MXPA99006221A - Improved process in a single step for the preparation of 7,16-dioxa-2-aza-10-o-cladinosil-12-o-desosaminil-4,5-dihidroxi-6-etil-3,5,9,11, 13,15-hexametilbiciclo [11.2.1] hexadeca-1 (2) -en-8-ona, from erythromycin - Google Patents
Improved process in a single step for the preparation of 7,16-dioxa-2-aza-10-o-cladinosil-12-o-desosaminil-4,5-dihidroxi-6-etil-3,5,9,11, 13,15-hexametilbiciclo [11.2.1] hexadeca-1 (2) -en-8-ona, from erythromycinInfo
- Publication number
- MXPA99006221A MXPA99006221A MXPA/A/1999/006221A MX9906221A MXPA99006221A MX PA99006221 A MXPA99006221 A MX PA99006221A MX 9906221 A MX9906221 A MX 9906221A MX PA99006221 A MXPA99006221 A MX PA99006221A
- Authority
- MX
- Mexico
- Prior art keywords
- erythromycin
- preparation
- single step
- aza
- dioxa
- Prior art date
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- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 title claims abstract description 24
- 229960003276 erythromycin Drugs 0.000 title claims abstract description 23
- 238000000034 method Methods 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- ODUCDPQEXGNKDN-UHFFFAOYSA-N Nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 claims abstract description 25
- MQTOSJVFKKJCRP-BICOPXKESA-N Azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims abstract description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229960004099 azithromycin Drugs 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 8
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- CHKQALUEEULCPZ-UHFFFAOYSA-N amino 2,4,6-trimethylbenzenesulfonate Chemical compound CC1=CC(C)=C(S(=O)(=O)ON)C(C)=C1 CHKQALUEEULCPZ-UHFFFAOYSA-N 0.000 claims description 7
- IFPNJQLAULGZTH-UHFFFAOYSA-N hexadec-1-en-8-one Chemical compound CCCCCCCCC(=O)CCCCCC=C IFPNJQLAULGZTH-UHFFFAOYSA-N 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- 230000002829 reduced Effects 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- 239000000284 extract Substances 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- RRPKGUUYTHFUPN-UHFFFAOYSA-N N-hydroxy-2,4,6-trimethylbenzenesulfonamide Chemical compound CC1=CC(C)=C(S(=O)(=O)NO)C(C)=C1 RRPKGUUYTHFUPN-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 claims 1
- 230000002194 synthesizing Effects 0.000 claims 1
- 238000006675 Beckmann reaction Methods 0.000 abstract description 6
- 238000005755 formation reaction Methods 0.000 abstract description 6
- 230000017105 transposition Effects 0.000 abstract description 4
- 230000003115 biocidal Effects 0.000 abstract description 2
- 238000011065 in-situ storage Methods 0.000 abstract description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 230000001131 transforming Effects 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 1
- 150000002923 oximes Chemical class 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-Toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 150000003335 secondary amines Chemical class 0.000 description 3
- 238000007792 addition Methods 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 230000011987 methylation Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000006485 reductive methylation reaction Methods 0.000 description 2
- HRKNNHYKWGYTEN-HOQMJRDDSA-N (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-11-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-3,4,10-trihydroxy-13-[(2R,4R,5S,6S)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,8,10,12,14-hexamethyl-1-oxa-6-azacyclopentadecan-15-one Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)NC[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 HRKNNHYKWGYTEN-HOQMJRDDSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N Adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 150000002596 lactones Chemical group 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 210000001519 tissues Anatomy 0.000 description 1
Abstract
Improved process for the preparation of 7,16-dioxa-2-aza-10-O-cladinosil-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3,5,9,11,13,15- hexametilbicic [11.2.1] hexa-deca-1 (2) -en-8-one from Erythromycin A, which consists in obtaining it in a single step from Erythromycin A, in good yield and under mild conditions and suitable for its production. The transformation of Erythromycin A, to an intermediate compound, called 6,9-iminoether, which is obtained in a single step, is carried out through the "in situ" formation of mesitylenesulphonyloxime of erythromycin, which in the presence of from a base in aqueous acetone undergoes a transposition of Beckmann, giving rise to the iminoether, by assisting the hydroxyl in position 6 of the macrolide ring, this intermediate, is transformed to the antibiotic called Azithromycin
Description
IMPROVED PROCESS IN A SINGLE STEP, FOR THE PREPARATION OF
7,16-DlOXA-2-AZA-10-O-CLADINOSIL-12-O-DESOSAMINIL-4,5-DIHYDROXY-6-ETHYL-3,5f9,11,13,15-HEXAMETILBICICLO [11.2.1] HEXADECA- 1 (2) -EN-8-ONA FROM ERYTHROMYCIN A.
FIELD OF THE INVENTION
The present invention consists in the preparation of azithromycin by means of an alternate path, which consists of the formation of an intermediate product called 6,9-iminoether, in a single step from erythromycin which is transformed to the compound azithromycin.
