CN110963928B - Preparation method of aprepitant intermediate impurity - Google Patents
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Abstract
The invention relates to a preparation method of aprepitant intermediate impurities. The preparation method comprises the following reaction steps: (A) carrying out Grignard reaction on the raw material 1 and Grignard reagent 4-fluorophenyl magnesium halide; (B) carrying out reduction reaction on the reaction product obtained in the step (A) and a reducing agent to obtain a compound 4; (C) carrying out debenzylation reaction on the obtained compound 4 and a deprotection reagent to obtain a crude product 5; (D) reacting the obtained crude product 5 with a protective reagent in the presence of a solvent and alkali to obtain a compound 6; (E) and carrying out deprotection reaction on the obtained compound 6 and acid or alkali in the presence of a solvent, and separating and purifying to obtain a refined product 5. The method of the invention firstly obtains the compound 4 through reduction reaction, and then synthesizes the compound 5 through debenzylation reaction, thus successfully synthesizing the compound 5 and greatly improving the yield and purity of the crude product 5. Further, the crude product 5 is reacted with a protective reagent and purified to obtain a compound 6, and the compound 5 with high purity can be separated through conventional column chromatography after deprotection reaction.
Description
Technical Field
The invention relates to the field of chemical synthesis, and in particular relates to a preparation method of an aprepitant intermediate impurity.
Background
Aprepitant, the chemical name of which is 5- [2(R) - [1(R) - [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -3(S) - (4-fluorophenyl) morpholin-4-ylmethyl ] -3, 4-dihydro-2H-1, 2, 4-triazol-3-one, has the structural formula shown in the following figure. Aprepitant is a highly selective NK1 receptor antagonist developed and produced by msandong. The composition is mainly used for preventing acute and delayed nausea and vomiting during primary and repeated treatment of high-emetogenic anti-tumor chemotherapy in clinic.
In the structural formula of the aprepitant, 3 chiral centers exist, and 7 chiral isomer impurities exist. With the addition of ICH (International conference on coordination of technical requirements for human drug registration) in China, the quality control of raw material drugs is more and more concerned, and the preparation and acquisition of related impurity reference substances are more and more important. The applicant found in the course of the quality control studies of aprepitant that the isomer impurity 5- [2(R) - [1(R) - [3, 5-bis (trifluoromethyl) phenyl group, as recorded in the United states pharmacopoeia]Ethoxy radical]-3(R) - (4-fluorophenyl) morpholin-4-ylmethyl]-3, 4-dihydro-2H-1, 2, 4-triazol-3-one
The preparation of (a) is particularly difficult. An impurity intermediate compound 5 (chemical name is (1S, 2R) -2- (2-aminoethoxy) -2- [ (R) -1- [3, 5-bis (trifluoromethyl) phenyl) related in the synthetic route]Ethoxy radical]-1- (4-fluorophenyl) ethanol; structural formula (xvi):
) Even if the process route for preparing aprepitant is combined with the preparation method described in the document J.AM.CHEM.SOC.2003,125,2129-2135, the repeated realization of the process is difficult in the practical preparation (the inventor finds in practice that the process is directly realized by a traditional synthetic methodWhen the pot is used for carrying out reduction and debenzylation reaction on the quenched Grignard reaction solution, the target compound 5 can hardly be detected in the product, and the meaning of obtaining the high-purity compound 5 by further separation and purification is avoided). The preparation methods in other related literature records cannot be obtained by conventional column chromatography separation and purification, but need liquid phase separation equipment for assistance, and have the disadvantages of complex preparation process, high labor cost and equipment cost, and greatly increased preparation cost of the reference substance.
Thus, how to provide an impurity intermediate compound 5
The high-purity preparation method is a technical problem to be solved urgently.
Disclosure of Invention
Based on the above, one of the purposes of the invention is to provide a synthesis process with high repeatability and simple and stable process aiming at the defects of complex synthesis route, low repetition rate and yield of an impurity intermediate (1S, 2R) -2- (2-aminoethoxy) -2- [ (R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] -1- (4-fluorophenyl) ethanol.
