AU2687001A

AU2687001A - Method for preparing and isolating 9-deoxo-9(z)-hydroxyiminoerythromycin

Info

Publication number: AU2687001A
Application number: AU26870/01A
Authority: AU
Inventors: Francois Basset; Thierry Durand; Ronan Guevel; Patrick Leon; Frederic Lhermitte; Gilles Oddon; Denis Pauze
Original assignee: Merial SAS
Current assignee: Boehringer Ingelheim Animal Health USA Inc
Priority date: 1999-12-20
Filing date: 2000-12-19
Publication date: 2001-07-03
Anticipated expiration: 2020-12-19
Also published as: FR2802534B1; BR0016506B1; ES2202215T3; EP1242439B1; DE60002922T2; NZ519802A; AU776674B2; EP1242439A1; ZA200205697B; AR027021A1; PL201837B1; ATE240967T1; CN1215077C; TR200300174T3; BR0016506A; PT1242439E; CN1411465A; WO2001046211A1; DE60002922D1; FR2802534A1

Description

WO 01/46211 PCT/FROO/03595 PROCESS FOR PREPARING AND ISOLATING 9-DEOXO-9 (Z) -HYDROXYIMINOERYTHROMYCIN A The present invention relates to a process for 5 preparing and isolating 9-deoxo-9(Z)-hydroxyimino erythromycin A (referred to hereinbelow as 9(Z) erythromycin oxime or 9(Z)-oxime) from the corresponding E isomer. The present invention lies in the field of 10 macrolide antibiotics of erythromycin type and relates more particularly to their aza-macrolide derivatives which are the subject of patent application EP 508 699 and correspond to the following general formula:

QH

3 NMe 2 HO

H

3 C 8a H 3 .. to' CH HO"'~ 0 H HOm"- OH . CH 3

H

3 C O OWe CH CH3 - '"CH3 0

-

NH

2 15 CH 3 in which R represents a hydrogen atom, a Ci-Cio alkyl group, a C 2

-C

1 0 alkenyl group or a C 6

-C

1 2 arylsulphonyl group, which may be substituted. 20 These compounds are obtained from erythromycin and their synthesis involves two major steps: - the creation of the 8a-azalide macrocycle from 9(E)-erythromycin oxime isomerized into the corresponding 9(Z)-oxime, which then undergoes a 25 stereospecific Beckmann rearrangement, and - the modification of the "cladinose" group in position 4, which consists in converting the 4(S)-OH into 4(R)-NH 2 . The present invention relates more particularly 30 to the first step of this synthesis and its subject is a new process for isomerizing 9 (E) -erythromycin oxime - 2 and isolating the resulting 9(Z)-oxime isomer, which can be illustrated as follows:

H

3 C\ ,CH 3 H3CN, CH3 NN OH QH 3 HO 9H 3 HO,

HO

H

3 C-., CH 3 H 3 C.,, CH 3 O HO...-- HO"' -.. 0 CH 3 HO..... HY - C H 3 HO HO

H

3 CH CH 3 3 H 3 C' CH 3 O0CH 3 C CH 3 'C3

CH

3

CH

3 0 0 C OH OH 6 H 3

CH

3 9(E) oxime (11) 9(Z)-oxime (1) 5 This isomerization step is, in particular, the subject of patent application EP 503 949, in which the 9(Z)-oxime of formula (I) is obtained by treating the E isomer of formula (II) with a base, preferably an 10 alkali metal hydroxide such as lithium hydroxide, in a protic or aprotic solvent which is preferably ethanol. The residue obtained after evaporating off the solvent is taken up in ethyl acetate and an aqueous solution which is then re-extracted with ethyl acetate to give a 15 crude product containing a mixture of oximes. The crude mixture of oximes is then taken up in methylene chloride, then filtered. The solid obtained is then taken up in ethyl acetate and a non-solvent (nitromethane) and then crystallized or purified in 20 ethyl acetate by successive steps of precipitation with methylene chloride, and filtrations. As it turns out, the current conditions cannot be extrapolated to the industrial scale. The reason for this is that this process 25 involves steps of concentrating to dryness of the reaction mass in ethanol and of that in ethyl acetate. It also involves the use of chlorinated solvents that are undesirable in terms of environmental protection.