BACKGROUND OF THE INVENTION
Azithromycin, known by its IUPAC name as 9a-aza-9a-methyl-9-deoxo-9a-omoerythromycin A, being its generic name azithromycin, is a broad-spectrum antibacterial compound derived from Erythromycin A. It differs structurally from This is caused by the insertion of a methylated nitrogen at position 9a into the lactone ring to create a 15-member macrolide. The structural modification significantly improves the potency of the antibiotic against gram-negative bacteria and the distribution of the drug at high concentrations within the tissues.
Azithromycin was independently discovered by Bright U. S. Pat. No. 4,474,768 and Kobregel et. to the. U. S. Pat. 4,517,359 and was designated N-methyl-11-aza-10-deoxo-10-dihydrictrimonin A in these patents.
The sequence of reactions reported in the literature to transform Erythromycin A (1) to Azithromycin (5) consists of 4 main steps, illustrated in Scheme 1, which are described below in a general manner:
a) Oxime formation (2)
From erythromycin A (I), by its reaction with hydroxylamine hydrochloride in methanol.
b) Beckmann's transposition of the oxime (2)
The intramolecular participation of the neighboring 6-hydroxy group is observed when the Beckmann transposition is carried out at 0 ° C with p-toluenesulfonyl chloride in aqueous acetone, giving as product the 6,9-iminoether (3). This iminoether (3) and the process for obtaining it have been described in WO 26,758 and Eur. Pat. 0,137,132. In U.S. Patent No. 4,328,334 this iminoether is erroneously assigned with the structure of a lactam obtained by the transposition of Beckmann from the oxime of Erythromycin A).
c) Imino ether reduction (3)
The reduction of the imino ether (3) to the secondary amine (4) with sodium borohydride in methanol (J. Chem Soc. Perkin Trans. 1, 1986, 1881; J. Org. Cbem. 1997, 62, 7479-7481) or by catalytic hydrogenation in the presence of platinum dioxide and acetic acid as solvent (Tetrahedron Lett, 1994, 35, 3025).
d) Reductive methylation of the secondary amine (4) to obtain Azithromycin (5)
This process is described in US Pat. No. 4,517,359 and in J. Chem Res, 1988, 132. The Escheweiler-Clarke reaction uses formaldehyde methylation in acetic acid for this methylation and has as its main drawback the formation of some reaction impurities as this is the case of formamide derived from amine 9-deoxo-9a-aza-9a-homoerythromycin A.
Recently, an alternative method was described in which the imino ether (3) can be reduced and the product obtained subsequently subjected to a reductive methylation in the presence of formaldehyde and a noble metal as a catalyst, without the need to isolate the intermediate. Under these conditions, Azithromycin is obtained with a good purity and good yield, in a single step, from the imino ether (3) (Eur. Pat. No. 0,879,823 A 1).
Structural elucidation studies of Azithromycin (J. Chem. Res. 1988, 132) have revealed their existence in two crystalline forms: hygroscopic monohydrate and non-hygroscopic crystalline dihydrate. The latter has been described as the preferred form for its manipulation for the purpose of preparing formulations for therapeutic use (Eur. Pat. No. 0,298,650).
It is therefore the object of the present invention to provide an alternate pathway of those already known, to form in a single step the 6,9-imino ether intermediate, to obtain azithromycin.
A further object of the present invention is to provide a process for obtaining azithromycin faster and more economically.
DESCRIPTION OF THE INVENTION
All the methods reported to date for the preparation of Azithromycin (5), involve the formation of oxime (2), of Erythromycin A, by treatment of Erythromycin with hydroxylamine hydrochloride and a base, in methanol at room temperature. reflux and a minimum time of 10 hours. This oxime is isolated, purified and subsequently subjected to the rearrangement of Beckmann to obtain the intermediate (3), in aqueous acetone in the presence of p-toluenesulfonyl chloride and base for 2 hours at 5 ° C and 2 hours at room temperature. The novelty of this invention is that iminoether (3) is prepared in a single step from Erythromycin A (1), which is operatively and economically more feasible than the methods cited. The reaction described in this invention consists in treating a solution of Erythromycin A (I), in acetone with O-mesitylenesulfonylhydroxylamine (MSH), to form "in situ" the mesitylenesulfonyloxime of Erythromycin A, which when treated with an aqueous base (sodium bicarbonate) at 0 ° C, carries out a rearrangement of Beckmann, giving rise to the intermediate 6,9-iminoether (3). The reaction conditions are smooth, with short times and the reagent used in this transformation (MSH) is easily prepared as described in Tetrahedron lett. No. 40, p. 4133-4135 (1972). Also the method described in the present invention is scalable to own quantities for an industrial level preparation. Once the known intermediate (3) is prepared, it is possible to obtain Azithromycin (5) according to the usual techniques reported in the literature (Eur. Pat. No. 0.827.965 A2, US Pat. No. 4,328,334, US Pat. No. 4,517,359; Eur. Pat. No. 0,879,823 A1).
