CN113929702A - Preparation method of everolimus - Google Patents
Preparation method of everolimus Download PDFInfo
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- CN113929702A CN113929702A CN202010610228.8A CN202010610228A CN113929702A CN 113929702 A CN113929702 A CN 113929702A CN 202010610228 A CN202010610228 A CN 202010610228A CN 113929702 A CN113929702 A CN 113929702A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
Abstract
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of everolimus, which comprises the following steps: reacting sirolimus with protected 31-hydroxyl with ethylene carbonate under the action of alkali to obtain everolimus with protected 31-hydroxyl, and deprotecting the 31-hydroxyl of the compound to obtain everolimus; according to the process, the hydroxyethyl group is introduced by the ethylene carbonate reagent, the obtained byproduct is carbon dioxide, the process is clean and environment-friendly, the post-treatment is convenient, the use of dangerous chemical reagents is avoided, the reaction is milder, the process is economic and environment-friendly, the yield is higher, and the process is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of everolimus.
Background
Everolimus (Everolimus) is a new generation of macrolide immunosuppressant and antitumor drug developed by Novartis, which is derived from 42-OH of rapamycin to 42-O- (2-hydroxyethyl), and is also called 42-O- (2-hydroxyethyl) -rapamycin. Everolimus is first marketed in sweden in 2003 as an immunosuppressant with the trade name: certican for treating rejection after organ transplantation; as a kinase inhibitor, was first marketed in the united states in 3 months 2009 under the trade name: the Afinitor is mainly suitable for treating patients with advanced renal carcinoma after the treatment failure of sunitinib or sorafenib (sorafenib), and has the following structural formula:
at present, the synthetic route of everolimus is prepared by taking sirolimus as a starting material and carrying out 2-step chemical synthesis, and the US patent US5665772 reports everolimus and a synthetic process thereof at first. The method takes rapamycin as a raw material to obtain everolimus through two steps of reactions: firstly, rapamycin reacts with 2- (tert-butyldimethylsilyloxy) ethyl trifluoromethanesulfonate under the catalysis of base to obtain an intermediate, and then a protecting group is removed to obtain a target product, wherein the synthetic route is as follows:
but the selectivity of the first step in the method is poor, the reaction yield is only 5-15%, and most raw materials are not converted; the second step reaction is easy to produce degradation products and isomerization, and the obtained product has low purity and is not suitable for large-scale production.
In order to further improve the selectivity of 42-position hydroxyl, Chinese patent applications CN102268015, CN1038448849, CN1402731, international application WO0123395 and the like further optimize the synthesis process of everolimus, 31-position mono-protected sirolimus reacts with mono-protected ethylene glycol monotrifluoromethane sulfonate under alkaline condition to synthesize an intermediate, and deprotection is carried out under acidic condition to obtain everolimus:
however, according to the process method, a large amount of degradation impurities generated by dehydration and ring opening of the macrolide are found, which brings difficulty to process purification, and the preparation process of the ethylene glycol mono-substituted triflate is complex, has low yield and is not suitable for industrial production.
Chinese patent application CN104876944 reports a more environment-friendly synthesis method, wherein the reaction takes rapamycin as raw material, ethylene oxide as ethanol source, and everolimus is obtained under catalysis of strong acid, the route is as follows:
however, the amount of ethylene oxide used in the process is large, and the stability of macrolide under strong acid is poor, so that the process is not suitable for actual industrial production.
Therefore, exploring a process which is simple in operation, high in efficiency, low in cost and high in quality for the synthesis of everolimus is a problem to be solved at present.
Disclosure of Invention
In order to optimize the synthesis process of everolimus, the invention provides a novel preparation method of everolimus, and the method has the advantages of mild reaction conditions, short route, simple operation and capability of synthesizing everolimus with high yield and high purity.
The invention is realized by the following technical scheme:
a preparation method of everolimus comprises the following steps: sirolimus with protected 31-hydroxyl group reacts with ethylene carbonate under the action of alkali to obtain a compound IV, and the compound IV is deprotected to obtain everolimus, wherein the process route is as follows:
preparation of Compound IV
The preparation method of the compound IV specifically comprises the following steps: at room temperature, dissolving a compound II, namely sirolimus with 31-position hydroxyl protected by TMS, in an organic solvent, adding alkali and a compound II, namely ethylene carbonate, and controlling the temperature until the reaction is finished to obtain a compound IV.
Preferably, the base may be one of potassium carbonate, sodium bicarbonate, triethylamine, pyridine, N-diisopropylethylamine or a combination thereof, and potassium carbonate is particularly preferred.
In a preferable scheme, the feeding molar ratio of the compound II, the alkali and the ethylene carbonate is 1: 1.2-1.8: 1.5-2.2, wherein 1:1.5:1.8 is particularly preferable.
Preferably, the organic solvent is one of toluene, xylene, tetrahydrofuran, N-dimethylformamide, 1, 4-dioxane or a combination thereof, and particularly preferably toluene.
In a preferred scheme, the reaction temperature is 80-100 ℃.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: after the reaction is finished, cooling to room temperature, adding deionized water and an extracting agent into the reaction solution, stirring, separating liquid, and concentrating an organic layer to obtain an intermediate IV; the extractant is one or the combination of ethyl acetate, dichloromethane and trichloromethane.
Preparation of everolimus
The specific preparation method of everolimus comprises the following steps: and dissolving the compound IV in an organic solvent, and adding acid in ice bath to obtain everolimus.
Preferably, the acid is one or a combination of hydrochloric acid, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid, and hydrochloric acid is particularly preferred.
Preferably, the concentration of the acid is 0.5M to 1.5M, with 1.0M being particularly preferred.
In a preferred embodiment, the feeding molar ratio of the compound IV to the acid is 1: 1.2-2.0, and 1:1.4 is particularly preferred.
Preferably, the organic solvent is one or a combination of tetrahydrofuran, methanol, ethanol and dichloromethane, and tetrahydrofuran is particularly preferred.
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: after the reaction is finished, adding saturated sodium bicarbonate aqueous solution into the reaction solution for washing, adding ethyl acetate for extraction, separating liquid, washing an organic phase by pure water to be nearly neutral, concentrating, and separating a product by column chromatography (an eluent is V)Petroleum ether：VEthyl acetate＝1:5)。
Compared with the prior art, the invention has the following technical effects:
1. the invention provides a novel method for preparing everolimus, and the whole synthesis method has the advantages of short route, simple operation steps, high reaction yield and high product purity.
2. The ethylene carbonate reagent product introduced with hydroxyethyl is carbon dioxide, so that the method is clean and environment-friendly and is convenient for post-treatment.
Detailed Description
The invention is further illustrated by the following examples. It should be properly understood that: the examples of the present invention are intended to be illustrative only and not to be limiting, and therefore, the present invention is intended to be simply modified within the scope of the present invention as claimed.
The invention adopts HPLC to measure the purity of everolimus, and the chromatographic conditions are as follows:
a chromatographic column: thermo Hypersil BDS C18 column (3 mm. times.250 mm, 5 um);
mobile phase: water acetonitrile (40: 60);
detection wavelength: 275 nm;
column temperature: 35 ℃;
flow rate: 1.1 ml/min.
Characterization data for everolimus prepared by the invention are as follows:
ESI-HRMS(m/z)：980.5800[M+Na]+；；1H NMR(400MHz,CDCl3):6.46(s,1H),6.32～6.42(m,1H),6.11～6.18(m,1H),6.02(d,J＝10.4Hz,1H),5.52～5.58(dd,J＝9.6、10.8Hz,1H),5.45(d,J＝9.6Hz,1H),5.26～5.30(m,1H),5.15～5.17(m,1H),4.19(d,J＝4.4Hz,1H),3.84～3.90(m,1H),3.75～3.80(m,1H),3.73(d,J＝6.0Hz,1H),3.70(t,J＝11.4Hz,2H),3.54～3.62(m,5H),3.45(s,3H),3.35(s,3H),3.15～3.23(m,1H),3.14(s,3H),2.70～2.75(m,1H),2.30～2.35(m,2H),2.27～2.35(m,1H),2.08～2.12(m,2H),1.98～2.01(m,2H),1.96～1.98(m,2H),1.83～1.85(m,2H),1.77～1.79(m,2H),1.75(s,3H),1.74～1.75(m,2H),1.65(s,3H),1.44～1.54(m,3H),1.29～1.39(m,1H),1.10～1.20(m,2H),1.10(d,J＝4.8Hz,3H),1.05(d,J＝4.8Hz,3H),0.99(d,J＝4.8Hz,3H),0.95(d,J＝4.8Hz,3H),0.92(d,J＝4.8Hz,3H)；13C NMR(100MHz,CDCl3):215.4,208.0,193.1,169.3,166.8,140.4,136.5,135.6,133.6,129.9,129.6,126.7,126.4,98.5,84.8,84.5,83.2,82.8,77.1,71.4,67.2,62.4,60.1,57.1,55.9,51.3,46.6,44.2,40.6,40.2,38.9,38.3,35.6,35.1,34.0,33.2,32.9,31.7,31.3,27.5,27.0,25.3,21.5,20.7,16.3,16.1,15.5,13.8,13.2,10.2。
example 1
Dissolving a compound II (985.60g, 1.0mol) in toluene (3.0L) at room temperature, adding potassium carbonate (207.32g, 1.5mol), stirring for 20min, adding ethylene carbonate (158.51g, 1.8mol), heating to 90 ℃ for reaction, detecting that a reaction solution is cooled to room temperature after the reaction is finished, adding deionized water (1.0L) and dichloromethane (1.5L) into the reaction solution, stirring for liquid separation, concentrating an organic layer, and drying in vacuum at 40 ℃ to obtain an intermediate IV, wherein the yield is 98.8%, and the HPLC purity is 99.94%.