- 3 Finally, the product isolated still contains the (E) isomer and needs to be taken up several times in a medium containing ethyl acetate and methylene chloride in order to crystallize (by "beating") the 5 desired (Z) isomer and to isolate it in an acceptable isomeric purity. The aim of the present invention is to provide an efficient alternative to the known process which makes it possible to overcome the abovementioned 10 drawbacks. The aim of the invention is thus to provide a simplified process, which is easy to carry out on the industrial scale and which gives the 9(Z)-oxime in a satisfactory isomeric purity. 15 The aim of the invention is, in particular, to avoid the use of chlorinated solvents, that are environmentally harmful, as well as the laborious purification by "beating" in an ethyl acetate/methylene chloride mixture. 20 A subject of the present invention is a process for preparing 9-deoxo-9 (Z) -hydroxyiminoerythromycin A corresponding to formula (I) below:

H

3 C, NCH 3 qH 3 HO

HO

H

3 C., CH 3 0 H 3 HO..". HO' g H HO

H

3 C O H 3

H

3

H

3 CH3 "CH3 O :OH

CH

3 (I) 25 successively comprising the steps consisting in: - reacting in water 9-deoxo-9(E)-hydroxyimino erythromycin A corresponding to formula (II) below: -4

H

3 CN NCH 3 ?H CH3 HO,

H

3 C, CH b HON... HO -, 0 CH 3 HO

H

3 C

CH

3 O',CH3 CH30 0CH ."CH3 Z OH

CH

3 (I1) with a base, 5 - acidifying the reaction mixture to a pH of between 9 and 11, - adding to the said mixture an organic solvent; - optionally concentrating under vacuum the 10 resulting organic phase; - isolating the desired 9(Z)-erythromycin oxime. According to a preferred variant of the invention, for the reaction of the 9(E)-oxime of 15 formula (II), an organic solvent of dialkyl ketone type, in particular acetone, is added to the water. The inventors have demonstrated, unexpectedly, that 9(E)-erythromycin oxime suspended in water, optionally with the addition of a solvent of the 20 dialkyl ketone type, can be isomerized with a base, without the presence of an alcoholic solvent, followed by directly extracting, after neutralization of the salt, the desired isomer from the reaction suspension and isolating it in a satisfactory purity. 25 They have thus demonstrated that the desired (Z) isomer can be obtained by adding to the reaction suspension an organic solvent such as ethyl acetate allowing it to be crystallized without addition of another solvent to the medium. Depending on the case, 30 this medium may be capable of forming an insoluble or - 5 sparingly soluble solvate with the 9(Z)-oxime. It does not require any subsequent crystallizations. According to one embodiment, the invention thus covers the use, after isomerization in water, of any 5 organic solvent capable of inducing the crystallization of the 9(Z)-oxime, in particular by concentration, in the said solvent, while the (E) isomer remains mainly dissolved in the medium. According to a preferred variant, it is the 10 actual isomerization which is carried out in water to which is added an organic solvent of dialkyl ketone type capable of forming a crystallizable solvate with the (Z) isomer as indicated above. The inventors have thus developed a simplified 15 process for dispensing with the precipitation with methylene chloride as well as the multi-step purification required in the known process. The inventors have also demonstrated that the mother liquors (containing a mixture of the E and Z 20 isomers) collected after isolation of the crystallized (Z) isomer can advantageously be recycled by reforming an aqueous suspension of the mixture of isomers they contain after removal of most of the organic solvent present. 25 The process according to the invention will be described in greater detail below. This process consists firstly in treating 9(E)-erythromycin oxime, suspended in water, with a base which is preferably water-soluble. 30 According to a preferred variant of the invention, the 9(E)-oxime is reacted with the base, in an aqueous medium formed of water mixed with an oraganic solvent of dialkyl ketone type and advantageously capable of forming a crystallizable 35 solvate with the 9(Z)-oxime, while the (E) isomer remains mainly in solution. The solvent of dialkyl ketone type is preferentially chosen from dialkyl ketones containing from 3 to 10 carbon atoms and it is typically acetone.

