CN113929721A - Azithromycin synthesis process - Google Patents
Azithromycin synthesis process Download PDFInfo
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- CN113929721A CN113929721A CN202111295171.8A CN202111295171A CN113929721A CN 113929721 A CN113929721 A CN 113929721A CN 202111295171 A CN202111295171 A CN 202111295171A CN 113929721 A CN113929721 A CN 113929721A
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- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- 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
Abstract
The invention relates to a drug synthesis technology, in particular to an azithromycin synthesis process. In the synthesis process of the dihydrohomoerythromycin, the pH value is adjusted to 9.5-10.0 after hydrolysis, the material is firstly transferred to a dichloromethane organic phase, the pH value is adjusted to 3.5-4.0 in the phase inversion step to transfer the material to a water phase, then the pH value is adjusted to 9.5-10.0 to transfer the material to the dichloromethane organic phase, and finally the pH value is adjusted to 6.0-6.5 to transfer the material to the water phase.
Description
Technical Field
The invention relates to a drug synthesis technology, in particular to an azithromycin synthesis process.
Background
Azithromycin is 15-membered ring macrolide antibiotic, which interferes with the synthesis of bacterial protein through blocking transpeptidic activity, has wider antibacterial range, obviously improves the antibacterial activity of gram-negative bacteria besides retaining the antibacterial activity to gram-positive bacteria, can inhibit streptococcus pneumoniae, streptococcus, Klebsiella catarrhalis, mycoplasma pneumoniae, legionella pneumophila, Chlamydia trachomatis, Haemophilus ducreyi and the like, has good effect on respiratory system, skin and soft tissue infection and sexually transmitted diseases caused by common sensitive bacteria, and has very wide application in the anti-infection field.
Azithromycin is usually synthesized by taking erythromycin thiocyanate as a raw material through oximation, Beckmann rearrangement, potassium borohydride reduction, acidic hydrolysis and methylation reaction. In the synthesis process of azithromycin, dihydrohomoerythromycin is an extremely important intermediate, and potassium borohydride reduction and acid hydrolysis are two process steps for preparing dihydrohomoerythromycin, and are key steps influencing azithromycin synthesis and production cost.
The azithromycin A which is the main raw material of the azithromycin is a fermentation product, a plurality of byproducts are generated in the fermentation process, and the structure and the physicochemical properties of a plurality of impurities are similar to those of the erythromycin A, such as erythromycin F and the like. These impurities may be reacted in the same manner during the synthesis of the latter intermediates and remain in the product. The impurity D of azithromycin (azithromycin F, CAS number: 612069-26-8) is brought about by the impurity erythromycin F in the raw material.
The literature (horse sensitive, Yao national Wei, Dengyulin research on hydrolysis of boric acid ester in azithromycin synthesis [ J ]. Fine chemical industry, 2006,23(6): 558. 587) reports that in the acidic hydrolysis process, the bond between the cladinose ring and the lactone ring on the erythromycin azoxide is weak, and the erythromycin azoxide is unstable and easily degradable in an acidic medium to generate degradation impurities. This degraded impurity, upon subsequent further methylation, yields azithromycin impurity J (azithromycin desosamine, CAS number: 117693-41-1).
CN104892697A discloses an azithromycin production process, wherein the preparation of an azithromycin intermediate dihydrohomoerythromycin is carried out by reducing with potassium borohydride and carrying out acid hydrolysis; azithromycin is refined by crystallization in a water and acetone system.
In the current azithromycin industrial production, azithromycin is refined and crystallized in a water and acetone system, the removing effect on azithromycin impurity D and impurity J is poor, and a product with higher quality cannot be obtained.
Disclosure of Invention
The invention provides an azithromycin synthesis process, which can obtain high-quality azithromycin with low content of azithromycin impurity D and impurity J.
