CN112174909B - Preparation method of aprepitant intermediate - Google Patents
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- CN112174909B CN112174909B CN202011124089.4A CN202011124089A CN112174909B CN 112174909 B CN112174909 B CN 112174909B CN 202011124089 A CN202011124089 A CN 202011124089A CN 112174909 B CN112174909 B CN 112174909B
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Abstract
The invention relates to a preparation method of an aprepitant intermediate.The preparation method comprises the following steps: mixing a compound with a structure shown in a formula 1, a chiral catalyst, an acid and a solvent, and stirring to prepare a compound with a structure shown in a formula 2; the chiral catalyst has a structure shown in formula (I). The method has high yield, purity and chiral purity, and is environment-friendly.
Description
Technical Field
The invention relates to the technical field of organic chemistry, in particular to a preparation method of an aprepitant intermediate.
Background
Aprepitant (Aprepitant), having the chemical name 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, having the formula:
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.
The aprepitant has a structure with 3 chiral centers, and a preparation route comprises an important chiral intermediate, wherein the chiral intermediate also has 3 chiral centers, and the structure is as follows:
the literature reports that the chiral intermediate is synthesized by using high-pressure hydrogen as a hydrogen source and adopting an asymmetric hydrogenation catalytic method, and the method has harsh reaction conditions and is not suitable for industrial production.
Disclosure of Invention
Based on the above, the preparation method of the aprepitant intermediate provided by the invention has the advantages of high yield, good optical purity, mild reaction conditions and no need of complex equipment.
The specific technical scheme is as follows:
a preparation method of an aprepitant intermediate comprises the following steps:
mixing a compound with a structure shown in a formula 1, a chiral catalyst, an acid and a solvent, and stirring to prepare a compound with a structure shown in a formula 2;
the chiral catalyst has a structure represented by formula (I):
the R is selected from a hydrogen atom, a straight chain alkyl group having 1 to 20 carbon atoms, a branched chain alkyl group having 3 to 20 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, or a substituted or unsubstituted phenyl group.
In a preferred embodiment, the molar ratio of the compound having the structure shown in formula 1 to the chiral catalyst is 1 (1-2).
In a preferred embodiment, the molar ratio of the compound having the structure shown in formula 1 to the chiral catalyst is 1 (1-1.5).
In a preferred embodiment, the compound having the structure shown in formula 1 and the acid are present in a molar ratio of 1: (0.1-0.5).
In a preferred embodiment, the acid is a protic acid.
In a preferred embodiment, the protonic acid is selected from one or more of trifluoroacetic acid, acetic acid, benzoic acid, sulfonic acid, hydrochloric acid and phosphoric acid.
In a preferred embodiment, the solvent is selected from one or more of chloroform, dichloromethane, toluene, tetrahydrofuran and acetonitrile.
In a preferred embodiment, said R is selected from the group consisting of a hydrogen atom, a linear alkyl group having a number of carbon atoms from 1 to 6, a branched alkyl group having a number of carbon atoms from 3 to 8.
In a preferred embodiment, R is selected from methyl, ethyl, isopropyl or tert-butyl.
In a preferred embodiment, the stirring time is 8h ± 2 h.
In a preferred embodiment, the temperature of the stirring is 45 ℃. + -. 5 ℃.
In a preferred embodiment, after the stirring is finished, the method further comprises the steps of quenching, extracting, concentrating and freeze-crystallizing the product.
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a novel method for preparing an aprepitant intermediate, which is reliable in synthesis process and high in repeatability. The bionic system green catalyst with the structure shown in the formula (I) is used as a chiral catalyst, the compound with the structure shown in the formula 1 is subjected to hydrogenation reduction in an acid-containing solvent to generate the aprepitant intermediate in one step, the yield is high, the optical purity is good, and in the reaction process, the used equipment is simple, complex high-pressure special equipment is not required, the environment is friendly, and the method is suitable for industrial production.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The present invention may be embodied in many different forms and is not limited to the embodiments described herein. Rather, 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.
In contrast to other literature reports, the present invention provides a novel process for the preparation of aprepitant intermediates. The specific technical scheme is as follows:
a preparation method of an aprepitant intermediate comprises the following steps:
mixing a compound with a structure shown in a formula 1, a chiral catalyst, an acid and a solvent, and stirring to prepare a compound with a structure shown in a formula 2;
the chiral catalyst has a structure represented by formula (I):
the R is selected from a hydrogen atom, a straight chain alkyl group having 1 to 20 carbon atoms, a branched alkyl group having 3 to 20 carbon atoms, a cycloalkyl group having 3 to 10 carbon atoms, or a substituted or unsubstituted phenyl group.
