MXPA98003916A - Novedoso process for the preparation of azitromic - Google Patents
Novedoso process for the preparation of azitromicInfo
- Publication number
- MXPA98003916A MXPA98003916A MXPA/A/1998/003916A MX9803916A MXPA98003916A MX PA98003916 A MXPA98003916 A MX PA98003916A MX 9803916 A MX9803916 A MX 9803916A MX PA98003916 A MXPA98003916 A MX PA98003916A
- Authority
- MX
- Mexico
- Prior art keywords
- formaldehyde
- process according
- hours
- imino ether
- azithromycin
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- 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 15
- ODUCDPQEXGNKDN-UHFFFAOYSA-N Nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229960004099 azithromycin Drugs 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 238000006722 reduction reaction Methods 0.000 claims abstract description 7
- 229910000510 noble metal Inorganic materials 0.000 claims abstract description 6
- 238000006485 reductive methylation reaction Methods 0.000 claims abstract description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 3
- 239000001257 hydrogen Substances 0.000 claims abstract description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims abstract 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 26
- 229910052703 rhodium Inorganic materials 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- 239000011541 reaction mixture Substances 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000012429 reaction media Substances 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 230000001105 regulatory Effects 0.000 claims 1
- 229910052707 ruthenium Inorganic materials 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 239000010948 rhodium Substances 0.000 description 15
- 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 description 14
- 229960003276 erythromycin Drugs 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- 239000007864 aqueous solution Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000002955 isolation Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000002829 reduced Effects 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 239000003120 macrolide antibiotic agent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000002378 acidificating Effects 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 150000002923 oximes Chemical class 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000001131 transforming Effects 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 206010001488 Aggression Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- SRMPHJKQVUDLQE-KUJJYQHYSA-N azithromycin dihydrate Chemical compound O.O.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 SRMPHJKQVUDLQE-KUJJYQHYSA-N 0.000 description 1
- 230000003115 biocidal Effects 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- 230000003197 catalytic Effects 0.000 description 1
- AJSDVNKVGFVAQU-BIIVOSGPSA-N cladinose Chemical group O=CC[C@@](C)(OC)[C@@H](O)[C@H](C)O AJSDVNKVGFVAQU-BIIVOSGPSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000005712 crystallization Effects 0.000 description 1
- -1 cyclic amine Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 150000002466 imines Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000005020 pharmaceutical industry Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000003638 reducing agent Substances 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
- 230000002194 synthesizing Effects 0.000 description 1
Abstract
The present invention relates to a new process for the preparation of azithromycin from an iminoether, suitable as a precursor, characterized in that the reduction and reductive methylation of the imino ether are carried out sequentially with a noble metal catalyst and hydrogen in the presence of formaldehyde or a source thereof, where the two reactions can be carried out in the same reaction vessel
Description
NOVEDOSO PROCESS FOR THE PREPARATION OF AZITRO ICINA
BACKGROUND AND FIELD OF THE INVENTION Azithromycin is a well-known semisynthetic macrolide antibiotic (U.S. Patent Nos. 4,474,768 and 4,517,359), which are prepared by expansion / inclusion of a nitrogen atom in the macrolide ring of erythromycin A, followed by reductive methylation. In this way, a more stable and more effective antibiotic is obtained than erythromycin A, particularly against gram-negative bacteria. The reaction sequences for transforming erythromycin A into azithromycin involves extremely strong and aggressive reaction conditions (compare, J. Chem. Soc. Perkin Trans. I, 1881 (1986)), and requires the isolation of intermediates which, under certain conditions , they are even more unstable than the starting material. The reaction conditions and the isolation procedures must at the same time be smooth and have strictly controlled parameters. This can result in other problems when a scale-to-laboratory process is implemented at an industrial scale. Under these circumstances, other restrictions must be implemented in the manufacturing process to ensure that azithromycin is obtained with good performance and high
P1292 / 98MX purity. The transformation of erythromycin A into azithromycin involves: the conversion of erythromycin into its oxime; the Beck ann rearrangement of the oxime to produce the imino ether of erythromycin A; the reduction of the imino ether in 9-deoxo-9a-aza-9a-homoerythromycin and, finally, the reductive N-methylation to obtain the final product. The reduction of imino ether and reductive methylation have been described to date as two-step processes (PCT Patent Application No. 94/02547 - Publication No. 94/26758; European Patent No. 0 109 253), perhaps because to that in these procedures the purification of 9-deoxo-9a-aza-9a-homoerythromycin is required before proceeding to the next step.
