CN116283832A - Preparation method of oseltamium Wei Gongyi impurity - Google Patents

Preparation method of oseltamium Wei Gongyi impurity Download PDF

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CN116283832A
CN116283832A CN202111563249.XA CN202111563249A CN116283832A CN 116283832 A CN116283832 A CN 116283832A CN 202111563249 A CN202111563249 A CN 202111563249A CN 116283832 A CN116283832 A CN 116283832A
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compound
solvent
acid
certain embodiments
reaction temperature
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陈玉林
田家林
王统贵
石韧韧
张建国
张燕
曾洁
梅良和
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Hunan Runxing Pharmaceutical Co ltd
Zhongke Suzhou Pharmaceutical Research Institute
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Hunan Runxing Pharmaceutical Co ltd
Zhongke Suzhou Pharmaceutical Research Institute
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C—CHEMISTRY; METALLURGY
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
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Abstract

The invention relates to preparation of an oseltamium Wei Gongyi impurity II, which has the advantages of easily obtained synthetic reaction raw materials, mild reaction conditions, easy control of operation, safe and reliable raw materials, avoidance of toxic substances and capability of laying a foundation for later industrialized amplification production. Meanwhile, the preparation method disclosed by the invention has high reaction yield and the obtained product has high purity.

Description

Preparation method of oseltamium Wei Gongyi impurity
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of an oseltamium Wei Gongyi impurity.
Background
Oseltamivir phosphate is a highly effective and highly selective influenza virus neuraminidase inhibitor which is developed by Roche pharmaceutical company. Clinically, the medicine is mainly used for preventing and treating diseases caused by neuraminidase such as influenza A and B, is the most effective medicine for resisting avian influenza at present, is approved to be marketed in the United states in 1999, and is marketed in China in 7 months 2004. Oseltamivir phosphate has been marketed in more than 60 countries and regions worldwide as a world-recognized effective anti-influenza virus drug and has entered into influenza preventive drug reserves in major countries and regions. During the 2009H 1N1 influenza pandemic, its global sales were more than $ 30 billion, and the global sales in 2014 and 2015 were also nearly $ 10 billion. Oseltamivir phosphate belongs to a strategic drug for outbreak of influenza and avian influenza, is different from a common cold drug, and has very broad market prospect along with gradual attention and importance of influenza in various countries and promotion of epidemic spreading and market demands.
(3R, 4S, 5S) -4, 5-epoxy-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester is a key intermediate for preparing oseltamivir phosphate. The preparation method of the commercial product takes shikimic acid extracted from plants as raw materials, and carries out esterification, 3-pentanone fork protection of ortho-dihydroxyl, ms protection on hydroxyl, further regioselective reaction under the action of Lewis acid, and finally, the epoxy product (3R, 4S, 5S) -4, 5-epoxy-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylic acid ethyl ester is prepared under alkaline conditions.
Figure BDA0003420893210000011
(3R, 4S, 5S) -4, 5-epoxy-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate as a key intermediate, the quality of which needs to be studied in detail and quality standards established. In the case of analyzing the related substances, confirmation of the content of the isomer impurities is required, and the preparation of an impurity control is required. Preparing high-purity impurity reference substances, establishing a detection method, determining reasonable impurity limit, effectively controlling the impurities and having important significance for monitoring the quality of products.
The ethyl (3R, 4S, 5S) -4, 5-epoxy-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate has 3 chiral centers and is most likely to form, in theory, 3 isomers, enantiomer II, and diastereomers III and IV.
Figure BDA0003420893210000012
The preparation of enantiomer II is also reported in patent application CN113024489 a. The patent takes an intermediate (3S, 4R, 5S) -3,4, 5-trihydroxycyclohex-1-ene-1-carboxylic acid as a raw material, and enantiomer II is obtained through esterification, photo-extension, waldensted inversion, hydrolysis and condensation reaction.
Figure BDA0003420893210000021
In the method, the trichloroacetonitrile used in the preparation process of the trichloroacetimidate is inflammable, toxic and has obvious stimulation effect on respiratory tract, and in addition, the yield of the second reaction is only 8.6 percent, so that the yield is extremely low, and the industrialized application of the trichloroacetimidate is influenced.
Disclosure of Invention
Technical problem to be solved by the invention
In order to solve the problems in the prior art, the present disclosure provides a method for synthesizing oseltamivir impurity II, which has the advantages of easily available reaction raw materials, mild reaction conditions, easy control of operation, safety and reliability.