The reaction route of the method is as follows:
the catalyst is a bionic system green chiral catalyst, belongs to the category of organic catalysis, can avoid transition metal residues caused by using transition metals, reduces pollution of the transition metals, particularly toxic heavy metals, and is green and environment-friendly. Meanwhile, the transfer hydrogenation characteristic can be realized based on the 1, 4-dihydropyridine derivative, so that high-pressure hydrogen with harsh use conditions is avoided as a hydrogen source, and the method is safe, reliable and suitable for industrialization. Further, chiral alpha-hydroxyphenylacetamide derivatives are introduced to the 1, 4-dihydropyridine derivatives, so that the control of the stereoconfiguration in the catalytic transfer hydrogenation reaction is realized. And the catalyst is easy to regenerate and reuse, has high catalytic efficiency and mild reaction regulation, is beneficial to asymmetric catalytic hydrogenation of industrial production, and has good application value and prospect.
Further, R is selected from a hydrogen atom, a straight chain alkyl group having 1 to 6 carbon atoms, a branched alkyl group having 3 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or a substituted or unsubstituted phenyl group.
When the phenyl group is further substituted, it is selected from the following substitutions: a straight chain alkyl having 1 to 6 carbon atoms, a branched alkyl having 3 to 8 carbon atoms, an alkoxy having 1 to 6 carbon atoms, or a halogen;
in a preferred embodiment, said R is selected from the group consisting of a hydrogen atom, a linear alkyl group having a number of carbon atoms from 1 to 6, a branched alkyl group having a number of carbon atoms from 3 to 8.
Further, R is selected from methyl, ethyl, 1-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl;
in a preferred embodiment, R is selected from methyl, ethyl, isopropyl or tert-butyl.
It is understood that the chiral catalysts described in the present invention include, but are not limited to:
the chiral catalyst can be obtained by the following synthetic route:
the method comprises the following steps:
s1, reacting chiral alpha-hydroxyphenylacetamide with 2,2, 6-trimethyl-1, 3-dioxin-4-one by taking toluene as a solvent to obtain a chiral alpha-hydroxyphenylacetamide derivative;
s2, reacting the chiral alpha-hydroxyphenylacetamide derivative with hexamethylenetetramine and ammonium acetate to obtain the 3, 5-amide-1, 4-dihydropyridine chiral catalyst.
Preferably, the molar ratio of the chiral α -hydroxyphenylacetamide to 2,2, 6-trimethyl-1, 3-dioxin-4-one in step S1 is 1: (0.5 to 2); the reaction temperature is 50-180 ℃;
preferably, the temperature in the step S2 is 50-180 ℃; the molar ratio of the chiral alpha-hydroxyphenylacetamide derivative to the hexamethylenetetramine to the ammonium acetate is 1: (0.5-2): (0.5 to 2); the reaction temperature is 50-180 ℃.
The method comprises the steps of taking a bionic system green catalyst with a structure shown in a formula (I) as a chiral catalyst, and carrying out hydrogenation reduction on a compound with the structure shown in the formula 1 in an acid-containing solvent to generate an aprepitant intermediate in one step.
In a preferred embodiment, the molar ratio of the compound having the structure shown in formula 1 to the chiral catalyst is 1 (1-2). In this ratio, the reaction of the raw materials is facilitated to be sufficient. It is understood that the molar ratio of the compound having the structure shown in formula 1 and the chiral catalyst includes, but is not limited to, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1: 2.
Preferably, the molar ratio of the compound with the structure shown in the formula 1 to the chiral catalyst is 1 (1-1.5). Preferably, the molar ratio of the compound having the structure shown in formula 2 to the chiral catalyst is 1: 1.2.
In a preferred embodiment, the molar ratio of the compound having the structure represented by formula 1 to the acid is 1 (0.1 to 0.5). It is understood that the molar ratio of the compound having the structure shown in formula 1 and the chiral catalyst includes, but is not limited to, 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1: 0.5.
In a preferred embodiment, the protonic acid is selected from one or more of trifluoroacetic acid, acetic acid, benzoic acid, sulfonic acid, hydrochloric acid and phosphoric acid.
Preferably, the protic acid is hydrochloric acid.
In a preferred embodiment, the solvent is selected from one or more of chloroform, dichloromethane, toluene, tetrahydrofuran and acetonitrile.
Preferably, the solvent is tetrahydrofuran.
In a preferred embodiment, the stirring time is 8h ± 2h, and it is understood that the stirring time includes, but is not limited to, 6h, 7h, 8h, 9h, 10 h.
In a preferred embodiment, the temperature of the agitation is 45 ℃. + -. 5 ℃, and it is understood that the time of the agitation includes, but is not limited to, 40 ℃, 41 ℃, 42 ℃, 43 ℃, 44 ℃, 45 ℃, 46 ℃, 47 ℃, 48 ℃, 49 ℃, 50 ℃.
In a preferred embodiment, after the stirring is finished, the method further comprises the steps of quenching, extracting, concentrating and freeze-crystallizing the product.
The quenching refers to terminating the reaction, and preferably, water is added to the reaction system for quenching.
The extractant is preferably methyl isobutyl ketone, and an organic phase is collected after extraction.
And concentrating the organic phase, and then freezing and crystallizing to obtain the aprepitant intermediate.
The aprepitant intermediate is generated in one step by the method, the yield is high, the optical purity is good, in addition, in the reaction process, the used equipment is simple, the complicated high-pressure special equipment is not required, the environment is friendly, and the method is suitable for industrial production.
The following examples and comparative examples are further described below, and the starting materials used in the following examples can be commercially available, unless otherwise specified, and the equipment used therein can be commercially available, unless otherwise specified.
Example 1
The embodiment provides a preparation method of an aprepitant intermediate, which comprises the following steps:
(1) preparation of chiral catalysts
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-methyl-2-phenylacetamide (165.1mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 187.0mg of a white solid compound a in a yield of 75%.
The above-mentioned white solid compound a (498.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in dioxane (5mL), and reacted by heating at 100 ℃ for 30 minutes. The reaction temperature was cooled to room temperature, water was added, and extraction was performed with dichloromethane. After the organic phase is concentrated, the organic phase is purified by silica gel column chromatography (the volume ratio of normal hexane to ethyl acetate is 10: 1) to obtain 368.7mg of light yellow target compound I-1, namely the chiral catalyst, with the yield of 75%.
(2) Preparation of aprepitant intermediates
Dissolving a compound (1.0 equivalent) with a structure shown in a formula 1, a chiral catalyst I-1(1.2 equivalent) and hydrochloric acid (0.5 equivalent) in tetrahydrofuran (120mL), reacting for 8 hours under vigorous stirring at 45 ℃, adding water to quench the reaction, extracting a reaction product by using methyl isobutyl ketone, collecting an organic phase, concentrating, and carrying out freeze crystallization on a system to obtain a white-like crude product 2, wherein the yield is 85%, and the ee value (enantiomeric excess) is 99.2%.
Example 2
This example provides a preparation method of an aprepitant intermediate, which is substantially the same as example 1 except that the chiral catalyst has a different structure, and includes the following steps:
(1) preparation of chiral catalysts
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-ethyl-2-phenylacetamide (179.2mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 243.0mg of a white solid compound b in 82% yield.
The above-mentioned white solid compound b (526.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in dioxane (5mL) and reacted by heating at 100 ℃ for 30 minutes. The reaction temperature was cooled to room temperature, water was added, and extraction was performed with dichloromethane. After the organic phase is concentrated, 426.1mg of light yellow target compound I-2, namely the chiral catalyst, is obtained by silica gel column chromatography purification (the volume ratio of normal hexane to ethyl acetate is 10: 1), and the yield is 82%.
(2) Preparation of aprepitant intermediates
Dissolving a compound (1.0 equivalent) with a structure shown in a formula 1, a chiral catalyst I-2(1.2 equivalent) and hydrochloric acid (0.5 equivalent) in tetrahydrofuran (120mL), reacting for 8 hours under vigorous stirring at 45 ℃, adding water to quench the reaction, extracting a reaction product by using methyl isobutyl ketone, collecting an organic phase, concentrating, and carrying out freeze crystallization on a system to obtain a white-like crude product 2, wherein the yield is 83% and the ee value is 99.0%.
Example 3
This example provides a method for preparing an aprepitant intermediate, which is substantially the same as in example 1 except that the molar ratio of the compound having the structure shown in formula 2 to the chiral catalyst is different, and the method includes the following steps:
(1) preparation of chiral catalysts
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-methyl-2-phenylacetamide (165.1mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 187.0mg of a white solid compound a in a yield of 75%.
The above-mentioned white solid compound a (498.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in dioxane (5mL), and reacted by heating at 100 ℃ for 30 minutes. The reaction temperature was cooled to room temperature, water was added, and extraction was performed with dichloromethane. After the organic phase is concentrated, the organic phase is purified by silica gel column chromatography (the volume ratio of normal hexane to ethyl acetate is 10: 1) to obtain 368.7mg of light yellow target compound I-1, namely the chiral catalyst, with the yield of 75%.
(2) Preparation of aprepitant intermediates
Dissolving a compound (1.0 equivalent) with a structure shown in a formula 1, a chiral catalyst I-1(2 equivalents) and hydrochloric acid (0.5 equivalent) in tetrahydrofuran (120mL), reacting for 8 hours under vigorous stirring at 45 ℃, adding water to quench the reaction, extracting the reaction product with methyl isobutyl ketone, collecting an organic phase, concentrating, and freezing and crystallizing the system to obtain a white-like crude product 2, wherein the yield is 82 percent, and the ee value is 98.5 percent.
Example 4
This example provides a method for preparing an aprepitant intermediate, which is substantially the same as in example 1 except that the molar ratio of the compound having the structure shown in formula 2 to the acid is different, and the steps are as follows:
(1) preparation of chiral catalysts
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-methyl-2-phenylacetamide (165.1mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 187.0mg of a white solid compound a in a yield of 75%.
The above-mentioned white solid compound a (498.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in dioxane (5mL), and reacted by heating at 100 ℃ for 30 minutes. The reaction temperature was cooled to room temperature, water was added, and extraction was performed with dichloromethane. After the organic phase is concentrated, the organic phase is purified by silica gel column chromatography (the volume ratio of normal hexane to ethyl acetate is 10: 1) to obtain 368.7mg of light yellow target compound I-1, namely the chiral catalyst, with the yield of 75%.
(2) Preparation of aprepitant intermediates
Dissolving a compound (1.0 equivalent) with a structure shown in a formula 1, a chiral catalyst I-1(1.2 equivalent) and hydrochloric acid (0.3 equivalent) in tetrahydrofuran (120mL), reacting for 8 hours under vigorous stirring at 45 ℃, adding water to quench the reaction, extracting a reaction product with methyl isobutyl ketone, collecting an organic phase, concentrating, and carrying out freeze crystallization on a system to obtain a white-like crude product 2, wherein the yield is 80 percent, and the ee value is 97 percent.
Example 5
This example provides a preparation method of an aprepitant intermediate, which is substantially the same as example 1 except that the acid is different, and the steps are as follows:
(1) preparation of chiral catalysts
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-methyl-2-phenylacetamide (165.1mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 187.0mg of a white solid compound a in a yield of 75%.
The above-mentioned white solid compound a (498.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in dioxane (5mL), and reacted by heating at 100 ℃ for 30 minutes. The reaction temperature was cooled to room temperature, water was added, and extraction was performed with dichloromethane. After the organic phase is concentrated, the organic phase is purified by silica gel column chromatography (the volume ratio of normal hexane to ethyl acetate is 10: 1) to obtain 368.7mg of light yellow target compound I-1, namely the chiral catalyst, with the yield of 75%.
(2) Preparation of aprepitant intermediates
Dissolving a compound (1.0 equivalent) with a structure shown in a formula 1, a chiral catalyst I-1(1.2 equivalent) and trifluoroacetic acid (0.5 equivalent) in tetrahydrofuran (120mL), reacting at 45 ℃ under vigorous stirring for 8 hours, adding water to quench the reaction, extracting a reaction product by using methyl isobutyl ketone, collecting an organic phase, concentrating, and carrying out freeze crystallization on a system to obtain a white-like crude product 2, wherein the yield is 82% and the ee value is 98.0%.
Example 6
This example provides a preparation method of an aprepitant intermediate, which is substantially the same as example 1 except that the stirring rate, temperature and time are different, and the steps are as follows:
(1) preparation of chiral catalysts
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-methyl-2-phenylacetamide (165.1mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 187.0mg of a white solid compound a in a yield of 75%.
The above-mentioned white solid compound a (498.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in dioxane (5mL), and reacted by heating at 100 ℃ for 30 minutes. The reaction temperature was cooled to room temperature, water was added, and extraction was performed with dichloromethane. After the organic phase is concentrated, the organic phase is purified by silica gel column chromatography (the volume ratio of normal hexane to ethyl acetate is 10: 1) to obtain 368.7mg of light yellow target compound I-1, namely the chiral catalyst, with the yield of 75%.
(2) Preparation of aprepitant intermediates
Dissolving a compound (1.0 equivalent) with a structure shown in a formula 1, a chiral catalyst I-1(1.2 equivalent) and hydrochloric acid (0.5 equivalent) in tetrahydrofuran (120mL), reacting at 47 ℃ under vigorous stirring for 10 hours, adding water to quench the reaction, extracting a reaction product with methyl isobutyl ketone, collecting an organic phase, concentrating, and carrying out freeze crystallization on a system to obtain a white-like crude product 2, wherein the yield is 84%, and the ee value is 99.3%.
Comparative example 1
The comparative example provides a preparation method of an aprepitant intermediate, which is basically the same as that in example 1, except that the chiral catalyst is different, and the steps are as follows:
dissolving a compound (1.0 equivalent) with a structure shown in a formula 1, a chiral catalyst II (1.2 equivalents) and hydrochloric acid (0.5 equivalent) in tetrahydrofuran (120mL), reacting for 8 hours under vigorous stirring at 45 ℃, adding water to quench the reaction, extracting the reaction product with methyl isobutyl ketone, collecting an organic phase, concentrating, and freezing and crystallizing the system to obtain a white-like crude product 2, wherein the yield is 65% and the ee value is 70%.
The structure and preparation method of the chiral catalyst II are as follows:
(1) 2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of methyl (S) - α -hydroxyphenylacetate (166.2mg,1mmol) in toluene (0.5 mL). Stirring and refluxing overnight, after the reaction is completed, cooling the reaction solution to 50 ℃, and removing the solvent in vacuum. Purifying, separating and purifying the crude product by silica gel column chromatography to obtain a white solid compound.
(2) Mixing the white solid compound (500.0mg,2mmol), ammonium acetate (77.1mg,1mmol), hexamethylenetetramine (140.2mg) and dioxane (5mL), reacting for 30 minutes at 100 ℃, cooling after the reaction is finished, adding water, extracting with dichloromethane for three times, combining organic phases, concentrating, and purifying by silica gel column chromatography to obtain chiral catalyst II.
Comparative example 2
The comparative example provides a preparation method of an aprepitant intermediate, which is basically the same as that in example 1, except that the chiral catalyst is different, and the steps are as follows:
dissolving a compound (1.0 equivalent) with a structure shown in a formula 1, a chiral catalyst III (1.2 equivalents) and hydrochloric acid (0.5 equivalent) in tetrahydrofuran (120mL), reacting for 8 hours under vigorous stirring at 45 ℃, adding water to quench the reaction, extracting the reaction product with methyl isobutyl ketone, collecting an organic phase, concentrating, and freezing and crystallizing the system to obtain a white-like crude product 2, wherein the yield is 60% and the ee value is 65%.
The structure and preparation method of the chiral catalyst III are as follows:
dissolving (S) -alpha-hydroxyphenylacetic acid (152.1mg,1mmol) and 2, 6-dimethyl-3, 5-diacid methyl ester-1, 4-dihydropyridine (253.3mg,1mmol) in dichloromethane, reacting for 2h at normal temperature, removing the solvent under reduced pressure, and quantitatively obtaining a white 1, 4-dihydropyridine chiral hybrid hydrogenation reagent, namely chiral catalyst III.
Comparative example 3
This example provides a process for the preparation of an aprepitant intermediate, substantially the same as example 1, except that no acid is added, the steps are as follows:
(1) preparation of chiral catalysts
2,2, 6-trimethyl-1, 3-dioxin-4-one (142.2mg,1mmol) was added dropwise to a solution of (S) - α -hydroxy-N-methyl-2-phenylacetamide (165.1mg,1mmol) in toluene (0.5 mL). Reflux with stirring overnight, cool the reaction mixture to 50 ℃ and remove the solvent in vacuo. The crude product was isolated and purified by silica gel column chromatography (n-hexane: ethyl acetate in a volume ratio of 20: 1) to give 187.0mg of a white solid compound a in a yield of 75%.
The above-mentioned white solid compound a (498.6mg,2mmol), ammonium acetate (77.1mg,1mmol) and hexamethylenetetramine (140.2mg) were dissolved in dioxane (5mL), and reacted by heating at 100 ℃ for 30 minutes. The reaction temperature was cooled to room temperature, water was added, and extraction was performed with dichloromethane. After the organic phase is concentrated, the organic phase is purified by silica gel column chromatography (the volume ratio of normal hexane to ethyl acetate is 10: 1) to obtain 368.7mg of light yellow target compound I-1, namely the chiral catalyst, with the yield of 75%.
(2) Preparation of aprepitant intermediates
Dissolving a compound (1.0 equivalent) with a structure shown in a formula 1 and a chiral catalyst I-1(1.2 equivalent) in tetrahydrofuran (120mL), reacting for 8 hours under vigorous stirring at 45 ℃, adding water to quench the reaction, extracting the reaction product with methyl isobutyl ketone, collecting an organic phase, concentrating, and carrying out freeze crystallization on the system to obtain a white-like crude product 2, wherein the yield is 50%, and the ee value is 60%.
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 present 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 (10)
1. A preparation method of an aprepitant intermediate is characterized by comprising the following steps:
mixing a compound with a structure shown in a formula 1, a chiral catalyst, an acid and a solvent, and stirring to prepare a compound with a structure shown in a formula 2;
the chiral catalyst has a structure represented by formula (I):
r is selected from methyl or ethyl
The acid is selected from trifluoroacetic acid or hydrochloric acid.
2. The preparation method of the aprepitant intermediate as claimed in claim 1, wherein the molar ratio of the compound with the structure shown in formula 2 to the chiral catalyst is 1 (1-2).
3. The preparation method of the aprepitant intermediate as claimed in claim 2, wherein the molar ratio of the compound with the structure shown in formula 2 to the chiral catalyst is 1 (1-1.5).
4. The method for preparing an aprepitant intermediate according to claim 3, wherein the molar ratio of the compound having the structure shown in formula 2 to the chiral catalyst is 1: 1.2.
5. The method for preparing an aprepitant intermediate according to claim 1, wherein the molar ratio of the compound having the structure shown in formula 2 to the acid is 1 (0.1-0.5).
6. The method for preparing an aprepitant intermediate according to claim 1, wherein the molar ratio of the compound having the structure shown in formula 2 to the acid is 1: 0.5.
7. The process for preparing an aprepitant intermediate according to any one of claims 1-6, wherein the solvent is selected from one or more of chloroform, dichloromethane, toluene, tetrahydrofuran and acetonitrile.
8. The process for the preparation of an aprepitant intermediate according to any one of claims 1-6, wherein the stirring time is 8h ± 2 h.
9. The process for the preparation of an aprepitant intermediate according to claim 8 wherein the temperature of the agitation is 45 ℃ ± 5 ℃.
10. The process for preparing an aprepitant intermediate according to any one of claims 1-6, wherein the process further comprises the steps of quenching, extracting, concentrating and freeze-crystallizing the product after the stirring is finished.
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| CN109956941A (en) * | 2017-12-25 | 2019-07-02 | 新发药业有限公司 | A kind of simple and convenient process for preparing of AVM hereinafter Batan |
| CN109970625A (en) * | 2017-12-28 | 2019-07-05 | 新发药业有限公司 | A kind of preparation method of 5R- benzyloxy amino piperidine -2S- formic acid or derivatives thereof |
| CN110683986A (en) * | 2019-11-04 | 2020-01-14 | 中山奕安泰医药科技有限公司 | Synthesis method of (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline |
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| CN109400521A (en) * | 2017-08-18 | 2019-03-01 | 新发药业有限公司 | A kind of preparation method of improved 5R- benzyloxy amino piperidine -2S- formic acid esters, its oxalates |
| CN109956941A (en) * | 2017-12-25 | 2019-07-02 | 新发药业有限公司 | A kind of simple and convenient process for preparing of AVM hereinafter Batan |
| CN109970625A (en) * | 2017-12-28 | 2019-07-05 | 新发药业有限公司 | A kind of preparation method of 5R- benzyloxy amino piperidine -2S- formic acid or derivatives thereof |
| CN110683986A (en) * | 2019-11-04 | 2020-01-14 | 中山奕安泰医药科技有限公司 | Synthesis method of (S) 1-phenyl-1, 2,3, 4-tetrahydroisoquinoline |
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