- 6 The base is then added to give rise to the isomerization reaction. Examples of bases which may be mentioned are alkali metal or alkaline-earth metal hydroxides, 5 ammoniums, carbonates and alkoxides. This base preferably consists of lithium hydroxide or sodium hydroxide. The base is used in an amount preferably of between 1 and 10 equivalents, preferably 2 molar 10 equivalents relative to the 9(E)-oxime. The addition of the base to the 9(E)-oxime leads to its deprotonation and makes it possible to reach the equilibrium conditions with the (Z) isomer. The pH of the reaction medium is generally 15 between 11.5 and 14. The subsequent treatment applied to the mixture makes it possible to shift this equilibrium and preferentially to isolate the 9(Z)-oxime in the form of solvate. 20 The reaction is generally carried out under an inert atmosphere. The Z/E ratio is temperature dependent and the reaction is preferably carried out at a temperature of between 100 and 250C, more preferably in the region of 200C. 25 The reaction medium is preferably stirred for 6 to 24 hours. The desired (Z) isomer is then extracted with an organic solvent, in particular with ethyl acetate or another equivalent solvent. 30 To do this, the reaction mixture is first acidified to a pH preferably of between 9 and 11, even more preferably to a pH of about 9.5-10. For this, hydrochloric acid, acetic acid or sodium bicarbonate is preferably used. 35 To carry out this acidification step, the said mixture is preferably cooled to a temperature below 20 0 C, and more preferably to a temperature of about 100C.