Next, the procedure of the best known production method for the formation of intermediate compound (3), named 7,16-dioxa-2-aza-10-O-cladinosyl-12-O-desosaminyl-4,5- is described. hydroxy-6-ethyl-3,5,9,11,13-hexamethylbicyclo [11.2.1] hexadeca-1 (2) -en-8-one, according to the following example:
A solution of Erythromycin A (6.0 g, 0.082 mol), in 30 ml. of acetone, under N2 atmosphere, cooled to 0 ° C and 1.62g was added. (1.05 eq.) Of O- (mesitylsulphonyl) hydroxylamine (MSH). Stirring was continued at 0 ° C for 5 minutes and then the temperature was allowed to rise to the room, stirring continuing for an additional hour. Subsequently, the reaction mixture was again cooled to 0 ° C and a 2.75 g solution was added dropwise. (0.032 mol) of sodium bicarbonate in 30 ml. of water, keeping the internal temperature between 0 and 5 ° C; the addition time was 30 minutes; When the addition was complete, the temperature was allowed to rise to the room and stirring was continued for a further 2 hours. Finally the acetone was evaporated under reduced pressure and the aqueous residue was adjusted to a pH of 5.5 with 2N HCl. This phase was extracted twice with CH2Cl2 (20 ml.). Extraction was repeated at a pH of 6.0 (2 x 20 ml.) And at pH 8.0 (3 x 20 ml.); the extracts of each pH were combined, dried with K2CO3 and evaporated to dryness. At pH 8.0, 4.48 g were isolated. (75%) of the compound (3). The final compound was identified by means of studies that fulfilled the following characteristics:
P.f. 128-131 ° C IR (CHC, 3) 1705 and 1725 crtr1 13C NMR (CDCI3) 178.1, 163.9, 87.3
Claims (3)
1. Improved process, in a single step, for the preparation of 7,16-dioxa-2-aza-10-O-cladnosnosyl-12-O-desosaminyl-4,5-dydroxy-6-eti l-3,5,9,11, 13,15-hexamethylbicyclo [11.2.1] hexadeca-1 (2) -en-8-one from Erythromycin A characterized in that an intermediate must be constituted in the preparation for synthesis, the erythromycin A being reacted in acetone, with the mesitylsulfonylhydroxylamine and the resulting mixture treated with aqueous sodium bicarbonate to obtain the intermediate compound, which is the 6,9-imino ether, resulting in good yield and good purity.
2. Improved process, in a single step, for the preparation of 7,16-dioxa-2-aza-10-O-cladinosil-12-O-desosaminyl-4,5-dihydroxy-6-ethyl-3I5I9, 11, 13,15-hexamethylbicyclo [11.2.1] hexadeca-1 (2) -en-8-one from Erythromycin A, in accordance with clause 1, characterized in that the erythromycin solution in 30 ml of acetone, under inert atmosphere; it is cooled to 0 ° C and 1.62 g (1.05 eq) of O- (mesitylenesulfonyl) hydroxylamine (MSH) is added; it is stirred at 0 ° C in 5 min intervals, then the temperature is raised; staying agitated for one more hour.
3. Improved process, in a single step, for the preparation of 7,16-dioxa-2-aza-10-O-cladinosM2-O-desosaminol-4,5-d-hydroxy-6-ethyl -3,15,9,11,13,15-hexamethylbicyclo [11.2.1] hexadeca-1 (2) -en-8-one from Erythromycin A, in accordance with clause 1 and characterized in that the mixture obtained is cooled from again at 0 ° C, putting a solution of sodium bicarbonate dropwise, in a concentration of 0.032 mol in 30 ml. of water, in a time of 30 minutes; the temperature is maintained, by an interval ranging from 0 to 5 ° C; the temperature is increased and kept stirring for two more hours. Improved process, in a single step, for the preparation of 7,16-dioxa-2-aza-10-O-adinosi-12-O-desosaminyl-5-dihydroxy-6-etl-3, 5,9,11,13,15-hexamethylbicyclo [11.2.1] hexadeca-1 (2) -en-8-one from Erythromycin A, in accordance with clause 3, characterized in that to reach the intermediate product, termed iminoether, proceed as follows: the acetone is evaporated under reduced pressure and the residue adjusted to pH 5.5 with 2N HCl; this phase is extracted with CH2Cl2, the extraction is repeated at pH 6.0 and at pH 8.0; the extracts of each pH are combined, dried with K2CO3, evaporated to dryness; at pH 8.0 it is isolated from the intermediate compound, the imino ether (3); which will finally be transformed to Azithromycin.
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99006221A true MXPA99006221A (en) | 2000-12-06 |
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