Solution for solving the problem
The preparation method of the oseltamium Wei Gongyi impurity II comprises the following steps:
Figure BDA0003420893210000022
1) Reacting the compound 1 with tert-butyldimethyl chlorosilane to obtain a compound 2;
2) Reacting the compound 2 with methylsulfonyl chloride to obtain a compound 3;
3) Removing TBS protection from the compound 3 to obtain a compound 4;
4) Closing the ring of the compound 4 to obtain a compound 5;
5) Reacting the compound 5 with p-nitrobenzoic acid to obtain a compound 6;
6) Ring opening the compound 6 to obtain a compound 7;
7) Hydrolyzing the compound 7 to obtain a compound 8;
8) Reacting the compound 8 with 3-pentanone to obtain a compound 9;
9) Reacting compound 9 with methylsulfonyl chloride to obtain compound 10;
10 Ring opening compound 10 to give compound 11;
11 Ring closure of compound 11 to give compound II.
Further, the preparation method as described above, wherein the step 1) is performed in a solvent;
preferably, the solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, DMF, dioxane, ethyl acetate and toluene, preferably DMF;
further, the preparation method as described above, wherein the step 1) is performed in the presence of a base;
preferably, the base is selected from one or more of triethylamine, imidazole, pyridine and DBU, preferably imidazole;
further, in the preparation method, the reaction temperature in the step 1) is 0-50 ℃, preferably room temperature.
Further, the preparation method as described above, wherein the steps 2) and 9) are performed in a solvent;
preferably, the solvent is selected from one or more of dichloromethane, tetrahydrofuran, ethyl acetate and toluene, preferably dichloromethane;
further, the preparation method as described above, wherein the steps 2) and 9) are performed in the presence of a base;
preferably, the base is selected from one or more of triethylamine, DMAP, DIPEA and pyridine, preferably triethylamine;
further, in the preparation method described above, the reaction temperature in the steps 2) and 9) is 0 to 50 ℃, preferably room temperature.
Further, the preparation method as described above, wherein the step 3) is performed in a solvent;
preferably, the solvent is selected from one or more of absolute ethanol, isopropanol, acetonitrile and ethyl acetate, preferably ethanol;
further, the preparation method as described above, wherein the step 3) is performed in the presence of an acid;
preferably, the acid is selected from one or more of hydrochloric acid, p-toluene sulfonic acid and trifluoroacetic acid, preferably hydrochloric acid;
further, in the preparation method, the reaction temperature in the step 3) is 0-50 ℃, preferably room temperature.
Further, the preparation method as described above, wherein the steps 4) and 11) are performed in a solvent;
preferably, the solvent is selected from one or more of ethanol, acetonitrile, tetrahydrofuran and water, preferably ethanol and water;
further, the preparation method as described above, wherein the steps 4) and 11) are performed in the presence of a base;
preferably, the base is selected from one or more of sodium bicarbonate, sodium carbonate and DBU, preferably sodium bicarbonate;
further, in the above preparation method, the reaction temperature in the steps 4) and 11) is 0 to 100 ℃, preferably 40 to 80 ℃.
Further, the preparation method as described above, wherein the step 5) is performed in a solvent;
preferably, the solvent is selected from one or more of tetrahydrofuran, dichloromethane and toluene, preferably tetrahydrofuran;
further, the preparation method is as described above, wherein the step 5) is a Mitsunobu reaction;
preferably, said step 5) is carried out in the presence of triphenylphosphine and diisopropyl azodicarboxylate or diethyl azodicarboxylate;
further, in the preparation method, the reaction temperature in the step 5) is 0-50 ℃, preferably room temperature.
Further, the preparation method as described above, wherein the step 6) is performed in a solvent;
preferably, the solvent is selected from one or more of tetrahydrofuran, ethanol, isopropanol, ethyl acetate and water, preferably tetrahydrofuran and water;
further, the preparation method as described above, wherein the step 6) is performed in the presence of an acid;
preferably, the acid is selected from one or more of trifluoroacetic acid, methanesulfonic acid and sulfuric acid, preferably trifluoroacetic acid;
further, in the preparation method described above, the reaction temperature in the step 6) is 0 to 50 ℃, preferably room temperature.
Further, the preparation method as described above, wherein the step 7) is performed in a solvent;
preferably, the solvent is selected from one or more of ethanol, acetonitrile, tetrahydrofuran and DMF, preferably ethanol;
further, the preparation method as described above, wherein the step 7) is performed in the presence of a base;
preferably, the base is selected from one or more of sodium carbonate, potassium carbonate and sodium hydroxide, preferably sodium carbonate;
further, in the preparation method as described above, the reaction temperature in the step 7) is 0 to 80 ℃, preferably 20 to 50 ℃.
Further, the preparation method as described above, wherein the step 8) is performed in a solvent;
preferably, the solvent is selected from triethyl orthoformate;
further, the preparation method as described above, wherein the step 8) is performed in the presence of a catalyst;
preferably, the catalyst is benzenesulfonic acid;
further, in the preparation method as described above, the reaction temperature in the step 8) is 0 to 80 ℃, preferably 20 to 40 ℃.
Further, the preparation method as described above, wherein the step 10) is performed in a solvent;
preferably, the solvent is selected from dichloromethane;
further, the preparation method as described above, wherein the step 10) is performed in the presence of triethylsilane and titanium tetrachloride;
further, according to the preparation method, the reaction temperature in the step 10) is-50 to-20 ℃, preferably-40 to-30 ℃.
ADVANTAGEOUS EFFECTS OF INVENTION
The method has the advantages of easily obtained synthetic reaction raw materials, mild reaction conditions, easy control of operation, safe and reliable raw materials, avoiding the use of toxic substances and laying a foundation for the later industrialized mass production. Meanwhile, the preparation method disclosed by the invention has high reaction yield and the obtained product has high purity.
Detailed Description
In order to make the technical scheme and the beneficial effects of the present disclosure more obvious and understandable, the following detailed description is given by way of example only. Unless defined otherwise, technical and scientific terms used herein have the same meaning as technical and scientific terms in the technical field to which this application belongs.
The present disclosure provides a method for preparing oseltamium Wei Gongyi impurity II, comprising the steps of:
Figure BDA0003420893210000051
1) Reacting the compound 1 with tert-butyldimethyl chlorosilane to obtain a compound 2;
2) Reacting the compound 2 with methylsulfonyl chloride to obtain a compound 3;
3) Removing TBS protection from the compound 3 to obtain a compound 4;
4) Closing the ring of the compound 4 to obtain a compound 5;
5) Reacting the compound 5 with p-nitrobenzoic acid to obtain a compound 6;
6) Ring opening the compound 6 to obtain a compound 7;
7) Hydrolyzing the compound 7 to obtain a compound 8;
8) Reacting the compound 8 with 3-pentanone to obtain a compound 9;
9) Reacting compound 9 with methylsulfonyl chloride to obtain compound 10;
10 Ring opening compound 10 to give compound 11;
11 Ring closure of compound 11 to give compound II.
In certain embodiments, the step 1) is performed in a solvent.
In certain embodiments, the solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, DMF, dioxane, ethyl acetate, and toluene.
In certain embodiments, the solvent is selected from DMF.
In certain embodiments, the step 1) is performed in the presence of a base.
In certain embodiments, the base is selected from one or more of triethylamine, imidazole, N-diisopropylethylamine, pyridine, and DBU.
In certain embodiments, the base is selected from imidazoles.
In certain embodiments, the reaction temperature of step 1) is from 0 to 50 ℃.
In certain embodiments, the reaction temperature of step 1) is from 10 to 40 ℃.
In certain embodiments, the reaction temperature of step 1) is room temperature.
In certain embodiments, the molar ratio of compound 1 to t-butyldimethylchlorosilane is from 1:1 to 5.
In certain embodiments, the molar ratio of compound 1 to t-butyldimethylchlorosilane is from 1:1 to 3.
In certain embodiments, the molar ratio of compound 1 to t-butyldimethylchlorosilane is 1:2.2.
In certain embodiments, the step 2) is performed in a solvent.
In certain embodiments, the solvent is selected from one or more of dichloromethane, tetrahydrofuran, ethyl acetate, and toluene.
In certain embodiments, the solvent is selected from dichloromethane.
In certain embodiments, the step 2) is performed in the presence of a base.
In certain embodiments, the base is selected from one or more of triethylamine, DMAP, DIPEA, and pyridine.
In certain embodiments, the base is selected from triethylamine.
In certain embodiments, the reaction temperature of step 2) is from 0 to 50 ℃.
In certain embodiments, the reaction temperature of step 2) is from 10 to 40 ℃.
In certain embodiments, the reaction temperature of step 2) is room temperature.
In certain embodiments, the molar ratio of compound 2 to methylsulfonyl chloride is 1:1-5.
In certain embodiments, the molar ratio of compound 2 to methylsulfonyl chloride is 1:1-3.
In certain embodiments, the molar ratio of compound 2 to methylsulfonyl chloride is 1:1.5.
In certain embodiments, the step 3) is performed in a solvent.
In certain embodiments, the solvent is selected from one or more of absolute ethanol, isopropanol, acetonitrile and ethyl acetate.
In certain embodiments, the solvent is selected from ethanol.
In certain embodiments, the step 3) is performed in the presence of an acid.
In certain embodiments, the acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, and trifluoroacetic acid.
In certain embodiments, the acid is selected from hydrochloric acid.
In certain embodiments, the reaction temperature of step 3) is from 0 to 50 ℃.
In certain embodiments, the reaction temperature of step 3) is 10 to 40 ℃.
In certain embodiments, the reaction temperature of step 3) is room temperature.
In certain embodiments, the step 4) is performed in a solvent.
In certain embodiments, the solvent is selected from one or more of ethanol, acetonitrile, tetrahydrofuran, and water.
In certain embodiments, the solvent is selected from ethanol and water.
In certain embodiments, the step 4) is performed in the presence of a base.
In certain embodiments, the base is selected from one or more of sodium bicarbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate, and DBU.
In certain embodiments, the base is selected from sodium bicarbonate.
In certain embodiments, the step 4) reaction temperature is from 0 to 100 ℃.
In certain embodiments, the step 4) reaction temperature is from 40 to 80 ℃.
In certain embodiments, the step 4) reaction temperature is 50 to 70 ℃.
In certain embodiments, the step 5) is performed in a solvent.
In certain embodiments, the solvent is selected from one or more of tetrahydrofuran, dichloromethane, and toluene.
In certain embodiments, the solvent is selected from tetrahydrofuran.
In certain embodiments, the step 5) is a Mitsunobu reaction.
In certain embodiments, the step 5) is performed in the presence of triphenylphosphine and diisopropyl azodicarboxylate or diethyl azodicarboxylate.
In certain embodiments, the reaction temperature of step 5) is from 0 to 50 ℃.
In certain embodiments, the reaction temperature of step 5) is from 10 to 40 ℃.
In certain embodiments, the reaction temperature of step 5) is room temperature.
In certain embodiments, the molar ratio of compound 5 to p-nitrobenzoic acid is from 1:1 to 5.
In certain embodiments, the molar ratio of compound 5 to p-nitrobenzoic acid is from 1:1 to 3.
In certain embodiments, the molar ratio of compound 5 to p-nitrobenzoic acid is 1:1.1.
In certain embodiments, the step 6) is performed in a solvent.
In certain embodiments, the solvent is selected from one or more of tetrahydrofuran, ethanol, isopropanol, ethyl acetate, and water.
In certain embodiments, the solvent is selected from tetrahydrofuran and water.
In certain embodiments, the step 6) is performed in the presence of an acid.
In certain embodiments, the acid is selected from one or more of trifluoroacetic acid, hydrochloric acid, phosphoric acid, methanesulfonic acid, and sulfuric acid.
In certain embodiments, the acid is selected from trifluoroacetic acid.
In certain embodiments, the reaction temperature of step 6) is from 0 to 50 ℃.
In certain embodiments, the reaction temperature of step 6) is from 10 to 40 ℃.
In certain embodiments, the reaction temperature of step 6) is room temperature.
In certain embodiments, the step 7) is performed in a solvent.
In certain embodiments, the solvent is selected from one or more of ethanol, acetonitrile, tetrahydrofuran, and DMF.
In certain embodiments, the solvent is selected from ethanol.
In certain embodiments, the step 7) is performed in the presence of a base.
In certain embodiments, the base is selected from one or more of sodium carbonate, potassium carbonate, cesium carbonate, potassium hydroxide, and sodium hydroxide.
In certain embodiments, the base is selected from sodium carbonate.
In certain embodiments, the step 7) reaction temperature is from 0 to 80 ℃.
In certain embodiments, the step 7) reaction temperature is from 20 to 50 ℃.
In certain embodiments, the step 7) reaction temperature is from 35 to 45 ℃.
In certain embodiments, the step 8) is performed in a solvent.
In certain embodiments, the solvent is selected from the group consisting of triethyl orthoformate.
In certain embodiments, the step 8) is performed in the presence of a catalyst.
In certain embodiments, the catalyst is benzenesulfonic acid.
In certain embodiments, the step 8) reaction temperature is from 0 to 80 ℃.
In certain embodiments, the step 8) reaction temperature is from 20 to 40 ℃.
In certain embodiments, the step 8) reaction temperature is from 20 to 30 ℃.
In certain embodiments, the molar ratio of compound 8 to 3-pentanone is 1:1-5.
In certain embodiments, the molar ratio of compound 8 to 3-pentanone is 1:1-3.
In certain embodiments, the molar ratio of compound 8 to 3-pentanone is 1:1.35.
In certain embodiments, the step 9) is performed in a solvent.
In certain embodiments, the solvent is selected from one or more of dichloromethane, tetrahydrofuran, ethyl acetate, and toluene.
In certain embodiments, the solvent is selected from dichloromethane.
In certain embodiments, the step 9) is performed in the presence of a base.
In certain embodiments, the base is selected from one or more of triethylamine, DMAP, DIPEA, and pyridine.
In certain embodiments, the base is selected from triethylamine.
In certain embodiments, the reaction temperature of step 9) is from 0 to 50 ℃.
In certain embodiments, the reaction temperature of step 9) is 10 to 40 ℃.
In certain embodiments, the reaction temperature of step 9) is room temperature.
In certain embodiments, the step 10) is performed in a solvent.
In certain embodiments, the solvent is selected from dichloromethane.
In certain embodiments, the step 10) is performed in the presence of triethylsilane and titanium tetrachloride;
in certain embodiments, the step 10) reaction temperature is from-50 ℃ to-20 ℃.