The invention firstly provides a dihydrohomoerythromycin synthesis process, which comprises the following steps: adding erythromycin A-6, 9-imine ether into water, cooling to 0-5 deg.C, adjusting pH to 5.5-6.5 with dilute hydrochloric acid, dissolving, adding potassium borohydride, reacting at 0-5 deg.C under constant temperature, adjusting pH to 5.5-6.5 with dilute hydrochloric acid, adding potassium borohydride, reacting under constant temperature, adding dichloromethane, adjusting pH to 9.5-10.0 with sodium hydroxide solution, separating, keeping dichloromethane layer, adding organic layer into water, hydrolyzing at 0-3 deg.C and pH 1.0-1.5, adjusting pH to 9.5-10.0 with sodium hydroxide solution, separating, collecting dichloromethane layer, adding water 1.1 times or more volume of dichloromethane layer, controlling temperature to 4-6 deg.C, adjusting pH to 3.5-4.0 with dilute hydrochloric acid, transferring to water phase, separating, collecting water layer, adding dichloromethane into water layer, adjusting pH to 9.5-10.0 with sodium hydroxide solution, transferring to organic phase, separating to obtain organic layer, adding water with volume more than or equal to 1.1 times of the organic layer, adjusting pH to 6.0-6.5 with dilute hydrochloric acid, transferring to water phase, separating to obtain water layer, transferring the water layer to a crystallization kettle, adjusting pH to neutral with sodium hydroxide solution, concentrating, adding acetone, controlling temperature at 30-35 deg.C, adding sodium hydroxide solution for crystallization, adjusting pH to 11.7-12.2, adding water dropwise, and filtering to obtain dihydrohomoerythromycin.
The dihydrohomoerythromycin (CAS: 11965-78-0) described herein may be useful as an intermediate in the synthesis of azithromycin.
The method for preparing the dihydrohomoerythromycin has the advantages of relatively simple process treatment, no complex operation and no need of treatment with higher cost. The dihydrohomoerythromycin intermediate synthesized by the method is used for synthesis of azithromycin, the impurity D + J of the prepared azithromycin is lower than that of the azithromycin prepared by the process before optimization by more than 30 percent, and the azithromycin with high quality and the impurity D + J content of less than 0.2 percent can be obtained after the process optimization.
Drawings
Figure 1 is a high performance liquid chromatography profile of azithromycin prepared as in example 1.
Figure 2 is an azithromycin related substance identification profile prepared in example 1.
Figure 3 is a high performance liquid chromatography chromatogram of azithromycin prepared in comparative example 1.
Detailed Description
The present invention will be described in detail below.
CN104892697A (see paragraphs 39-40 of the specification) describes the synthesis of dihydrohomoerythromycin (9-deoxo-9 a-aza-9 a-homoerythromycin). Wherein, the methylene dichloride layer after hydrolysis and delamination is added with 0.75 times of process water to be stirred and cooled to 1-3 ℃, the pH value is adjusted to 4.5-5.5 by dilute hydrochloric acid, standing and delamination are carried out, and the water layer is removed from a crystallization kettle to be crystallized.
The inventor finds that the water consumption of the phase inversion process in the steps is relatively low, so that the impurity removal in the subsequent crystallization step is not facilitated; in the step, the pH value of the material is adjusted by dilute hydrochloric acid to transfer the material from an organic phase to a water phase, the pH value of the phase inversion is in the range of 4.5-5.5, more impurities are brought into the water phase and enter a subsequent process, and the removal effect of some impurities (such as azithromycin impurity D and impurity J) through acetone and water system crystal is poor, so that some impurities of azithromycin are relatively high; the phase inversion temperature in the step is low, methylene dichloride and a water layer are easy to emulsify under the stirring condition, liquid separation is not facilitated, the liquid separation effect is not good, and impurities can be brought in.
Aiming at the problems, the invention optimizes the process: adding more than or equal to 1.1 times of process water into a dichloromethane layer after hydrolysis and delamination, stirring and cooling to 4-6 ℃, adjusting the pH value to 3.5-4.0 by using dilute hydrochloric acid, separating and taking a water layer (the industrial production adopts a centrifugal extractor to separate liquid), adding more than or equal to 1.1 times of process water into the water layer, stirring and cooling to 4-6 ℃, adjusting the pH value to 6.0-6.5 by using dilute hydrochloric acid, adding dichloromethane into the water layer, adjusting the pH value to 9.5-10.0, separating and taking the dichloromethane layer (the industrial production adopts a centrifugal extractor to separate liquid), adding the water layer into the dichloromethane layer, stirring and cooling to 4-6 ℃, adjusting the pH value to 6.0-6.5 by using dilute hydrochloric acid, separating liquid and taking the water layer (the industrial production adopts a centrifugal extractor to separate liquid), and removing the water layer from a crystallization kettle for crystallization. In the phase inversion step, the pH value is adjusted to 3.5-4.0 firstly to transfer the material to a water phase, then the pH value is adjusted to 9.5-10.0 to transfer the material to an organic phase, finally the pH value is adjusted to 6.0-6.5 to transfer the material to a water phase, partial impurities can remain in the waste dichloromethane phase and the water phase in the phase inversion process, the impurities which finally participate in the crystallization water phase are reduced, the removal rate of the impurities is much higher than that of the phase inversion pH value of 4.5-5.5, and particularly, the removal effect of related impurities corresponding to the impurities D and the impurities J of the azithromycin is obvious. The adjustment of the temperature in the phase inversion step is beneficial to liquid separation, and the risk of bringing impurities into the subsequent process steps is reduced.
