CN114133364B - Synthesis method of oseltamivir intermediate - Google Patents
Synthesis method of oseltamivir intermediate Download PDFInfo
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- CN114133364B CN114133364B CN202111310213.0A CN202111310213A CN114133364B CN 114133364 B CN114133364 B CN 114133364B CN 202111310213 A CN202111310213 A CN 202111310213A CN 114133364 B CN114133364 B CN 114133364B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
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- C07C231/00—Preparation of carboxylic acid amides
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
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- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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Abstract
Description
Technical Field
The invention relates to the technical field of compound synthesis, in particular to a synthesis method of oseltamivir intermediates.
Background
Influenza is a disease that seriously affects normal life of human beings, and is also one of the diseases with high infectious diseases in the world. Influenza virus is one of the pathogens responsible for human influenza, and influenza virus neuraminidase is an important component of influenza virus that can prevent virus aggregation and assist in the release of progeny virions from infected cells. Therefore, inhibition of neuraminidase function, i.e. prevention of release of virus, to control influenza, is an important target of anti-influenza virus drugs, and oseltamivir phosphate (commercially available as darfein) is a representative drug on the market, mainly used for treating uncomplicated influenza a and b.
Oseltamivir phosphate is named (3R, 4R, 5S) -4-acetamido-5-amino-3 (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester phosphate, the structural formula of which is shown as formula I, is successfully developed by Gilead company in 1996, is first marketed in Sweden in 1999, is marketed in the United states in the same time, is marketed in China in 10 months in 2001, and has become a heavy-weight variety in the anti-influenza field.
Ethyl (3 r,4r,5 s) -4, 5-epoxy-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate is a key intermediate (epoxide for short hereinafter) in oseltamivir phosphate synthesis. At present, two methods for synthesizing the epoxide mainly exist, one method is that as disclosed by Gilead company, compound 1 is used as a substrate, potassium bicarbonate or sodium bicarbonate is used as alkali, ethanol water is used as a mixed solvent, n-hexane is used for extraction after the reaction is finished, and the epoxide is obtained after vacuum concentration, and the yield of the step is about 60 percent without purification.
The method uses mixed solvent ethanol/water, the ethanol and the water are mutually dissolved, the recovery process is complex, and the waste liquid is discharged more. After the reaction is completed, the solvent of the system is evaporated to dryness to obtain a crude product of the compound 2, and then the crude product is refined to obtain the compound 2 with high purity, namely epoxide, and the product has darker color and high impurity content.
In addition, the ammonia water used for the Shandong Kadsuo medicine is used as alkali for catalyzing the elimination reaction, the yield is improved, but the ethanol/water is still used as solvent, a small amount of laboratory experiments can be carried out, and the defects of complex recovery process, large waste liquid discharge, large energy consumption caused by evaporating the solvent and the like still exist in industrialized mass production.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems existing in the prior art. Therefore, the invention provides a synthesis method of oseltamivir intermediate, which has the advantages of easy separation and recovery of solvent, repeated application, reduced waste liquid discharge and environmental protection. The post-treatment operation is simple, the product purity is high, and the method is suitable for industrial mass production.
Specifically, the invention adopts the following technical scheme:
a synthesis method of oseltamivir intermediate comprises the following steps:
mixing the compound 1, alkali and a phase transfer catalyst with a mixed solvent, and performing an elimination reaction to obtain an oseltamivir intermediate shown in a compound 2; the mixed solvent contains a water-insoluble organic solvent and water.
According to the invention, the compound 1 is dissolved in a mixed solvent of a water-insoluble organic solvent and water, and a phase transfer catalyst is added into a reaction system, so that the compound 2 generated by the reaction can be enriched into the water-insoluble organic solvent, and the solvent can be separated only through a simple post-treatment method, so that the compound 2 with high purity is obtained.
In some embodiments of the invention, the water-insoluble organic solvent comprises C 5~15 Aliphatic hydrocarbon, aromatic hydrocarbon, C 5~11 At least one of alicyclic hydrocarbons. Wherein C is 5~15 The aliphatic hydrocarbon preferably comprises C 5~10 Aliphatic hydrocarbons such as n-heptane, n-hexane, etc.; aromatic hydrocarbons include benzene, toluene, xylene, and the like; c (C) 5~11 Alicyclic hydrocarbons include cyclohexane, cyclopentane and the like.
In some embodiments of the invention, the phase transfer catalyst comprises at least one of a quaternary ammonium salt, a quaternary phosphonium salt. The quaternary ammonium salt comprises at least one of tetrabutylammonium bromide, tetrabutylammonium bisulfate and tetrabutylammonium chloride.
In some embodiments of the invention, the base comprises at least one of a carbonate (e.g., sodium carbonate, potassium carbonate, ammonium carbonate, etc.), a bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, etc.), aqueous ammonia.
In some embodiments of the invention, the mass ratio of the water-insoluble organic solvent to water is 0.5 to 2.5:1, preferably 0.8 to 1.8:1.
in some embodiments of the invention, the mass ratio of the mixed solvent to the compound 1 is 2-10: 1, preferably 5 to 10:1, more preferably 5.5 to 8.5:1.
in some embodiments of the invention, the mass ratio of the compound 1 to the base is 1 to 5:1, preferably 1.5 to 3:1, more preferably 1.5 to 2.5:1.
in some embodiments of the invention, the mass ratio of the compound 1 to the phase transfer catalyst is 5 to 15:1, preferably 8 to 12:1.
in some embodiments of the invention, the temperature at which the compound 1, base, phase transfer catalyst and mixed solvent are mixed is 10 to 40 ℃, preferably 20 to 30 ℃, more preferably 20 to 25 ℃.
In some embodiments of the invention, the temperature of the elimination reaction is 50 to 80 ℃, preferably 60 to 70 ℃.
In some embodiments of the invention, the abatement reaction is carried out under a shielding gas comprising nitrogen, argon, or the like.
In some embodiments of the invention, the time for the elimination reaction is from 0.5 to 5 hours, preferably from 2 to 3 hours.
In some embodiments of the present invention, after the elimination reaction is finished, a post-treatment step is further included, and the post-treatment step sequentially includes liquid separation, crystallization and solid-liquid separation.
Wherein, the liquid separation is to separate the reaction system after the elimination reaction is finished, and the organic phase is kept and the water phase is discarded. The step of standing can be set according to actual needs before liquid separation, and the water phase and the organic phase are separated more thoroughly through standing, so that liquid separation is easier to carry out. In general, the standing time is from 0.2 to 1 hour, preferably from 0.3 to 0.5 hour. For convenience of operation, the temperature of the reaction system is lowered, for example, to 40 to 50 ℃ or below, before standing and liquid separation. After the elimination reaction, the product (compound 2) is enriched in an organic phase, and the organic phase is mutually soluble with water, so that liquid separation can be directly carried out, the aqueous phase and the organic phase are separated, and the organic phase enriched with the product is reserved for subsequent purification, thereby avoiding the defect that a large amount of organic solvent is required to be added for extraction after the reaction is finished and a large amount of organic solvent is consumed in the prior art under the condition that ethanol/water is taken as a solvent.
The crystallization adopts a low-temperature crystallization method, and specifically comprises the steps of cooling an organic phase obtained after liquid separation to-5 ℃ (preferably-2 ℃, more preferably about 0 ℃), and precipitating crystals (from the organic phase). After separating, the product is enriched in the organic phase, and the product can be separated from the organic solvent by a simple low-temperature crystallization method, so that the energy consumption is greatly saved compared with the method for removing the organic solvent by evaporation in the prior art.
The solid-liquid separation method includes filtration, centrifugation, etc., and centrifugation is preferably employed.
In some embodiments of the invention, the solid-liquid separation is followed by drying. The drying method comprises at least one of drying under reduced pressure and freeze drying, preferably drying under reduced pressure.
In some embodiments of the invention, the yield of compound 2 is greater than or equal to 95% and the purity is greater than or equal to 99.5%.
The invention also provides an application of the synthesis method of the oseltamivir intermediate in preparation of oseltamivir and pharmaceutically acceptable salts thereof (such as oseltamivir phosphate).
Compared with the prior art, the invention has the following beneficial effects:
according to the invention, a proper solvent system is adopted to dissolve the compound 1, a phase transfer catalyst is added into a reaction system, the solvent is easy to separate after the reaction, the post-treatment operation is simple, the steps of extraction, evaporation, washing and the like which are needed to be additionally added with other solvents in the prior art can be omitted, the use amount of the solvent can be greatly reduced, and the operation is simple; and the mixed solvent can be easily recovered after separation, can be repeatedly used, obviously reduces the discharge of waste liquid, and is environment-friendly. The product has white color and high purity, and is suitable for industrial mass production.
Detailed Description
The technical scheme of the invention is further described below with reference to specific examples. The starting materials used in the examples below, unless otherwise specified, are all commercially available from conventional sources; the processes used, unless otherwise specified, are all conventional in the art.
The "room temperature" of the invention refers to the ambient temperature at which the experiment is conducted, typically 20-25 ℃.
Example 1
12.96kg of the compound, 16.2kg of n-heptane, 1.42kg of sodium bicarbonate, 0.296kg of tetrabutylammonium bromide and 8.88kg of water are mixed at room temperature, and the mixture is heated to 65 ℃ under the protection of nitrogen and stirred for 2 hours at a constant temperature. Cooling to 40-50 ℃, standing for 0.5h, separating liquid, discarding water phase, cooling organic phase to 0 ℃ for crystallization for 2h, centrifuging, decompressing and drying to obtain 2.05kg of white pure product of compound 2, wherein the purity of HPLC is 99.73%, and the yield is 95.3%.
Example 2
At room temperature, 13.1kg of the compound, 7.85kg of n-heptane, 1.49kg of sodium bicarbonate, 0.31kg of tetrabutylammonium bisulfate and 9.3kg of water are mixed, and the mixture is heated to 60 ℃ under the protection of nitrogen, and stirred for 2.5h under heat preservation. Cooling to 40-50 ℃, standing for 0.5h, separating liquid, discarding water phase, cooling organic phase to 0 ℃ for crystallization for 2h, centrifuging, decompressing and drying to obtain 2.19kg of white pure product of compound 2, wherein the purity of HPLC is 99.59%, and the yield is 97.5%.
Example 3
12.9kg of compound, 12kg of normal hexane, 1.49kg of sodium bicarbonate, 0.28kg of tetrabutylammonium chloride and 8.5kg of water are mixed at room temperature, and the mixture is heated to 70 ℃ under the protection of nitrogen, and stirred for 2 hours under heat preservation. Cooling to 40-50 ℃, standing for 0.5h, separating liquid, discarding water phase, cooling organic phase to 0 ℃ for crystallization for 2h, centrifuging, decompressing and drying to obtain 2.04kg of white pure product of compound 2, wherein the purity of HPLC is 99.61%, and the yield is 96.7%.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (6)
1. The synthesis method of oseltamivir intermediate is characterized in that: the method comprises the following steps:
mixing the compound 1, alkali and a phase transfer catalyst with a mixed solvent, and performing an elimination reaction to obtain an oseltamivir intermediate shown in a compound 2; the mixed solvent contains a water-insoluble organic solvent and water; the water-insoluble organic compoundThe solvent comprises C 5~15 Aliphatic hydrocarbon, aromatic hydrocarbon, C 5~11 At least one of alicyclic hydrocarbons; the phase transfer catalyst comprises at least one of quaternary ammonium salt and quaternary phosphonium salt; the mass ratio of the water-insoluble organic solvent to the water is 0.5-2.5: 1, a step of; the mass ratio of the compound 1 to the phase transfer catalyst is 5-15: 1.
2. the method for synthesizing oseltamivir intermediate according to claim 1, wherein: the mass ratio of the mixed solvent to the compound 1 is 2-10: 1.
3. the synthesis method of oseltamivir intermediate according to claim 1 or 2, characterized in that: the method is characterized by further comprising a post-treatment step after the elimination reaction is finished, wherein the post-treatment step sequentially comprises liquid separation, crystallization and solid-liquid separation.
4. A process for the synthesis of oseltamivir intermediate according to claim 3, characterized in that: the method also comprises a step of standing before liquid separation.
5. The method for synthesizing oseltamivir intermediate according to claim 4, wherein: the crystallization step is specifically to cool the organic phase obtained after liquid separation to-5 to 5 ℃ to precipitate crystals.
6. Use of the synthesis of oseltamivir intermediate according to any one of claims 1 to 5 for the preparation of oseltamivir and pharmaceutically acceptable salts thereof.
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