CN110563607B - Refining method of MK-2866 - Google Patents
Refining method of MK-2866 Download PDFInfo
- Publication number
- CN110563607B CN110563607B CN201911024110.0A CN201911024110A CN110563607B CN 110563607 B CN110563607 B CN 110563607B CN 201911024110 A CN201911024110 A CN 201911024110A CN 110563607 B CN110563607 B CN 110563607B
- Authority
- CN
- China
- Prior art keywords
- solid
- stirring
- silica gel
- column chromatography
- crude
- 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.)
- Active
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/32—Separation; Purification; Stabilisation; Use of additives
- C07C253/34—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention provides a refining method of MK-2866, which comprises the steps of mixing a crude MK-2866 product with a benzene solvent, stirring, heating to 80-140 ℃, adding column chromatography silica gel, stirring, filtering, cooling the obtained filtrate, carrying out solid-liquid separation after crystallization, washing the obtained solid with the benzene solvent, adding the solid into water with the volume of at least 5 times of the volume of the benzene solvent, heating to 100-120 ℃ external temperature, keeping the external temperature at 120 ℃ all the time to enable the reaction system to be in a reflux state, separating distillate, cooling to room temperature, carrying out solid-liquid separation, and drying to obtain the product MK-2866. The product refined by the method has high purity, chemical purity of over 99.5 percent, chiral purity of over 99.5 percent, ee value of over 99 percent, simple operation, high yield, short period, easy solvent recovery and low cost, and is particularly beneficial to industrial production.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a refining method of MK-2866.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
MK-2866, chemical name (S) -N- [ 4-cyano-3- (trifluoromethyl) phenyl]-3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide (C)19H14F3N3O3) MK-2866, a selective androgen receptor modulator developed by GTX, Ml.2013, 1 month 8, the United states food and drug administration awards MK-2866 fast channel identification for the prevention and treatment of muscular atrophy in patients with non-small cell lung cancer, and has the structural formula shown in formula (1):
PCT application WO2009036206, US patent US20160106702A1 and the like disclose a preparation method of MK-2866, which adopts the following reaction route to synthesize:
however, the inventors have found that the crude product is prepared as an oil by using CH2Cl2EtOAc (80:20) column chromatography of the oil to obtain an oil which is separated from CH2Cl2Recrystallization from hexane to give (S) -N- [ 4-cyano-3- (trifluoromethyl) phenyl]-3- (4-cyanophenoxy) -2-hydroxy-2-methylpropanamide as a colorless solid (cotton type) in 59.9% yield. The purification method of firstly adopting column chromatography and then adopting dichloromethane/n-hexane mixed solvent for recrystallization has the advantages of complex operation process, low product yield, long purification period (the experimental period of the column chromatography at a kilogram level is generally 5-6 days, and the product obtained after the column chromatography is finished is still oily, which indicates that the product still contains more impurities), high time cost, large silica gel consumption (the silica gel consumption is at least more than 20 times of the crude product quality even in the purification process at a laboratory level), and difficult recovery of the mixed solvent in production, high raw material cost and difficult industrial production.
Disclosure of Invention
Therefore, the invention aims to provide a refining method of MK-2866, which has the advantages of high purity of the product, chemical purity of over 99.5 percent, chiral purity of over 99.5 percent, ee value of over 99 percent, simple operation, high yield, short period, easy solvent recovery, low cost and particular contribution to industrial production.
Specifically, the technical scheme of the invention is as follows:
the invention provides a refining method of MK-2866, which comprises the steps of mixing a crude MK-2866 product with a benzene solvent, stirring, heating to 80-140 ℃, adding column chromatography silica gel, stirring, filtering, cooling the obtained filtrate, carrying out solid-liquid separation after crystallization, washing with the benzene solvent, carrying out suction filtration to obtain a solid, adding the solid into water with the volume being at least 5 times (relative to the crude product), heating to the external temperature of 120 ℃ when the temperature is 100 plus materials, keeping the external temperature at 120 ℃ all the time to enable a reaction system to be in a reflux state, separating a distillate (containing toluene and water), cooling to the room temperature, carrying out solid-liquid separation, and drying to obtain the product MK-2866.
The room temperature of the invention refers to normal temperature unless otherwise stated, and refers to 10-30 ℃ according to the regulation of the general example of pharmacopoeia of 2015 edition.
In the present invention, unless otherwise specified, the internal temperature or the external temperature is not specifically defined and is referred to as the internal temperature.
The column chromatography silica gel is normal phase column chromatography silica gel, preferably 200-300 meshes.
The crude MK-2866 is prepared by the following reaction route:
specifically, bromo amide ((2R) -3-bromo-N- [ 4-cyano-3- (trifluoromethyl) phenyl)]-2-hydroxy-2-methylpropionamide, anhydrous K2CO3And 4-cyanophenol in 2-propanol were heated to reflux, then concentrated under reduced pressure to give a solid, and the resulting residue (resulting solid) was added with water, followed by extraction with ethyl acetate. The combined ethyl acetate extracts were washed with 10% NaOH and brine. The organic layer is dried and then concentrated under reduced pressure to obtain oil, namely the crude MK-2866 product.