Example 2
Dissolving a compound II (985.60g, 1.0mol) in p-xylene (3.0L) at room temperature, adding potassium carbonate (165.85g, 1.2mol), stirring for 20min, adding ethylene carbonate (158.51g, 1.8mol), heating to 100 ℃ for reaction, detecting the reaction, cooling the reaction liquid to room temperature, adding deionized water (1.0L) and dichloromethane (1.5L) into the reaction liquid, stirring for liquid separation, concentrating an organic layer, and drying in vacuum at 40 ℃ to obtain an intermediate IV, wherein the yield is 94.4% and the HPLC purity is 99.86%.
Example 3
Dissolving a compound II (985.60g, 1.0mol) in DMF (3.0L) at room temperature, adding potassium carbonate (248.78g, 1.8mol), stirring for 20min, adding ethylene carbonate (158.51g, 1.8mol), heating to 80 ℃ for reaction, detecting reaction liquid, cooling to room temperature after the reaction is finished, adding deionized water (1.0L) and trichloromethane (1.5L) into the reaction liquid, stirring for liquid separation, concentrating an organic layer, and drying in vacuum at 40 ℃ to obtain an intermediate IV, wherein the yield is 95.7%, and the HPLC purity is 99.77%.
Example 4
Dissolving a compound II (985.60g, 1.0mol) in tetrahydrofuran (3.0L) at room temperature, adding potassium carbonate (138.21g, 1.0mol), stirring for 20min, adding ethylene carbonate (158.51g, 1.8mol), heating to 70 ℃ for reaction, detecting reaction liquid, cooling the reaction liquid to room temperature after the reaction is finished, adding deionized water (1.0L) and ethyl acetate (1.5L) into the reaction liquid, stirring for liquid separation, concentrating an organic layer, and drying in vacuum at 40 ℃ to obtain an intermediate IV, wherein the yield is 85.7% and the HPLC purity is 99.56%.
Example 5
Dissolving a compound II (985.60g, 1.0mol) in 1.4-dioxane (3.0L) at room temperature, adding potassium carbonate (276.42g, 2.0mol), stirring for 20min, adding ethylene carbonate (158.51g, 1.8mol), heating to 100 ℃ for reaction, detecting the reaction, cooling the reaction liquid to room temperature, adding deionized water (1.0L) and ethyl acetate (1.5L) into the reaction liquid, stirring for liquid separation, concentrating an organic layer, and drying in vacuum at 40 ℃ to obtain an intermediate IV, wherein the yield is 86.8% and the HPLC purity is 99.58%.
Example 6
Dissolving a compound II (985.60g, 1.0mol) in toluene (3.0L) at room temperature, adding sodium bicarbonate (126.02g, 1.5mol), stirring for 20min, adding ethylene carbonate (132.09g, 1.5mol), heating to 90 ℃ for reaction, detecting the reaction solution after the reaction is finished, cooling the reaction solution to room temperature, adding deionized water (1.0L) and dichloromethane (1.5L) into the reaction solution, stirring for liquid separation, concentrating an organic layer, and drying in vacuum at 40 ℃ to obtain an intermediate IV, wherein the yield is 92.3% and the HPLC purity is 99.74%.
Example 7
Dissolving a compound II (985.60g, 1.0mol) in toluene (3.0L) at room temperature, adding triethylamine (151.79g, 1.5mol), stirring for 20min, adding ethylene carbonate (193.73g, 2.2mol), heating to 90 ℃ for reaction, detecting the reaction solution after the reaction is finished, cooling the reaction solution to room temperature, adding deionized water (1.0L) and dichloromethane (1.5L) into the reaction solution, stirring for liquid separation, concentrating an organic layer, and drying in vacuum at 40 ℃ to obtain an intermediate IV, wherein the yield is 94.2%, and the HPLC purity is 99.79%.
