CN114671891A - Preparation method of everolimus ethylation impurities - Google Patents
Preparation method of everolimus ethylation impurities Download PDFInfo
- Publication number
- CN114671891A CN114671891A CN202011585140.1A CN202011585140A CN114671891A CN 114671891 A CN114671891 A CN 114671891A CN 202011585140 A CN202011585140 A CN 202011585140A CN 114671891 A CN114671891 A CN 114671891A
- Authority
- CN
- China
- Prior art keywords
- everolimus
- preparation
- impurities
- ethylation
- ethyl acetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 title claims abstract description 30
- 229960005167 everolimus Drugs 0.000 title claims abstract description 29
- 239000012535 impurity Substances 0.000 title claims abstract description 26
- 230000006203 ethylation Effects 0.000 title claims abstract description 14
- 238000006200 ethylation reaction Methods 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical group ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 238000001308 synthesis method Methods 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000006317 isomerization reaction Methods 0.000 abstract description 2
- 238000000746 purification Methods 0.000 abstract description 2
- 230000035484 reaction time Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N ethyl acetate Substances CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000001035 drying Methods 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000012071 phase Substances 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 239000008367 deionised water Substances 0.000 description 7
- 229910021641 deionized water Inorganic materials 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000003208 petroleum Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 239000003480 eluent Substances 0.000 description 6
- 238000010828 elution Methods 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 5
- 239000011259 mixed solution Substances 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 4
- 229960002930 sirolimus Drugs 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 3
- HKVAMNSJSFKALM-CPXURSODSA-N everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)\C(C)=C\C=C\C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-CPXURSODSA-N 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003120 macrolide antibiotic agent Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 1
- JHUUPUMBZGWODW-UHFFFAOYSA-N 3,6-dihydro-1,2-dioxine Chemical compound C1OOCC=C1 JHUUPUMBZGWODW-UHFFFAOYSA-N 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000010174 renal carcinoma Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229960001796 sunitinib Drugs 0.000 description 1
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
Images
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of an everolimus ethylation impurity. According to the method, chiral isomerization impurities caused by acidic conditions can be avoided, the purification of a target product is facilitated, meanwhile, compared with the original synthesis method, the reaction time is shortened, the labor cost is greatly reduced, the operation is simple, the yield and the purity are greatly improved, and the method is more suitable for industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of an everolimus ethylation impurity.
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. The medicine is mainly suitable for treating patients with advanced renal carcinoma after failure of treatment of sunitinib or sorafenib, and has the following structural formula:
The commonly used synthesis methods of everolimus reported at present are the following two methods:
the method comprises the following steps: under the condition of organic base, rapamycin or silicon-based selective protection of 31-hydroxyl of rapamycin and mono-protection of oxyethyl trifluoromethanesulfonate are used as reactants, and the obtained product is deprotected by silyl ether to obtain everolimus.
The second method comprises the following steps: taking a rapamycin 31-hydroxyl or a rapamycin derivative selectively protected by a silicon substrate as a raw material, reacting with trifluoromethanesulfonic anhydride, activating the 42-hydroxyl of the raw material, reacting with mono-protected glycol, and then removing a silicon ether protecting group to obtain everolimus.
Research on two synthetic methods has found that contacting everolimus macrolide with ethanol produces ethylated impurities, and the structure is as follows:
because the structure of the everolimus is similar to that of everolimus, the physical and chemical properties of the everolimus, such as stability and the like, of the everolimus are extremely similar to those of products, and a large amount of everolimus can not be obtained by a conventional method such as degradation, separation and the like, but the existing synthetic patent literature on everolimus ethylation impurities is few, and only Chinese patent application CN104530112 reports a preparation method for synthesizing the ethylation impurities, wherein everolimus and absolute ethyl alcohol are used as reactants and react under an acidic condition to obtain the ethylation impurities.
Therefore, the problem to be solved at present is to explore a process route with low production cost, simple operation and higher yield for the everolimus ethylation impurities.
Disclosure of Invention
In order to optimize the synthesis process of everolimus ethylation impurities, the invention provides a novel preparation method of everolimus ethylation impurities, the method has the advantages of mild reaction conditions, short route, low cost, simple operation, high purity of the obtained ethylation impurities and high yield.