The specific technical scheme is as follows:
a preparation method of aprepitant intermediate impurities comprises the following reaction route:
the preparation method comprises the following reaction steps:
(A) carrying out Grignard reaction on the raw material 1 and Grignard reagent 4-fluorophenyl magnesium halide;
(B) carrying out reduction reaction on the reaction product obtained in the step (A) and a reducing agent to obtain a compound 4;
(C) carrying out debenzylation reaction on the obtained compound 4 and a deprotection reagent to obtain a crude product 5;
(D) reacting the obtained crude product 5 with a protective reagent in the presence of a solvent and alkali to obtain a compound 6;
(E) carrying out deprotection reaction on the obtained compound 6 and acid or alkali in the presence of a solvent, and then separating and purifying to obtain a refined product 5;
the protective agent is selected from: fluorenylmethoxycarbonylcarbonyl chloride, benzyloxycarbonyl chloride or Boc-anhydride.
Compared with the prior art, the invention has the following beneficial effects:
through a large number of experimental researches, the inventor of the invention finds that the compound 5 can be successfully synthesized and the yield and the purity of the crude product 5 can be greatly improved by a method of firstly obtaining the compound 4 through reduction reaction and then synthesizing the compound 5 through debenzylation reaction. Further, the crude product 5 is reacted with a protective reagent and purified to obtain a compound 6, and the compound 5 with high purity can be separated through conventional column chromatography after deprotection reaction.
The preparation method of the invention has simple equipment, does not need precise equipment such as liquid chromatogram and the like, and the used reagent is environment-friendly.
Drawings
FIG. 1 is a thin layer chromatogram of the reaction solution of step (D) of example 1;
FIG. 2 is the nuclear magnetic hydrogen spectrum of purified top-quality product 5 of example 1;
FIG. 3 is an HPLC chromatogram of Compound 4 obtained in step (B) of example 1 (wherein the retention time of the chromatographic peak of Compound 4 is 7.857 min);
FIG. 4 is an HPLC chromatogram of crude product 5 obtained in step (C) of example 1 (wherein the retention time of the chromatographic peak of Compound 5 is 4.883 min);
FIG. 5 is a GC-MS spectrum of crude product 5 obtained in step (C) of example 1;
FIG. 6 is an HPLC chromatogram of purified top-quality product 5 of step (E) of example 1 (wherein the retention time of the chromatographic peak of Compound 5 is 4.647 min);
FIG. 7 is an HPLC chromatogram of the product obtained in step (B) of comparative example 1.
Detailed Description
In order that the invention may be more readily understood, reference will now be made to the following more particular description of the invention, examples of which are set forth below. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. These embodiments are provided so that this disclosure will be thorough and complete.
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 to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.
The embodiment provides a preparation method of aprepitant intermediate impurities, which comprises the following reaction route:
the preparation method comprises the following reaction steps:
(A) carrying out Grignard reaction on the raw material 1 and Grignard reagent 4-fluorophenyl magnesium halide;
(B) carrying out reduction reaction on the reaction product obtained in the step (A) and a reducing agent to obtain a compound 4;
(C) carrying out debenzylation reaction on the obtained compound 4 and a deprotection reagent to obtain a crude product 5;
(D) reacting the obtained crude product 5 with a protective reagent in the presence of a solvent and alkali to obtain a compound 6;
(E) carrying out deprotection reaction on the obtained compound 6 and acid or alkali in the presence of a solvent, and then separating and purifying to obtain a refined product 5;
the protective agent is selected from: fluorenylmethoxycarbonylcarbonyl chloride, benzyloxycarbonyl chloride or Boc-anhydride.
In some of these embodiments, the base in reaction (D) is at least one of triethylamine, N-diisopropylethylamine, potassium bicarbonate, and sodium bicarbonate. Preferably, the base in the reaction (D) is DIPEA, in which case the reaction conditions are mild, the system is homogeneous, and the side reactions are less.
In some of these embodiments, the solvent in reaction (D) is at least one of dichloromethane, ethyl acetate, toluene, and water. Preferably, the solvent in reaction (D) is dichloromethane. At this time, the post-treatment can directly enter the purification stage through simple water washing without further separation, the solvent is easy to remove, and unnecessary cost and other solvent residues which are difficult to remove are saved.
In some of these embodiments, the base in reaction (E) is at least one of diethylamine, triethylamine, morpholine, pyridine, potassium carbonate, and sodium carbonate. In the reaction (E), the acid is at least one of hydrochloric acid, sulfuric acid or nitric acid. Specifically, when the deprotection reagent in reaction (C) is fluorenylmethoxycarbonyl chloride, the reagent for performing the deprotection reaction in reaction (E) is preferably a base, and more preferably morpholine. When the deprotection reagent in reaction (C) is Boc-acid anhydride, the reagent for performing the deprotection reaction in reaction (E) is preferably an acid, and more preferably concentrated hydrochloric acid.