Example 8
Dissolving compound II (985.60g, 1.0mol) in toluene (3.0L) at room temperature, adding pyridine (118.65g, 1.5mol), stirring for 20min, adding ethylene carbonate (105.67g, 1.2mol), heating to 90 ℃ for reaction, detecting reaction liquid, cooling the reaction liquid to room temperature after the reaction is finished, adding deionized water (1.0L) and dichloromethane (1.5L) into the reaction liquid, stirring for liquid separation, concentrating an organic layer, and drying in vacuum at 40 ℃ to obtain an intermediate IV, wherein the yield is 84.2%, and the HPLC purity is 99.54%.
Example 9
Dissolving the compound II (985.60g, 1.0mol) in toluene (3.0L) at room temperature, adding N, N-diisopropylethylamine (193.86g, 1.5mol), stirring for 20min, adding ethylene carbonate (220.15g, 2.5mol), heating to 90 ℃ for reaction, detecting the reaction, cooling the reaction liquid to room temperature, adding deionized water (1.0L) and dichloromethane (1.5L) into the reaction liquid, stirring for liquid separation, concentrating an organic layer, and drying in vacuum at 40 ℃ to obtain an intermediate IV, wherein the yield is 86.8% and the HPLC purity is 99.61%.
Preparation of everolimus
Example 10
Dissolving compound IV (514.81, 0.5mol) in 2.0L tetrahydrofuran solution at room temperature, dropwise adding 1.0M dilute hydrochloric acid (600mL, 1.0mol) under ice bath, reacting for 1h under ice bath, adding 500mL ethyl acetate into the reaction solution, extracting, adding 500mL saturated sodium bicarbonate solution into the organic layer, washing, concentrating the organic layer, and performing column chromatography (eluent is V)Petroleum ether：VEthyl acetate1:5) to obtain everolimus with the yield of 97.5 percent and the HPLC purity of 99.88 percent.
Example 11
Dissolving compound IV (514.81, 0.5mol) in 2.0L tetrahydrofuran solution at room temperature, dropwise adding 1.5M acetic acid (400mL, 1.0mol) under ice bath, reacting for 1h under ice bath, adding 500mL ethyl acetate into the reaction solution, extracting, adding 500mL saturated sodium bicarbonate solution into the organic layer, washing, concentrating the organic layer, and performing column chromatography (eluent is V)Petroleum ether：VEthyl acetate1:5) to obtain everolimus with yield of 92.5% and HPLC purity of 99.75%.
Example 12
Dissolving compound IV (514.81, 0.5mol) in 2.0L tetrahydrofuran solution at room temperature, dropwise adding 0.5M trifluoroacetic acid (1200mL, 1.0mol) under ice bath, reacting for 1h under ice bath, adding 500mL ethyl acetate into the reaction solution, extracting, adding 500mL saturated sodium bicarbonate solution into the organic layer, washing, concentrating the organic layer, and performing column chromatography (eluent is V)Petroleum ether：VEthyl acetate1:5) to obtain everolimus with the yield of 93.7 percent and the HPLC purity of 99.78 percent.
Example 13
Dissolving compound IV (514.81, 0.5mol) in 2.0L tetrahydrofuran solution at room temperature, dropwise adding 1.8M tetraethylammonium fluoride (334mL, 1.0mol) under ice bath, reacting for 1h under ice bath, adding 500mL ethyl acetate into the reaction solution for extraction, adding 500mL saturated sodium bicarbonate solution into the organic layer for washing, concentrating the organic layer, and performing column chromatography (eluent is V)Petroleum ether：VEthyl acetate1:5) to obtain everolimus with the yield of 93.7 percent and the HPLC purity of 99.78 percent。
Example 14
Dissolving compound IV (514.81, 0.5mol) in 2.0L methanol solution at room temperature, dropwise adding 1.0M dilute hydrochloric acid (600mL, 0.6mol) under ice bath, reacting for 1h under ice bath, adding 500mL ethyl acetate into the reaction solution, extracting, adding 500mL saturated sodium bicarbonate solution into the organic layer, washing, concentrating the organic layer, and performing column chromatography (eluent is V)Petroleum ether：VEthyl acetate1:5) to obtain everolimus with the yield of 93.7 percent and the HPLC purity of 99.78 percent.
Example 15
Dissolving compound IV (514.81, 0.5mol) in 2.0L methanol solution at room temperature, dropwise adding 1.0M dilute hydrochloric acid (100mL, 1.0mol) under ice bath, reacting for 1h under ice bath, adding 500mL ethyl acetate into the reaction solution, extracting, adding 500mL saturated sodium bicarbonate solution into the organic layer, washing, concentrating the organic layer, and performing column chromatography (eluent is V)Petroleum ether：VEthyl acetate1:5) to obtain everolimus with yield of 90.3% and HPLC purity of 99.65%.
