 2 or 3, wherein the bridge structure comprises a hydrocarbon group, a substituted hydrocarbon group, an alkylidene group or a bridge having the formula: -alkyl-C(=alkylidene)-alkyk

5. A method according to any preceding Claim, wherein the macrolide to be converted has the formula Il

in which formulas R₁ and R₂ Independently are alkyl, or taken together are alkylidene;

R₃ is OH or alkoxy; R₄ is H or alkyl;

R₅ is H or alkyl;

R₈ is OH or alkoxy; and Z is an acyl group (such as alkanoyl).

6. The method according to Claim 5, wherein R₁ and R₂ taken together are =CH₂, R₃ is OH, R₄ is CH₂CH₃, R₅ is H, R₈ is OH and Z Is Acetyl.

7. The method according to any of Claims 1 to 4, wherein the macrolide to be converted has the formula IV

in which formulas R₁ and R₂ independently are H or alkyl, or taken together are alkyliden;

R₃ is OH or alkoxy;

R₄ is H or alkyl;

R₅ is H or alkyl; and Z is an acyl group (such as alkanoyl).

8. The method according to Claim 7, wherein R₁ and R₂ taken together are =CH₂, R₃ is OH, R₄ is CH₂CH₃, R₅ is H, and Z is Acetyl.

9. A method according to any preceding Claim, wherein the deoximating agent is an oxidative deoximating agent, such as a compound being a derivative of 2- lodoxybenzoic acid.

10. A method according to any preceding claim, wherein the deoximating agent is Dess-Martin periodinane.

11. A method according to any preceding claim, said method comprises treatment with a deoximating agent, followed by treatment with an oxidizing agent.

12. A method according to Claim 11, wherein the oxidizing agent is 2- lodoxybenzoic acid or a derivative thereof.

13. A method according to Claim 11 or 12, wherein the oxidizing agent is Dess- Martin periodinane.

14. The method according to Claim 7 or 8, in which the macrolide is reacted with two equivalents of Dess-Martin periodinane.

15. A one-step method for the following conversion

in whicn Tormulas R₁ and R₂ independently are H or _^..../l, or taken together are alkyliden;

R₃ is OH or alkoxy; R₄ is H or alkyl; R₅ is H or alkyl; the method comprising reacting the starting material with an oxidative deoximating agent.

16. A method according to Claim 15, wherein X is

and Z is H, acyl, alkanoyl or acetyl.

17. A method according to Claim 15 or 16, wherein the oxidative deoximating agent is 2-lodoxybenzoic acid or a derivative thereof.

18. A method according to Claim 15, 16 or 17, wherein the oxidative deoximating agent is Dess-Martin Periodinane.

19. A method according to any preceding Claim, wherein the reaction is carried out at room temperature or below.

20. A compound of the following formula

in which formula

Z represents H, acyl, alkanoyl or acetyl;

R₁ and R₂ independently represent H, C₁-C₆ alkyl, or together they represent

=CH₂ or C₁-C₆ alkyliden;

R₃, R₄, R_δ, R7 independently represent H₁ or C₁-C₆ alkyl;

R₆ represents OH, or together with the adjacent R₇, an =0 group.