OBJECTS AND ADVANTAGES OF THE INVENTION Accordingly to the present invention, it has been found that a suitable erythromycin i ether can be reduced and the product obtained in this form can subsequently be subjected to reductive aetilation in the presence of the same noble metal catalyst and in the presence of formaldehyde or a source of misir.o, sir. No isolation of the intermediate product. The two reactions already known per se can subsequently be carried out using the same catalytic system er.
P1292 / 98MX the same reaction vessel and in the same reaction medium. By carefully selecting the reaction conditions, a product of good purity and good performance can be obtained. Therefore, the present process represents a considerable industrial advantage over the prior art since it reduces the number of reactors and manipulations, as well as the isolation of intermediate product. The preferred reaction conditions are described below.
DETAILED DESCRIPTION OF THE INVENTION According to the previously published literature, the conditions that have been found most effective for effecting the imino ether reaction are: use of reducing agents in stoichiometric quantities or high pressure hydrogenation using platinum (PCT Patent Application No 94/02547 - Publication No. 94/26758), followed by cyclic amine isolation, which is then subjected to reductive merization, using the well-known conditions of Esch eiler-Clarke formaldehyde and formic acid in chloroform. by hydrogenation - formaldehyde and hydrogen in the presence of a noble metal catalyst (U.S. Patent No. 4,517,359, Chem. Res., 1988, 1239-1261). The reduction with sodium borohydride (Patent of
P1292 / 98MX United States No. 0109253, J. Chem Soc. Perkin Trans. , I, 986, 1881), involves an extremely accurate procedure in regard to the recovery of product and the completion of the reaction. The initial intermediate present in the reaction medium is apparently a complex containing boron which must be destroyed in order that 9-deoxo-9a-asa-9a-homoerythromycin can be isolated. the complex in question must be disposed of in acidic conditions and, as is already known, because the macrolide in question is sensitive to the acidic medium, the conditions for this stage must be strictly controlled. This process is more problematic on an industrial scale, since the contact times between the sensitive intermediate and the undesirable aqueous acid medium are more inevitably prolonged. In the present invention, these difficulties are solved by synthesizing the intermediate of 9-deoxo-9a-aza-9a-homoerythromycin under mild conditions, which does not need to be isolated or purified before the next step. Naturally, the isolation of this isolate can be carried out if desired. The reduction is carried out at a temperature between 0-50 ° C, the preferred range is between 2C-25 ° C. At this temperature, lateral reactions such as hydrolysis of the glycosides
P1292 / 98MX present in the molecule, are reduced, especially the hydrolysis that involves the cladinose unit. The preferred solvents are acetic acid containing different percentages of water. Organic solvents such as ethanol, tetrahydrofuran, dioxane or mixtures thereof with water can also be used. The pressures that lead to the best results and acceptable reaction times are those that are between 20-70 bar, but other pressures outside these limits can be used. The preferred catalyst is 5% rhodium on carbon, although other noble metal catalysts such as platinum, palladium or rubtenium can be employed. The amount of rhodium used can vary between 0.5 and 2% calculated with respect to the starting material, although other percentages outside this range can be used. However, the reaction times as a result of this are less suitable. Suitable sources of formaldehyde are a 3% aqueous solution of formaldehyde, although other sources may be used. The amount of formaldehyde used can vary between 23 and 100 r.oles / mol of the imino ether. A smaller amount of catalyst may be added in addition in order to complete the reaction center of a reasonable time.
P1292 / 98MX If desired, the catalyst can be recycled and reused several times, making the process more economical. Azithromycin is isolates by adjusting the pH of the reaction mixture between 9 and 10. In this form, it is possible to obtain azithromycin of acceptable purity by crystallization from an ethanol / water mixture, and therefore a product with a purity high enough to be used is obtained. as starting material in the pharmaceutical industry. Therefore, this invention achieves, among others, the following advantages. - 2 chemical reactions in only one reaction vessel; - the use of less sophisticated industrial equipment, given that one of the intermediaries is not isolated;
- milder reaction conditions, in view of a pure product with high performance.
DESCRIPTION OF THE PREFERRED MODALITY The following examples serve to illustrate the present invention and in no sense are considered as limitations thereof:
EXAMPLE 1
P1292 / 98MX EXAMPLE 1 To a solution of 2g (2.7 mmol) of the imino ether of erythromycin A, prepared by the standard techniques, in 20 ml of acetic acid, 0.03 g (0.38 mmol) of sodium acetate and 0.5 g were added. of Rh / C to 5% wet (11.25 mg Rh). The mixture is subsequently hydrogenated at a pressure of 70 bar and at 40 ° C for 3 hours. At the end of this period, 27 ml of an aqueous solution containing 37% formaldehyde (0.36 moles) were added under atmospheric pressure and at room temperature, and the mixture was hydrogenated at 40 bar and at a temperature of 40 ° C for 20 hours. The catalyst was removed by filtration and the filtrate was evaporated until an oil was obtained. To the oil obtained in this way 45 ml of water was added, and the pH of the solution was adjusted to 9.3 with 4N NaOH. After stirring for 2 hours at room temperature, the solid was filtered, washed with water and dried to give 1.2 g of the crude azithromycin with a purity of 97% after recrystallization.
EXAMPLE 2 To a solution of 4 g (5.4 mmol) of erythromycin A imine ether prepared by the usual techniques, 1 g of moist 5% Rh / C (22.5 mg Rh) was dissolved in 20 ml of acetic acid. The rub is hydrogenated at 60 bar and
P1292 / 98MX temperature of 40 ° C for 5 hours. At the end of this period, 22.5 ml of an aqueous solution containing 37% formaldehyde (0.3 moles) were added under atmospheric pressure and at room temperature, and the mixture was then hydrogenated at 40 bar and at a temperature of 40 ° C for 20 hours. The catalyst was removed by filtration and the filtrate was evaporated until an oil was obtained. To this oil was added 90 ml of water, and the pH of the solution was adjusted to 9.4 with 4N NaOH. After stirring for 2 hours at room temperature, the solid was filtered, washed with water and dried to give 2 g of the crude azithromycin with a purity of 97% after recrystallization.
EXAMPLE 3 To a solution of 8g (10.9 mmoles) of erythromycin A imino ether, prepared by standard techniques, in 32 ml of acetic acid and 8 ml of water, 8 g of moist 5% Rh / C were added (180 g. Rh mg). The mixture is then hydrogenated at 70 bar and at room temperature for 2 hours. At the end of this period, 40 ml of an acucsa solution containing 37% formaldehyde (0.54 mol) were added, and the mixture was hydrogenated at 40 bar and at a temperature of 3-45 ° C for 20 hours. The catalyst was removed by filtration and the pH of the filtrate was adjusted to 9.4 with 4N NaOH. After stirring for 2 hours at room temperature, the solid
P1292 / 98MX filter, washed with water and dried to give 7 g of the crude azithromycin with a purity of 95% after recrystallization.
EXAMPLE 4 To a solution of 4 g (5.4 mmol) of erythromycin A imino ether, prepared by standard techniques, in 4 ml of acetic acid and 16 ml of water, 4 g of moist 5% Rh / C was added (90 g. Rh mg). The mixture is hydrogenated at 70 bar and at room temperature for 2 hours. At the end of this period, 25 ml of an aqueous solution containing 37% formaldehyde (0.34 mole) was added at atmospheric pressure and room temperature, and the mixture was hydrogenated at 40 bar and at a temperature of 40-45 ° C for 24 hours. . The catalyst was removed by filtration and the pH of the filtrate was adjusted to 9.4 with 4N NaOH. After stirring for 2 hours at room temperature, the precipitate was separated by filtration, washed with water and dried to give 2.8 g of crude azithromycin with a purity of 98% after recrystallization.
EXAMPLE 5 To a solution of 8g (10.9 mmoles) of erythromycin A imino ether, prepared by standard techniques, in
24 ml of acetic acid, 8 g of 5% Rh / C was added
Wet P1292 / 98MX (180 mg Rh). The mixture is hydrogenated at 70 bar and at room temperature for 2 hours. At the end of this period, 50 ml of an aqueous solution containing 37% formaldehyde (0.67 mol) were added at atmospheric pressure and room temperature, and the mixture was hydrogenated at 40 bar and 40-45 ° C for 24 hours. The catalyst was filtered off and the pH of the filtrate was adjusted to 9.5 with 4N NaOH. After stirring for 2 hours at room temperature, the solids were filtered, washed with water and dried giving 6.1 g of the crude azithromycin with a purity of 98% after recrystallization.
EXAMPLE 6 To a solution of 4 g (5.4 mmol) of erythromycin A imino ether, prepared by standard techniques, in
18 ml of acetic acid and 2 ml of water, 2 g of water were added.
% moist Rh / C (45 mg Rh). The mixture is then hydrogenated at 70 bar and at room temperature for 2 hours.
At the end of this period, 35 ml of an aqueous solution containing 37% formaldehyde (0.47 moles) was added under atmospheric pressure at room temperature, and the pH was adjusted between 3 and 4 with 4N NaOH. The mixture is hydrogenated at 40 bar and at a temperature of 40-45 ° C for 24 hours. The catalyst was filtered off and the? H of the filtrate was adjusted to 9.4 with 4N NaOH. After shaking
P1292 / 98MX for 2 hours at room temperature, the solid was filtered, washed with water and dried to give 2.7 g of crude azithromycin with a purity of 96% after recrystallization.
EXAMPLE 7 To a solution of 8 g (10.9 mmol) of erythromycin A imino ether, prepared by standard techniques, in 8 ml of acetic acid and 32 ml of water, 8 g of moist 5% Rh / C was added (180 g. Rh mg). The mixture is hydrogenated at 70 bar and at 40 ° C for 2 hours. At the end of this period, 10 g (0.33 mole) of formaldehyde was added under atmospheric pressure and room temperature, and the pH of the reaction mixture was adjusted to 4 with NaOH. The hydrogenation was carried out at a pressure of 40 bar and at a temperature of 40-45 ° C for 24 hours. The catalyst was removed by filtration and the pH of the reaction mixture was adjusted to 9.2 with 4N NaOH. After stirring for 2 hours at room temperature, the solids were filtered, washed with water and dried, giving 4.98 g of the crude azithromycin with a purity of 97% after recrystallization.
P1292 / 98MX
Claims (9)
- NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property: 1. Novel process for the preparation of azithromycin from a suitable imino ether used as precursor, characterized in that the reduction and reductive methylation of the imino ether are carried out sequentially with a noble metal catalyst and hydrogen in the presence of formaldehyde, or a source thereof, wherein the two reactions can be carried out in the same reaction vessel.
- 2. Process according to claim 1, characterized in that the formaldehyde or a source thereof is added at the start of the reduction phase.
- 3. Process according to claim 1, characterized in that the formaldehyde or a source thereof is "swamped at the beginning of the reductive methylation phase." 4.
- Process according to claim 4, characterized by the - fact that the noble metal is selected from the group of Pf,? t, Rh and Ru.
- Process according to claim 1, P1292 / 98MX characterized by the fact that formaldehyde can be present as formalin or formaldehyde.
- Process according to claim 1, characterized in that the solvent of the reaction mixture is selected from acetic acid and formic acid, optionally in the presence of an organic solvent.
- Process according to claim 6, characterized in that the organic solvent is ethanol.
- Process according to claim 1, characterized in that the acidity of the reaction medium is controlled by the addition of a pH regulating salt.
- 9. Process according to claim 8, characterized in that the sodium acetate is used as a pH regulator. P1292 / 98MX
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PT102.006 | 1997-05-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA98003916A true MXPA98003916A (en) | 2000-08-01 |
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