Example 16
Dissolving compound IV (514.81, 0.5mol) in 2.0L ethanol solution at room temperature, dropwise adding 1.0M dilute hydrochloric acid (500mL, 0.5mol) under ice bath, reacting for 2h under ice bath, adding 500mL ethyl acetate into the reaction solution, extracting, adding 500mL saturated sodium bicarbonate solution into the organic layer, washing, concentrating the organic layer, and performing column chromatography (eluent is V)Petroleum ether：VEthyl acetate1:5) to obtain everolimus with yield of 85.4% and HPLC purity of 99.63%.
Example 17
Dissolving compound IV (514.81, 0.5mol) in 2.0L dichloromethane solution at room temperature, dropwise adding 1.0M dilute hydrochloric acid (900mL, 0.9mol) under ice bath, reacting for 2h under ice bath, adding 500mL saturated sodium bicarbonate solution into the reaction solution, washing, condensing the organic layer, and performing column chromatography (eluent is V)Petroleum ether：VEthyl acetate1:5) to obtain everolimus with yield of 82.2% and HPLC purity of 99.51%.
Claims (10)
1. A preparation method of everolimus is characterized in that sirolimus with protected 31-hydroxyl is reacted with ethylene carbonate under the action of alkali to obtain a compound IV, and the compound IV is deprotected to obtain everolimus, wherein the synthetic route is as follows:
2. the method of claim 1, comprising the steps of:
step 1: dissolving a compound II, namely sirolimus with 31-hydroxyl protected by TMS, in an organic solvent at room temperature, adding alkali and a compound II, namely ethylene carbonate, and controlling the temperature until the reaction is finished to obtain a compound IV;
step 2: and dissolving the compound IV in an organic solvent, and adding acid in ice bath to obtain everolimus.
3. The preparation method according to claim 2, wherein the base in step 1 can be one or a combination of potassium carbonate, sodium bicarbonate, triethylamine, pyridine, and N, N-diisopropylethylamine.
4. The preparation method according to claim 2, wherein the compound II, the base and the ethylene carbonate are fed in the step 1 in a molar ratio of 1: 1.2-1.8: 1.5-2.2.
5. The method according to claim 2, wherein the organic solvent in step 1 is one of toluene, xylene, tetrahydrofuran, N-dimethylformamide, 1, 4-dioxane, or a combination thereof.
6. The method according to claim 2, wherein the reaction temperature in step 1 is 80 ℃ to 100 ℃.
7. The method according to claim 2, wherein the acid in step 2 is one or a combination of hydrochloric acid, acetic acid, trifluoroacetic acid and p-toluenesulfonic acid.
8. The method according to claim 2, wherein the concentration of the acid in the step 2 is 0.5M to 1.5M.
9. The preparation method according to claim 2, wherein the feeding molar ratio of the compound IV to the acid in the step 2 is 1: 1.2-2.0.
10. The preparation method according to claim 2, wherein the organic solvent in step 2 is one or a combination of tetrahydrofuran, methanol, ethanol and dichloromethane.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146536A (en) * | 2015-04-25 | 2016-11-23 | 山东新时代药业有限公司 | A kind of preparation method of everolimus |
| JP2017222625A (en) * | 2016-06-17 | 2017-12-21 | 三菱ケミカル株式会社 | Diol compound, and polycarbonate resin, polycarbonate polyol resin, polyester resin, polyester polyol resin and polyurethane resin produced from the diol compound |
| CN109206441A (en) * | 2017-06-30 | 2019-01-15 | 正大天晴药业集团股份有限公司 | A kind of purification process of everolimus |
| CN109776569A (en) * | 2017-11-14 | 2019-05-21 | 上海医药工业研究院 | A kind of preparation method of everolimus |
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2020
- 2020-06-29 CN CN202010610228.8A patent/CN113929702A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106146536A (en) * | 2015-04-25 | 2016-11-23 | 山东新时代药业有限公司 | A kind of preparation method of everolimus |
| JP2017222625A (en) * | 2016-06-17 | 2017-12-21 | 三菱ケミカル株式会社 | Diol compound, and polycarbonate resin, polycarbonate polyol resin, polyester resin, polyester polyol resin and polyurethane resin produced from the diol compound |
| CN109206441A (en) * | 2017-06-30 | 2019-01-15 | 正大天晴药业集团股份有限公司 | A kind of purification process of everolimus |
| CN109776569A (en) * | 2017-11-14 | 2019-05-21 | 上海医药工业研究院 | A kind of preparation method of everolimus |
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