WO2000058327A1 - Procede pour reduire imidates pour produire un macrocycle 8a-azalide - Google Patents
Procede pour reduire imidates pour produire un macrocycle 8a-azalide Download PDFInfo
- Publication number
- WO2000058327A1 WO2000058327A1 PCT/FR2000/000753 FR0000753W WO0058327A1 WO 2000058327 A1 WO2000058327 A1 WO 2000058327A1 FR 0000753 W FR0000753 W FR 0000753W WO 0058327 A1 WO0058327 A1 WO 0058327A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- borohydride
- activated
- general formula
- compound
- reaction medium
- Prior art date
Links
- 0 CC[C@]([C@](C)([C@@]([C@@](C)C([C@](C)C[C@](C)([C@@]([C@@](C)[C@@]([C@@]1C)O[C@@](C[C@@]2(C)OC)O[C@@](C)[C@@]2O)O[C@@]([C@]2O)O[C@](C)C[C@@]2N(C)C)O)=*CCO)O)O)OC1=O Chemical compound CC[C@]([C@](C)([C@@]([C@@](C)C([C@](C)C[C@](C)([C@@]([C@@](C)[C@@]([C@@]1C)O[C@@](C[C@@]2(C)OC)O[C@@](C)[C@@]2O)O[C@@]([C@]2O)O[C@](C)C[C@@]2N(C)C)O)=*CCO)O)O)OC1=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
- C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins
Definitions
- the subject of the present invention is a method useful for effectively reducing the imidate intermediates resulting from a Beckmann rearrangement of an 8a-azalide macrocycle.
- the present invention relates more particularly to the field of macrolide antibiotics of the erythromycin type and more particularly their aza-macrolide derivatives which are the subject of patent EP 508 699 and correspond to the following general formula:
- R represents a hydrogen atom, an alkyl group d- C-io alkenyl, C 2 -C- ⁇ 0 or arylesulfonyie C 6 -C ⁇ 2, optionally substituted.
- the present invention relates more particularly to the first step and aims to propose a new process for the reduction of the imidate intermediates obtained at the end of the Beckmann rearrangement of the erythromycin derivative 9 (Z) oxime.
- the conventional synthetic route can be schematized as follows:
- the object of the present invention is precisely to propose an effective alternative to the synthetic route discussed above.
- the subject of the present invention is a process for the preparation of a compound of general formula I via Beckmann stereospecific rearrangement in a pyridine-based reaction medium of a compound of general formula II
- the activated borohydride adopted in the context of the present invention has a reduction power greater than that of sodium borohydride under the operating conditions of the claimed process.
- activated borohydride is intended to cover a borohydride activated by a Lewis acid cation, a quaternary ammonium borohydride, or alternatively a borohydride activated by a solvent.
- the borohydrides activated by a Lewis acid cation By way of representative of the borohydrides activated by a Lewis acid cation, mention may in particular be made of the borohydrides activated by a cation chosen from lithium and calcium atoms.
- a solvent chosen from alcohols in Ci to C ⁇ 0 . It is preferably methanol and ethylene glycol. They are preferably used in a proportion of 1 to 100 equivalents relative to the derivative of general formula II.
- quaternary ammonium borohydrides mention may more particularly be made of tetrabutylammonium borohydride.
- the activated borohydride is introduced in a sufficient quantity, at the end of the Beckmann rearrangement reaction.
- borohydrides activated by a Lewis acid cation or a quaternary ammonium cation it is also possible to generate it in said reaction medium, at the end of the Beckmann rearrangement. It can thus be prepared in situ from sodium or potassium borohydride by cation exchange with halides, preferably chlorides or bromides, Lewis acid cations or quaternary ammonium cations such as tetrabutylammonium.
- the activated borohydride can be used in a proportion of approximately 1 to 20 and preferably from 1 to 8 equivalents relative to the erythromycin 9 (Z) oxime derivative of formula II.
- the reduction reaction is generally carried out at low temperature and preferably at a temperature between 0 ° C and 5 ° C and in a period of time sufficient to lead to the formation of the compound of general formula I.
- said compound of general formula I can be isolated from the reaction medium according to a conventional procedure which generally involves extraction, washing and then drying operations.
- Beckmann rearrangement undergone by the compound of general formula II it is carried out under conventional experimental conditions and more preferably in accordance with the process described in application EP 508 699.