Specifically, the invention provides a dihydrohomoerythromycin synthesis process, which comprises the following steps: adding erythromycin A-6, 9-imine ether into water, cooling to 0-5 deg.C, adjusting pH to 5.5-6.5 with dilute hydrochloric acid, dissolving, adding potassium borohydride, reacting at 0-5 deg.C under constant temperature, adjusting pH to 5.5-6.5 with dilute hydrochloric acid, adding potassium borohydride, reacting under constant temperature, adding dichloromethane, adjusting pH to 9.5-10.0 with sodium hydroxide solution, separating, retaining dichloromethane layer, adding organic layer into water, hydrolyzing at 0-3 deg.C and pH 1.0-1.5, adjusting pH to 9.5-10.0 with sodium hydroxide solution, separating, collecting dichloromethane layer, adding water 1.1 times or more volume of dichloromethane layer, controlling temperature to 4-6 deg.C, adjusting pH to 3.5-4.0 (optionally 3.7-3.9) with dilute hydrochloric acid, transferring the material to water phase, separating, collecting water layer, adding dichloromethane, adjusting pH to 9.5-10.0 with sodium hydroxide solution, transferring to organic phase, separating to obtain organic layer, adding water with volume of 1.1 times or more into the organic layer, adjusting pH to 6.0-6.5 (optionally 6.1-6.4) with dilute hydrochloric acid, transferring to water phase, separating to obtain water layer, transferring the water layer to crystallization kettle, adjusting pH to neutral with sodium hydroxide solution, concentrating, adding acetone, controlling temperature at 30-35 deg.C, adding sodium hydroxide solution for crystallization, adjusting pH to 11.7-12.2, adding water dropwise, and filtering to obtain dihydrohomoerythromycin.
According to the present example, the weight ratio of erythromycin A-6, 9-imino ether to potassium borohydride is 50 (5-6), e.g., 50: 5.65.
According to the present example, the weight ratio of erythromycin A-6, 9-imino ether to first added potassium borohydride is 50 (3-4), e.g., 50: 4.
According to the present example, the weight ratio of erythromycin A-6, 9-imino ether to the second addition of potassium borohydride is 50 (1-2), e.g., 50: 1.65.
According to the embodiment of the invention, the weight ratio of the erythromycin A-6, 9-imino ether to the water is 1 (3-4), that is, the erythromycin A-6, 9-imino ether is added into the water with the weight of 3-4 times.
According to an embodiment of the invention, the concentration of the dilute hydrochloric acid is between 5% and 15%, for example 5%.
According to an embodiment of the invention, the concentration of the sodium hydroxide solution is 10% to 20%, for example 20%.
According to the embodiment of the invention, the time for the first addition of potassium borohydride is 1-3h, for example 2.5 h.
According to an embodiment of the present invention, the time for the second addition of potassium borohydride is 0.5-1.5h, for example 1 h.
According to the embodiment of the invention, after the second addition of potassium borohydride, the volume weight ratio of the added dichloromethane to the erythromycin A-6, 9-imino ether in ml/g is (6-10):1, for example 8: 1.
According to the embodiment of the invention, after the separation (i.e. the first separation), the dichloromethane layer is taken, and 1.1 to 1.5 times of water is added into the dichloromethane layer.
According to the embodiment of the invention, the organic layer is taken for the liquid separation (i.e. the second liquid separation), and 1.1 to 1.5 times of water is added into the organic layer.
According to an embodiment of the present invention, the concentration of the sodium hydroxide solution in the crystallization step is 10-15%.