The invention is realized by the following technical scheme:
a preparation method of everolimus ethylated impurities comprises the following steps: and (3) adding the compound SM-1 into ethanol and an organic solvent at room temperature for dissolving, controlling the temperature, adding inorganic base, and continuously controlling the temperature and stirring for reacting to obtain an everolimus ethylated impurity.
Preferably, the inorganic base is selected from one or a combination of sodium hydroxide, sodium carbonate and potassium carbonate, wherein sodium hydroxide is particularly preferred.
Preferably, the feeding molar ratio of the compound SM-1 to the inorganic base is 1: 0.5-1.5, and particularly preferably 1: 0.8.
Preferably, the organic solvent is selected from one or a combination of chloroform, 1, 4-dioxane and tetrahydrofuran, wherein tetrahydrofuran is particularly preferred.
Preferably, the volume ratio of the organic solvent to the ethanol is 2: 1-4: 1.
Preferably, the reaction temperature after the inorganic base is added and the base is added is 30-65 ℃, wherein the reaction temperature is particularly preferably 40-45 DEG C
In a preferred embodiment, after the reaction is finished, a post-treatment operation is required, specifically: adding deionized water and an extracting agent into the reaction solution after the reaction is finished, stirring and separating the solution, extracting the water phase once by using the extracting agent, combining the organic phases, and respectively using saturated NaHCO3Washing the solution with saturated saline solution, separating, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (eluting with VPetroleum ether：VEthyl acetateEluting with ethyl acetate after 1: 1); the extraction solvent is one or the combination of dichloromethane, trichloromethane and ethyl acetate.
Compared with the prior art, the invention has the following technical effects:
1. the invention provides a novel method for synthesizing everolimus ethylation impurities, which can avoid the generation of chiral isomerization impurities caused by acidic conditions, is more beneficial to the purification of target products, shortens the reaction time compared with the original synthesis method, greatly reduces the labor cost, is simple to operate, greatly improves the yield and the purity, and is more suitable for industrial production;
2. The preparation method is simple to operate, and the obtained impurities are high in purity and yield.
Drawings
FIG. 1: nuclear magnetic resonance hydrogen spectrum of compound I
FIG. 2 is a drawing: HPLC profile of Compound I (example 4)
FIG. 3: mass spectrometric profile of Compound I
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.
Example 1
Everolimus (10.00g, 0.01mol) was added to 50mL of tetrahydrofuran and ethanol (V) at room temperatureTetrahydrofuran (THF)：VEthanol3: 1) stirring and dissolving the mixed solution, heating the system to 40-45 ℃ after dissolving, adding NaOH (0.32g, 0.008mol), continuing to keep the temperature and stir for reaction for 1h after adding, cooling to room temperature after the reaction is finished, adding 50mL of deionized water and 50mL of ethyl acetate, shaking uniformly, standing and separating, extracting the water phase once by using 25mL of ethyl acetate, combining the organic phases, washing and separating the liquid by using saturated sodium bicarbonate solution and saturated saline solution respectively, drying the organic phase by using anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (the eluent is firstly V by using V) Petroleum ether：VEthyl acetatePre-impurity was eluted with 1:1, then eluted with ethyl acetate) to give compound I in 88.5% yield and 99.97% HPLC purity.
Example 2
Everolimus (10.00g, 0.01mol) was added to 50mL of chloroform and ethanol (V) at room temperatureTrichloromethane：VEthanol4: 1) stirring and dissolving the mixed solution, heating the system to 40-45 ℃ after dissolving and cleaning, and adding Na2CO3(0.85g, 0.008mol), continuing to keep the temperature and stir for reaction for 1h, cooling to room temperature after the reaction is finished, adding 50mL of deionized water and 50mL of dichloromethane, shaking uniformly, standing for liquid separation, extracting the water phase with 25mL of dichloromethane once, combining the organic phases, washing the liquid separation with saturated sodium bicarbonate solution and saturated saline solution respectively, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (the eluent is V firstly usedPetroleum ether：VEthyl acetateEluting with ethyl acetate before eluting at 1: 1) gave compound I in 86.5% yield with 99.84% HPLC purity.