In some of these embodiments, the solvent in reaction (E) is at least one of dichloromethane, ethyl acetate, toluene, dioxane, and water. Preferably, the solvent in the reaction (E) is dichloromethane, in which case the system is uniform, side reactions are less, and post-treatment separation is easier.
In some of these embodiments, the reducing agent in reaction (B) is sodium borohydride, potassium borohydride, or a borane-based reducing agent. Among them, sodium borohydride is preferred as a reducing agent, which is economical and easily available and has a low risk coefficient.
In some of these embodiments, the deprotecting reagent in reaction (C) is Pd/C-H2Or Pd/C-ammonium formate. The preferred deprotection reagent is Pd/C-H2The deprotection system is simple and easy to operate and has few side reactions.
In some of these embodiments, the reaction solvent in reaction (a) is at least one of tetrahydrofuran, methyltetrahydrofuran, toluene, and diethyl ether.
In some examples, in reaction (A), after reacting raw material 1 with 4-fluorophenyl magnesium halide, adding a quenching agent for quenching, and then carrying out step (B) on the obtained product; the quenching agent is at least one of methanol, ethanol, isopropanol and water.
In some of these embodiments, the reaction solvent in reaction (C) is at least one of methanol, ethanol, isopropanol, and water.
In some of the embodiments, the reaction temperature of the reaction (A) is 5 to 20 ℃;
and/or the reaction temperature of the reaction (C) is 15-40 ℃;
and/or the reaction temperature of the reaction (D) is-5-0 ℃;
and/or the reaction temperature of the reaction (E) is 20-40 ℃.
In some of these embodiments, the 4-fluorophenyl magnesium halide in reaction (a) is: 4-fluorophenyl magnesium bromide grignard reagent, 4-fluorophenyl magnesium chloride grignard reagent or 4-fluorophenyl magnesium iodide grignard reagent.
In some embodiments, in the reaction step (D), after the crude intermediate impurity 5 reacts with the protecting reagent, the compound 6 is obtained through a separation and purification step; the separation and purification process comprises the following steps:
(D1) purifying the reaction solution by silica gel column chromatography to obtain a crude product 6;
(D2) purifying the obtained crude product 6 by using a neutral alumina column chromatography;
the eluent used for the silica gel column chromatography in the step (D1) is petroleum ether and ethyl acetate; the silica gel column chromatography adopts gradient elution, and the gradient change rule is that petroleum ether: the volume ratio of the ethyl acetate is from (90-100)%: (0-10)% → (70-90)%: (10-30)%;
the eluent used for the neutral alumina column chromatography in the step (D2) is petroleum ether and ethyl acetate; the neutral alumina column chromatography adopts gradient elution, and the gradient change rule is that petroleum ether: the volume ratio of the ethyl acetate is from (7-9) → (5-7) → (2-4): 1.
In some embodiments, the separation and purification process of step (E) comprises: the separation and purification process of step (E) comprises: purifying the reaction liquid by using a silica gel column chromatography, wherein an eluant used by the silica gel column chromatography is ethyl acetate and methanol, the silica gel column chromatography adopts gradient elution, and the gradient change rule is that the volume ratio of the ethyl acetate to the methanol is from (90-100)%: (0% -10%) → (70-80)%: (20-30)%.
The present invention will be described in further detail with reference to specific examples.
The following examples relate to the following abbreviations for some of the raw materials and their full names:
APT 04: (2R) -4-benzyl-2- [ (1R) -1- [3, 5-bis (trifluoromethyl) phenyl ] ethoxy ] morpholin-3-one; homemade, reference is made to j.am. chem. soc.2003,125, 2129-2135.
PE: petroleum ether;
EA: ethyl acetate;
DCM: dichloromethane;
THF: tetrahydrofuran;
TLC: thin layer chromatography;
DIPEA: n, N-diisopropylethylamine;
Fmoc-Cl: fluorenylmethoxycarbonylcarbonyl chloride;
MeOH: methanol.
Example 1
(A) 50g of APT04 (raw material 1) and 50mL of THF are added into a 500mL three-necked bottle, stirred and dissolved, and then cooled to about 10 ℃ in an ice water bath under the protection of nitrogen. And (3) dropwise adding 168mL (1mol/L) of p-fluorophenyl magnesium bromide Grignard reagent at the temperature of 10-20 ℃, stirring and reacting for 0.5h at the constant temperature of 5-20 ℃ after the dropwise adding is finished, slowly dropwise adding the reaction system into 190mL of cold methanol to quench after the TLC monitoring reaction is finished, and controlling the temperature to be below 5 ℃.