Wherein, the first and the second end of the pipe are connected with each other,
can be prepared by the following reaction:
the preparation process can be as described in PCT application WO2009036206 and US20160106702A 1. The contents of PCT application WO2008008433, U.S. patent US20160106702a1, are incorporated herein by reference in their entirety.
In an embodiment of the present invention, the mass ratio of the crude product to the benzene-based solvent is 1:3 to 1:30, preferably 1:5 to 1: 30. In some embodiments of the invention, the mass ratio of crude to benzene-based solvent may be 1:5 to 1:15, 1:5 to 1:30, 1:15 to 1: 30. When the mass ratio is less than 1:3, the purity is affected and the purity is lowered, and when the mass ratio is more than 1:30, the yield is affected and the yield is lowered.
In the embodiment of the invention, the mass ratio of the addition amount of the column chromatography silica gel to the crude product is 0.05-3: 1. in some embodiments of the present invention, the mass ratio of the added amount of the column chromatography silica gel to the crude product is 0.5-3:1, more preferably 0.5-2: 1. The column chromatography silica gel has different adsorptivity to impurities and products, and when the mass ratio of the addition amount of the column chromatography silica gel to the crude product is 0.5-2:1, especially 2:1, the adsorption amount to the impurities is better, and the products are rarely adsorbed.
The conventional impurity removal mode in the field is column chromatography, and the method usually requires that the mass ratio of a crude product (namely a sample loading sample) to filler silica gel is more than 1:15 when a small column is adopted, the requirement is higher when a large column is adopted, the consumption of the silica gel is higher, and dead adsorption is easy to occur. The method adopts the method of directly adding the column chromatography silica gel to adsorb impurities, greatly reduces the use amount of the silica gel, reduces the cost, avoids the desorption process, directly carries out solid-liquid separation after the adsorption of the silica gel is finished, can realize the separation of the product, the silica gel and the impurities, and is simpler and more convenient.
In the embodiment of the invention, the cooling crystallization temperature is-15-35 ℃, in some embodiments, the temperature can be 5-35 ℃, 5-15 ℃, 15-25 ℃, 25-35 ℃, and-15 to-5 ℃, and-5 to 5 ℃, namely, the invention can successfully realize crystal precipitation in a wider temperature range, and especially, the crystallization condition is better in the range of-15 to 5 ℃, especially, 15 to-5 ℃.
In an embodiment of the present invention, the benzene solvent is toluene or xylene, wherein the boiling point of toluene is 110.5 ℃ and the boiling point of xylene is 137-140 ℃. Toluene and xylene were immiscible with water, but the azeotropic point of water and toluene was 85 ℃ and the azeotropic point of water and xylene was 92 ℃.
In an embodiment of the invention, the amount of water is 5 to 10 times the amount of crude product.
In the embodiment of the invention, the adsorption time of the column chromatography silica gel is 10 minutes to 5 hours. In some embodiments the decolorization time is 30 minutes to 4 hours. In some embodiments the adsorption time is from 1 hour to 3 hours. In still other embodiments the adsorption time is from 2 hours to 3 hours.
In embodiments of the invention, the crystallization time is from 1 hour to 5 hours, and in some embodiments, the crystallization time is from 2 hours to 4 hours. In still other embodiments, the crystallization time is from 3 hours to 4 hours.
The solid-liquid separation method of the present invention may be a method of separating solid from liquid, such as filtration, suction filtration, centrifugation, and filter pressing. The separated solid can be washed with benzene solvent. The mass ratio of the benzene solvent used for washing to the crude MK-2866 product is 1:1-1: 10.
The solid obtained in the invention is dried to be dry (constant weight) to obtain a product, and available drying methods comprise methods such as forced air drying, vacuum drying and the like; the resulting solid can be dried under vacuum at 40-80 deg.C, preferably 50 deg.C to dryness to give the product.
In some embodiments of the invention, the method comprises adding crude MK-2866 into toluene, stirring, heating to 80-110 ℃, adding column chromatography silica gel, stirring, filtering while hot, cooling the obtained filtrate to-15-35 ℃, stirring, crystallizing, filtering, washing the obtained solid with toluene, and performing suction filtration until no liquid drips; adding the solid into water with the volume at least 5 times, heating to the external temperature of 100-120 ℃, azeotroping toluene and water, keeping the external temperature at 100-120 ℃ all the time, leading the system to be in a reflux state, separating distillate, cooling to the room temperature, then carrying out solid-liquid separation, and drying the solid to obtain white powder, namely MK-2866.
In still other embodiments of the present invention, the method comprises adding crude MK-2866 into xylene, stirring, heating to 80-140 ℃, adding column chromatography silica gel, stirring, filtering while hot, cooling the obtained filtrate to-15-35 ℃, stirring for crystallization, filtering, and washing the obtained solid with toluene; adding the solid into water with the volume at least 5 times that of the solid, heating to the external temperature of 100-120 ℃, carrying out azeotropic distillation on the xylene and the water, keeping the external temperature not lower than 100-120 ℃ all the time, leading the system to be in a reflux state, separating distillate, cooling to the room temperature, carrying out solid-liquid separation, and drying the solid to obtain white powder, namely MK-2866.