According to the embodiment of the invention, the volume weight ratio (in ml/g) of the acetone added in the crystallization step to the erythromycin A-6, 9-imino ether is (1.8-2.4): 1, e.g. 2: 1.
According to the examples of the present invention, the ratio by volume of water to erythromycin A-6, 9-imino ether (in ml/g) added in the crystallization step is (1.1-1.3):1, for example 1.125: 1.
In the synthesis process of the dihydrohomoerythromycin, the pH value is adjusted to 9.5-10.0 after hydrolysis, the material is firstly transferred to a dichloromethane organic phase, the pH value is adjusted to 3.5-4.0 in the phase inversion step to transfer the material to a water phase, then the pH value is adjusted to 9.5-10.0 to transfer the material to the dichloromethane organic phase, and finally the pH value is adjusted to 6.0-6.5 to transfer the material to the water phase.
The invention also comprises the dihydrohomoerythromycin prepared by the process.
The dihydrohomoerythromycin prepared by the optimized process has low content of azithromycin impurities D + J, and can be further prepared into high-quality azithromycin.
The invention also provides an azithromycin synthesis process, which comprises the following steps: preparing dihydrohomoerythromycin by the process; and further preparing the dihydrohomoerythromycin to obtain the azithromycin.
Among them, dihydrohomoerythromycin can be prepared into azithromycin by a method conventional in the art, for example, by methylation reaction and crystallization.
The present invention will be further described with reference to the following examples.
The following raw materials are commercially available or prepared by conventional methods. The erythromycin A-6, 9-imino ether used in the following is a product of the same batch.
Example 1
Adding 50g of erythromycin A-6, 9-imine ether into 160ml of water, adjusting the pH value to 6.1 by using 5% dilute hydrochloric acid at 2.6 ℃, adding 4g of potassium borohydride after dissolution, keeping the temperature at 2.2 ℃ for reaction for 2.5 hours, adjusting the pH value back to 6.2 by using 5% dilute hydrochloric acid after heat preservation, adding 1.65g of residual potassium borohydride, keeping the temperature for 1 hour, adding 330ml of dichloromethane after reaction is finished, adjusting the pH value to 9.7 by using 20% sodium hydroxide solution, separating, reserving a dichloromethane layer, adjusting the pH value to 1.0 by using 5% dilute hydrochloric acid, hydrolyzing for 20 minutes at 1 ℃, adjusting the pH value to 9.7 by using 20% sodium hydroxide solution, taking the dichloromethane layer after liquid separation, adding 55ml of water into the dichloromethane layer, adjusting the pH value to 4.4 ℃ by using 5% dilute hydrochloric acid, transferring the material to an aqueous phase, taking a water layer by liquid separation, adding 200ml of dichloromethane into an aqueous layer, transferring to an organic phase by adjusting the pH value to 9.7 by using 20% sodium hydroxide solution, taking an organic layer, adding 55ml of water into an organic layer, adjusting the pH value to 6.2 by using 5% dilute hydrochloric acid, separating, collecting water layer, transferring the water layer into crystallization kettle, adjusting pH to neutral with 10% sodium hydroxide solution, concentrating, adding acetone 100ml, controlling temperature at 35 deg.C, adding 10% sodium hydroxide solution for crystallization, adjusting pH to 11.8, adding water 56ml, and filtering to obtain dihydrohomoerythromycin.
The crystallized dihydrohomoerythromycin is methylated and crystallized to obtain azithromycin. Taking 30g of crystallized dihydrohomoerythromycin, adding 84ml of acetone, heating to 35 ℃, adding 5.25g of formaldehyde, adding 7.02g of formic acid, heating to reflux reaction for 2.5h, cooling to 20 ℃ after the reaction is finished, adding 20% of sodium hydroxide solution to adjust the pH value to 11.2, standing for layering, taking an organic layer, dripping water at 20 ℃ to precipitate crystals, growing the crystals for 15 minutes, continuously dripping the total water to 186ml, stirring and filtering to obtain the azithromycin.
The purity of the azithromycin prepared by the embodiment is 98.88 percent, and the impurity of D + J is 0.15 percent (refer to the method for detecting related substances of the azithromycin in European pharmacopoeia). The high performance liquid chromatography spectrum of the azithromycin prepared in the embodiment is shown in figure 1, and the identification spectrum of related substances is shown in figure 2. In fig. 2, imp. represents an impurity, "imp.l" is an impurity L.