In certain embodiments, the step 10) reaction temperature is from-40 ℃ to-30 ℃.
In certain embodiments, the molar ratio of compound 10 to triethylsilane is 1:1-5.
In certain embodiments, the molar ratio of compound 10 to triethylsilane is 1:1-3.
In certain embodiments, the molar ratio of compound 10 to triethylsilane is 1:1.3.
In certain embodiments, the molar ratio of compound 10 to titanium tetrachloride is from 1:1 to 5.
In certain embodiments, the molar ratio of compound 10 to titanium tetrachloride is from 1:1 to 3.
In certain embodiments, the molar ratio of compound 10 to titanium tetrachloride is 1:1.1.
In certain embodiments, step 11) is performed in a solvent.
In certain embodiments, the solvent is selected from one or more of ethanol, acetonitrile, tetrahydrofuran, and water.
In certain embodiments, the solvent is selected from ethanol and water.
In certain embodiments, step 11) is performed in the presence of a base.
In certain embodiments, the base is selected from one or more of sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, and DBU.
In certain embodiments, the base is selected from sodium bicarbonate.
In certain embodiments, the step 11) reaction temperature is from 0 to 100 ℃.
In certain embodiments, the step 11) reaction temperature is from 40 to 80 ℃.
In certain embodiments, the step 11) reaction temperature is 50 to 70 ℃.
Unless stated to the contrary, the english abbreviations used in the specification and claims have the following meanings:
DIPEA: n, N-diisopropylethylamine.
DMF: n, N-dimethylformamide.
DMAP: 4-dimethylaminopyridine.
DBU:1, 8-diazabicyclo [5.4.0] undec-7-ene.
The process of the present invention is illustrated by the following specific examples, it being understood that these examples are illustrative of the basic principles, main features and advantages of the present invention, and the present invention is not limited by the scope of the following examples; the implementation conditions employed in the examples may be further adjusted according to specific requirements, and the implementation conditions not specified are generally those in routine experiments.
In the following examples 1 The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation method: s=singlet, d=doublet, t=triplet,q=quartet, m=multiplet, br=broad, dd=doublet of doublet, dt=doublet of triplet. If coupling constants are provided, they are in Hz.
The mass spectrum is measured by an LC/MS instrument, and the ionization mode is ESI.
High performance liquid chromatograph model: agilent 1260, siemens flying U3000; chromatographic column model: waters xbridge C18 (4.6. Times.150 mm,3.5 μm); mobile phase: ACN, B Water (0.1% H) 3 PO 4 ) The method comprises the steps of carrying out a first treatment on the surface of the Flow rate: 1.0mL/min; gradient: 5%Afor 1min,increase to 20%A within 4min,increase to 80%A within 8min,80%A for 2min,back to5%A within 0.1min; wavelength: 220nm; column incubator: 35 ℃.
TLC: thin layer chromatography. The thin layer chromatography silica gel plate is a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.2mm-0.3mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm.
Column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, and are used without further purification, and unless otherwise indicated, commercially available manufacturers include, but are not limited to, the national pharmaceutical community, the carbofuran technologies, the tencel (Shanghai) chemical industry development limited, the Shanghai Pico pharmaceutical technologies limited, the Shanghai Michelson chemical technologies limited, and the like.
The examples are not particularly described, and the solution in the reaction is an aqueous solution.
The examples are not specifically described, and the reaction temperature is room temperature and is 20℃to 30 ℃.
The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound or the developing reagent system of thin layer chromatography included: a: petroleum ether and ethyl acetate systems; b: methylene chloride and methanol systems; c: n-hexane: ethyl acetate; the volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine.
EXAMPLE 1 (3R, 4S, 5R) -3, 5-bis ((tert-butyldimethylsilyl) oxy) -4-hydroxycyclohex-1-ene-1-carboxylic acid ethyl ester 2
Ethyl shikimate 1 (7.27 g,35.9 mmol) was dissolved in DMF (40 ml), imidazole (7.34 g,108 mmol) was added, after stirring for 5 min, t-butyldimethylchlorosilane (11.92 g,79.09 mmol) was added, after addition, the reaction was stirred at room temperature for 2 hours, and TLC detection of complete reaction of starting material. The reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and the crude product was purified by silica gel column chromatography to give the title compound 2 (6.9 g, yield 44.5%) as a colorless oil.
Example 2: (3R, 4S, 5R) -3, 5-bis ((tert-butyldimethylsilyl) oxy) -4- ((methylsulfonyl) oxy) cyclohex-1-ene-1-carboxylic acid ethyl ester 3
Compound 2 (6.9 g,16 mmol) was dissolved in dichloromethane (100 ml), triethylamine (3.3 g,32 mmol) and DMAP (195 mg,1.60 mmol) were added, and the mixture was cooled to about 0deg.C under nitrogen, and a solution of methylsulfonyl chloride (2.8 g,24 mmol) in dichloromethane (5 ml) was added dropwise over about half an hour. The reaction was allowed to warm to room temperature for 2 hours, and TLC detected complete reaction of starting materials. The reaction solution was quenched with water, separated, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give the title compound 3 (7.4 g, yield 90%) as a colorless oil.
Example 3: (3R, 4S, 5R) -3, 5-dihydroxy-4- ((methylsulfonyl) oxy) cyclohex-1-ene-1-carboxylic acid ethyl ester 4
Compound 3 (5.0 g,9.9 mmol) was dissolved in absolute ethanol (50 ml), concentrated hydrochloric acid (5 ml) was slowly added, and the reaction was completed by TLC at room temperature overnight after the addition. The reaction solution was poured into saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate 2 times, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and the crude product was purified by silica gel column chromatography to give the title compound 4 (2.0 g, yield 73%) as a colorless oil.
Example 4: (1R, 5R, 6S) -5-hydroxy-7-oxabicyclo [4.1.0] hept-3-ene-3-carboxylic acid ethyl ester 5
Compound 4 (1.5 g,5.35 mmol) was dissolved in ethanol (4 ml) and water (8 ml), sodium bicarbonate (674 mg,8.03 mmol) was added at room temperature and the solution was heated to 60℃for 6 hours and a small amount of starting material remained by TLC. The reaction solution was cooled to room temperature, water was then added thereto, extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography to give the title compound 5 (360 mg, yield 36.5%) as a colorless oil.
1 H NMR(400MHz,CDCl 3 )δ6.82-6.80(m,1H),4.70-4.62(m,1H),4.21(q,J＝7.2Hz,2H),3.47-3.41(m,1H),3.33-3.29(m,1H),3.01-2.89(m,1H),2.70-2.36(m,1H),2.14(d,J＝7.2Hz,1H),1.30(t,J＝7.2Hz,3H).
Example 5: (1R, 5S, 6R) -5- ((4-nitrobenzoyl) oxy) -7-oxabicyclo [4.1.0] hept-3-ene-3-carboxylic acid ethyl ester 6
Compound 5 (340 mg,1.83 mmol) was dissolved in tetrahydrofuran (5 ml), p-nitrobenzoic acid (336 mg,2.01 mmol) and triphenylphosphine (575 mg,2.20 mmol) were added sequentially, cooled to 0deg.C under nitrogen protection, a solution of diisopropyl azodicarboxylate (444 mg,2.20 mmol) in tetrahydrofuran (2 ml) was added dropwise, and the reaction was slowly warmed to room temperature for 1 hour, and TLC detection was essentially complete. The reaction solution was quenched with water, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and the crude product was purified by silica gel column chromatography to give the title compound 6 (470 mg, yield 76%) as a pale yellow solid.
1 H NMR(400MHz,CDCl 3 )δ8.31(s,4H),6.75-6.71(m,1H),6.16-6.00(m,1H),4.24(q,J＝7.2Hz,2H),3.73-3.67(m,1H),3.63-3.57(m,1H),3.20-3.15(m,1H),2.60-2.55(m,1H),1.31(t,J＝7.2Hz,3H).
Example 6: (1S, 5S, 6R) -3- (ethoxycarbonyl) -5, 6-dihydroxycyclohex-2-en-1-yl 4-nitrobenzoate 7
Compound 6 (470 mg,1.40 mmol) was suspended in tetrahydrofuran (3 ml) and water (3 ml), trifluoroacetic acid (2 ml) was added and reacted overnight at room temperature, and a small amount of starting material remained by TLC. The reaction solution was neutralized with saturated aqueous sodium hydrogencarbonate, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography to give the title compound 7 (330 mg, yield 66.7%) as an off-white solid.
1 H NMR(400MHz,CDCl 3 )δ8.34-8.27(m,2H),8.25-8.17(m,2H),6.91-6.86(m,1H),5.92(t,J＝4.6Hz,1H),4.30-4.21(m,2H)，4.20-4.13(m,1H),3.99-3.90(m,1H),3.06(dd,J＝18.4,5.6Hz,1H),2.54-2.48(m 2H),2.38-2.29(m,1H),1.31(t,J＝7.2Hz,3H).
Example 7: (3S, 4R, 5S) -3,4, 5-Trihydroxycyclohex-1-ene-1-carboxylic acid ethyl ester 8
Compound 7 (313 mg,0.61 mmol) was dissolved in ethanol (7 ml), sodium carbonate (192 mg,1.81 mmol) was added at room temperature, and the reaction was heated to 40℃for 1 hour, and the reaction was complete by TLC. The reaction solution was cooled to room temperature, water was then added thereto, extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, whereby the crude product was purified by silica gel column chromatography to give the title compound 8 (155 mg, yield 86.1%) as a white solid.
1 H NMR(400MHz,DMSO-d 6 )δ6.62(s,1H),4.84-4.62(m,2H),4.63(d,J＝4.2Hz,1H),4.26-4.20(m,1H),4.13(q,J＝7.2Hz,2H),3.86-3.82(m,1H),3.59-3.54(m,1H),2.48-2.37(m,1H),2.12-2.00(m,1H),1.22(t,J＝7.2Hz,3H).
Example 8: (3 aS,7S,7 aR) -2, 2-diethyl-7-hydroxy-3 a,6,7 a-tetrahydrobenzo [ d ] [1,3] dioxazole-5-carboxylic acid ethyl ester 9
A mixture of 3-pentanone (90 mg,1.0 mmol), triethyl orthoformate (154 mg,1.04 mmol), ethanol (48 mg,1.0 mmol) and benzenesulfonic acid (catalytic amount) was reacted at 25℃for 4 hours, compound 8 (150 mg,0.740 mmol) was added in portions, and the reaction was continued at 25℃for 2 hours after the addition, and the TLC detection was essentially complete. The reaction solution was cooled to room temperature, water was then added thereto, extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to give the title compound 9 (210 mg, crude) as a yellow oil, which was used directly in the next step.
Example 9: (3 aS,7S,7 aS) -2, 2-diethyl-7- ((methylsulfonyl) oxy) -3a,6, 7a tetrahydrobenzo [ d ] [1,3] dioxolane-5-carboxylic acid ethyl ester 10
Compound 9 (210 mg, crude) was dissolved in dichloromethane (5 ml), triethylamine (158 mg,0.56 mmol) and DMAP (catalytic amount) were added at room temperature, cooled to 0deg.C under nitrogen protection, methanesulfonyl chloride (133 mg,1.17 mmol) was added dropwise, and after addition, the reaction was slowly resumed to room temperature for 2 hours, and TLC detection was complete. The reaction solution was diluted with dichloromethane, quenched with water, separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product as a colorless oily title compound 10 (210 mg, two-step yield 81.4%) by purification on silica gel column chromatography.
Example 10: (3S, 4S, 5S) -4-hydroxy-5- ((methylsulfonyl) oxy) -3- (pent-3-yloxy) cyclohex-1-ene-1-carboxylic acid ethyl ester 11
Compound 10 (210 mg,0.60 mmol) was dissolved in dichloromethane (3 ml), triethylsilane (91 mg,0.78 mmol) was added at room temperature, cooled to about-36℃under nitrogen protection, a solution of titanium tetrachloride (125 mg,0.66 mmol) in dichloromethane (1 ml) was added dropwise, and the reaction was continued at-36℃for 1 hour after the dropwise addition, and the TLC detection was essentially complete. The reaction solution was quenched with water, separated, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give the title compound 11 (300 mg, crude) as a pale yellow oil, which was used directly in the next step.
Example 11: (1R, 5S, 6R) -5- (pentan-3-yloxy) -7-oxabicyclo [4.1.0] hept-3-ene-3-carboxylic acid ethyl ester II
Compound 11 (300 mg, crude) was dissolved in ethanol (6 ml), sodium bicarbonate (144 mg,1.72 mmol) was added at room temperature, and the reaction was heated to 60℃for 2 hours, and the reaction was essentially complete by TLC. The reaction solution was cooled to room temperature, water was then added thereto, extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated, and the crude product was purified by silica gel column chromatography to give the title compound II (120 mg, two-step yield 78.4%) as a white solid.
1 H NMR(400MHz,CDCl 3 )δ6.73(s,1H),4.43-4.36(m,1H),4.26-4.16(m,2H),3.55-3.44(m,3H),3.08(d,J＝19.6Hz,1H),2.48-2.39(m,1H),1.67-1.58(m,4H),1.34-1.24(t,J＝7.2Hz,3H),1.01-0.95(m,6H).
It should be understood that the above examples are illustrative and are not intended to encompass all possible implementations encompassed by the claims. Various modifications and changes may be made in the above embodiments without departing from the scope of the disclosure. Likewise, the individual features of the above embodiments can also be combined arbitrarily to form further embodiments of the invention which may not be explicitly described. Therefore, the above examples merely represent several embodiments of the present invention and do not limit the scope of protection of the patent of the present invention.

Claims (10)

1. The preparation method of the oseltamium Wei Gongyi impurity II is characterized by comprising the following steps:
Figure FDA0003420893200000011
1) Reacting the compound 1 with tert-butyldimethyl chlorosilane to obtain a compound 2;
2) Reacting the compound 2 with methylsulfonyl chloride to obtain a compound 3;
3) Removing TBS protection from the compound 3 to obtain a compound 4;
4) Closing the ring of the compound 4 to obtain a compound 5;
5) Reacting the compound 5 with p-nitrobenzoic acid to obtain a compound 6;
6) Ring opening the compound 6 to obtain a compound 7;
7) Hydrolyzing the compound 7 to obtain a compound 8;
8) Reacting the compound 8 with 3-pentanone to obtain a compound 9;
9) Reacting compound 9 with methylsulfonyl chloride to obtain compound 10;
10 Ring opening compound 10 to give compound 11;
11 Ring closure of compound 11 to give compound II.
2. The method of claim 1, wherein step 1) is performed in a solvent;
preferably, the solvent is selected from one or more of dichloromethane, tetrahydrofuran, acetonitrile, DMF, dioxane, ethyl acetate and toluene, preferably DMF;
preferably, said step 1) is carried out in the presence of a base;
preferably, the base is selected from one or more of triethylamine, imidazole, pyridine and DBU, preferably imidazole;
preferably, the reaction temperature of step 1) is 0 to 50 ℃, preferably room temperature.
3. The method of claim 1, wherein steps 2) and 9) are performed in a solvent;
preferably, the solvent is selected from one or more of dichloromethane, tetrahydrofuran, ethyl acetate and toluene, preferably dichloromethane;
preferably, said steps 2), 9) are carried out in the presence of a base;
preferably, the base is selected from one or more of triethylamine, DMAP, DIPEA and pyridine, preferably triethylamine;
preferably, the reaction temperature of steps 2) and 9) is 0 to 50 ℃, preferably room temperature.
4. The method of claim 1, wherein step 3) is performed in a solvent;
preferably, the solvent is selected from one or more of absolute ethanol, isopropanol, acetonitrile and ethyl acetate, preferably ethanol;
preferably, said step 3) is carried out in the presence of an acid;
preferably, the acid is selected from one or more of hydrochloric acid, p-toluene sulfonic acid and trifluoroacetic acid, preferably hydrochloric acid;
preferably, the reaction temperature of step 3) is 0 to 50 ℃, preferably room temperature.
5. The method of claim 1, wherein steps 4) and 11) are performed in a solvent;
preferably, the solvent is selected from one or more of ethanol, acetonitrile, tetrahydrofuran and water, preferably ethanol and water;
preferably, said steps 4), 11) are carried out in the presence of a base;
preferably, the base is selected from one or more of sodium bicarbonate, sodium carbonate and DBU, preferably sodium bicarbonate;
preferably, the reaction temperature in the steps 4) and 11) is 0 to 100 ℃, preferably 40 to 80 ℃.
6. The method of claim 1, wherein step 5) is performed in a solvent;
preferably, the solvent is selected from one or more of tetrahydrofuran, dichloromethane and toluene, preferably tetrahydrofuran;
preferably, said step 5) is a Mitsunobu reaction;
preferably, said step 5) is carried out in the presence of triphenylphosphine and diisopropyl azodicarboxylate or diethyl azodicarboxylate;
preferably, the reaction temperature of step 5) is 0 to 50 ℃, preferably room temperature.
7. The method of claim 1, wherein step 6) is performed in a solvent;
preferably, the solvent is selected from one or more of tetrahydrofuran, ethanol, isopropanol, ethyl acetate and water, preferably tetrahydrofuran and water;
preferably, said step 6) is carried out in the presence of an acid;
preferably, the acid is selected from one or more of trifluoroacetic acid, methanesulfonic acid and sulfuric acid, preferably trifluoroacetic acid;
preferably, the reaction temperature of step 6) is 0 to 50 ℃, preferably room temperature.
8. The method of claim 1, wherein step 7) is performed in a solvent;
preferably, the solvent is selected from one or more of ethanol, acetonitrile, tetrahydrofuran and DMF, preferably ethanol;
preferably, said step 7) is carried out in the presence of a base;
preferably, the base is selected from one or more of sodium carbonate, potassium carbonate and sodium hydroxide, preferably sodium carbonate;
preferably, the reaction temperature of step 7) is 0 to 80 ℃, preferably 20 to 50 ℃.
9. The method of claim 1, wherein step 8) is performed in a solvent;
preferably, the solvent is selected from triethyl orthoformate;
preferably, said step 8) is carried out in the presence of a catalyst;
preferably, the catalyst is benzenesulfonic acid;
preferably, the reaction temperature in step 8) is 0 to 80 ℃, preferably 20 to 40 ℃.
10. The method of claim 1, wherein step 10) is performed in a solvent;
preferably, the solvent is selected from dichloromethane;
preferably, said step 10) is carried out in the presence of triethylsilane and titanium tetrachloride;
preferably, the reaction temperature in the step 10) is-50 to-20 ℃, preferably-40 to-30 ℃.
CN202111563249.XA 2021-12-20 2021-12-20 Preparation method of oseltamium Wei Gongyi impurity Pending CN116283832A (en)

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