According to the method disclosed by the invention, the refined ML-2866 is high in purity, the chemical purity can reach more than 99.5%, the single impurity is less than 0.1%, the chiral purity reaches more than 99.5%, and the ee value is more than 99.0% (the enantiomer composition of the compound can be described by terms of enantiomeric excess (enantiomeric excess) or e.e.%), which means the excess of one enantiomer to the other enantiomer, usually expressed by percentage), and the method is simple to operate, short in production period, high in yield and favorable for industrial production.
Compared with the prior art, the invention has the following advantages:
the method adopts column chromatography silica gel (the column chromatography silica gel is white uniform particles, the main component is silicon dioxide), the method is cheap and easy to obtain, the column chromatography silica gel is directly added into a purification system to adsorb impurities (can also be decolorized), compared with column chromatography, the use amount of the silica gel is reduced by more than 20 times, the effect is obviously superior to that of a conventional adsorbent (such as activated carbon), and in addition, the activated carbon has a main function of decolorization in a refining process and a very weak impurity adsorption effect. Silica gel can decolorize and can absorb a large amount of impurities.
In addition, compared with the application of the silica gel as column chromatography filler in column chromatography, the direct addition of the column chromatography silica gel has different adsorption mechanisms, the principle of the column chromatography silica gel is to separate substances according to different adsorption forces of the substances on the silica gel, the substances with larger polarity are easy to be adsorbed by the silica gel, the substances with weaker polarity are not easy to be adsorbed by the silica gel in general, and the whole chromatography process is the adsorption, desorption, re-adsorption and re-desorption processes; the invention directly selects and adds column chromatography silica gel, and the adsorption capacity difference between the impurity and the product and silica gel is utilized, the impurity and silica gel are adsorbed, the adsorption capacity is strong, the adsorption capacity between the product and silica gel is weak, (according to HPLC spectrogram, the impurity RT is less than the product, the polarity of most impurities is more than that of the product, and the characteristics between substances are shown in the specification, the silica gel contains a large amount of hydroxyl, and can form hydrogen bonds with strong binding force with impurities with large polarity, thereby adsorbing the impurities with large polarity, while the active carbon provides a large amount of surface area due to the porous structure and is adsorbed by the internal pore structure and intermolecular Van der Waals force), solid-liquid separation is carried out after full adsorption, the impurities can be directly removed without desorption, the use amount of the silica gel is greatly reduced, the operation is simpler, the operation time is obviously shortened, under the operation environment of a laboratory, the conventional chromatography column chromatography treatment of 10g crude product requires at least 1 day, whereas the present application requires only 0.1-5 hours, this difference is particularly evident in scale-up experiments, where conventional column chromatography requires at least 5-6 days for treatment of kilogram grade product, whereas the present invention requires only 10-24 hours for treatment of the same amount of product.
And the product obtained by the prior art after the impurity removal through column chromatography is still oily, which indicates that the product still contains more impurities, because the melting point of a plurality of compounds is reduced after the compounds are mixed, the pure product is white or white-like powder, and the white or white-like powder is obtained after the operations of silica gel treatment and solid-liquid separation.
In addition, the solvent of the present invention is easily recovered, and the solvent system commonly used in the prior art such as CH2Cl2And hexane or a combination of hexane and cyclohexane, the mixed solvent is not easy to recover in the production process, so that the cost of raw materials is high, and the industrial production is not facilitated.
The refining method can obtain higher yield, the yield is over 79 percent and can reach over 90 percent at most, the purity of the refined product can be ensured while the yield is high, the purity of the refined product is over 99.5 percent (HPLC area percent) and can reach over 99.8 percent at most, and the yield and the purity can still be kept stable when the experiment is amplified to a kilogram level.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this application, illustrate embodiments of the application and, together with the description, serve to explain the application and are not intended to limit the application. Embodiments of the invention are described in detail below with reference to the attached drawing figures, wherein:
FIG. 1 is a liquid phase diagram of related substances of crude MK-2866 in example 1.
FIG. 2 is a liquid phase diagram of related substances of the MK-2866 refined product in example 2.
FIG. 3 is a chiral purity liquid phase diagram of the crude MK-2866 in example 1.
FIG. 4 is a liquid phase diagram of chiral purity of MK-2866 refined product in example 2.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specifications. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only. The chemical purity in the examples of the present invention is, unless otherwise specified, referred to as HPLC area%.
Example 1
Crude MK-2866 was prepared according to the following reaction:
bromo amide ((2R) -3-bromo-N- [ 4-cyano-3- (trifluoromethyl) phenyl)]-2-hydroxy-2-methylpropionamide, 50g, 0.14mol), anhydrous K2CO3A mixture of (59.04g, 0.43mol) and 4-cyanophenol (25.44g, 0.21mol) in 500mL 2-propanol was heated to reflux for 3h, then concentrated under reduced pressure to give a solid. 500mL of H was added to the resulting residue2O, then extracted with ethyl acetate (2X 300 mL). The combined ethyl acetate extracts were washed with 10% NaOH (4 × 200mL) and brine. The organic layer was washed with MgSO4Drying, and concentrating under reduced pressure to obtain oil, i.e. crude MK-2866.