Example 2
Adding 50g of erythromycin A-6, 9-imine ether into 160ml of water, adjusting the pH value to 5.6 by using 5% dilute hydrochloric acid after dissolving the erythromycin A-6, 9-imine ether, adding 4g of potassium borohydride after dissolving the erythromycin A-6, keeping the temperature of 1.8 ℃ for reaction for 2.5 hours, adjusting the pH value to 6.2 by using 5% dilute hydrochloric acid after keeping the temperature, adding 1.65g of residual potassium borohydride, keeping the temperature for 1 hour, adding 330ml of dichloromethane after finishing the reaction, adjusting the pH value to 9.7 by using 20% sodium hydroxide solution, separating the dichloromethane layer, adding 55ml of water into the dichloromethane layer, adjusting the pH value to 3.7 by using 5% dilute hydrochloric acid, transferring the mixture to an aqueous phase by using 5% dilute hydrochloric acid, transferring the mixture to an organic phase by using 20% sodium hydroxide solution after transferring the mixture to the pH value to 9.7 by using 20% sodium hydroxide solution, transferring the mixture to an aqueous phase by using 55ml of water in the dichloromethane layer, adjusting the pH value to an aqueous phase by using 5% dilute hydrochloric acid, transferring the aqueous phase by using 200ml of water solution to an organic phase by using 20% sodium hydroxide solution, separating, collecting water layer, transferring the water layer into crystallization kettle, adjusting pH to neutral with 10% sodium hydroxide solution, concentrating, adding acetone 100ml, controlling temperature at 32 deg.C, adding 10% sodium hydroxide solution for crystallization, adjusting pH to 12.1, adding water 56ml, and filtering to obtain dihydrohomoerythromycin.
The crystallized dihydrohomoerythromycin is methylated and crystallized to obtain azithromycin. Taking 30g of crystallized dihydrohomoerythromycin, adding 84ml of acetone, heating to 35 ℃, adding 5.25g of formaldehyde, adding 7.02g of formic acid, heating to reflux reaction for 2.5h, cooling to 20 ℃ after the reaction is finished, adding 20% of sodium hydroxide solution to adjust the pH value to 11.2, standing for layering, taking an organic layer, dripping water at 20 ℃ to precipitate crystals, growing the crystals for 15 minutes, continuously dripping the total water to 186ml, stirring and filtering to obtain the azithromycin.
The purity of the azithromycin prepared by the embodiment is 98.81 percent, and the impurity of D and J is 0.17 percent (refer to a method for detecting related substances of the azithromycin in European pharmacopoeia).
Example 3
Adding 50g of erythromycin A-6, 9-imine ether into 160ml of water, adjusting the pH value to 6.2 by using 5% dilute hydrochloric acid at 4.6 ℃, adding 4g of potassium borohydride after dissolving, keeping the temperature at 3.4 ℃ for reaction for 2.5 hours, adjusting the pH value to 6.0 by using 5% dilute hydrochloric acid after keeping the temperature, adding 1.65g of residual potassium borohydride, keeping the temperature for 1 hour, adding 330ml of dichloromethane after finishing the reaction, adjusting the pH value to 9.7 by using 20% sodium hydroxide solution, separating, reserving the dichloromethane layer, adjusting the pH value to 1.0 by using 5% dilute hydrochloric acid, hydrolyzing for 20 minutes at 2.0 ℃, adjusting the pH value to 9.7 by using 20% sodium hydroxide solution, taking the dichloromethane layer after separating, adding 55ml of water into the dichloromethane layer, adjusting the pH value to 5.1 ℃ by using 5% dilute hydrochloric acid, taking the water layer by separating, adding 200ml of dichloromethane into the water layer, adjusting the pH value to 9.7 by using 20% sodium hydroxide solution again, transferring to the organic phase by separating, taking the organic layer by adding 55ml of water, adjusting the pH value to 6.1 by using 5% dilute hydrochloric acid, separating, collecting water layer, transferring the water layer into crystallization kettle, adjusting pH to neutral with 10% sodium hydroxide solution, concentrating, adding 100ml acetone, controlling temperature at 34 deg.C, adding 10% sodium hydroxide solution for crystallization, adjusting pH to 12.0, adding 56ml water dropwise, and filtering to obtain dihydrohomoerythromycin.