(B) And cooling the obtained quenched reaction system to below 0 ℃, adding 8.5g of sodium borohydride in batches, stirring for 10min, removing an ice water bath, and naturally heating the temperature to room temperature for reaction. TLC after 0.5h monitored the reaction to completion. And (3) concentrating the system to be dry at 48-50 ℃ under reduced pressure, adding 300mL of ethyl acetate and 900mL of water, fully washing, standing, separating, washing an organic phase with 200mL of water, then washing with 200mL of saturated saline solution, and finally concentrating the organic phase to be dry to obtain 60g of a viscous oily crude product of the compound 4. Crude petroleum ether-petroleum ether: the ethyl acetate 20:1 column chromatography was used to remove small polar impurities, and 435g of the intermediate compound was obtained as a yellow oil (HPLC results are shown in fig. 3).
(C) 415 g of compound and 65mL of methanol are added into a 100mL single-neck flask, after uniform stirring, 10% palladium carbon with the wet weight of 0.5g (55% of water) is added, normal-pressure hydrogenation is carried out for 18h, after TLC monitoring reaction is finished, the palladium carbon is removed by suction filtration, and filtrate is concentrated to dryness under reduced pressure at 40 ℃ to obtain 12.7g of crude product of the compound 5 as a gray-black oily matter (HPLC results are shown in figure 4, and a liquid mass spectrum is shown in figure 5, which indicates that a target product is generated).
(D) Dissolving the oily matter with 70mL of DCM, adding 6.2mL of DIPEA, cooling to-5-0 ℃, dropwise adding a dichloromethane solution of Fmoc-Cl (7.86g of fluorenylmethoxycarbonyl chloride is dissolved in 25mL of EDC) at the temperature range, sampling TLC to monitor the reaction progress after dropwise adding, supplementing 20mL of DCM for dilution after the reaction is finished, simultaneously adding 50mL of water, stirring for 10min, standing for layering, washing an organic phase with 50mL of saturated saline solution, and concentrating to dryness to obtain 20.8g of a gray-black sticky crude product of the compound 6. Petroleum ether to petroleum ether: ethyl acetate 4:1 was separated by silica gel column chromatography as eluent to remove small polar impurity spots, and further to obtain 19g of crude compound 6. Crude 6g of compound 6, 250g neutral alumina were packed into a column and purified with petroleum ether: ethyl acetate 8: 1-petroleum ether: ethyl acetate 6: 1-petroleum ether: crude compound 6 was separated by column chromatography on alumina using ethyl acetate 3:1 as a gradient eluent to collect 6400 mg of the purer compound.
(E) Adding 5mL of DCM and 4mL of morpholine into the obtained pure compound 6, deprotecting overnight at room temperature, filtering the reaction solution after TLC monitoring reaction is finished, concentrating the mother solution to dryness, adding 10mL of water, stirring for 5min, filtering, and collecting yellow filter cake solid. Adding 10mL of methanol into the obtained yellow filter cake solid, stirring and pulping for 10min, filtering, collecting filtrate, concentrating the filtrate to obtain 0.34g of solid-liquid mixture, and adding EA-EA: silica gel column chromatography purification with MeOH 3:1 as eluent to obtain refined product 50.07 g, purity 99.2%, nuclear magnetic hydrogen spectrum shown in figure 2, and HPLC spectrum shown in figure 6.
Example 2
This example differs from example 1 in that in reaction (D), the protecting reagent is selectedBoc-anhydrideInstead of Fmoc-Cl.
(D) Dissolving 5g of crude oily matter of the compound 5 obtained in the step (C) in the example 1 by 70mL of dioxane, adding 6.2mL of DIPEA, cooling to-5-0 ℃, dropwise adding 2.5g of Boc-anhydride in the temperature range, monitoring the reaction progress by sampling TLC after the dropwise adding is finished, adding 50mL of water after the reaction is finished, adding 80mL of DCM for extraction, standing for demixing, washing an organic phase by 50mL of saturated saline solution, and concentrating to be dry to obtain 8g of crude gray-black sticky matter of the compound 6. Petroleum ether to petroleum ether: ethyl acetate 4:1 as eluent was separated by silica gel column chromatography to remove small polar impurity spots, and further to obtain 6g of crude compound 5 protected with amine group. The crude product 6g, 250g neutral alumina were packed into a column and purified with petroleum ether: ethyl acetate 8: 1-petroleum ether: ethyl acetate 6: 1-petroleum ether: the crude compound 6 was subjected to alumina column chromatography using ethyl acetate 3:1 as a gradient eluent to collect a total of 300mg of the purer "amino boc protected compound 5 product".
(E) Adding 5mL of dioxane and 3mL of concentrated hydrochloric acid into the obtained pure amino boc protection product of the compound 5, deprotecting overnight at room temperature, adding 5mL of water after TLC monitoring reaction is finished, adding DCM10mL for extraction, collecting an organic phase, concentrating to obtain 0.2g of a solid-liquid mixture, and reacting the solid-liquid mixture with EA-EA: silica gel column chromatography purification is carried out by using MeOH as eluent, wherein the MeOH is 3:1, and refined product 50.04 g is obtained.
Example 3
This example differs from example 1 in that the base in reaction (D) is triethylamine instead of DIPEA.
(D) Taking 12.7g of the crude grayish black oily matter of the compound 5 obtained in the step (C) of the example 1, dissolving the grayish black oily matter with 70mL of EDCM, adding 7.2mL of triethylamine, cooling to-5-0 ℃, dropwise adding a dichloromethane solution of Fmoc-Cl (7.86g of fluorenylmethoxycarbonyl chloride is dissolved in 25mL of dichloromethane) at the temperature range, monitoring the reaction progress by sampling TLC after dropwise adding, supplementing 20mL of DCM for dilution after the reaction is finished, adding 50mL of water at the same time, stirring for 10min, standing for layering, washing an organic phase with 50mL of saturated saline solution, and concentrating to be dry to obtain 19.1g of the crude grayish black oily matter of the compound 6. Petroleum ether to petroleum ether: ethyl acetate 4:1 was separated by silica gel column chromatography as an eluent to remove small polar impurity spots, and further to obtain 15.2g of a crude product of compound 6. Crude 6g of compound 6, 250g neutral alumina were packed into a column and purified with petroleum ether: ethyl acetate 8: 1-petroleum ether: ethyl acetate 6: 1-petroleum ether: the crude compound 6 was subjected to alumina column chromatography using ethyl acetate 3:1 as a gradient eluent to collect 6500 mg of the purer compound.
(E) Adding 5mL of DCM and 4mL of morpholine into the obtained pure compound 6, deprotecting overnight at room temperature, filtering the reaction solution after TLC monitoring reaction is finished, removing white solid, concentrating the mother solution to dryness, adding 10mL of water, stirring for 5min, filtering, and collecting yellow filter cake solid. Adding 10mL of methanol into the obtained yellow filter cake solid, stirring and pulping for 10min, filtering, collecting filtrate, concentrating the filtrate to obtain 0.27g of solid-liquid mixture, and adding EA-EA: silica gel column chromatography purification is carried out by using MeOH as eluent, wherein the MeOH is 3:1, and refined product 50.065 g is obtained.
Example 4
(A) 20g of APT04 (raw material 1) and 20mL of THF are added into a 500mL three-necked bottle, stirred and dissolved, and then cooled to about 10 ℃ in an ice water bath under the protection of nitrogen. And (2) dropwise adding 60mL (1mol/L) of p-fluorophenyl magnesium bromide Grignard reagent at the temperature of 10-20 ℃, stirring and reacting for 0.5h at the constant temperature of 5-20 ℃ after dropwise adding, slowly dropwise adding the reaction system into 80mL of cold methanol to quench after TLC monitoring reaction, concentrating to remove methanol, washing with 400g of 10% citric acid aqueous solution and 120mL of n-heptane, separating, and directly using the obtained organic phase for the next reaction.
(B) And cooling the obtained quenched reaction system to below 0 ℃, dripping 2.6mL of 10M borane dimethylsulfide, stirring for 10min, removing an ice water bath, and naturally heating to room temperature for reaction. TLC after 0.5h monitored the reaction to completion. And (3) dropwise adding 6mL of concentrated hydrochloric acid at a temperature of 0-5 ℃ for quenching, separating liquid, concentrating the organic phase at a temperature of 48-50 ℃ under reduced pressure until the organic phase is dry, adding 300mL of ethyl acetate and 900mL of water, fully washing, standing for separating liquid, washing the organic phase with 200mL of water, then washing with 200mL of saturated saline solution, and finally concentrating the organic phase until the organic phase is dry to obtain 25g of a viscous oily crude product of the compound 4. Crude petroleum ether-petroleum ether: and (3) separating and purifying the ethyl acetate by column chromatography with a ratio of 20:1 to remove small polar impurities to obtain 415.2 g of a purified yellow oily intermediate compound.
(C) 415 g of compound and 65mL of methanol are added into a 100mL single-neck bottle, after uniform stirring, 10% palladium carbon with the wet weight of 0.5g (55% of water) is added, hydrogenation is carried out for 18h under normal pressure, after TLC monitoring reaction is finished, the palladium carbon is removed by suction filtration, and the filtrate is concentrated to dryness under reduced pressure at 40 ℃ to obtain 12g of crude product of the compound 5 as a gray-black oily substance.
(D) Dissolving the oily matter with 70mL of DCM, adding 6.0mL of DIPEA, cooling to-5-0 ℃, dropwise adding a dichloromethane solution of Fmoc-Cl (7.8g of fluorenylmethoxycarbonyl chloride is dissolved in 25mL of dichloromethane) at the temperature range, monitoring the reaction progress by sampling TLC after the dropwise adding is finished, supplementing 20mL of DCM for dilution after the reaction is finished, simultaneously adding 50mL of water, stirring for 10min, standing for layering, washing an organic phase with 50mL of saturated saline solution, and concentrating to be dry to obtain 19.4g of a gray-black sticky matter crude product of the compound 6. Petroleum ether to petroleum ether: ethyl acetate 4:1 was separated by silica gel column chromatography as an eluent to remove small polar impurity spots, and further to obtain 16.7g of a crude product of compound 6. Crude 6g of compound 6, 250g neutral alumina were packed into a column and purified with petroleum ether: ethyl acetate 8: 1-petroleum ether: ethyl acetate 6: 1-petroleum ether: the crude compound 6 was subjected to alumina column chromatography using ethyl acetate 3:1 as a gradient eluent to collect 6340 mg of the purer compound.
(E) Adding 5mL of DCM and 4mL of morpholine into the obtained pure compound 6, deprotecting overnight at room temperature, filtering the reaction solution after TLC monitoring reaction is finished, removing white solid, concentrating the mother solution to dryness, adding 10mL of water, stirring for 5min, filtering, and collecting yellow filter cake solid. Adding 10mL of methanol into the obtained yellow filter cake solid, stirring and pulping for 10min, filtering, collecting filtrate, concentrating the filtrate to obtain 0.28g of solid-liquid mixture, and adding EA-EA: silica gel column chromatography purification is carried out by using MeOH as eluent, wherein the MeOH is 3:1, and refined product 50.048 g is obtained.
Example 5
(E) 5mL of DCM and 5mL of pyridine were added to the relatively pure compound 6 obtained in example 1, deprotection was carried out overnight at room temperature, the reaction solution was filtered with suction after TLC monitoring reaction was completed, the mother liquor was concentrated to dryness, 10mL of water was added, stirring was carried out for 5min, and then filtration was carried out to collect a yellow cake solid. Adding 10mL of methanol into the obtained yellow filter cake solid, stirring and pulping for 10min, filtering, collecting filtrate, concentrating the filtrate to obtain 0.31g of solid-liquid mixture, and adding EA-EA: silica gel column chromatography purification is carried out by using MeOH as eluent, wherein the MeOH is 3:1, and refined product 50.062 g is obtained.
Example 6
(A) 50g of APT04 (raw material 1) and 50mL of toluene are added into a 500mL three-necked bottle, stirred and dissolved, and then cooled to about 10 ℃ in an ice water bath under the protection of nitrogen. And (3) dropwise adding 168mL (1mol/L) of p-fluorophenyl magnesium bromide Grignard reagent at the temperature of 10-20 ℃, stirring and reacting for 0.5h at the constant temperature of 5-20 ℃ after dropwise adding, slowly dropwise adding the reaction system into 190mL of cold ethanol to quench after TLC monitoring reaction, and controlling the temperature to be below 5 ℃.
(B) And cooling the obtained quenched reaction system to below 0 ℃, adding 8.5g of sodium borohydride in batches, stirring for 10min, removing an ice water bath, and naturally heating to room temperature for reaction. TLC after 0.5h monitored the reaction to completion. And (3) concentrating the system to be dry at 48-50 ℃ under reduced pressure, adding 300mL of ethyl acetate and 900mL of water, fully washing, standing, separating, washing an organic phase with 200mL of water, then washing with 200mL of saturated saline solution, and finally concentrating the organic phase to be dry to obtain 62g of crude viscous oily matter of the compound 4. Crude petroleum ether-petroleum ether: and (3) separating and purifying the ethyl acetate by column chromatography with a ratio of 20:1 to remove small polar impurities to obtain 432.4 g of a purified yellow oily intermediate compound.
(C) 415 g of compound and 65mL of isopropanol are added into a 100mL single-neck bottle, after uniform stirring, 10% palladium carbon with the wet weight of 0.5g (55% of water) is added, hydrogenation is carried out for 18h under normal pressure, after TLC monitoring reaction is finished, suction filtration is carried out to remove the palladium carbon, and filtrate is concentrated to dryness under reduced pressure at 40 ℃ to obtain 11.8g of crude product of the compound 5 as a gray-black oily substance.
(D) Dissolving the oily matter with 70mL of ethyl acetate, adding 6.0mL of DIPEA, cooling to-5-0 ℃, dropwise adding an ethyl acetate solution of Fmoc-Cl (7.3g of Fmoc-Cl is dissolved in 25mL of ethyl acetate) in the temperature range, monitoring the reaction progress by sampling TLC after the dropwise adding is finished, supplementing 20mL of ethyl acetate for dilution after the reaction is finished, simultaneously adding 50mL of water, stirring for 10min, standing for layering, washing an organic phase with 50mL of saturated saline solution, and concentrating to dryness to obtain 15.4g of a gray-black sticky crude product of the compound 6. Petroleum ether to petroleum ether: ethyl acetate 4:1 was separated by silica gel column chromatography as an eluent to remove small polar impurity spots, and further to obtain 11.5g of crude compound 6. Crude 6g of compound 6, 250g neutral alumina were packed into a column and purified with petroleum ether: ethyl acetate 8: 1-petroleum ether: ethyl acetate 6: 1-petroleum ether: the crude compound 6 was subjected to alumina column chromatography using ethyl acetate 3:1 as a gradient eluent to collect 6318 mg of the purer compound.
(E) 4mL of DCM and 3.2mL of morpholine are added into the obtained pure compound 6 for deprotection at 45 ℃ overnight, after TLC monitoring reaction is finished, reaction liquid is filtered, white solid is removed, mother liquor is concentrated to be dry, 10mL of water is added, stirring is carried out for 5min, then filtering is carried out, and yellow filter cake solid is collected. Adding 10mL of methanol into the obtained yellow filter cake solid, stirring and pulping for 10min, filtering, collecting filtrate, concentrating the filtrate to obtain 0.29g of solid-liquid mixture, and adding EA-EA: silica gel column chromatography purification is carried out by using MeOH as eluent, wherein the MeOH is 3:1, and refined product 50.04 g is obtained.
Comparative example 1
This comparative example does not include the reduction step of step (B) of example 1, but directly uses Pd/C-H2Reducing and debenzylating the product obtained in the step (A).
(A) 50g of APT04 (raw material 1) and 50mL of THF are added into a 500mL three-necked bottle, stirred and dissolved, and then cooled to about 10 ℃ in an ice water bath under the protection of nitrogen. And (3) dropwise adding a p-fluorophenyl magnesium bromide Grignard reagent (1mol/L) at the temperature of 10-20 ℃, stirring and reacting for 0.5h at the constant temperature of 5-20 ℃ after the dropwise adding is finished, slowly dropwise adding the reaction system into 190mL of cold methanol to quench after the TLC monitoring reaction is finished, and controlling the temperature to be below 5 ℃.
(B) Reduction and debenzylation reaction: adding 10% palladium carbon with wet weight of 0.8g (water content of 55%) into the quenched Grignard reaction solution under stirring, hydrogenating at normal pressure for 18h, performing TLC monitoring reaction, then performing suction filtration to remove the palladium carbon, concentrating the filtrate at 40 ℃ under reduced pressure until the filtrate is dry, and detecting by the obtained liquid phase HPLC that no target product 5 is generated, wherein the HPLC is shown in figure 7.
In contrast to example 1, comparative example 1 attempted to prepare compound 5 by directly reducing the product obtained in step a with palladium on carbon, and in fact no target product 5 was formed as analyzed on the pattern 7 of the HPCL.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (12)
1. A preparation method of aprepitant intermediate impurities is characterized by comprising the following reaction route:
the preparation method comprises the following reaction steps:
(A) carrying out Grignard reaction on the raw material 1 and Grignard reagent 4-fluorophenyl magnesium halide;
(B) carrying out reduction reaction on the reaction product obtained in the step (A) and a reducing agent to obtain a compound 4; the reducing agent is sodium borohydride, potassium borohydride or borane reducing agent;
(C) carrying out debenzylation reaction on the obtained compound 4 and a deprotection reagent to obtain a crude product 5;
(D) reacting the obtained crude product 5 with a protective reagent in the presence of a solvent and alkali to obtain a compound 6; the protective agent is selected from: fluorenylmethoxycarbonylcarbonyl chloride, benzyloxycarbonyl chloride or Boc-anhydride;
(E) carrying out deprotection reaction on the obtained compound 6 and acid or alkali in the presence of a solvent, wherein the reaction temperature is 20-40 ℃, and then separating and purifying to obtain a refined product 5; the alkali is at least one of diethylamine, triethylamine, morpholine, pyridine, potassium carbonate and sodium carbonate; the acid is at least one of hydrochloric acid, sulfuric acid or nitric acid.
2. The production method according to claim 1, wherein the base in the reaction (D) is at least one of triethylamine, N-diisopropylethylamine, potassium hydrogencarbonate, and sodium hydrogencarbonate; and/or the presence of a gas in the gas,
the solvent in the reaction (D) is at least one of dichloromethane, ethyl acetate, toluene, dioxane and water.
3. The production method according to claim 1,
the solvent in the reaction (E) is at least one of dichloromethane, ethyl acetate, toluene, dioxane and water.
4. The process according to claim 1, wherein the reducing agent in the reaction (B) is sodium borohydride or borane dimethylsulfide.
5. The process according to claim 1, wherein the deprotecting agent in the reaction (C) is Pd/C-H2Or Pd/C-ammonium formate.
6. The production method according to any one of claims 1 to 5, wherein the reaction solvent in the reaction (A) is at least one of tetrahydrofuran, methyltetrahydrofuran, toluene and diethyl ether.
7. The process according to any one of claims 1 to 5, wherein in the reaction (A), after the starting material 1 is reacted with 4-fluorophenyl magnesium halide, a quenching agent is added for quenching, and the obtained product is subjected to the step (B); the quenching agent is at least one of methanol, ethanol, isopropanol and water.
8. The production method according to any one of claims 1 to 5, wherein the reaction solvent in the reaction (C) is at least one of methanol, ethanol, isopropanol and water.
9. The production method according to any one of claims 1 to 5,
the reaction temperature of the reaction (A) is 5-20 ℃;
and/or the reaction temperature of the reaction (C) is 15-40 ℃;
and/or the reaction temperature of the reaction (D) is-5-0 ℃.
10. The process according to any one of claims 1 to 5, wherein the 4-fluorophenyl magnesium halide in the reaction (A) is selected from: 4-fluorophenyl magnesium bromide grignard reagent, 4-fluorophenyl magnesium chloride grignard reagent or 4-fluorophenyl magnesium iodide grignard reagent.
11. The preparation method according to any one of claims 1 to 5, wherein in the reaction step (D), after the crude intermediate impurity 5 is reacted with a protecting reagent, the compound 6 is obtained through a separation and purification step; the separation and purification process comprises the following steps:
(D1) purifying the reaction solution by silica gel column chromatography to obtain a crude product 6;
(D2) purifying the obtained crude product 6 by using a neutral alumina column chromatography;
in the step (D1), the eluent used for the silica gel column chromatography is petroleum ether and ethyl acetate, and the silica gel column chromatography adopts gradient elution, wherein the gradient change rule is petroleum ether: the volume ratio of the ethyl acetate is from (90-100)%: (0-10)% → (70-90)%: (10-30)%;
in the step (D2), the eluent used for the neutral alumina column chromatography is petroleum ether and ethyl acetate, the neutral alumina column chromatography adopts gradient elution, and the gradient change rule is petroleum ether: the volume ratio of the ethyl acetate is from (7-9) → (5-7) → (2-4): 1.
12. The method according to any one of claims 1 to 5, wherein the separation and purification process of step (E) comprises: purifying the reaction liquid by using a silica gel column chromatography, wherein an eluant used by the silica gel column chromatography is ethyl acetate and methanol, the silica gel column chromatography adopts gradient elution, and the gradient change rule is that the volume ratio of the ethyl acetate to the methanol is from (90-100)%: (0% -10%) → (70-80)%: (20-30)%.
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