- the reaction is in this particular case carried out in pyridine anhydrous, with a solution of tosyl chloride and in an organic solvent of ether type such as THF, diethyl ether, methylterbutylether or in toluene.
- the organic solvent is generally present in an amount sufficient to dissolve the tosyl chloride.
- the claimed process therefore has the advantage, compared to the conventional process discussed above, of allowing the sequence of Beckmann rearrangement on erythromycin 9 (Z) oxime and the reduction of the imidate intermediates thus formed without requiring the isolation of said imidate intermediates. .
- the reaction mixture is then poured onto a mixture of water (100 ml) and dichloromethane (50 ml).
- the pH of the aqueous phase is 11.5.
- the pH is reduced to 9 by addition of concentrated hydrochloric acid at 36%.
- the organic phase is separated and then washed with water (100 ml) for ⁇ 0 min.
- the organic phase is again separated and mixed with water (50 ml).
- the pH of the aqueous phase is brought to 4.5 by addition of 36% concentrated hydrochloric acid (13.5 g).
- the aqueous phase is separated and washed with dichloromethane (50 ml) for 10 min.
- the clear and colorless aqueous phase is separated: the pH value is reduced to 9 by addition of a 9N aqueous sodium hydroxide solution (15 g). The aqueous phase becomes cloudy. Three extractions are then carried out with dichloromethane (3 ⁇ 50 ml). The combined organic phases are evaporated. The residue is then taken up in acetate ethyl (25 ml) and heptane (50 ml). After evaporation of the solvents, 3.8 g of crude oil are finally recovered.
- EXAMPLE 2 To a solution of oxime- (Z) (5.0 g, 6.53 mmol, 1 equiv.) In anhydrous pyridine (30 ml) at 0 ° C is added dropwise a solution of tosyl chloride (3.2 g, 0.1 mmol, 2.6 equiv.) in anhydrous MTBE (14 ml). The addition time is 45 min. The reaction mixture has a yellow color. After 1 h 30 min at 0 ° C (control by HPLC) is added in 20 min. tetrabutylammonium borohydride (7.06 g, 0.158 mmol, 4 equiv.).
- the reaction is finished according to the HPLC analysis.
- the reaction mixture is then poured onto a mixture of water (100 ml) and dichloromethane (50 ml).
- the pH of the aqueous phase is 9.8.
- the pH is reduced to 9 by adding a 2N aqueous solution of hydrochloric acid (1 g).
- the organic phase is separated and then washed with water (100 ml) for 10 min.
- the pH of the aqueous phase is 8.7.
- the organic phase is again separated and mixed with water (100 ml).
- the pH of the aqueous phase is reduced from 8.9 to 4.0 by addition of a 2N aqueous solution of hydrochloric acid (104.9 g).
- the aqueous phase is separated and washed with dichloromethane (50 ml) for 10 min.
- the clear and colorless aqueous phase is separated: the pH value is reduced to 9 by addition of a 9N aqueous sodium hydroxide solution (22 g).
- the aqueous phase becomes cloudy.
- Three extractions are then carried out with dichloromethane (3 ⁇ 50 ml).
- the combined organic phases are evaporated.
- the residue is then taken up in ethyl acetate (25 ml) and heptane (100 ml). After evaporation of the solvents, 5.28 g of crude product is finally recovered.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU34394/00A AU3439400A (en) | 1999-03-29 | 2000-03-24 | Method for reducing imidates to produce an 8a-azalide macrocycle |
EP00912740A EP1165583A1 (fr) | 1999-03-29 | 2000-03-24 | Procede pour reduire imidates pour produire un macrocycle 8a-azalide |
CA002361043A CA2361043A1 (fr) | 1999-03-29 | 2000-03-24 | Procede pour reduire imidates pour produire un macrocycle 8a-azalide |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9903885A FR2791680B1 (fr) | 1999-03-29 | 1999-03-29 | Procede utile pour reduire les intermediaires imidates issus d'un rearrangement de beckmann d'un macrocycle 8a-azalide |
FR99/03885 | 1999-03-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2000058327A1 true WO2000058327A1 (fr) | 2000-10-05 |
Family
ID=9543746
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR2000/000753 WO2000058327A1 (fr) | 1999-03-29 | 2000-03-24 | Procede pour reduire imidates pour produire un macrocycle 8a-azalide |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP1165583A1 (fr) |
AU (1) | AU3439400A (fr) |
CA (1) | CA2361043A1 (fr) |
FR (1) | FR2791680B1 (fr) |
WO (1) | WO2000058327A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2806724A1 (fr) * | 2000-03-24 | 2001-09-28 | Merial Sas | Procede pour la preparation de derives 9-deoxo-8a-aza- (8a-alkyl)-8a-homoerythromycine a a partir de la 9-deoxo-9 (z)-hydroxyiminoerythromycine a |
US6482931B2 (en) | 2000-03-24 | 2002-11-19 | Merial | Process for the preparation of 9-deoxo-8a-aza-(8a-alkyl)-8a-homoerythromycin A derivatives from 9-deoxo-9 (Z)-hydroxyiminoerythromycin A |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1100504A (en) * | 1967-08-16 | 1968-01-24 | Pliva Pharm & Chem Works | Erythromycin oxime and 9-amino-3-o-cladinosyl-5-o-desosaminyl-6,11,12-trihydroxy-2,4,6,8,10,12-hexamethylpentadecane-13-olide |
EP0508699A1 (fr) * | 1991-04-04 | 1992-10-14 | Merck & Co. Inc. | Dérivés de 9-Deoxo-8a-aza-8a-homoérythromycin a modifiés aux positions 4'' et 8a |
EP0879823A1 (fr) * | 1997-05-19 | 1998-11-25 | Hovione Inter Ltd. | Préparation de l'azithromycine |
-
1999
- 1999-03-29 FR FR9903885A patent/FR2791680B1/fr not_active Expired - Fee Related
-
2000
- 2000-03-24 EP EP00912740A patent/EP1165583A1/fr not_active Withdrawn
- 2000-03-24 AU AU34394/00A patent/AU3439400A/en not_active Abandoned
- 2000-03-24 CA CA002361043A patent/CA2361043A1/fr not_active Abandoned
- 2000-03-24 WO PCT/FR2000/000753 patent/WO2000058327A1/fr not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB1100504A (en) * | 1967-08-16 | 1968-01-24 | Pliva Pharm & Chem Works | Erythromycin oxime and 9-amino-3-o-cladinosyl-5-o-desosaminyl-6,11,12-trihydroxy-2,4,6,8,10,12-hexamethylpentadecane-13-olide |
EP0508699A1 (fr) * | 1991-04-04 | 1992-10-14 | Merck & Co. Inc. | Dérivés de 9-Deoxo-8a-aza-8a-homoérythromycin a modifiés aux positions 4'' et 8a |
EP0879823A1 (fr) * | 1997-05-19 | 1998-11-25 | Hovione Inter Ltd. | Préparation de l'azithromycine |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2806724A1 (fr) * | 2000-03-24 | 2001-09-28 | Merial Sas | Procede pour la preparation de derives 9-deoxo-8a-aza- (8a-alkyl)-8a-homoerythromycine a a partir de la 9-deoxo-9 (z)-hydroxyiminoerythromycine a |
WO2001072763A1 (fr) * | 2000-03-24 | 2001-10-04 | Merial | Procede pour la preparation de derives 9-deoxo-8a-aza-(8a-alkyl)-8a-homoerythromycine a a partir de la 9-deoxo-9(z)-hydroxyiminoerythromycine a |
US6482931B2 (en) | 2000-03-24 | 2002-11-19 | Merial | Process for the preparation of 9-deoxo-8a-aza-(8a-alkyl)-8a-homoerythromycin A derivatives from 9-deoxo-9 (Z)-hydroxyiminoerythromycin A |
JP2003528882A (ja) * | 2000-03-24 | 2003-09-30 | メリアル | 9−デオキソ−9(Z)−ヒドロキシイミノエリスロマイシンAから9−デオキソ−8a−アザ−(8a−アルキル)−8a−ホモエリスロマイシンA誘導体を製造する方法 |
JP4975933B2 (ja) * | 2000-03-24 | 2012-07-11 | メリアル エス アー エス | 9−デオキソ−9(Z)−ヒドロキシイミノエリスロマイシンAから9−デオキソ−8a−アザ−(8a−アルキル)−8a−ホモエリスロマイシンA誘導体を製造する方法 |
Also Published As
Publication number | Publication date |
---|---|
AU3439400A (en) | 2000-10-16 |
FR2791680A1 (fr) | 2000-10-06 |
EP1165583A1 (fr) | 2002-01-02 |
FR2791680B1 (fr) | 2001-06-29 |
CA2361043A1 (fr) | 2000-10-05 |
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