Wherein the content of the first and second substances,
can be prepared by the following reaction, and can be specifically carried out according to the method described in PCT application WO2009036206 or U.S. Pat. No. 3, 20160106702, 1.
The contents of PCT application WO2008008433, U.S. patent US20160106702a1 are incorporated in their entirety by reference herein.
The chemical purity detection and the chiral purity detection are carried out on the prepared crude MK-2866 product (oily matter), the detection method is as follows, and if no special description is given, the chemical purity and the chiral purity of the refined product in the embodiment of the invention adopt the following methods:
the chemical purity detection method comprises the following steps:
accurately weighing a proper amount of a sample to be tested, dissolving and diluting the sample to prepare a solution containing about 0.5mg of the sample in each 1ml by adding a solvent [ acetonitrile-water (50:50) ], shaking up, accurately weighing 1ml, placing the solution in a 100ml measuring flask, adding the solvent to dilute the solution to a scale, and shaking up to obtain a sample solution. Performing high performance liquid chromatography (appendix V D of the second part of the 2010 edition of Chinese pharmacopoeia) with octadecylsilane chemically bonded silica as filler (YMC-Pack ODS-AQ,250mm × 4.6mm,5 μm); phosphate buffer solution (0.02mol/L potassium dihydrogen phosphate solution, adding 0.2% perchloric acid, adjusting pH value to 2.5 with ammonia water) -acetonitrile (80:20) is used as a mobile phase A, methanol is used as a mobile phase B, and linear gradient elution is carried out according to the following table 1; the column temperature is 30 ℃; the flow rate was 1.0ml per minute; the detection wavelength was 271nm (UV). And (2) injecting 10 mu l of test solution into a liquid chromatograph, adjusting the detection sensitivity to enable the peak height of the main component chromatographic peak to be about 10% -20% of the full range, recording a chromatogram, wherein the liquid chromatogram of related substances of the MK-2866 crude product is shown in figure 1, and the information of retention time, peak height and the like of the related substances in the chromatogram is shown in table 2. The chemical purity of the crude product was 94.48%.
TABLE 1
TABLE 2
The chiral purity detection method comprises the following steps:
taking a proper amount of a sample to be tested (about 25mg of the sample), putting the sample in a 50ml measuring flask, adding a proper amount of absolute ethyl alcohol, performing ultrasonic dissolution, cooling, adding absolute ethyl alcohol for dilution to a scale, and shaking up to obtain a sample solution; taking a sample of an isomer reference substance of about 12.5mg, accurately weighing, placing in a 100ml measuring flask, adding a proper amount of absolute ethyl alcohol, performing ultrasonic dissolution, cooling, adding absolute ethyl alcohol to dilute to a scale, shaking up, accurately weighing 1ml, placing in a 50ml measuring flask, adding absolute ethyl alcohol to dilute to a scale, shaking up, and taking as a reference substance solution. Measured by high performance liquid chromatography (appendix V D of the second part of the Chinese pharmacopoeia 2010 edition) using CHIRALPAK AS-H (250 mm. times.4.6 mm,5 μm); using absolute ethyl alcohol-n-hexane-n-butylamine (85:15:0.1) as a mobile phase; flow rate 1.0ml per minute; the detection wavelength is 271nm (UV); the column temperature was 30 ℃. Precisely measuring 20 μ l of each of the test solution and the reference solution, injecting into a liquid chromatograph, and recording chromatogram, wherein chiral purity liquid chromatogram of MK-2866 crude product is shown in FIG. 3.
Example 2
Adding 10.0g of MK-2866 crude product (prepared by the method of example 1) into 80ml of toluene, stirring, heating to 100 ℃, adding 10g of column chromatography silica gel, stirring for 1h, filtering while hot, cooling the obtained clear solution to-15 to-5 ℃, stirring for crystallization for 4h, filtering, washing the obtained solid with toluene for 2 times, 15ml each time, and filtering until no liquid drips. Adding the solid into 5 times volume of water, heating to 100 ℃, keeping the external temperature not lower than 100 ℃ all the time, carrying out azeotropy on water and toluene, gradually changing the solid into a light yellow oily substance to form a two-phase system, enabling the system to be in a reflux state for 1h, separating distillate, then cooling to 25-30 ℃, separating out the solid, carrying out solid-liquid separation to obtain the solid, and drying in vacuum at 50 ℃ until the solid is dried to obtain white powder MK-28669.2 g, wherein the chemical purity is 99.75%, and the ee value of chiral purity is greater than 99%.
1H NMR(CDCl3/TMS)δ1.63(s，3H，CH3) 3.40(s, 1H, OH), 4.07(d, J ═ 9.2Hz, 1H, CH), 4.51(d, J ═ 9.2Hz, 1H, CH), 6.97(d, J ═ 8.8Hz, 2H, ArH), 7.68(d, J ═ 8.8Hz, 2H, ArH), 7.80(d, J ═ 8.0Hz, 1H, ArH), 7.97(dd, J ═ 2.0, 8.0Hz, 1H, ArH), 8.12(d, J ═ 2.0Hz, 1H, ArH), 9.14bs, 1H, NH). Calculating the mass: 389.00, [ M-H ]]-388.0。
Detecting the chemical purity and chiral purity of the refined product, and the corresponding spectrograms are shown in FIGS. 2 and 4, respectively. The information on the retention time, peak height, etc. in the liquid chromatogram of the purified product shown in FIG. 2 is shown in Table 3. As shown in Table 3, the impurity types of the refined product are greatly reduced, and the single impurity content is less than 0.1%.
TABLE 3
Example 3
Adding 10.0g of MK-2866 crude product (prepared by the method of example 1) into 150ml of toluene, stirring, heating to 110 ℃, adding 5.0g of column chromatography silica gel, stirring for 0.5h, filtering while hot, cooling the obtained clear solution to-15 to-5 ℃, stirring for crystallization for 2h, filtering, washing the obtained solid with toluene for 2 times, 10ml each time, and filtering until no liquid drips. Adding the solid into 10 times volume of water, heating to an external temperature of 110 ℃, keeping the external temperature not lower than 110 ℃ all the time, carrying out azeotropic distillation on water and toluene to ensure that the system is in a reflux state, the solid gradually becomes a light yellow oily substance to form a two-phase system, separating distillate for 1h, then cooling to 25-30 ℃, carrying out solid-liquid separation, and drying the obtained solid in vacuum at 50 ℃ until the solid is dry to obtain white powder MK-28668.6 g, wherein the chemical purity is 99.83%, and the ee value of the chiral purity is more than 99%.
Example 4
Adding 10.0g of MK-2866 crude product (prepared by the method of example 1) into 60ml of toluene, stirring, heating to 90 ℃, adding 0.5g of column chromatography silica gel, stirring for 10min, filtering while hot, cooling the obtained clear solution to 15-25 ℃, stirring for crystallization for 3h, filtering, washing the obtained solid with toluene for 2 times, 5ml each time, and filtering until no liquid drips. Adding the solid into 10 times volume of water, heating to 100 ℃, keeping the external temperature not lower than 100 ℃ all the time, carrying out azeotropy on water and toluene, gradually changing the solid into a light yellow oily substance to form a two-phase system, enabling the system to be in a reflux state for 1h, separating distillate for 1h, then cooling to 15-25 ℃, carrying out solid-liquid separation to obtain a solid, drying in vacuum at 50 ℃ until the solid is dry, and obtaining white powder MK-28669.1 g, wherein the chemical purity is 99.51% (single impurities are less than 0.1%), and the ee value of the chiral purity is more than 99%.
Example 5
Adding 10.0g of MK-2866 crude product (prepared by the method of example 1) into 50ml of toluene, stirring, heating to 80 ℃, adding 30g of column chromatography silica gel, stirring for 5h, filtering while hot, cooling the obtained clear solution to-5-5 ℃, stirring for crystallization for 5h, filtering, washing the obtained solid with toluene for 2 times, 50ml each time, and filtering until no liquid drips. Adding the solid into 10 times volume of water, heating to 100 ℃, keeping the external temperature not lower than 100 ℃ all the time, carrying out azeotropy on water and toluene, gradually changing the solid into a light yellow oily substance to form a two-phase system, enabling the system to be in a reflux state, separating distillate for 1h, then cooling to 10-15 ℃, carrying out solid-liquid separation, and drying the obtained solid in vacuum at 50 ℃ until the solid is dry to obtain white powder MK-28668.9 g, wherein the chemical purity is 99.84% (the single impurity is less than 0.1%), and the ee value of the chiral purity is more than 99%.
Example 6
10.0g of crude MK-2866 (prepared by the method of example 1) is taken and added into 300ml of toluene, the mixture is stirred and heated to 110 ℃, 20.0g of column chromatography silica gel is added, the mixture is stirred for 1 hour, the hot mixture is filtered, the obtained clear solution is cooled to minus 15 to minus 5 ℃, the mixture is stirred and crystallized for 1 hour and then filtered, and the obtained solid is washed by toluene for 2 times, 20ml each time. Adding the solid into 10 times volume of water, heating to an external temperature of 110 ℃, keeping the external temperature not lower than 110 ℃ all the time, carrying out azeotropy on water and toluene, gradually changing the solid into a light yellow oily substance to form a two-phase system, enabling the system to be in a reflux state, separating distillate for 1h, then cooling to 25-30 ℃, carrying out solid-liquid separation, and drying the obtained solid in vacuum at 50 ℃ until the solid is dry to obtain white powder MK-28667.9 g, wherein the chemical purity is 99.86% (single impurities are less than 0.1%), and the ee value of chiral purity is more than 99%.
Example 7
Adding 10.0g of MK-2866 crude product (prepared according to the method of example 1) into 200ml of dimethylbenzene, stirring, heating to 140 ℃, adding 20.0g of column chromatography silica gel, stirring for 1h, filtering while hot, cooling the obtained clear solution to-15 to-5 ℃, stirring for crystallization for 3h, filtering, and washing the obtained solid with dimethylbenzene for 2 times, wherein 30ml of dimethylbenzene is used each time. Adding the solid into 10 times volume of water, heating to 120 ℃ of external temperature, keeping the external temperature not lower than 120 ℃ all the time, carrying out azeotropic distillation on water and xylene, gradually changing the solid into a light yellow oily substance to form a two-phase system, enabling the system to be in a reflux state, separating distillate for 1h, then cooling to 25-30 ℃, carrying out solid-liquid separation after crystallization, and drying the obtained solid in vacuum at 50 ℃ until the solid is dry to obtain white powder MK-28668.4 g, wherein the purity is 99.82% (single impurities are less than 0.1%), and the ee value of chiral purity is more than 99%.
Examples8
10.0g of crude MK-2866 (prepared by the method of example 1) is taken and added into 150ml of dimethylbenzene, the mixture is stirred and heated to 140 ℃, 5.0g of column chromatography silica gel is added, the mixture is stirred for 0.5h, the hot mixture is filtered, the obtained clear solution is cooled to-15 to-5 ℃, stirred and crystallized for 2h and then filtered, and the obtained solid is washed by toluene for 2 times, 10ml each time. Adding the solid into 10 times volume of water, heating to 120 ℃ of external temperature, azeotroping water and toluene, keeping the external temperature not lower than 120 ℃ all the time, gradually changing the solid into a light yellow oily substance to form a two-phase system, enabling the system to be in a reflux state, separating distillate for 1h, then cooling to 25-30 ℃, carrying out solid-liquid separation after crystallization, and drying the obtained solid in vacuum at 50 ℃ until the solid is dry to obtain white powder MK-28669.0 g, wherein the purity is 99.80% (the single impurity is less than 0.1%), and the ee value of chiral purity is more than 99%.
Comparative examples
Example 9
10.0g of crude MK-2866 (prepared by the method of example 1) is taken and added into 200ml of toluene, the mixture is stirred and heated to 50 ℃, 20.0g of column chromatography silica gel is added, the mixture is stirred for 1 hour, the mixture is filtered while the mixture is hot, the obtained clear solution is cooled to minus 15 to minus 5 ℃, the mixture is stirred and crystallized for 1 hour and then filtered, the obtained solid is dried in vacuum at 50 ℃ until the solid is dried, and white powder 5.1g is obtained, and the chemical purity of MK-2866 is 92.2 percent. The low yield is presumed to be due to the fact that the temperature is too low, the crude product is not completely dissolved in toluene, and the purity is reduced compared to the crude product, probably because a solvate of toluene is produced.
Example 10
10.0g of crude MK-2866 (prepared by the method of example 1) is taken and added into 200ml of toluene, stirred and heated to 110 ℃, 20.0g of activated carbon is added, stirred for 1h, filtered while hot, the obtained clear solution is cooled to-15 to-5 ℃, stirred and crystallized for 1h and then filtered, and the obtained solid is washed with toluene for 2 times, 20ml each time. Adding the solid into 10 times volume of water, heating to an external temperature of 110 ℃, keeping the external temperature not lower than 110 ℃ all the time, carrying out azeotropy on water and toluene, enabling the solid to gradually become a light yellow oily substance to become a two-phase system, enabling the system to be in a reflux state, separating distillate for 1h, then cooling to 25-30 ℃, carrying out solid-liquid separation after crystallization, and drying the obtained solid in vacuum at 50 ℃ until the solid is dry to obtain white powder MK-28668.9 g with chemical purity of 96.68%.
Example 11
10.0g of crude MK-2866 (prepared by the method of example 1) is taken and added into 200ml of toluene, stirred and heated to 110 ℃, 20.0g of activated carbon is added, stirred for 1h, filtered while hot, the obtained clear solution is cooled to-15 to-5 ℃, stirred and crystallized for 1h and then filtered, and the obtained solid is washed with toluene for 2 times, 20ml each time. The resulting solid was dried under vacuum at 50 ℃ to dryness to give 7.3g of white powder with MK-2866 chemical purity of 92.1%. It is assumed that the purity is reduced compared to the crude product, probably because a solvate of toluene is produced.
Example 12
Adding 10.0g of MK-2866 crude product (prepared by the method of example 1) into 200ml of toluene, stirring, heating to 110 ℃, adding 20.0g of column chromatography silica gel, stirring for 1h, filtering while hot, cooling the obtained clear solution to-15 to-5 ℃, stirring for crystallization for 1h, filtering, adding 50ml of dichloromethane and 50ml of n-hexane, heating to 40 ℃, dissolving, cooling to 15 to-5 ℃, stirring for crystallization for 1h, filtering, and drying to obtain 4.5g of white-like solid with the chemical purity of 99.81%.
Example 13
10.0g of crude MK-2866 (prepared as in example 1) was taken and CH was used2Cl2EtOAc (80:20) was purified by column chromatography to give an oil using CH2Cl2N-hexane (1:1, v/v), crystallization temperature-10 to 0 ℃, and crystallization to obtain white powder MK-28666.2 g with purity of 98.79%.
Example 14
Adding 10.0g of MK-2866 crude product (prepared by the method of example 1) into 30mL of ethyl acetate and 50mL of n-hexane, stirring, heating to 70 ℃, adding 20g of column chromatography silica gel, stirring for 1h, filtering while hot, cooling the obtained clear solution to-15 to-5 ℃, stirring for crystallization for 3h, filtering, and washing the obtained solid with ethyl acetate/n-hexane mixed solution (3:5, v/v) for 3 times, wherein 10mL of the mixed solution is used for each time. The resulting solid was dried under vacuum at 50 ℃ to dryness to give MK-28662.1 g as a white powder with a chemical purity of 98.12%.
Example 15
Adding 10.0g of MK-2866 crude product (prepared by the method of example 1) into 30mL of dichloromethane and 20mL of n-hexane, stirring, heating to 40 ℃, adding 20g of column chromatography silica gel, stirring for 1h, filtering while hot, cooling the obtained clear solution to-15 to-5 ℃, stirring for crystallization for 3h, filtering, and washing the obtained solid with dichloromethane/n-hexane (3:2, v/v) for 3 times, wherein 10mL of the solid is used for each time. The resulting solid was dried under vacuum at 50 ℃ to dryness to give MK-28666.2 g as a white powder with a chemical purity of 97.15%.
Example 16
10.0g of crude MK-2866 (prepared by the method of example 1) is taken and added into 30mL of absolute ethyl alcohol and 50mL of purified water, the mixture is stirred and heated to 70 ℃, 20g of column chromatography silica gel is added, the mixture is stirred for 1h, the hot solution is filtered, the obtained clear solution is cooled to-15 to-5 ℃, the mixture is stirred and crystallized for 3h and then filtered, and the obtained solid is washed 3 times by absolute ethyl alcohol/water (3:5, v/v), and 10mL of the solid is added each time. The resulting solid was dried under vacuum at 50 ℃ to dryness to give MK-28663.8 g as a white powder with a chemical purity of 96.21%.
Example 17
10.0g of crude MK-2866 (prepared according to the method of example 1) is taken and added into 50mL of isopropyl ether and 50mL of normal hexane, the mixture is stirred and heated to 65 ℃, 20g of column chromatography silica gel is added, the mixture is stirred for 1 hour, the hot mixture is filtered, the obtained clear solution is cooled to-15 to-5 ℃, the mixture is stirred and crystallized for 3 hours and then filtered, and the obtained solid is washed 3 times with isopropyl ether/normal hexane (1:1), 10mL of the solid is added each time. The resulting solid was dried under vacuum at 50 ℃ to dryness to give MK-28665.9 g as a white powder with a chemical purity of 96.56%.
Although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (4)
1. Mixing an MK-2866 crude product with a benzene solvent, stirring, heating to 80-140 ℃, adding column chromatography silica gel, stirring, filtering, cooling the obtained filtrate, crystallizing at-15-35 ℃, performing solid-liquid separation, washing the obtained solid with the benzene solvent, adding the obtained solid into water with a volume 5-10 times that of the MK-2866 crude product, heating to an external temperature of 100 ℃ and 120 ℃, keeping the external temperature of 100 ℃ and 120 ℃ all the time to enable the reaction system to be in a reflux state, separating distillate, cooling to room temperature, performing solid-liquid separation, and drying to obtain a product MK-2866;
wherein the column chromatography silica gel is normal phase column chromatography silica gel of 200-300 meshes;
the mass ratio of the crude product to the benzene solvent is 1:3-1: 30;
the mass ratio of the addition amount of the column chromatography silica gel to the crude product is 0.05-3: 1;
the benzene solvent is toluene or xylene;
wherein, the crude MK-2866 is prepared by the following reaction route:
2. the refining method of claim 1, wherein the method comprises adding crude MK-2866 into toluene, stirring, heating to 80-110 ℃, adding column chromatography silica gel, stirring, filtering while hot, cooling the obtained filtrate to-15-35 ℃, stirring for crystallization, filtering, and washing the obtained solid with toluene; adding the solid into water with the volume at least 5 times that of the crude MK-2866, heating to 100-120 ℃, keeping the external temperature at 100-120 ℃ all the time, leading the system to be in a reflux state, separating distillate, cooling to room temperature, carrying out solid-liquid separation, and drying the solid to obtain white powder, namely MK-2866.
3. The refining method of claim 1, wherein the method comprises adding crude MK-2866 into xylene, stirring, heating to 80-140 ℃, adding column chromatography silica gel, stirring, filtering while hot, cooling the obtained filtrate to-15-35 ℃, stirring for crystallization, filtering, and washing the obtained solid with toluene; adding the solid into water with the volume at least 5 times that of the crude MK-2866, heating to 100-120 ℃, keeping the external temperature at 100-120 ℃ all the time, leading the system to be in a reflux state, separating distillate, cooling to room temperature, carrying out solid-liquid separation, and drying the solid to obtain white powder, namely MK-2866.