The crystallized dihydrohomoerythromycin is methylated and crystallized to obtain azithromycin. Taking 30g of crystallized dihydrohomoerythromycin, adding 84ml of acetone, heating to 35 ℃, adding 5.25g of formaldehyde, adding 7.02g of formic acid, heating to reflux reaction for 2.5h, cooling to 20 ℃ after the reaction is finished, adding 20% of sodium hydroxide solution to adjust the pH value to 11.2, standing for layering, taking an organic layer, dripping water at 20 ℃ to precipitate crystals, growing the crystals for 15 minutes, continuously dripping the total water to 186ml, stirring and filtering to obtain the azithromycin.
The purity of the azithromycin prepared by the embodiment is 98.78 percent, and the impurity of D + J is 0.17 percent (refer to a method for detecting related substances of the azithromycin in European pharmacopoeia).
Comparative example 1
Adding 50g of erythromycin A-6, 9-imine ether into 160ml of water, adjusting the pH value to 5.8 by using 5% dilute hydrochloric acid at 3.2 ℃, adding 4g of potassium borohydride after dissolution, keeping the temperature at 3.5 ℃ for reaction for 2.5 hours, adjusting the pH value back to 6.4 by using 5% dilute hydrochloric acid after the heat preservation is finished, adding 1.65g of residual potassium borohydride, keeping the temperature for 1 hour, adding 330ml of dichloromethane after the reaction is finished, adjusting the pH value to 9.7 by using 20% sodium hydroxide solution, separating, reserving the dichloromethane layer, adjusting the pH value by using 5% dilute hydrochloric acid, hydrolyzing at the pH value of 1.0 for 20 minutes at 2.1 ℃, adjusting the pH value to 9.7 by using 20% sodium hydroxide solution, taking the dichloromethane layer after separation, adding 38ml of water into the dichloromethane layer, adjusting the temperature to 2.2 ℃, adjusting the pH value to 4.8 by using 5% dilute hydrochloric acid, taking the water layer after separation, transferring the water layer into a crystallization kettle, adjusting the pH value to neutrality by using 10% sodium hydroxide solution, adding 100ml of acetone after concentration, controlling the temperature to 33 ℃, adding 10% sodium hydroxide solution for crystallization, adjusting pH to 11.9, adding 56ml water dropwise, and filtering to obtain dihydrohomoerythromycin.
Taking 30g of crystallized dihydrohomoerythromycin, adding 84ml of acetone, heating to 35 ℃, adding 5.25g of formaldehyde, adding 7.02g of formic acid, heating to reflux reaction for 2.5h, cooling to 20 ℃ after the reaction is finished, adding 20% of sodium hydroxide solution to adjust the pH value to 11.2, standing for layering, taking an organic layer, dripping water at 20 ℃ to separate out crystals, growing the crystals for 15 minutes, continuously dripping the total water to 186ml, stirring and filtering to obtain the azithromycin.
The purity of the azithromycin prepared by the comparative example is 98.18 percent, and the impurity of D and J is 0.46 percent (refer to the method for detecting related substances of the azithromycin in European pharmacopoeia).
The high performance liquid chromatography pattern of azithromycin prepared by the comparative example is shown in figure 3.
Comparative example 2
Adding 50g of erythromycin A-6, 9-imine ether into 160ml of water, adjusting the pH value to 5.8 by using 5% dilute hydrochloric acid at 3.2 ℃, adding 4g of potassium borohydride after dissolution, keeping the temperature at 3.5 ℃ for reaction for 2.5 hours, adjusting the pH value to 6.4 by using 5% dilute hydrochloric acid after heat preservation, adding 1.65g of residual potassium borohydride, keeping the temperature for 1 hour, adding 330ml of dichloromethane after reaction is finished, adjusting the pH value to 9.7 by using 20% sodium hydroxide solution, separating, reserving the dichloromethane layer, adjusting the pH value to 5.2 by using 5% dilute hydrochloric acid, hydrolyzing at the pH value of 1.0 for 20 minutes at 2.1 ℃, adjusting the pH value to 9.7 by using 20% sodium hydroxide solution, taking the dichloromethane layer after liquid separation, adding 55ml of water into the dichloromethane layer, adjusting the temperature to 1.9 ℃, adjusting the pH value to 5.2 by using 5% dilute hydrochloric acid, taking the water layer by using liquid separation, transferring the water layer into a crystallization kettle, adjusting the pH value to neutrality by using 10% sodium hydroxide solution, adding 100ml of acetone after concentration, controlling the temperature to 33 ℃, adding 10% sodium hydroxide solution for crystallization, adjusting pH to 11.9, adding 56ml water dropwise, and filtering to obtain dihydrohomoerythromycin.
Taking 30g of crystallized dihydrohomoerythromycin, adding 84ml of acetone, heating to 35 ℃, adding 5.25g of formaldehyde, adding 7.02g of formic acid, heating to reflux reaction for 2.5h, cooling to 20 ℃ after the reaction is finished, adding 20% of sodium hydroxide solution to adjust the pH value to 11.2, standing for layering, taking an organic layer, dripping water at 20 ℃ to separate out crystals, growing the crystals for 15 minutes, continuously dripping the total water to 186ml, stirring and filtering to obtain the azithromycin.
The azithromycin prepared by the comparative example has the purity of 98.41 percent and the D + J impurity of 0.36 percent (refer to the method for detecting related substances of the azithromycin in European pharmacopoeia).
Comparative example 3
Adding 50g of erythromycin A-6, 9-imine ether into 160ml of water, adjusting the pH value to 5.8 by using 5% dilute hydrochloric acid at 3.2 ℃, adding 4g of potassium borohydride after dissolution, keeping the temperature at 3.5 ℃ for reaction for 2.5 hours, adjusting the pH value back to 6.4 by using 5% dilute hydrochloric acid after the heat preservation is finished, adding 1.65g of residual potassium borohydride, keeping the temperature for 1 hour, adding 330ml of dichloromethane after the reaction is finished, adjusting the pH value to 9.7 by using 20% sodium hydroxide solution, separating, reserving the dichloromethane layer, adjusting the pH value by using 5% dilute hydrochloric acid, hydrolyzing at the pH value of 1.0 for 20 minutes at 2.1 ℃, adjusting the pH value to 9.7 by using 20% sodium hydroxide solution, taking the dichloromethane layer after separation, adding 38ml of water into the dichloromethane layer, adjusting the temperature to 5.2 ℃, adjusting the pH value to 4.6 by using 5% dilute hydrochloric acid, taking the water layer by using liquid separation, transferring the water layer into a crystallization kettle, adjusting the pH value to neutrality by using 10% sodium hydroxide solution, adding 100ml of acetone after concentration, controlling the temperature to 33 ℃, adding 10% sodium hydroxide solution for crystallization, adjusting pH to 11.9, adding 56ml water dropwise, and filtering to obtain dihydrohomoerythromycin.
Taking 30g of crystallized dihydrohomoerythromycin, adding 84ml of acetone, heating to 35 ℃, adding 5.25g of formaldehyde, adding 7.02g of formic acid, heating to reflux reaction for 2.5h, cooling to 20 ℃ after the reaction is finished, adding 20% of sodium hydroxide solution to adjust the pH value to 11.2, standing for layering, taking an organic layer, dripping water at 20 ℃ to separate out crystals, growing the crystals for 15 minutes, continuously dripping the total water to 186ml, stirring and filtering to obtain the azithromycin.
The azithromycin prepared by the comparative example has the purity of 98.37 percent and the D + J impurity of 0.41 percent (refer to the method for detecting related substances of the azithromycin in European pharmacopoeia).
Although the invention has been described in detail hereinabove with respect to a general description and specific embodiments thereof, it will be apparent to those skilled in the art that modifications or improvements may be made thereto based on the invention. Accordingly, such modifications and improvements are intended to be within the scope of the invention as claimed.
Claims (10)
1. A process for synthesizing dihydrohomoerythromycin is characterized by comprising the following steps: adding erythromycin A-6, 9-imine ether into water, cooling to 0-5 deg.C, adjusting pH to 5.5-6.5 with dilute hydrochloric acid, dissolving, adding potassium borohydride, reacting at 0-5 deg.C under constant temperature, adjusting pH to 5.5-6.5 with dilute hydrochloric acid, adding potassium borohydride, reacting under constant temperature, adding dichloromethane, adjusting pH to 9.5-10.0 with sodium hydroxide solution, separating, keeping dichloromethane layer, adding organic layer into water, hydrolyzing at 0-3 deg.C and pH 1.0-1.5, adjusting pH to 9.5-10.0 with sodium hydroxide solution, separating, collecting dichloromethane layer, adding water 1.1 times or more volume of dichloromethane layer, controlling temperature to 4-6 deg.C, adjusting pH to 3.5-4.0 with dilute hydrochloric acid, transferring the material to water phase, separating, collecting water layer, adding dichloromethane into water layer, adjusting pH to 9.5-10.0 with sodium hydroxide solution, transferring to organic phase, separating to obtain organic layer, adding water with volume more than or equal to 1.1 times of the organic layer, adjusting pH to 6.0-6.5 with dilute hydrochloric acid, transferring to water phase, separating to obtain water layer, transferring the water layer to a crystallization kettle, adjusting pH to neutral with sodium hydroxide solution, concentrating, adding acetone, controlling temperature at 30-35 deg.C, adding sodium hydroxide solution for crystallization, adjusting pH to 11.7-12.2, adding water dropwise, and filtering to obtain dihydrohomoerythromycin.
2. The process according to claim 1, wherein the dichloromethane layer is taken after liquid separation, water with a volume of 1.1 times or more is added into the dichloromethane layer, the temperature is controlled to be 4-6 ℃, the pH is adjusted to be 3.7-3.9 by dilute hydrochloric acid, and the material is transferred to the water phase; and/or the presence of a gas in the gas,
separating to obtain organic layer, adding water with volume of 1.1 times or more to the organic layer, adjusting pH to 6.1-6.4 with dilute hydrochloric acid), transferring to water phase, separating to obtain water layer.
3. A synthesis process of dihydrohomoerythromycin as claimed in claim 1 or 2, wherein the weight ratio of erythromycin A-6, 9-imino ether to potassium borohydride is 50 (5-6).
4. A synthesis process of dihydrohomoerythromycin as described in any one of claims 1-3, wherein the weight ratio of erythromycin A-6, 9-imino ether to the first added potassium borohydride is 50 (3-4); the weight ratio of the erythromycin A-6, 9-imino ether to the potassium borohydride added for the second time is 50 (1-2).
5. A synthesis process of dihydrohomoerythromycin as claimed in any one of claims 1-4, wherein after the second addition of potassium borohydride, the volume weight ratio of dichloromethane to erythromycin A-6, 9-imino ether added in ml/g is (6-10): 1.
6. A synthesis process of dihydrohomoerythromycin as described in any one of claims 1-5, wherein a dichloromethane layer is taken after liquid separation, and water is added to the dichloromethane layer in an amount of 1.1-1.5 times by volume.
7. A synthesis process of dihydrohomoerythromycin as described in any one of claims 1-6, wherein the organic layer is obtained by separating liquid, and water is added to the organic layer in an amount of 1.1-1.5 times by volume.
8. A synthesis process according to any one of claims 1 to 7, wherein the volume weight ratio of acetone to erythromycin A-6, 9-imino ether added in the crystallization step is (1.8-2.4): 1; and/or the presence of a gas in the gas,
the volume weight ratio of the added water to the erythromycin A-6, 9-imino ether in the crystallization step is (1.1-1.3):1 in ml/g.
9. Dihydrohomoerythromycin, characterized in that it is obtained by a process as claimed in any one of claims 1 to 8.
10. The azithromycin synthesis process is characterized by comprising the following steps: preparing dihydrohomoerythromycin by the process of any one of claims 1-8; and further preparing the dihydrohomoerythromycin to obtain the azithromycin.
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| CN101712703A (en) * | 2009-11-18 | 2010-05-26 | 上海华理生物医药有限公司 | Method for preparing azithromycin and method for preparing intermediate of azithromycin |
| CN102127064A (en) * | 2010-12-29 | 2011-07-20 | 开封制药(集团)有限公司 | Preparation method of azithromycin intermediate |
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| CN101712703A (en) * | 2009-11-18 | 2010-05-26 | 上海华理生物医药有限公司 | Method for preparing azithromycin and method for preparing intermediate of azithromycin |
| CN102127064A (en) * | 2010-12-29 | 2011-07-20 | 开封制药(集团)有限公司 | Preparation method of azithromycin intermediate |
| CN104892697A (en) * | 2015-05-05 | 2015-09-09 | 黄石世星药业有限责任公司 | Azithromycin production technology |
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