Example 3
Everolimus (10.00g, 0.01mol) was added to 50mL of tetrahydrofuran and ethanol (V) at room temperatureTetrahydrofuran (THF)：VEthanol2: 1) stirring and dissolving the mixed solution, heating the system to 30-35 ℃ after dissolving, adding NaOH (0.2g, 0.005mol), continuing to keep the temperature and stir for reaction for 1h after adding, cooling to room temperature after the reaction is finished, adding 50mL of deionized water and 50mL of ethyl acetate, shaking uniformly, standing and separating, extracting the water phase once by using 25mL of ethyl acetate, combining the organic phases, washing and separating the liquid by using saturated sodium bicarbonate solution and saturated saline solution respectively, drying the organic phase by using anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (the eluent is firstly separated by using V) Petroleum ether：VEthyl acetatePre-impurity elution followed by ethyl acetate elution ═ 1: 1) gave compound I in 85.2% yield and 99.60% HPLC purity.
Example 4
The compound 42-O- (2-hydroxy) ethyl rapamycin (10.00g, 0.01mol) was added to 50mL1, 4-dioxane and ethanol (V)1, 4-dioxane：VEthanol2: 1) stirring and dissolving the mixed solution, adding NaOH (0.60g and 0.015mol) at the temperature of 60-65 ℃, continuously stirring and reacting for 1h at room temperature after the addition is finished, adding 50mL of deionized water and 50mL of ethyl acetate after the reaction is finished, shaking uniformly, standing and separating, extracting the water phase once by using 25mL of ethyl acetate, combining the organic phases, washing and separating the water phase by using saturated sodium bicarbonate solution and saturated saline solution respectively, drying the organic phase by using anhydrous sodium sulfate, then concentrating under reduced pressure, and separating by column chromatography (eluent is firstly separated by using V)Petroleum ether：VEthyl acetateEluting with ethyl acetate before eluting at 1: 1) gave compound I in 84.7% yield with an HPLC purity of 99.54%.
Example 5
At room temperature, adding a compound 42-O- (2-hydroxy) ethyl rapamycin (10.00g, 0.01mol) into 50mL of absolute ethyl alcohol, stirring and dissolving, heating the system to 25-30 ℃ after dissolving, adding NaOH (0.012g, 0.003mmol), continuing to keep the temperature and stirring for reaction for 1h after adding, and cooling to room temperature after reaction Adding 50mL of deionized water and 50mL of ethyl acetate, shaking uniformly, standing, separating, extracting the water phase with 25mL of ethyl acetate, combining the organic phases, washing the separated liquid with saturated sodium bicarbonate solution and saturated saline solution respectively, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (eluent is V firstly usedPetroleum ether：VEthyl acetatePre-impurity elution followed by ethyl acetate elution ═ 1: 1) gave compound I in 80.2% yield and 98.93% HPLC purity.
Example 6
The compound 42-O- (2-hydroxy) ethyl rapamycin (10.00g, 0.01mol) was added to 50mL of 1.4-dioxane and ethanol (V) at room temperature1, 4-dioxane：VEthanol1: 1) stirring and dissolving the mixed solution, heating to 65-70 ℃, and adding K2CO3(2.35g, 0.017mol), continuously stirring at room temperature for reaction for 1h, after the reaction is finished, adding 50mL of deionized water and 50mL of ethyl acetate, shaking uniformly, standing for liquid separation, extracting the water phase once by using 25mL of ethyl acetate, combining the organic phases, washing the liquid separation by using a saturated sodium bicarbonate solution and a saturated saline solution respectively, drying the organic phases by using anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography (the eluent is firstly V by using V)Petroleum ether：VAcetic acid ethyl esterPre-impurity elution with 1:1 followed by ethyl acetate elution) gave compound I in 79.6% yield with HPLC purity 98.86%.
Comparative examples
Everolimus (0.2g) is dissolved in absolute ethyl alcohol (20ml), 0.1N hydrochloric acid (10ml) is added, stirring is carried out at 20-30 ℃ for 24 hours, 200ml of water is added, ethyl acetate extraction (150ml multiplied by 3) is carried out, organic phases are combined, saturated sodium bicarbonate is washed for 1 time, and saturated brine is washed for 2 times. Anhydrous Na2SO4Drying, filtering, and vacuum concentrating the filtrate at 25 deg.C to dryness. The crude product is purified by a preparation liquid phase to obtain the target product ethylated impurities, wherein the yield is 42%, the HPLC purity is 93.2%, and the isomer impurities are 4.25%.
Claims (6)
1. A preparation method of everolimus ethylation impurities is characterized in that a compound SM-1 is added into ethanol and an organic solvent at room temperature for dissolution, inorganic base is added at controlled temperature, and everolimus ethylation impurities are obtained by continuous temperature-controlled stirring reaction, wherein the synthetic route is as follows:
2. the method according to claim 1, wherein the inorganic base is selected from sodium hydroxide, sodium carbonate, and potassium carbonate.
3. The preparation method according to claim 1, wherein the compound SM-1 and the inorganic base are fed in a molar ratio of 1: 0.5-1.5.
4. The method according to claim 1, wherein the organic solvent is selected from chloroform, 1.4-dioxane, tetrahydrofuran, or a combination thereof.
5. The preparation method according to claim 1, wherein the volume ratio of the organic solvent to the ethanol is 2:1 to 4: 1.
6. The preparation method according to claim 1, wherein the reaction temperature after the addition of the inorganic base and the addition of the base is 30-65 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011585140.1A CN114671891A (en) | 2020-12-24 | 2020-12-24 | Preparation method of everolimus ethylation impurities |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011585140.1A CN114671891A (en) | 2020-12-24 | 2020-12-24 | Preparation method of everolimus ethylation impurities |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114671891A true CN114671891A (en) | 2022-06-28 |
Family
ID=82070211
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011585140.1A Pending CN114671891A (en) | 2020-12-24 | 2020-12-24 | Preparation method of everolimus ethylation impurities |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114671891A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115716839A (en) * | 2022-11-15 | 2023-02-28 | 无锡福祈制药有限公司 | Synthesis method of everolimus impurity |
-
2020
- 2020-12-24 CN CN202011585140.1A patent/CN114671891A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115716839A (en) * | 2022-11-15 | 2023-02-28 | 无锡福祈制药有限公司 | Synthesis method of everolimus impurity |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN113874359B (en) | Process for preparing 1-deoxy-1-methylamino-D-glucitol 2- (3, 5-dichlorophenyl) -6-benzoxazole carboxylate | |
| CN116751136A (en) | Novel preparation method of oxo-pyridine compound and key intermediate | |
| CN110183445B (en) | Synthetic method of moxifloxacin and derivatives thereof | |
| CN106749445B (en) | epirubicin hydrochloride intermediate compound III | |
| CN110078695B (en) | Quercetin derivative and preparation method thereof | |
| CN114671891A (en) | Preparation method of everolimus ethylation impurities | |
| EP2840088B1 (en) | Method for preparing 5,6,4'-trihydroxyflavone-7-0-d-glucuronic acid | |
| CN106543220A (en) | Phosphoramidate compounds and preparation method thereof and crystal | |
| CN116730861A (en) | Novel preparation method of oxo-pyridine compound and key intermediate | |
| CN103694291B (en) | Synthesis method for valrubicin | |
| CN116874387A (en) | Novel preparation method of oxo-pyridine compound and key intermediate | |
| CN113372375B (en) | Preparation method of temsirolimus intermediate | |
| WO2018145578A1 (en) | Method for synthesizing astragaloside iv | |
| KR102592374B1 (en) | How to Convert Crude Ascomycin to Purified Pimecrolimus | |
| CN114057710A (en) | Silibinin chemical modifier with anti-tumor activity and preparation method thereof | |
| CN108147988B (en) | Preparation method of lactam compound with high chiral purity | |
| CN111138386A (en) | Docetaxel semi-synthesis method | |
| CN108290921B (en) | Crystallization of 25-hydroxy-7-dehydrocholesterol | |
| CN114539288B (en) | Preparation method of everolimus | |
| CN110627845A (en) | Synthetic method of Luoxinwei | |
| CN113121413B (en) | Preparation method of key intermediate of JAK3 enzyme inhibitor | |
| CN110105361B (en) | Preparation method of Evodikine and derivative thereof | |
| CN115109104B (en) | Synthesis method of 3' -deoxyadenosine | |
| CN113354573B (en) | Method for large-scale production of alpha, alpha-terpyridine | |
| CN113372404B (en) | Purification method of pancuronium bromide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |