CN110746371B - Intermediate for preparing aprepitant and preparation method and application thereof - Google Patents
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Abstract
The invention belongs to the technical field of compounds and synthesis thereof, and provides an intermediate for preparing aprepitant, and a preparation method and application thereof. Hair brushCompared with the existing method for preparing aprepitant, the method avoids preparing the intermediate
The method has the advantages of simple synthesis process of aprepitant, enhanced safety and process control of industrial production, higher yield, no pollution, easily obtained raw materials, simple industrial operation, low energy consumption, low cost, safety and environmental protection, and is suitable for industrial application.
Description
Technical Field
The invention relates to the technical field of compounds and synthesis thereof, in particular to an intermediate for preparing aprepitant, a preparation method and application thereof.
Background
Aprepitant was first approved by the U.S. drug administration (FDA) for marketing by the company misandong at 26/3/2003 under the trade name of enden, under the U.S. chemical abstracts accession number 170729-80-3, and has the structural formula:
aprepitant is a high-affinity NK-1 receptor inhibitor, is a novel antiemetic drug, is used for preventing acute and delayed nausea and vomiting caused by chemotherapy, can occupy NK-1 receptors in the brain through a blood brain barrier, has high selectivity and affinity, and has lower affinity for NK-2 and NK-3 receptors, so that the effect of reducing nausea and vomiting is obviously better than that of other drugs, and the drug has good market prospect.
Currently, there are few methods for preparing aprepitant. Chinese patent CN1106390C discloses the following preparation process:
according to the route, a compound X and a compound VIII are adopted to react in a mixed solvent of DMSO and toluene under the catalysis of potassium carbonate to prepare a compound IX, and the compound IX is condensed at the temperature of 140-150 ℃ to prepare a target product aprepitant.
The reaction step of the method is short, but the reaction condition is harsh, the reaction is required to be carried out at 140-150 ℃, the requirement on reaction equipment is high, the energy consumption is high, and the safety and the economical efficiency during industrial production are not high. Therefore, this route is not suitable for industrial production.
Another synthetic route of aprepitant is disclosed in literature (Tetrahedron Letters 41(2000)8661-8664), and the preparation method comprises the following steps:
the route adopts a compound X and a compound II to react directly at room temperature in a DMF solution under the catalysis of potassium carbonate to prepare the target product aprepitant.
In the two preparation processes, the compound X is used as a raw material to prepare aprepitant, and through Research and Research of documents, the main synthetic route of the compound X is prepared according to the preparation method reported in the documents Organic Process Research & Development 2006,10,109-117, and the preparation method comprises the following steps:
the method comprises the steps of dripping a tetrahydrofuran solution of fluorophenyl magnesium bromide into a tetrahydrofuran solution of a compound I, adding a methanol solution of p-toluenesulfonic acid for quenching after the reaction is finished, then adding palladium-carbon for catalytic hydrogenation, extracting and concentrating a reaction solution, salifying a residue and hydrochloric acid, crystallizing in methyl isobutyl ketone, filtering and drying to obtain a target compound X.
Although the method has a short synthetic route and is simple and convenient to operate, the reaction process is complex, a series of reaction processes such as debenzylation, ring opening, rearrangement, ring closing, addition and the like are required in the catalytic hydrogenation process, the intermediate state in the process is more, the quality control is not facilitated, and fluorine atoms in benzene rings can be removed in the hydrogenation process to generate defluorinated impurities which are difficult to remove and influence the product quality, so that the quality of each batch can not be ensured when the compound X is used as a raw material to produce aprepitant.
Therefore, there is a need to provide a new intermediate for preparing aprepitant to solve the problems in the prior art.
Disclosure of Invention
In view of this, the present invention aims to provide an intermediate for preparing aprepitant, and a preparation method and applications thereof. The aprepitant intermediate prepared by the invention can simplify the preparation method of aprepitant and obtain aprepitant with good quality.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides an intermediate for preparing aprepitant, which has a structure shown in a formula I:
the invention also provides a preparation method of the intermediate with the structure shown in the formula I in the technical scheme, which comprises the following steps:
the (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholine-3-ketone is hydrogenated to obtain an intermediate with a structure shown in a formula I.
Preferably, the hydrogenation pressure of the hydrogenation reaction is 0.5-5 MPa, the temperature is 30-70 ℃, and the time is 2-8 h.
The invention also provides an intermediate for preparing aprepitant, which has a structure shown in a formula II:
the invention also provides a preparation method of the intermediate with the structure shown in the formula II, which comprises the following steps:
the intermediate with the structure shown in the formula I and 3-chloromethyl-1, 2, 4-triazoline-5-ketone are subjected to coupling reaction to obtain the intermediate with the structure shown in the formula II.
Preferably, the temperature of the coupling reaction is 30-60 ℃ and the time is 2-3 h.
The invention also provides application of the intermediate with the structure shown in the formula II in preparation of aprepitant.
Preferably, the method for preparing aprepitant by using the intermediate with the structure shown in the formula II comprises the following steps:
performing Grignard reaction on an intermediate with a structure shown in a formula II and p-fluorophenyl magnesium bromide to obtain an intermediate product;
carrying out salt forming reaction on the intermediate product and acid to obtain a compound V;
and carrying out reduction reaction on the compound V and triethylsilane under the action of Lewis acid to obtain the aprepitant.
Preferably, the temperature of the Grignard reaction is 0-30 ℃, and the time is 1-2 h.
Preferably, the temperature of the reduction reaction is 25-55 ℃, and the time is 4-6 h.
Has the advantages that:
the invention provides an intermediate for preparing aprepitant, shown as a formula I and a formula II, and the aprepitant is prepared by utilizing the two intermediates through condensation and reduction reactions
The method has the advantages of simple synthesis process of aprepitant, enhanced safety and process control of industrial production, higher yield, no pollution, easily obtained raw materials, simple industrial operation, low energy consumption, low cost, safety and environmental protection, and suitability for industrial application.
Drawings
FIG. 1 is a mass spectrum of aprepitant obtained in example 1;
FIG. 2 is a nuclear magnetic spectrum of aprepitant obtained in example 1;
FIG. 3 shows HPLC chromatogram and map results of aprepitant obtained in example 1;
FIG. 4 shows HPLC chromatogram and map results of aprepitant obtained in comparative example 1.
Detailed Description
The compounds, solvents and the like used below are, unless otherwise specified, commercially available, analytically pure or chemically pure products and are commercially available.
The invention provides an intermediate for preparing aprepitant, which has a structure shown in a formula I:
the invention also provides a preparation method of the intermediate with the structure shown in the formula I, which comprises the following steps:
the (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholine-3-ketone is hydrogenated to obtain an intermediate with a structure shown in a formula I.
In the present invention, the solvent for the hydrogenation reaction is preferably a protic solvent; the protic solvent is preferably methanol, the amount of the solvent used is not particularly limited in the present invention as long as it can sufficiently dissolve (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholin-3-one, and in the specific embodiment of the present invention, the ratio of the amount of the (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholin-3-one to the amount of methanol is preferably 100 g: 600 mL.
In the present invention, the catalyst for the hydrogenation reaction is preferably 5% palladium on carbon; the water content of the 5% palladium carbon is preferably 60%; the mass ratio of the (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholine-3-one to 5% palladium carbon is preferably 1: 0.0625-0.125, and more preferably 1: 0.125.
In the invention, the hydrogenation pressure of the hydrogenation reaction is preferably 0.5-5 MPa, more preferably 3-4 MPa, and more preferably 3.5 MPa; the temperature is preferably 30-70 ℃, and more preferably 50-60 ℃; the time is preferably 2 to 8 hours, more preferably 4 to 5 hours, and still more preferably 4.5 hours.
In the present invention, the specific process of the hydrogenation reaction is preferably: dissolving and mixing (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholin-3-one and a solvent, then adding a catalyst, heating to the temperature of hydrogenation reaction, replacing hydrogen for 3 times, and keeping the hydrogenation pressure to carry out hydrogenation reaction.
After the hydrogenation reaction is finished, the invention preferably further comprises the steps of cooling the obtained hydrogenation reaction liquid to room temperature, filtering, and concentrating the obtained filter cake at 40 ℃ in vacuum to dryness to obtain the intermediate with the structure shown in the formula I.
The filtration method is not particularly limited in the present invention, and a filtration method known to those skilled in the art may be used.
In the invention, the structure of the (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholin-3-one is shown as formula A, and a flow chart of preparing an intermediate with the structure shown as formula I by utilizing the formula A through hydrogenation reaction is shown as formula 1:
the invention uses (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholine-3-ketone as a raw material to prepare an intermediate with a structure shown in a formula I, and further prepares an intermediate with a structure shown in a formula II, so that a new raw material and a new method are provided for the subsequent synthesis of aprepitant, the method changes the conventional mode of preparing aprepitant from (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholine-3-ketone, and avoids the generation of defluorinated aprepitant which is difficult to remove and toxic impurities due to the reduction of fluorine atoms on a benzene ring in the hydrogenation process.
The invention also provides an intermediate for preparing aprepitant, which has a structure shown in a formula II:
the invention also provides a preparation method of the intermediate with the structure shown in the formula II, which comprises the following steps:
the intermediate with the structure shown in the formula I and 3-chloromethyl-1, 2, 4-triazoline-5-ketone are subjected to coupling reaction to obtain the intermediate with the structure shown in the formula II.
In the invention, the molar ratio of the intermediate with the structure shown in the formula I to the 3-chloromethyl-1, 2, 4-triazolin-5-one is preferably 1: 1.0-2.0, and more preferably 1: 1.5.
In the present invention, the coupling reaction is preferably carried out in the presence of an alkaline substance, preferably sodium hydroxide; the molar ratio of the intermediate with the structure shown in the formula I to sodium hydroxide is preferably 1: 1.0-2.0, and more preferably 1: 2.0.
In the present invention, the solvent for the coupling reaction is preferably acetonitrile, dimethyl sulfoxide or N, N-dimethylformamide, and is more preferably acetonitrile; the amount of the solvent used in the present invention is not particularly limited, as long as the intermediate having the structure represented by formula I and 3-chloromethyl-1, 2, 4-triazolin-5-one can be sufficiently dissolved and reacted.
In the invention, the temperature of the coupling reaction is preferably 30-60 ℃, and further preferably 35-40 ℃; the time is preferably 2-3 h.
In the present invention, the specific process of the coupling reaction is preferably: dissolving an intermediate with a structure shown in formula I in a solvent, adding an alkaline substance, stirring and dispersing uniformly, heating to a coupling reaction temperature, and adding 3-chloromethyl-1, 2, 4-triazoline-5-one to feed liquid in batches to carry out coupling reaction.
In the present invention, the reaction end point of the coupling reaction was monitored by TLC.
After the coupling reaction is finished, the present invention preferably further comprises post-treating the obtained coupling reaction solution, wherein the post-treating preferably comprises the following steps:
cooling the obtained coupling reaction liquid to room temperature, filtering, washing the obtained filter cake, and combining the filtrates; concentrating the filtrate to obtain a concentrate; and recrystallizing the concentrate to obtain the intermediate with the structure shown in the formula II.
In the present invention, the reagent for washing the cake is preferably acetonitrile, and the number of washing is not particularly limited in the present invention. In the invention, the temperature of the concentration is preferably 40-45 ℃, and the time of the concentration is not particularly limited as long as the solid is concentrated.
In the present invention, the recrystallization reagent is preferably ethyl acetate and n-hexane; the specific process of recrystallization is preferably as follows:
adding the concentrate into ethyl acetate, heating to dissolve, filtering while hot, cooling the obtained filtrate to 20-25 ℃, adding n-hexane to precipitate a large amount of solids, cooling the feed liquid to 10-15 ℃, and crystallizing for 2 hours; and (4) carrying out suction filtration on the feed liquid, and drying the obtained filter cake to obtain the intermediate shown in the formula II. In the present invention, the n-hexane is preferably added under stirring.
In the invention, the structure of the 3-chloromethyl-1, 2, 4-triazoline-5-one is shown as a formula B, and the flow of preparing the intermediate with the structure shown as a formula II by coupling reaction of the intermediate with the structure shown as the formula I and the compound with the structure shown as the formula B is shown as a formula 2:
the invention also provides application of the intermediate with the structure shown in the formula II in preparation of aprepitant.
In the present invention, the process for preparing aprepitant using the intermediate having the structure represented by formula II preferably comprises the steps of:
performing Grignard reaction on an intermediate with a structure shown in a formula II and p-fluorophenyl magnesium bromide to obtain an intermediate product;
carrying out salt forming reaction on the intermediate product and acid to obtain a compound V;
and carrying out reduction reaction on the compound V and triethylsilane under the action of Lewis acid to obtain the aprepitant.
The intermediate with the structure shown in the formula II and p-fluorophenyl magnesium bromide are subjected to Grignard reaction to obtain an intermediate product.
In the invention, the molar ratio of the intermediate with the structure shown in the formula II to the p-fluorophenyl magnesium bromide is preferably 1: 1.0-2.0, and more preferably 1: 1.5.
In the invention, the intermediate with the structure shown in the formula II is prepared from the intermediate with the structure shown in the formula I; the intermediate with the structure shown in the formula I is obtained by hydrogenating (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholine-3-ketone; the preparation methods of the intermediate having the structure shown in formula II and the intermediate having the structure shown in formula I herein are the same as the preparation methods of the intermediate having the structure shown in formula I and the intermediate having the structure shown in formula II described in the above technical solutions, and are not described herein again.
In the present invention, the solvent for the grignard reaction is preferably tetrahydrofuran, and the amount of tetrahydrofuran used in the present invention is not particularly limited as long as the intermediate having the structure represented by formula II and p-fluorophenyl magnesium bromide can be sufficiently dissolved and mixed.
In the invention, the temperature of the Grignard reaction is preferably 0-30 ℃, and further preferably 15-25 ℃; the time is preferably 1 to 2 hours, and more preferably 1 hour.
In the present invention, the specific process of the grignard reaction is preferably: adding an intermediate with a structure shown in a formula II into a solvent, stirring until the intermediate is clear, cooling to 0-15 ℃, controlling the temperature at the Grignard reaction temperature, dropwise adding a p-fluorophenyl magnesium bromide tetrahydrofuran solution, and carrying out the Grignard reaction; the concentration of the p-fluorophenyl magnesium bromide tetrahydrofuran solution is preferably 1.0 mol/L.
In the present invention, the end point of the Grignard reaction is preferably monitored by TLC.
After the completion of the grignard reaction, the present invention preferably performs a post-treatment on the obtained grignard reaction solution, and the post-treatment preferably comprises the following steps:
pouring the obtained Grignard reaction solution into a saturated ammonium chloride aqueous solution, standing and separating, extracting the obtained aqueous phase with tetrahydrofuran, and combining the organic phases; and drying and concentrating the obtained organic phase to obtain the intermediate product.
In the present invention, the drying agent is preferably anhydrous sodium sulfate; the concentration is preferably reduced pressure concentration, and the temperature of the reduced pressure concentration is preferably 40-50 ℃.
After obtaining the intermediate product, the invention performs salt forming reaction on the intermediate product and acid to obtain a compound V.
In the present invention, the acid is preferably an acid that forms a salt with the intermediate product free base, and the acid is preferably hydrochloric acid or p-toluenesulfonic acid, and more preferably p-toluenesulfonic acid. In the present invention, the solvent for the salt-forming reaction is preferably methyl isobutyl ketone.
In the present invention, the temperature of the salt forming reaction is preferably 65 ℃ and the time is preferably 1 h.
In the present invention, the specific process of the salt-forming reaction preferably comprises the following steps:
and dissolving the intermediate product in a solvent, adding acid, heating to 65 ℃, cooling to 15-20 ℃ after the feed liquid is clear, and stirring for 1 h. In the present invention, the acid is preferably added dropwise.
After the salt-forming reaction is finished, the method preferably comprises the steps of filtering the obtained salt-forming reaction liquid, leaching and drying the obtained filter cake (the filter cake is a crystal) to obtain the compound V.
In the present invention, the agent for rinsing is preferably methyl isobutyl ketone; the temperature and time of the drying are not particularly limited in the present invention as long as the crystals can be dried.
After the compound V is obtained, the compound V and triethylsilane are subjected to reduction reaction under the action of Lewis acid to obtain the aprepitant.
In the present invention, the molar ratio of the compound V to triethylsilane is preferably 1:2.0 to 4.0, and more preferably 1: 3.0. In the present invention, the lewis acid is preferably boron trifluoride diethyl etherate; the molar ratio of the compound V to the Lewis acid is preferably 1:2.0 to 4.0, and more preferably 1: 2.0.
In the present invention, the solvent for the reduction reaction is preferably acetonitrile, and the amount of acetonitrile used in the present invention is not particularly limited as long as the compound V, triethylsilane and lewis acid can be sufficiently dissolved and mixed.
In the invention, the temperature of the reduction reaction is preferably 25-55 ℃, and further preferably 30-35 ℃; the time is preferably 4-6 h.
In the present invention, the specific steps of the reduction reaction are preferably:
and mixing the compound V, triethylsilane and a solvent, stirring until the mixture is clear, cooling to 0 ℃, dropwise adding a boron trifluoride diethyl etherate solution at the temperature of 0-10 ℃, and carrying out reduction reaction after dropwise adding is finished.
After the reduction reaction is finished, the invention preferably further comprises directly filtering the obtained reduction reaction liquid, and washing and pumping the obtained filter cake to obtain the aprepitant. In the present invention, the washing reagent is preferably acetonitrile.
Obtaining aprepitant, preferably, the invention further comprises refining the aprepitant to obtain refined aprepitant, and the refining step is preferably as follows:
dissolving the obtained aprepitant in methanol, heating to 50-60 ℃, adding water, cooling to a crystallization temperature, crystallizing, filtering, washing and drying the obtained filter cake to obtain the refined aprepitant.
In the present invention, the mass ratio of aprepitant to methanol is preferably 1: 8 to 16. In the invention, the mass ratio of aprepitant to water is preferably 1: 5-10, and the water is preferably added dropwise.
In the invention, the crystallization temperature is preferably 10-40 ℃, and more preferably 15-25 ℃; the time for crystallization is preferably 1 to 4 hours, and more preferably 1 hour.
In the present invention, the washing agent for washing the filter cake is preferably a mixed solution of methanol and water, and the weight ratio of methanol to water in the mixed solution is preferably 8: 5. In the invention, the drying mode is preferably vacuum drying, the temperature of the vacuum drying is preferably 50 ℃, and the time is preferably 7-8 h.
In the present invention, the principle of preparing aprepitant from the most original raw material (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholin-3-one (formula a) is shown in formula 3.
The intermediates for preparing aprepitant, the preparation method and the application thereof provided by the invention are described in detail by the following examples, but the intermediates are not to be construed as limiting the scope of the invention.
The HPLC high performance liquid chromatogram test conditions used in the embodiment of the invention are as follows:
and (3) chromatographic column: agilent SB-Aq column, 4.6X 250mm, 5 μm;
mobile phase: 0.1% phosphoric acid as mobile phase A and acetonitrile as mobile phase B;
column temperature: 35 ℃, detection wavelength: 220nm, sample size: 20 μ L, flow rate: 1.5 mL/min;
gradient elution conditions:
example 1
This example provides a specific example of the preparation of intermediates having the structure shown in formula I and intermediates having the structure shown in formula II from (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholin-3-one (formula a), and the further preparation of aprepitant.
The specific synthesis reaction formula is shown as formula 3:
the specific synthesis method comprises the following steps:
(1) carrying out hydrogenation reaction on a compound with a structure shown in a formula A to prepare an intermediate with a structure shown in a formula I;
adding 100.00g (0.224mol) of the compound with the structure shown in the formula A and 600mL of methanol into a reaction bottle, stirring to dissolve the mixture clearly, adding 12.5g of 5% palladium-carbon (containing 60% of water) after the solution is dissolved clearly, heating to 55 ℃, replacing hydrogen for 3 times, keeping the hydrogenation pressure at 3.5MPa, controlling the temperature to 50-60 ℃, and stirring to react for 4.5 hours. After the reaction is finished, the temperature is reduced to room temperature, the feed liquid is filtered, and a filter cake is concentrated to be dry in vacuum at 40 ℃ to obtain 79.50g of colorless transparent oily substance (the intermediate with the structure shown in the formula I), wherein the yield is 99%.1H-NMR(600MHz,d6-DMSO)δ1.481(d,3H),3.382(m,2H),3.667(m,2H),4.693(m,1H),5.340～4.345(m,1H),5.936(br,1H),7.558～7.562(d,2H),7.832(s,1H)；LC/MS ES+The ratio of nucleus to nucleus of [ M + H ]]-＝358.1。
(2) Carrying out coupling reaction on the intermediate with the structure shown in the formula I and the compound with the structure shown in the formula B to prepare an intermediate with the structure shown in the formula II;
dissolving 70.00g (0.196mol) of the intermediate with the structure shown in the formula I prepared in the step in 560mL of acetonitrile, transferring the acetonitrile into a reaction bottle, adding 15.67g (0.392mol) of sodium hydroxide (particles), stirring and dispersing uniformly, heating to 35 ℃, adding 39.25g (0.294mol) of the compound with the structure shown in the formula B into the feed liquid in batches, controlling the temperature to be 30-40 ℃, stirring for 2.5 hours, monitoring by TLC, and cooling to room temperature after the raw material point disappears. Filtering the feed liquid, leaching a filter cake with a small amount of acetonitrile, combining filtrates, concentrating at 40 ℃ to obtain a light yellow solid, adding the light yellow solid into 300mL of ethyl acetate, heating to dissolve, hot filtering, cooling the filtrate to 25 ℃, adding 150mL of n-hexane while stirring, precipitating a large amount of solid, cooling the feed liquid to 10 ℃, crystallizing for 2h, performing suction filtration, and drying to obtain 79.38g of a white solid (an intermediate with a structure shown in formula II), wherein the yield is 89%.1H-NMR(600MHz,d6-DMSO)δ1.496(d,3H),3.341～3.344(m,2H),3.450～3.454(m,2H),4.119～4.126(s,2H),4.640～4.645(m,1H),5.836～5.847(br,1H),7.629～7.631(d,2H),7.829(s,1H),11.168(s,1H),11.326(s,1H)；LC/MS ES+A mass-to-nuclear ratio of [ M + H ]]-＝455.5。
(3) Reacting the intermediate with a structure shown in a formula II with p-fluorophenyl magnesium bromide, and reacting with acid to obtain a compound V;
150mL of tetrahydrofuran was added to 75.00g (0.165mol) of the intermediate having the structure represented by formula II prepared in the above step, stirred until it was clear, and then cooled to 15 ℃. And (2) controlling the temperature to be 15-25 ℃, dropwise adding 247.5mL of p-fluorophenyl magnesium bromide tetrahydrofuran solution (0.248mol, c is 1.0mol/L), stirring at 15-25 ℃ for 1h after the addition is finished, monitoring the reaction by TLC, pouring the material liquid into 200mL of saturated ammonium chloride solution after the reaction is completed, stirring for 15min, standing, separating, extracting the water phase by 200mL of tetrahydrofuran, combining the organic phases, drying by anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 40 ℃ until the water phase is dry to obtain a light yellow oily intermediate product. Adding 250mL of methyl isobutyl ketone into the oily intermediate product, stirring for dissolving, adding 34.56g (0.182mol) of p-toluenesulfonic acid monohydrate under the stirring state after the solution is dissolved, heating to 65 ℃, cooling to 20 ℃ after the solution is dissolved, stirring for crystallization for 1h, filtering, leaching a filter cake with methyl isobutyl ketone, and drying to obtain 104.15g of a white solid compound V, wherein the yield is 87 percent, and the LC/MS ES is LC/MS+The ratio of nucleus to nucleus of [ M + H ]]-550.1 (free base).
(4) The compound V is subjected to reduction reaction to prepare an aprepitant crude product;
100.00g (0.138mol) of the compound V prepared in the above step, 32.18g (0.279mol) of triethylsilane and 800mL of acetonitrile were put into a reaction flask, stirred until clear, and then cooled to 0 ℃. Controlling the temperature to be 0-10 ℃, dropwise adding 39.28g (0.277mol) of boron trifluoride ether solution, and after the addition is finished, keeping the temperature to be 25-35 ℃ for reaction for 5 hours. A large amount of solid is separated out, filtered, and a filter cake is washed by a small amount of acetonitrile and pumped to dryness to obtain 69.65g of crude aprepitant white solid with the yield of 94 percent which is directly used in the next step.
(5) Refining an aprepitant crude product;
adding 520.00g of methanol into 65.00g (0.122mol) of aprepitant crude product prepared in the step, heating to 55 ℃, and stirring until the feed liquid is clear; after the solution is clear, 325.00g of purified water is dropped into the solution under the condition of stirring and controlling the temperature to be 50-60 ℃, a large amount of solid is separated out, the temperature is reduced to 20 ℃, the temperature is kept to be 15-25 ℃, crystallization is carried out for 1h, filtration is carried out, a filter cake is washed by a methanol-water mixed solution (the weight ratio is 8:5), the filter cake is pumped to be dry, the filter cake is placed in a 50 ℃ vacuum drying oven to be dried for 7h, 61.86g of white solid is obtained, the yield is 95%, the HPLC purity is more than or equal to 99.50%, and the total yield of the product is 68%.
The obtained white solid is confirmed to be aprepitant by nuclear magnetism, and the specific data are as follows: MS ESI+A mass-to-nuclear ratio of [ M + H ]]+The mass spectrum of aprepitant obtained in this example is shown in fig. 1, 534.5.
1H-NMR(600MHz,d6DMSO) delta 1.360(d,3H), 2.393-2.399 (m,1H), 2.747-2.770 (d,1H), 2.840-2.859 (d,1H), 3.350-3.384 (m,1H), 3.490-3.494 (d,1H), 3.619-3.640 (m,1H), 4.110-4.129 (m,1H), 4.340-4.345 (m,1H), 4.936-4.947 (m,1H), 7.058-7.087 (m,2H), 7.369(s,2H), 7.513(s,2H)7.829(s,1H), 11.278(s,1H),11.385(s,1H), and the nuclear magnetic spectrum of aprepitant obtained in the embodiment is shown in figure 2.
The HPLC purity is more than or equal to 99.0 percent, the content of defluorinated aprepitant (RRT0.97) is 0.02 percent, the HPLC high performance liquid chromatogram and the chromatogram result of the obtained aprepitant are shown in figure 3, the peak number 1 is a compound II, the peak number 2 is defluorinated aprepitant, the peak number 3 is aprepitant, and the peak number 4 is an impurity.
Example 2
This example provides a specific example of preparing an intermediate having a structure represented by formula I, an intermediate having a structure represented by formula II, and further preparing aprepitant, including the following specific steps:
(1) carrying out hydrogenation reaction on a compound with a structure shown in a formula A to obtain an intermediate with a structure shown in a formula I;
adding 100.00g (0.224mol) of the compound with the structure shown in the formula A and 600mL of methanol into a reaction bottle, stirring to dissolve the mixture clearly, adding 12.5g of 5% palladium-carbon (containing 60% of water) after the solution is dissolved clearly, heating to 50 ℃, replacing 3 times of hydrogen, keeping the hydrogenation pressure at 4.0MPa, controlling the temperature to 50-60 ℃, and stirring to react for 4 hours. After the reaction is finished, the temperature is reduced to room temperature, the feed liquid is filtered, and a filter cake is concentrated to be dry in vacuum at 45 ℃ to obtain 78.64g of the intermediate of which the colorless transparent oily substance has the structure shown in the formula I, the yield is 98%, and the intermediate is confirmed to have the structure shown in the formula I through nuclear magnetism.
(2) Carrying out coupling reaction on the intermediate with the structure shown in the formula I and the compound with the structure shown in the formula B to prepare an intermediate with the structure shown in the formula II;
dissolving 70.00g (0.196mol) of the intermediate with the structure shown in the formula I prepared in the step in 560mL of acetonitrile, transferring the mixture into a reaction bottle, adding 15.67g (0.392mol) of sodium hydroxide (particles), stirring and dispersing uniformly, heating to 35 ℃, adding 39.25g (0.294mol) of the compound with the structure shown in the formula B into the feed liquid in batches, controlling the temperature to be 30-40 ℃, stirring for 3 hours, monitoring by TLC, and cooling to room temperature after the raw material point disappears. Filtering the feed liquid, leaching a filter cake with a small amount of acetonitrile, combining filtrates, concentrating at 45 ℃ to obtain a light yellow solid, adding the light yellow solid into 300mL of ethyl acetate, heating to dissolve, hot filtering, cooling the filtrate to 20 ℃, adding 150mL of n-hexane while stirring, precipitating a large amount of solid, cooling the feed liquid to 10 ℃, crystallizing for 2h, suction filtering, and drying to obtain 77.38g of white solid, wherein the yield is 86%, and the white solid is confirmed to be an intermediate with the structure shown in formula II through nuclear magnetism.
(3) Reacting the intermediate with a structure shown in a formula II with p-fluorophenyl magnesium bromide, and reacting with acid to obtain a compound V;
150mL of tetrahydrofuran was added to 75.00g (0.165mol) of the intermediate having the structure represented by formula II prepared in the above step, stirred until it was clear, and then cooled to 0 ℃. And (2) dropwise adding 330.0mL of p-fluorophenyl magnesium bromide tetrahydrofuran solution (0.33mol and c being 1.0mol/L) at the temperature of 20-30 ℃, stirring at 15-25 ℃ for 1h after the addition is finished, monitoring the reaction by TLC, pouring the material liquid into 200mL of saturated ammonium chloride solution after the reaction is completed, stirring for 15min, standing, separating, extracting the water phase by 200mL of tetrahydrofuran, combining the organic phases, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 45 ℃ until the water phase is dry to obtain a light yellow oily intermediate product. Adding 250mL of methyl isobutyl ketone into the oily intermediate product, stirring for dissolving, adding 34.56g (0.182mol) of p-toluenesulfonic acid monohydrate under the stirring state after the feed liquid is dissolved, heating to 65 ℃, cooling to 15 ℃ after the feed liquid is dissolved, stirring for crystallization for 1 hour, filtering, leaching a filter cake with methyl isobutyl ketone, and drying to obtain 103.57g of a white solid compound V with the yield of 87%.
(4) The compound V is subjected to reduction reaction to prepare an aprepitant crude product;
100.00g (0.138mol) of the compound V prepared in the above step, 47.72g (0.414mol) of triethylsilane and 800mL of acetonitrile were added to a reaction flask, stirred until clear, and then cooled to 0 ℃. And (3) dropwise adding 58.76g (0.414mol) of boron trifluoride ether solution at the temperature of 0-10 ℃, and after the addition, keeping the temperature at 25-35 ℃ for reaction for 6 hours. A large amount of solid is separated out, filtered, and a filter cake is washed by a small amount of acetonitrile and pumped to dryness to obtain 67.12g of a white solid crude aprepitant product, the yield is 91 percent, and the aprepitant is directly used in the next step.
(5) Refining an aprepitant crude product;
adding 520.00g of methanol into 65.00g (0.122mol) of aprepitant crude product prepared in the step, heating to 60 ℃, and stirring until the feed liquid is clear; after the solution is clear, 325.00g of purified water is dropped into the solution under the stirring and temperature control of 50-60 ℃, a large amount of solid is separated out, the temperature is reduced to 15 ℃, the temperature is kept for 15-25 ℃ for crystallization for 1h, the filtration is carried out, a filter cake is washed by a methanol-water mixed solution (the weight ratio is 8:5), the filtration is carried out, the filter cake is placed in a 50 ℃ vacuum drying oven for drying for 8h, 61.31g of white solid aprepitant finished product is obtained, the yield is 94%, the total yield of the product is 63%, the HPLC purity is not less than 99.0%, and the content of defluorinated aprepitant (RRT0.97) is 0.01%.
Example 3
This example provides a specific example of preparing an intermediate having a structure represented by formula I, an intermediate having a structure represented by formula II, and further preparing aprepitant, including the following specific steps:
(1) carrying out hydrogenation reaction on a compound with a structure shown in a formula A to prepare an intermediate with a structure shown in a formula I;
adding 100.00g (0.224mol) of the compound with the structure shown in the formula A and 600mL of methanol into a reaction bottle, stirring to dissolve the mixture clearly, adding 6.25g of 5% palladium-carbon (containing 60% of water) after the solution is dissolved clearly, heating to 55 ℃, replacing 3 times of hydrogen, keeping the hydrogenation pressure at 3.0MPa, controlling the temperature to 50-60 ℃, and stirring to react for 5 hours. After the reaction is finished, cooling to room temperature, filtering the feed liquid, and concentrating a filter cake at 45 ℃ in vacuum to be dry to obtain 76.98g of colorless transparent oily matter, wherein the yield is 96%, and the obtained product is confirmed to be an intermediate with the structure shown in the formula I through nuclear magnetism.
(2) Carrying out coupling reaction on the intermediate with the structure shown in the formula I and the compound with the structure shown in the formula B to prepare an intermediate with the structure shown in the formula II;
dissolving 70.00g (0.196mol) of the intermediate with the structure shown in the formula I prepared in the step in 560mL of acetonitrile, transferring the acetonitrile into a reaction bottle, adding 15.67g (0.392mol) of sodium hydroxide (particles), stirring and dispersing uniformly, heating to 35 ℃, adding 52.33g (0.392mol) of the compound shown in the formula B into the feed liquid in batches, controlling the temperature to be 30-40 ℃, stirring for 2 hours, monitoring by TLC, and cooling to room temperature after the raw material point disappears. Filtering the feed liquid, leaching a filter cake with a small amount of acetonitrile, combining filtrates, concentrating at 45 ℃ to obtain a light yellow solid, adding the light yellow solid into 300mL of ethyl acetate, heating to dissolve, hot filtering, cooling the filtrate to 20 ℃, adding 150mL of n-hexane while stirring, precipitating a large amount of solid, cooling the feed liquid to 15 ℃, crystallizing for 2h, suction filtering, and drying to obtain 77.67g of white solid, wherein the yield is 87%, and the white solid is confirmed to be a structural intermediate shown in formula II through nuclear magnetism.
(3) Reacting the intermediate with a structure shown in a formula II with p-fluorophenyl magnesium bromide, and reacting with acid to obtain a compound V;
to 75.00g (0.165mol) of the intermediate having the structure represented by formula II prepared in the above step, 150mL of tetrahydrofuran was added, stirred until it was clear, and then cooled to 10 ℃. And (2) controlling the temperature to be 20-30 ℃, dropwise adding 330.0mL of p-fluorophenyl magnesium bromide tetrahydrofuran solution (0.33mol, c is 1.0mol/L), stirring and reacting at 15-25 ℃ for 1h after the addition is finished, monitoring the reaction by TLC, pouring the material liquid into 200mL of saturated ammonium chloride solution after the reaction is completed, stirring for 15min, standing, separating, extracting the water phase by 200mL of tetrahydrofuran, combining the organic phases, drying by anhydrous sodium sulfate, filtering, and concentrating under reduced pressure at 45 ℃ until the water phase is dried to obtain a light yellow oily intermediate product. Adding 250mL of methyl isobutyl ketone into the oily intermediate product, stirring for dissolving, adding 62.77g (0.330mol) of p-toluenesulfonic acid monohydrate under the stirring state after the feed liquid is dissolved, heating to 65 ℃, cooling to 15 ℃ after the feed liquid is dissolved, stirring for crystallization for 1h, filtering, leaching a filter cake with methyl isobutyl ketone, and drying to obtain 101.63g of a white solid compound V, wherein the yield is 85%.
(4) The compound V is subjected to reduction reaction to prepare an aprepitant crude product;
100.00g (0.138mol) of the compound V prepared in the above step, 32.18g (0.279mol) of triethylsilane and 800mL of acetonitrile were added to a reaction flask, stirred until clear and then cooled to 0 ℃. Controlling the temperature to be 0-10 ℃, dropwise adding 39.28g (0.277mol) of boron trifluoride ether solution, and after the addition is finished, keeping the temperature to be 25-35 ℃ for reaction for 4 hours. A large amount of solid is separated out, filtered, and a filter cake is washed by a small amount of acetonitrile and pumped to dryness to obtain 68.94g of crude aprepitant white solid with the yield of 93 percent which is directly used in the next step.
(5) Refining an aprepitant crude product;
adding 520.00g of methanol into 65.00g (0.122mol) of aprepitant crude product prepared in the step, heating to 60 ℃, and stirring until the feed liquid is clear; after the solution is clear, 325.00g of purified water is dropped into the solution under the condition of stirring and controlling the temperature to be 50-60 ℃, a large amount of solid is separated out, the temperature is reduced to 20 ℃, the temperature is kept to be 15-25 ℃ for crystallization for 1h, the solution is filtered, a filter cake is washed by a methanol-water mixed solution (the weight ratio is 8:5), the filter cake is drained, and the filter cake is placed in a vacuum drying oven at 50 ℃ for drying for 8h, so that 60.28g of white solid aprepitant finished product is obtained, the yield is 93%, the total yield of the product is 61%, the HPLC purity is not less than 99.0%, and the content of defluorinated aprepitant (RRT0.97) is 0.02%.
Comparative example 1
This comparative example provides a specific example of the synthesis of Aprepitant (Aprepitant) according to the scheme shown in formula 4:
synthesis of Compound X:
100mL of tetrahydrofuran was added to 100.00g (0.224) of Compound I, and the mixture was stirred to dissolve and then cooled to 0 ℃. And (3) dropwise adding 300mL of p-fluorophenyl magnesium bromide tetrahydrofuran solution (0.300mol), stirring for 30min after dropwise adding, controlling the temperature to be 0-10 ℃ after complete reaction, dropwise adding the reaction solution into 150mL of methanol for quenching, and continuously dropwise adding methanol solution (70.05g/150mL) of p-toluenesulfonic acid (0.368mol) after dropwise adding. After the addition, the feed liquid is poured into a 1L hydrogenation reaction kettle, the hydrogenation pressure is kept at 20psi, the temperature is controlled at 20-30 ℃, and the hydrogenation is carried out for 4 h. After the reaction is finished, filtering the feed liquid, concentrating the feed liquid in vacuum to dryness, adding 500mL of methyl isobutyl ketone and 100mL of buffer solution of sodium citrate and sodium bicarbonate, stirring, separating the liquid, washing the organic phase with purified water and saturated salt water in turn, separating the liquid, adding 7.5mL of concentrated hydrochloric acid into the organic phase, stirring, heating to reflux, evaporating to remove a small amount of solvent until a large amount of solid is separated out from the system, cooling to 20 ℃, crystallizing for 3 hours, filtering, leaching and drying to obtain 76.6g of a white-like solid compound X, wherein the yield is as follows: 72.33 percent.
Synthesis of Compound VI:
adding 500mLN, N-dimethylformamide into 55.00g (0.116mol) of compound X, stirring for dissolving, adding 43.75g (0.317mol) of anhydrous potassium carbonate after the solution of the feed liquid is dissolved, cooling to 5 ℃, keeping the temperature at 0-10 ℃, adding N, N-dimethylformamide solution (22.15g/250mL) of compound II (0.166mol) into the system in a dropwise manner, controlling the temperature at 0-10 ℃ for reacting for 4 hours after the dropwise addition, stirring after the reaction is finished, adding 1500mL of purified water into the feed liquid in a dropwise manner, keeping the temperature at 20-30 ℃ for crystallizing for 1 hour, filtering, washing the filter cake with purified water, draining, drying to obtain 57.05g of crude white solid compound VI, and obtaining the yield: 92 percent.
Purification of Compound VI:
456.00g of methanol is added into 57.00g (0.107mol) of the compound VI, and the temperature is raised to 55 ℃ and the mixture is stirred until the solution is clear; after the solution is clear, 285.00g of purified water is dropwise added into the solution under stirring and temperature control of 50-60 ℃, a large amount of solid is separated out, the temperature is reduced to 20 ℃, the temperature is kept for 15-25 ℃ for crystallization for 1h, the solution is filtered, a filter cake is washed by a methanol-water mixed solution (the weight ratio is 8:5), the filter cake is drained, the filter cake is placed in a 50 ℃ vacuum drying oven for drying for 7h, 51.30g of white solid aprepitant finished product is obtained, and the yield is as follows: 90 percent and HPLC purity more than or equal to 99.00 percent. The content of defluorinated aprepitant (RRT0.97) is 0.127 percent, and the total yield of the product is as follows: 60 percent.
The HPLC high performance liquid chromatogram and the spectrum result of the aprepitant obtained in the comparative example are shown in figure 4, in the figure 4, the peak number 1 is a compound II, the peak number 2 is defluorinated aprepitant, and the peak number 3 is aprepitant.
According to the detection result, the content of defluorinated aprepitant in the aprepitant prepared in the reaction process is far higher than that of the aprepitant prepared in the embodiment of the invention by 0.127 percent, and the total yield of the product is only 60 percent and is lower than that of the aprepitant prepared in the embodiment of the invention.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (1)
1. A preparation method of aprepitant is characterized by comprising the following steps:
hydrogenating (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholin-3-one to obtain an intermediate with a structure shown in a formula I; the intermediate has a structure shown in formula I:
carrying out coupling reaction on the intermediate with the structure shown in the formula I and 3-chloromethyl-1, 2, 4-triazoline-5-one to obtain the intermediate with the structure shown in the formula II; the intermediate has a structure represented by formula II:
performing Grignard reaction on the intermediate with p-fluorophenyl magnesium bromide to obtain an intermediate 5- (((2R,3R) -2- ((R) -1- (3, 5-bis (trifluoromethyl) phenyl) ethoxy) -3- (4-fluorophenyl) -3-hydroxymorpholino) methyl) -2, 4-dihydro-3H-1, 2, 4-triazole-3-one;
carrying out salt forming reaction on the intermediate product and acid to obtain a compound V;
the compound V has the following structural formula:
the compound V and triethylsilane are subjected to reduction reaction under the action of Lewis acid to obtain the aprepitant; the Lewis acid is boron trifluoride diethyl etherate; the molar ratio of the compound V to the triethylsilane is 1: 2.0-4.0, and the molar ratio of the compound V to the Lewis acid is 1: 2.0-4.0;
the solvent of the hydrogenation reaction is a protic solvent; the protic solvent is methanol; the catalyst for the hydrogenation reaction is 5% palladium carbon; the water content of the 5% palladium-carbon is 60%; the mass ratio of the (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholine-3-one to 5% palladium carbon is 1: 0.0625-0.125;
the hydrogenation pressure of the hydrogenation reaction is 0.5-5 MPa; the temperature is 30-70 ℃; the time is 2-8 h;
the temperature of the coupling reaction is 30-60 ℃, and the time is 2-3 h;
the temperature of the Grignard reaction is 0-30 ℃, and the time is 1-2 h;
the temperature of the reduction reaction is 25-55 ℃, and the time is 4-6 h.
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| AR030284A1 (en) * | 2000-06-08 | 2003-08-20 | Merck & Co Inc | PROCESS FOR THE SYNTHESIS OF (2R, 2-ALFA-R, 3A) -2- [1- (3,5-BIS (TRIFLUOROMETIL) PHENYL) ETOXI] -3- (4-FLUOROPHENIL) -1,4-OXAZINE; SUCH COMPOUND AND ITS POLYMORPHIC FORMS |
| WO2009001203A2 (en) * | 2007-06-27 | 2008-12-31 | Orchid Chemicals & Pharmaceuticals Limited | An improved process for the preparation of aprepitant |
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