- 7 An organic solvent is then added to the reaction medium in order to induce the crystallization of the desired (Z) isomer. When the isomerization reaction is conducted in 5 water, according to one preferred embodiment of the invention, ethyl acetate or other solvents which have equivalent properties in terms of crystallization of the (Z) isomer is used. The expression "solvents which have equivalent 10 properties of crystallizing the (Z) isomer" means any solvent capable of inducing crystallization of the 9(Z)-oxime, in particular by concentrating the organic extraction phase, while the (E) isomer remains mainly in solution. 15 Specifically, according to this embodiment of the invention, it is thought that the (Z) isomer can be extracted directly from the reaction medium and can crystallize by concentration in the organic extraction solvent. When the isomerization reaction is carried out 20 in a water/dialkyl ketone mixture, it is the solvate of the (Z) oxime with the dialkyl ketone which precipitates at the end of neutralization. The use of an organic solvent such as ethyl acetate or methyl butyl ether makes it possible to improve the Z/E ratio 25 in favour of the desired (Z) isomer, during the filtration of the solvate with the dialkyl ketone. Moreover, an ester such as ethyl acetate also makes it possible to improve the subsequent drying of the (Z) oxime by promoting the removal of the solvent of 30 dialkyl ketone type. During the extraction step, the temperature of the reaction medium is preferably returned to room temperature (about 25-30 0 C) which facilitates the separation of the phases by settling. 35 After separation of the phases by settling, the aqueous phase is preferably re-extracted under the abovementioned conditions. Where appropriate, the organic extraction phases are combined and then concentrated under vacuum - 8 in order to bring about crystallization of the desired (Z) isomer in the medium. The temperature of the reaction medium is preferably maintained below 35OC during this 5 concentration operation and is preferably carried out for several hours (for about 4 to 5 hours). The desired (Z) isomer is then isolated by filtration. For this, the reaction mass is preferably maintained between 10 and 250C, preferably cooled to a 10 temperature of about 10OC. The (Z) isomer is recovered in a Z/E ratio of greater than 90/10, typically between 93/7 and 98/2. According to the invention, the mother liquors collected after filtration, which essentially contain 15 the 9(E)-oxime, can be reprocessed as indicated above. In this case, most of the ethyl acetate or other extraction solvent is distilled off under vacuum on a tail of water, until only 3 to 4% remains, for example. 20 A solvent of dialkyl ketone type and base are then added, if appropriate, as indicated above, in order to carry out a new isomerization of the 9(E)-oxime present, followed by isolation of the 9(Z)-oxime formed under the conditions indicated above. 25 Depending on the extraction solvent, a larger amount of base may need to be introduced on account of a possible saponification of the solvent. The process according to the present invention has the advantage of using only one extraction solvent, 30 which is generally not a chlorinated solvent, and of not requiring multiple repeats in order to obtain the crystallization of the desired isomer. It can be carried out easily in industrial terms. The process according to the invention is 35 illustrated below by examples which should not be considered as limiting. EXAMPLE 1: isomerization reaction in water: 9 (E) -Erythromycin oxime (II) (50 g, 0.065 mol, 1 equiv.) and lithium hydroxide LiOH-H 2 0 (5.7 g, - 9 0.133 mol) are placed in a 1 litre homothetic reactor with a nitrogen atmosphere and distilled water (500 ml) is then added, while carefully rinsing out the conical flask used for adding the solids. 5 The 9(E)-erythromycin oxime suspension thus obtained is stirred for 9 hours or more at a temperature of about 16 0 C (or at room temperature) . The set temperature is then cooled to about 100C and 1N HCl solution is added over 1 h 30 min or more so as to 10 bring the pH of the reaction mass to a value of about 9.5. The suspension thus obtained is extracted with ethyl acetate (300 g) . To improve the extraction, the reaction mass is heated to about 25-30 0 C. After 15 separation of the phases by settling, the aqueous phase is back-extracted with ethyl acetate (2 x 225 g). The combined organic phases are then concentrated under vacuum by partial distillation of the ethyl acetate and the reaction mass is then cooled to about lOC for 20 about 1 h 30 min and then filtered. After filtration and drying, 32 g of 9(Z)-erythromycin oxime (I) are isolated (Z:E ratio = 96:4 by 1H NMR) . The mother liquors isolated (97 g) can be recycled as described in Example 2. 25 EXAMPLE 2: recycling of the mother liquors: The filtration mother liquors (97 g) are placed in a 1 litre homothetic reactor under a nitrogen atmosphere and distilled water (500 ml) is then added. The ethyl acetate is distilled off under vacuum until 30 only about 3 to 4% by weight of ethyl acetate remains. Lithium hydroxide LiOH-H 2 0 (4.7 g, 0.109 mol) is then loaded in. The suspension of the mixture of Z and E erythromycin oximes thus obtained is stirred at about 35 800 rpm for 10 hours or more at a temperature of about 160C (or at room temperature) . The set temperature is then cooled to about 100C and 1N HCl solution is added over 1 h 30 min or more so as to bring the pH of the reaction mass to a value of about 9.5. Ethyl acetate - 10 (300 g) is then added and the mass is then heated to about 25-300C. After separation of the phases by settling, the aqueous phase is back-extracted with ethyl acetate (2 X 225 g). The organic phase is rapidly 5 transferred into the reactor and then concentrated under vacuum by partial distillation of the ethyl acetate down to a minimum stirrable volume. The reaction mass obtained is then cooled to about 100C for about 1 h 30 min and then filtered. 10 After filtration and drying, 6 g of 9(Z) erythromycin oxime (I) are isolated (Z:E ratio 96:4 by 1 H NMR). Weight yield = 76% EXAMPLE 3: isomerization reaction in a water/acetone 15 mixture: 9(E)-erythromycin oxime A (115 g, 0.150 mol, 1 eq.) is loaded into a 1-litre reactor placed under an inert atmosphere of nitrogen, followed by addition of drinking water (220 g) and acetone (272 g), rinsing the 20 funnel carefully. The suspension thus obtained is treated with 30% sodium hydroxide (38 g; 1.9 eq.) and then stirred for 8 hours or more at room temperature. The solution is then neutralized by addition of acetic acid over about 1 hour or more so as to bring the pH of 25 the reaction mass to a value of about 10. At this stage, a solvate is formed of the erythromycin oximes with the acetone (molar ratio 1:1 by 1 H-NMR) which precipitates in the reaction medium. The suspension thus obtained is treated with 30 ethyl acetate (200 g) and then stirred for a minimum of 3 hours at room temperature, after which it is cooled to about 0 0 C. After stirring for about 3 hours at 0 0 C, the suspension is filtered and then washed with drinking water (360 g). 35 The product obtained is then taken up in ethyl acetate (173 g) at about 40 0 C and stirred at this temperature for about 3 hours. The suspension obtained is cooled to room temperature and then filtered.

- 11 After filtration and drying at 50OC, 78 g of 9-(Z)-erythromycin oxime are isolated (Z:E ratio 97 : 3 by HPLC). The data (distance and relative intensity) 5 obtained by X-ray analysis of the 9(Z)-oxime (I) in the form of a solvate with acetone are given below: d(hkl)A Intensity (%) 13.12 27 11.86 23 11.69 26 11.31 46 10.05 30 9.78 67 9.02 33 8.79 63 8.04 100 7.44 26 7.38 31 7.09 29 7.03 35 6.79 25 6.59 26 6.54 30 5.97 43 5.63 26 5.59 24 5.23 17 5.01 25 4.93 49 4.87 31 4.75 25 4.58 36 4.26 18 4.14 25 3.90 10 3.75 12 3.68 11 - 12 d (hkl) A Intensity (%) 3.35 8 3.17 7 3.10 5 2.98 6 2.71 5 2.42 5

Claims

1. Process for preparing 9-deoxo-9(Z)-hydroxy iminoerythromycin A corresponding to formula (I) below 5 H 3 C NCH 3 QH 3 HO I HO H3C. CH3 HOt.s-. HO"' CH3 HO H 3 C CH 3 H3 H~e0 CHO CH3 0 "CH3 !OH CH 3 (I) successively comprising the steps consisting in: - reacting in water 9-deoxo-9 (E) -hydroxyimino 10 erythromycin A corresponding to formula (II) below: H3C ,CH 3 OH QH 3 HO H 3 C, CH 3 HO"- H0 * 0 CH 3 HO H 3 C CH 3 0 ,CH 3 H O CH H 0 0 OH 15 with a base, - acidifying the reaction mixture to a pH of between 9 and 11; - adding to the said mixture an organic solvent; - optionally concentrating under vacuum the 20 resulting organic phase; - 14 - isolating the desired 9(Z)-erythromycin oxime.

2. Process according to Claim 1, characterized in that, to make the 9(E)-oxime of formula (II) react with a base, an organic solvent of dialkyl ketone type 5 capable of forming a crystallizable solvate with the 9(Z)-oxime is added to the water.

3. Process according to Claim 2, characterized in that the organic solvent of dialkyl ketone type is chosen from dialkyl ketones containing 3 to 10 carbon 10 atoms and consists preferably of acetone.

4. Process according to any one of Claims 1 to 3, characterized in that the base is preferably water soluble and is chosen from alkali metal or alkaline earth metal hydroxides, ammoniums, carbonates and 15 alkoxides.

5. Process according to Claim 4, characterized in that the alkali metal hydroxide consists of lithium hydroxide or sodium hydroxide.

6. Process according to any one of Claims 1 to 5, 20 characterized in that 1 to 10 molar equivalents of base, preferably 2 molar equivalents, are used relative to the 9(E)-oxime.

7. Process according to any one of the preceding claims, characterized in that the isomerization 25 operation is carried out at a temperature of between 10 and 25 0 C, preferably in the region of 20 0 C.

8. Process according to any one of the preceding claims, characterized in that the reaction mixture is acidified to a pH of about 9.5-10. 30

9. Process according to any one of the preceding claims, characterized in that the acidification is carried out with the aid of hydrochloric acid, acetic acid or sodium bicarbonate.

10. Process according to any one of the preceding 35 claims, characterized in that the acidification step is carried out at a temperature below 20 0 C, preferably at a temperature of about 10 0 C.

11. Process according to any one of the preceding claims, characterized in that, when the isomerization - 15 reaction is conducted in water, the organic solvent added is ethyl acetate or a solvent which has equivalent properties in terms of solvation of the (Z) isomer. 5

12. Process according to Claim 11, characterized in that the organic solvent is ethyl acetate.

13. Process according to any one of Claims 1 to 11, characterized in that when the isomerization reaction is carried out in a water/dialkyl ketone mixture, the 10 organic solvent added is of ester type.

14. Process according to Claim 13, characterized in that the organic solvent is ethyl acetate.

15. Process according to any one of the preceding claims, characterized in that, during the step of 15 concentration under vacuum of the organic phase, the temperature of the medium is maintained below 35 0 C.

16. Process according to any one of the preceding claims, characterized in that the mother liquors collected after filtration are treated by the process 20 defined according to any one of the preceding claims, most of the organic solvent being removed beforehand from the medium before addition of water, optionally the solvent of dialkyl ketone type, and the base.

17. 9-Deoxo-9(Z)-hydroxyiminoerythromycin A 25 compound of formula (I) below: H 3 C% ,CH 3 QH 3 HO, H H 3 C, CH3 HO'*--- HOO' -- "O 0 CH3 HO H 3 C0 CH 3 0 -CH 3 CH3O CH "CH3 OH CH 3 (I) in the form of a solvate with an organic solvent of 30 dialkyl ketone type. - 16

18. Compound according to Claim 17, in the form of a solvate with a dialkyl ketone containing from 3 to 10 carbon atoms.

19. Compound according to Claim 18, in the form of 5 a solvate with acetone.