4. The refining process of claim 1, wherein the crude product is prepared by: the reactants are mixed and heated to reflux according to the reaction, and then concentrated under reduced pressure to obtain a solid, water is added into the obtained solid, then ethyl acetate is used for extraction, the combined ethyl acetate extract is washed by 10% NaOH and brine, an organic layer is dried, and then concentrated under reduced pressure to obtain oil, namely crude MK-2866.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911024110.0A CN110563607B (en) | 2019-10-25 | 2019-10-25 | Refining method of MK-2866 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911024110.0A CN110563607B (en) | 2019-10-25 | 2019-10-25 | Refining method of MK-2866 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110563607A CN110563607A (en) | 2019-12-13 |
| CN110563607B true CN110563607B (en) | 2022-07-08 |
Family
ID=68785966
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911024110.0A Active CN110563607B (en) | 2019-10-25 | 2019-10-25 | Refining method of MK-2866 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110563607B (en) |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3128275A (en) * | 1962-06-07 | 1964-04-07 | Jefferson Chem Co Inc | Method for the purification of triethylenediamine |
| GB1174190A (en) * | 1967-11-22 | 1969-12-17 | Dow Chemical Co | Production of purified salicylic acid |
| US7968721B2 (en) * | 2003-01-13 | 2011-06-28 | University Of Tennessee Research Foundation | Large-scale synthesis of selective androgen receptor modulators |
| DK2205552T3 (en) * | 2007-09-11 | 2018-04-16 | Gtx Inc | CRYSTALLINIC POLYMORPH OF THE SELECTIVE ANDROGEN MODULATORS (R) - OR (S) -N- (4-CYANO-3- (TRIFLUOROMETHYL) PHENYL) -3- (4-CYANOPHENOXY) -2-HYDROXY-2-METHYLPROPANAMIDE |
| US7968603B2 (en) * | 2007-09-11 | 2011-06-28 | University Of Tennessee Research Foundation | Solid forms of selective androgen receptor modulators |
| CN105753733B (en) * | 2016-04-15 | 2019-06-18 | 苏州晶云药物科技股份有限公司 | Crystal form of AHU377 and preparation method thereof and purposes |
| CN109467557B (en) * | 2017-09-07 | 2020-09-04 | 湖北一半天制药有限公司 | Refining method of temozolomide |
| CN107722005B (en) * | 2017-10-12 | 2019-05-03 | 山东裕欣药业有限公司 | A kind of refining methd of pa Berkeley |
| CN109694315A (en) * | 2017-10-24 | 2019-04-30 | 湖北迅达药业股份有限公司 | A kind of felbinac crude product refining process |
| CN108997355B (en) * | 2018-08-13 | 2020-05-26 | 山东罗欣药业集团恒欣药业有限公司 | Refining method of tofacitinib citrate compound |
-
2019
- 2019-10-25 CN CN201911024110.0A patent/CN110563607B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN110563607A (en) | 2019-12-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105440040B (en) | The purification process of Buddhist nun is replaced according to Shandong | |
| CN102516096B (en) | Refining method of hydrochloric acid ambroxol compound | |
| CN101948450B (en) | Method for preparing orlistat | |
| CN104887673B (en) | A kind of pharmaceutical composition containing Esomeprazole sodium and preparation method thereof | |
| CN107033079B (en) | Preparation method of eslicarbazepine acetate | |
| CN106226426B (en) | A kind of method that high performance liquid chromatography splits canagliflozin five-membered ring impurity enantiomer | |
| CN114249711A (en) | Method for preparing nicotine by resolution | |
| CN110563607B (en) | Refining method of MK-2866 | |
| US8765196B2 (en) | Method for separating and purifying Ginkgolide C from root bark of ginkgo | |
| CN105968042A (en) | Preparation method of migltol | |
| CN110922439A (en) | Method for separating and preparing gram-grade high-purity natural product | |
| CN111450574B (en) | Chromatographic column for purifying tacrolimus and purification method of tacrolimus | |
| CN102321029B (en) | Ornidazole compound and novel preparation method thereof | |
| CN113563326A (en) | Atropine separated and purified from alkaloid extract and preparation method thereof | |
| CN108912018B (en) | Preparation method and application of impurity compound in key intermediate for synthesizing sulpiride | |
| CN108285443B (en) | Refining method of silybin | |
| CN111825636B (en) | Timolol hydrate and process for preparing same | |
| CN112094239A (en) | Urapidil impurity compound, preparation method and application thereof | |
| CN105820213A (en) | Method for efficiently separating and purifying pnemocandin | |
| US20220204483A1 (en) | Process for the Production of Ethyl 3-Amino-1-[(3R,4S)-4-Cyanotetrahydropyran-3-YL]pyrazole-4-Carboxylate Through Chiral Separation of a Racemic Mixture | |
| CN112441962A (en) | Tirofiban and purification method thereof | |
| CN113820402A (en) | HPLC analysis method of impurity reference substance of mirabegron | |
| CN110579537B (en) | High performance liquid chromatography separation method for p-fluorobenzonitrile and impurities thereof | |
| CN114874199B (en) | Method for simultaneously preparing epoxy orange peel oleosin and epoxy bergamotin | |
| CN112409338B (en) | Midazolam hydrochloride syrup impurity C and impurity D and application thereof |
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 | ||
| CB03 | Change of inventor or designer information | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zhou Weifeng Inventor after: Zhang Zhiyong Inventor after: Sun Zhaozhu Inventor after: Wu Yingchun Inventor after: Xie Zhiyu Inventor after: Shi Xiang Inventor after: Zhang Guangyan Inventor after: Wang Huan Inventor before: Zhou Weifeng Inventor before: Zhang Zhiyong Inventor before: Sun Zhaozhu Inventor before: Wu Yingchun Inventor before: Xie Zhiyu Inventor before: Shi Xiang Inventor before: Zhang Guangyan Inventor before: Wang Huan |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant |