CN116715663A - Preparation method of non-neridrone and intermediate thereof - Google Patents

Preparation method of non-neridrone and intermediate thereof Download PDF

Info

Publication number
CN116715663A
CN116715663A CN202310567956.9A CN202310567956A CN116715663A CN 116715663 A CN116715663 A CN 116715663A CN 202310567956 A CN202310567956 A CN 202310567956A CN 116715663 A CN116715663 A CN 116715663A
Authority
CN
China
Prior art keywords
formula
compound
reaction
solvent
iii
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202310567956.9A
Other languages
Chinese (zh)
Inventor
褚定军
金健
谢晓强
唐健
李凡
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aurisco Pharmaceutical Co ltd
Original Assignee
Aurisco Pharmaceutical Co ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Aurisco Pharmaceutical Co ltd filed Critical Aurisco Pharmaceutical Co ltd
Priority to CN202310567956.9A priority Critical patent/CN116715663A/en
Publication of CN116715663A publication Critical patent/CN116715663A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/78—Benzoic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present application provides a process for the preparation of a non-nelidamide intermediate (compound of formula II) by racemate resolution using D-tartrate. The method can obtain the compound of the formula II with the ee value reaching 99.7 percent and the purity reaching 99.8 percent, and has high resolution yield. The preparation method provided by the application has the advantages of mild reaction conditions, simple post-treatment, no need of special reagents and suitability for industrial production.

Description

Preparation method of non-neridrone and intermediate thereof
Technical Field
The application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method of non-neridrone and an intermediate thereof.
Background field
Non-nerenone (english name: finerenone), a non-steroidal antagonist developed by bayer corporation, acts as a mineralocorticoid receptor and is useful as a pharmaceutical agent for the prevention and/or treatment of cardiovascular and renal diseases such as heart failure and diabetic nephropathy, under the chemical name (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide. The structural formula of the non-neridone is as follows:
there are several documents reporting the preparation of non-nefarious ketone, wherein the preparation disclosed in WO2016016287A1 is shown in scheme 1.
Route 1
The preparation process disclosed in WO2017032673A1 is shown in scheme 2.
Route 2
The processes described in the routes 1 and 2 are all carried out after the non-nelidone racemate is obtained, the total yield is uneconomical, and chiral HPLC resolution methods are adopted, so that the production cost of the method is very high, and the method is not suitable for industrial mass production. Later, WO2021074072 and WO2021074078 report the resolution of intermediates with resolving agents as shown in scheme 3 and scheme 4, respectively:
route 3
Route 4
The ee value of the diastereomer salt of the intermediate obtained by resolution in the route 3 is less than 85%, the ee value of the diastereomer salt is improved to 98% after further purification, the ee value of the intermediate obtained by adding alkali for dissociation is less than 99%, and the total resolution yield is less than 40%. The ee value of the diastereomer salt of the intermediate obtained by resolution in the scheme 4 is less than 80%, the ee value of the diastereomer salt is improved to 99% after further purification, the ee value of the intermediate obtained after the addition of alkali for dissociation is 99%, and the total resolution yield is about 40%. Both routes give intermediate diastereomeric salts with low ee values, which require further purification to increase the ee esters.
CN115340539a discloses a preparation method of non-nefarious ketone and intermediate thereof, comprising the steps of (1) mixing a racemic compound of formula ii with a resolving agent shown as a compound of formula iiia or a compound of formula iiib, carrying out salification reaction, and separating to obtain salts shown as a compound of formula iva or a compound of formula ivc respectively; (2) Treating the salt shown in the formula IVa compound or the formula IVc compound obtained in the step 1 with alkali to obtain a compound shown in the formula I; the reaction formula is as follows:
or (b)
The de value of the intermediate diastereomer salt IVa and IVc obtained by resolution in the method is 99.0-99.4%, the HPLC purity of the intermediate I obtained after alkali addition and ionization is 98.6-99.8%, and the total resolution yield is 93.6-98.8%. Although the purity and the total resolution yield of the intermediate obtained by the route are ideal, the defect is that benzyl ester of the compound of the formula I cannot be directly subjected to ammonolysis reaction to obtain amide, and the benzyl ester can be removed only by palladium catalytic reaction to obtain carboxylic acid, and then amidation is carried out. Palladium catalysts are expensive, resulting in high commercial production costs and problems of heavy metal residues.
Therefore, there is an urgent need in the art to develop a process for industrially producing feoneli ketone with high yield, simple operation, better quality control and low cost.
Disclosure of Invention
Aiming at the problems of high resolution cost of racemate, low diastereoisomeric value of intermediate, high route cost and the like in the preparation method of the non-nefarious ketone and the intermediate thereof in the prior art, the application provides a novel preparation method of the non-nefarious ketone and the intermediate thereof.
In a first aspect, the present application provides a process for the preparation of a non-nefarone intermediate, a compound of formula II, comprising the steps of:
1) Reacting a racemic compound of formula III with a compound of formula IX to form a salt, and separating to obtain a salt of a compound of formula IIa;
2) Treating the salt of the compound of formula IIa obtained in step 1) with a base to obtain a compound of formula II, wherein the reaction formula is as follows:
wherein Ar is unsubstituted or substituted C 6 -C 14 An aromatic or heteroaromatic group, wherein said substitution means substitution with a group selected from the group consisting of: c (C) 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, halogen, nitro, cyano, carboxyl, hydroxyl, amide,
wherein in the compound of formula IIIRepresenting the racemic structure.
In another preferred embodiment, ar is an unsubstituted or substituted phenyl group.
In another preferred embodiment, ar is a compound having the structure shown in formula X:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 Each independently is hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, phenoxy, nitro, cyano, amido, wherein x represents the point of attachment.
In another preferred embodiment, R 1 、R 2 、R 3 、R 4 、R 5 In which four substituents are hydrogen and one substituent is other than hydrogen, preferably R 3 Is not hydrogen. In another preferred embodiment, the amide group refers to a group having a structure selected from the group consisting of: -NHCOR, -NR 'COR, -CONHR, -CONRR' wherein each of said R, R 'groups is independently methyl, ethyl or phenyl, or N, R, R' together with the carbon atom to which it is attached form a 5-7 membered nitrogen heterocycle.
In another preferred embodiment, ar is a monosubstituted phenyl. In another preferred embodiment, ar is para-substituted phenyl. In another preferred example, ar is benzyl, phenyl, nitrophenyl, chlorophenyl, bromophenyl, benzyloxy, cyanophenyl. In another preferred example, ar is benzyl, phenyl, benzyloxy. In another preferred embodiment, ar is phenyl or benzyl. In another preferred embodiment, ar is benzyl. In another preferred embodiment, ar is selected from the group consisting of:
wherein, represents the connection point.
In another preferred embodiment Ar is unsubstituted or substituted C 10 -C 14 For example naphthyl, anthracenyl. In another preferred embodiment Ar is unsubstituted or substituted C 5 -C 10 Heteroaryl groups such as piperidinyl, piperazinyl, quinolinyl.
In another preferred embodiment, in step 1), the molar ratio of the compound of formula III to the compound of formula IX is from 1:0.4 to 1.2, preferably from 1:0.6 to 1.2, more preferably 1:1.
In another preferred embodiment, in step 1), the salification reaction is performed in an organic solvent or a mixed solvent of water and an organic solvent, wherein the organic solvent is selected from ethanol, methanol, isopropanol, n-butanol, sec-butanol, ethylene glycol dimethyl ether, acetone, ethyl acetate, or a combination thereof.
In another preferred embodiment, in step 1), the mass to volume ratio of compound III to solvent is from 0.01 to 0.1g/mL.
In another preferred embodiment, in step 1), the salt formation reaction is carried out at a temperature of 50 to 70℃for a period of 1 to 3 hours.
In another preferred embodiment, in step 1), the separation is a precipitation separation.
In another preferred embodiment, in step 1), the separating comprises: the reaction system is cooled to room temperature, stirred for 10 to 15 hours to separate out, filtered and separated. In another preferred embodiment, the solid obtained by filtration is a compound of formula IIa, and the compound of formula IIb in the filtrate is subjected to a base treatment and diastereoisomeric recovery is carried out by the method disclosed in WO 2017032678.
In another preferred embodiment, the alkali treatment process in step 2) comprises the steps of: dissolving the compound of formula IIa obtained in the step 1) in a solvent, regulating the pH of the obtained solution to 7.5-9.5, more preferably 8.0-8.5 by using alkali, stirring at room temperature for 8-18h, and filtering and separating to obtain the compound of formula II. In another preferred embodiment, the base is selected from potassium hydroxide, potassium phosphate or sodium phosphate. In another preferred embodiment, the solvent for dissolving the compound of formula IIa is water, an organic solvent, or a mixture of water and an organic solvent, wherein the organic solvent is selected from ethanol, methanol, isopropanol, n-butanol, sec-butanol, or a combination thereof.
In a further preferred embodiment, in step 2), the mass to volume ratio of the compound of the formula IIa to the solvent is from 0.01 to 0.1g/mL.
In a second aspect the present application provides a process for the preparation of a compound of formula III comprising the steps of:
(a) Reacting the compound of formula VI with a compound of formula VII to obtain a compound of formula V-1 and a compound of formula V-2, wherein the reaction formula is as follows:
(b) The compound of formula IV is obtained by reacting a mixture of a compound of formula V-1 and a compound of formula V-2 with a compound of formula VIII, wherein the reaction formula is as follows:
wherein in formula IVThe term "racemic structure" is used to refer to a racemic structure,
(c) The compound of formula IV is subjected to ethyl esterification to obtain a compound of formula III, wherein the reaction formula is as follows:
wherein in formula IIIRepresenting the racemic structure.
In a further preferred embodiment, in step a), the VI compound is reacted with a compound of formula VII in the presence of 0.05 to 0.15 equivalents of piperidine and 0.05 to 0.15 equivalents of acetic acid at a temperature of 10 to 50 ℃, more preferably 20 to 40 ℃, to obtain a mixture of a compound of formula V-1 and a compound of formula V-2, preferably the solvent used for the reaction is selected from methanol, ethanol, isopropanol, n-butanol, sec-butanol, dichloromethane or a combination thereof.
In another preferred embodiment, in step b), the reaction temperature is from 75 to 130 ℃, preferably the solvent used for the reaction is selected from isopropanol, n-butanol, sec-butanol or a combination thereof.
In another preferred embodiment, in step c), the ethylation reaction uses triethyl orthoformate as an esterifying agent at a temperature of 80 to 120 ℃ for 4 to 8 hours in the presence of an acid, preferably the solvent used in the ethylation reaction is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or a combination thereof.
In a third aspect, the present application provides a method for preparing non-nefarnesone, comprising the steps of:
(i) Providing a compound of formula III;
(ii) Taking a compound of a formula III as a raw material, and resolving to obtain a compound of a formula II, wherein the compound of the formula II is obtained according to the preparation method;
(iii) Ammonification of the compound of formula II to obtain non-nereidone,
the reaction formula is as follows:
wherein in formula IIIRepresenting the racemic structure.
In another preferred embodiment, the ammoniation process in step (iii) is: and heating the solution of the compound of the formula II for 15-25 hours at 60-100 ℃ in the presence of an organic base catalyst in an ammonia atmosphere to generate the non-nereirenone. Preferably, the organic base catalyst is selected from 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylamine, N-diisopropylethylamine, piperidine, N-methylmorpholine. More preferably, the organic base catalyst is selected from 1, 8-diazabicyclo [5.4.0] undec-7-ene.
In another preferred embodiment, the solvent used to dissolve the compound of formula II is selected from N, N-dimethylacetamide, dimethylsulfoxide, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran or a combination thereof.
In a fourth aspect, the present application provides a process for the preparation of non-nelidane, the process comprising the steps of:
s1 provides a compound of formula III;
s2, taking a compound of a formula III as a raw material, and resolving to obtain a compound of a formula II, wherein the compound of the formula II is obtained according to the preparation method;
s3, hydrolyzing the compound shown in the formula II to obtain a compound shown in the formula I:
the S4 compound of the formula I is aminated to obtain the non-neridrone,
the reaction formula is as follows:
wherein in formula IIIRepresenting the racemic structure.
In another preferred embodiment, in step S3, the hydrolysis of the compound of formula II is carried out by dissolving the compound of formula II in a solvent to obtain a solution of 15 to 20 equivalents of acetic acid and 1 to 1.5 equivalents of CuCl 2 Reacting for 3-8 hours at the temperature of minus 5-10 ℃ in the presence of 8-15 equivalent Zn powder to generate the compound shown in the formula I. Preferably, the solvent used to dissolve the compound of formula II is selected from tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, or a combination thereof.
In another preferred embodiment, in step S4, the compound of formula I is aminated by dissolving the compound of formula I in a solvent to obtain a solution, and heating the solution in the presence of 1 to 2 equivalents (more preferably, 1 to 1.5 equivalents) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, 1 to 2 equivalents (more preferably, 1 to 1.5 equivalents) of 1-hydroxybenzotriazole in an ammonia atmosphere at 40 to 70℃for 5 to 10 hours to produce non-nefarnesone. Preferably, the solvent used to dissolve the compound of formula I is selected from tetrahydrofuran, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, or a combination thereof.
In another preferred embodiment, step S3 and step S4 are performed in a "one pot" manner.
In a fifth aspect, the present application provides a non-nelidamide intermediate having the structure:
wherein Ar is as defined above,
wherein, in the formula IV and the formula III,representing the racemic structure.
In a sixth aspect of the application there is provided the use of a diastereomer of formula II, or a pharmaceutically acceptable salt thereof, or a compound of formula III, or a pharmaceutically acceptable salt thereof, for the synthesis of non-nefarnesone as an intermediate in the preparation of non-nefarnesone.
Detailed Description
The present inventors have conducted extensive and intensive studies and have found a process for producing non-nelidane having a high ee value and an intermediate thereof. Specifically, the inventors found that the ee value of the intermediate diastereoisomer II compound obtained by salifying the compound of formula III with D-tartrate and then using the base for dissociation is as high as 99.8%, and the resolution yield is as high as 48.5%. In addition, the intermediate diastereoisomer can be subjected to one-step organic base catalytic ammonification to obtain the non-nereidone with the ee value of more than 99.9%. Even if the intermediate diastereoisomer is hydrolyzed to an acid and then aminated to give the non-neridone, the heavy metal catalysis step is not required. The preparation method provided by the application is simple and convenient to operate, high in yield, high in product purity, low in cost, free of heavy metal residue, and very suitable for industrial production and preparation of the non-neridone.
In the description of the application, the term "room temperature" or "normal temperature" means 4 to 40℃and preferably 20 to 35 ℃.
In the description of the present application, the "one pot method" means that two-step reactions are continuously performed, and the product of the former-step reaction is directly performed to the next-step reaction without separation.
Non-nereirenone intermediates
The application provides a non-nefardone intermediate, which is a racemic compound of formula III or a pharmaceutically acceptable salt thereof:
wherein, the liquid crystal display device comprises a liquid crystal display device,representing the racemic structure.
The application also provides a non-nefardone intermediate, which is a compound of formula II, and an (S) -isomer obtained by resolution of the compound of formula III.
In the resolution process, the carboxyl of the resolving agent and the secondary amino of the dihydropyridine ring in the compound of the formula II form diastereomeric resolution salt. The dihydropyridine ring is a rigid planar structure, so the steric hindrance of the ester group attached to the chiral center should not have a significant effect on resolution. Surprisingly, however, the application replaces cyanoethyl of the resolved compound with trichloromethyl (compound of formula II), and the diastereomer salt is found to be obtained by simple separation without further purification in the resolution reaction process, the yield reaches 48.5%, the purity reaches 99.8%, and the ee value reaches 99.7%. Moreover, compared with benzyl ester (compound of formula I) disclosed in CN115340539A, the compound of formula II can be ammonolyzed by ammonia under the catalysis of organic base, and the non-neridrone bulk drug can be obtained through one-step reaction. Alternatively, the heavy metal catalysis step is not required even if the intermediate diastereoisomer is first hydrolyzed to the acid and then aminated to yield the non-neridone. In the prior art, benzyl ester is required to be debenzylated to form carboxylic acid under the catalysis of palladium, and then amidated to obtain the non-neridrone bulk drug. Thus, the preparation method of the application has obvious advantages.
Preparation of Compounds of formula III
The preparation method of the compound of the formula III comprises the following steps:
(a) Reacting the compound of formula VI with a compound of formula VII to obtain a compound of formula V-1 and a compound of formula V-2,
(b) Reacting a mixture of the compound of formula V-1 and the compound of formula V-2 with a compound of formula VIII to obtain a compound of formula IV,
(c) The compound of the formula IV is subjected to ethyl esterification to obtain a compound of the formula III,
the reaction formula is as follows:
the reaction of the compound of formula VI in step (a) with the compound of formula VII is analogous to the processes described in the prior art, for example WO2017032673A 1. In one embodiment of the application, the compounds of formula VI are reacted with the compounds of formula VII in the presence of 0.05 to 0.15 equivalents of piperidine and 0.05 to 0.15 equivalents of acetic acid at 20 to 40℃to give the compounds V-1 and V-2. Solvents used in the reaction include, but are not limited to, methanol, ethanol, isopropanol, n-butanol, sec-butanol, methylene chloride, or combinations thereof. The molar ratio of the compound of formula VI to the compound of formula VII is conventional, for example 1:1.0 to 1.5, more preferably 1:1.0 to 1.2. The mixture of the compound of formula V-1 and the compound of formula V-2 in step (b) is reacted with a compound of formula VIII at elevated temperature to give a compound of formula IV, for example at 75 to 130 ℃. Solvents used in the reaction include, but are not limited to, isopropanol, n-butanol, sec-butanol, or combinations thereof. In step c), the compound of formula IV is reacted with an esterifying agent to obtain the compound of formula IV. In one embodiment of the application, the esterification agent used in the esterification reaction is triethyl orthoformate, concentrated sulfuric acid is used as a catalyst, the reaction temperature is 80-120 ℃, and the solvent used in the reaction comprises N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone or a combination thereof.
Preparation of non-nelidane intermediate compound of formula II
The preparation method of the non-nelidamide intermediate compound as shown in the formula II comprises the following steps:
1) Reacting a racemic compound of formula III with a compound of formula IX to form salts, and separating to obtain salts of the compound of formula IIa;
2) Treating the salt of the compound of formula IIa obtained in step 1 with a base to obtain a compound of formula II,
the reaction formula is as follows:
wherein Ar is unsubstituted or substituted C 6 -C 14 An aromatic or heteroaromatic group, wherein said substitution means substitution with a group selected from the group consisting of: c (C) 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, halogen, nitro, cyano, carboxyl, hydroxyl, and amido.
Ar is a compound having the structure shown in formula X:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 Each independently is hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, phenoxy, nitro, cyano, amido.
In step 1), the molar ratio of the compound of formula III to the compound of formula IX is in a conventional amount in the art, preferably 1:0.4 to 1.5, more preferably 1:0.6 to 1.2. The salification reaction is carried out in an organic solvent or a mixed solvent of water and an organic solvent, wherein the organic solvent comprises but is not limited to ethanol, methanol, isopropanol, n-butanol, sec-butanol, ethylene glycol dimethyl ether, acetone and ethyl acetate. Preferably, the salt forming reaction is carried out at a temperature of 50 to 70 ℃ for 1 to 3 hours. After the salification reaction is completed, the reaction solution is cooled to room temperature, stirred for 10 to 18 hours at room temperature, and filtered and separated to obtain the white solid IIa compound.
The alkali treatment process in the step 2) comprises the following steps: dissolving the compound of the formula IIa obtained in the step 1) in a solvent, regulating the pH of the obtained solution to 7.5-9.5, more preferably 8.0-8.5 by using alkali, stirring at room temperature for 8-18h, and filtering and separating to obtain the compound of the formula II. The base used includes, but is not limited to, potassium hydroxide, potassium phosphate or sodium phosphate. The solvent for dissolving the compound of formula IIa is an organic solvent or a mixture of water and an organic solvent, including but not limited to ethanol, methanol, isopropanol, n-butanol, sec-butanol.
Preparation of non-nereirenone
The first method for preparing the non-nelidane comprises the following steps:
(i) Providing a compound of formula III;
(ii) Taking a compound of a formula III as a raw material, and obtaining a compound of a formula II through resolution, wherein the method for obtaining the compound of the formula II is as described above;
(iii) Ammonification of the compound of formula II gives the non-neridone, the reaction formula is as follows:
in the application, the ammoniation process of the compound of the formula II in the step (iii) is to introduce ammonia into a solution containing the compound of the formula II in the presence of organic alkali, and then heat the solution to react under a certain ammonia pressure. In one embodiment of the application, the ammonification process of the compound of formula II is: introducing ammonia gas into a solution containing a compound of formula II in the presence of 1, 8-diazabicyclo [5.4.0] undec-7-ene, sealing the reactor when the pressure in the reactor is 0.3-0.6Mpa, and reacting for 15-25 h at 60-100 ℃. After the completion of the reaction, the solvent used for the reaction is removed, and, for example, recrystallization is performed using an alcohol, for example, ethanol, to obtain non-nelidanone.
Solvents used to dissolve the compound of formula II during the ammoniation process include, but are not limited to, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran.
The second method for preparing the non-nelidane comprises the following steps:
s1 provides a compound of formula III;
s2, taking a compound of a formula III as a raw material, and resolving to obtain a compound of a formula II, wherein the method for obtaining the compound of the formula II is as described above;
s3, hydrolyzing the compound shown in the formula II to obtain a compound shown in the formula I:
the S4 compound of the formula I is aminated to obtain the non-neridrone,
the reaction formula is as follows:
s3 and S4 can be performed step by step or by 'one pot' process.
In one embodiment of the present application, the hydrolysis process of the compound of formula II in step S3 is: dissolving a compound of formula II in a solvent to obtain a solution containing 15 to 20 equivalents of acetic acid and 1 to 1.5 equivalents of CuCl 2 And (3) reacting at-5-10 ℃ in the presence of 8-15 equivalent Zn powder until the raw material disappears to obtain the compound shown in the formula I. Solvents used to dissolve the compound of formula II include, but are not limited to, tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide. After the reaction, the reaction solution is adjusted to be alkaline by using an inorganic alkaline aqueous solution, washed by using an organic solvent, and the aqueous phase obtained after the separation is adjusted to be acidic (for example, pH is 5.5-6.5), and the solid compound of the formula I is obtained by filtering and separating.
In step S4, the ammoniation of the compounds of formula I may be carried out according to the prior art, for example as disclosed in WO2021074072, WO2021074078 and CN115340539 a. In one embodiment of the present application, the ammonification process of the compound of formula I in step S4 is: the solution of the compound of formula I is heated in an ammonia atmosphere (e.g., an ammonia atmosphere of 0.1MPa to 1.0 MPa) in the presence of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1-hydroxybenzotriazole at 40 to 70℃for 5 to 10 hours to obtain the non-neridrone. Solvents used to dissolve the compound of formula I include, but are not limited to, tetrahydrofuran, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, or combinations thereof.
In one embodiment of the application, step S3 and step S4 are performed in a "one pot" manner. That is, the reaction can be carried out without purifying the product obtained in the step S3 by merely filtering the reaction solution to remove solid matters, adding the reaction material used in the step S4 to the obtained mother solution, and replacing the reaction material with an ammonia atmosphere.
The preparation method of the non-neridrone and the intermediate thereof has the advantages that:
the method has the advantages of simple reaction steps, mild reaction conditions, no need of special reagents, simple operation and suitability for industrial production; the compound of the formula III is separated by chiral tartrate, a chiral phase chromatographic method with high cost and low efficiency is not used for separation, and the yield of the obtained S-type II compound is more than 48%, and the ee value can reach 99.7%.
The intermediate compound of the formula II is obtained through resolution, and the compound is subjected to one-step ammoniation or is subjected to non-heavy metal catalysis to form carboxyl, and then the carboxyl is subjected to ammoniation to obtain the non-neridrone bulk drug, wherein the ee value can reach more than 99.9%. The preparation method has the advantages of few reaction steps, simple operation, high refining yield of over 82 percent, no use of noble metal catalyst, low cost and no heavy metal residue.
The application will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present application and are not intended to limit the scope of the present application. The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are weight percentages and parts unless otherwise indicated.
Unless otherwise indicated, all the starting materials or reagents used in the examples were either commercially available or were prepared according to conventional methods.
Example 1 preparation of Compounds V-1 and V-2
4-Formaldehyde-3-methoxybenzonitrile (20.0 g,124.10 mmol), piperidine (1.06 g,12.45 mmol), acetic acid (0.74 g,12.32 mmol) and sec-butanol (100 ml) were added to a reaction vessel, stirring was started, heating was performed to 30℃and a solution of acetoacetic acid- (2, 2) -trichloroethyl ester (34.8 g,149.04 mmol) in sec-butanol (100 ml) was slowly added dropwise over a period of 5h, stirring was continued for 1h after the dropwise addition, cooling was continued to-10℃for 1.5h, filtration was performed, the filter cake was rinsed with methanol (5 ml) and dried under vacuum at 50℃for 10h to give 43.35g as a white solid with a purity of 99.2% (based on 4-formyl-3-methoxybenzonitrile).
MS：m/z＝376[M+1] + 。
EXAMPLE 2 preparation of Compounds of formula IV
/>
A mixture of the compound of formula V-1 and the compound of formula V-2 (40.0 g,106.67 mmol), 4-amino-5-methylpyrrolidone (11.03 g,88.85 mmol) and sec-butanol (400 ml) was added to the reaction vessel, warmed to reflux, stirred for 17h, slowly cooled to 0℃and stirred at that temperature for 2h, filtered, rinsed with dichloromethane (4 ml), dried in vacuo at 40℃for 16h to give a white solid 40.62g in 95.01% (based on 4-amino-5-methylpyrrolidone) with an HPLC purity of 98.8%.
1 H NMR(400MHz,[D6]DMSO):δ＝2.06(s,3H),2.43(s,3H),3.74(s,3H),4.68–4.90(m,2H),5.24(s,1H),6.98(s,1H),7.25(d,1H),7.28(d,1H),7.33(s,1H),7.40(s,1H)。MS：m/z＝482[M+1] + 。
EXAMPLE 3 preparation of Compounds of formula III
Compound IV (18.5 g,38.46 mmol) and triethyl orthoformate (34.2 g,230.77 mmol) were dissolved in N, N-dimethylacetamide (185 ml) and concentrated sulfuric acid (0.9 g,9.18 mmol) was added, warmed to 105℃and stirred for 6h, then cooled to room temperature, solvent N, N-dimethylacetamide was distilled off under reduced pressure, methanol (55 ml) was added to slurry, and filtered to give 18.6g of a white solid with a yield of 95.0% and an HPLC purity of 99.2%.
1 H NMR(400MHz,[D6]DMSO):δ＝1.24(t,3H),2.24(s,3H),2.53(s,3H),3.77(s,3H),4.06–4.18(m,2H),4.70(d,1H)，4.90(m,1H),5.42(s,1H),7.20(d,2H),7.54(m,1H),7.61(s,1H)。MS：m/z＝510[M+1] + 。
EXAMPLE 4-1 preparation of Compounds of formula IIa-1
To a reaction flask was added a compound of formula iii (10.0 g,19.58 mmol), dibenzoyl-D-tartaric acid (i.e. Ar in formula IX is phenyl) (7.0 g,19.58 mmol) and a mixture of ethanol and water (ethanol/water=3/1, 150 ml) at room temperature (about 20 ℃), stirred for 2h at 60 ℃, slowly cooled to room temperature (4 h), stirred for 12h at room temperature, isolated as a white solid by filtration (i.e. compound of formula IIa-1), dried in vacuo at 50 ℃ for 10h, about 8.4g (98.7% of theory) and de 99.1%.
EXAMPLE 4-2 preparation of Compounds of formula IIa-2
To a reaction flask was added a mixture of a compound of formula iii (10.0 g,19.58 mmol), di-p-nitrobenzoyl-D-tartaric acid (i.e. Ar is p-nitrophenyl in formula IX) (8.8 g,19.58 mmol) and methanol and water (methanol/water=4/1, 150 ml) at room temperature (about 20 ℃), stirred for 2h at 50 ℃, slowly cooled to room temperature (4 h), stirred for 12h at room temperature, isolated as a white solid (i.e. compound of formula IIa) by filtration, dried in vacuo at 50 ℃ for 10h, about 9.4g (100.1% of theory) and de 99.0%.
EXAMPLE 4-3 preparation of Compounds of formula IIa-3
To a reaction flask was added a compound of formula iii (10.0 g,19.58 mmol), di-p-methylbenzoyl-D-tartaric acid (i.e. Ar is p-methylphenyl in formula IX) (7.6 g,19.58 mmol) and a mixture of isopropanol and water (isopropanol/water=3/1, 150 ml) at room temperature, stirred for 2h, slowly cooled to room temperature (4 h), stirred for 12h at room temperature, isolated by filtration to give a white solid (i.e. a compound of formula IIa), dried in vacuo at 50 ℃ for 10h, about 8.7g (99.1% of theory) and de 98.8%.
Examples 4-4 preparation of Compounds of formula IIa-4
To a reaction flask was added, at room temperature (about 20deg.C), a compound of formula III (10.0 g,19.58 mmol), di-p-chlorobenzoyl-D-tartaric acid (i.e., ar is p-chlorophenyl in formula IX) (8.4 g,19.58 mmol) and ethylene glycol dimethyl ether (150 ml), stirred at 50deg.C for 2h, slowly cooled to room temperature (4 h), stirred at room temperature for 12h, isolated by filtration to give a white solid (i.e., a compound of formula IIa), dried in vacuo at 50deg.C for 10h, about 8.9g (96.9% of theory) and de 99.2%.
EXAMPLES 4-5 preparation of Compounds of formula IIa-5
To a reaction flask was added, at room temperature (about 20deg.C), a compound of formula III (10.0 g,19.58 mmol), di-p-methoxybenzoyl-D-tartaric acid (i.e., ar is p-methoxyphenyl in formula IX) (8.2 g,19.58 mmol) and acetone (150 ml), stirred at 50deg.C for 2h, slowly cooled to room temperature (4 h), stirred at room temperature for 12h, and isolated by filtration to give a white solid (i.e., a compound of formula IIa), dried in vacuo at 50deg.C for 10h, about 9.0g (98.9% of theory) and a de of 99.0%.
EXAMPLES 4-6 preparation of Compounds of formula IIa-6
To a reaction flask was added, at room temperature (about 20deg.C), a compound of formula III (10.0 g,19.58 mmol), di-p-cyanobenzoyl-D-tartaric acid (i.e., ar is p-cyanophenyl in formula IX) (8.0 g,19.58 mmol) and ethyl acetate (150 ml), stirred at 50deg.C for 2h, slowly cooled to room temperature (4 h), stirred at room temperature for 12h, isolated by filtration to give a white solid (i.e., a compound of formula IIa), dried in vacuo at 50deg.C for 10h, about 8.5g (94.4% of theory) and de 99.2%.
EXAMPLE 5-1 preparation of Compounds of formula II
8.4g of the white solid compound of formula IIa-1 obtained in example 4-1 was added to 84ml of a mixture of ethanol and water (ethanol/water=1:5), the pH was adjusted to 8.0 to 8.5 using saturated sodium phosphate, stirred at room temperature for 12 hours, and 4.54g of a white solid (compound of formula II) was obtained by filtration and separation, the yield was 91.9%, the purity was 99.8%, and the ee value was 99.7%. MS: m/z=510 [ m+1 ]] + 。
EXAMPLE 5-2 preparation of Compounds of formula II
9.4g of the white solid compound of formula IIa-2 obtained in example 4-2 were added to 94ml of a mixture of methanol and water (methanolWater=1:5), the pH was adjusted to 8.0 to 8.5 using saturated sodium phosphate, stirred at room temperature for 12 hours, and isolated by filtration to give 4.9g of a white solid (compound of formula II) in 98.0% yield, 99.6% purity, 99.6% ee value. MS: m/z=510 [ m+1 ]] + 。
EXAMPLE 5-3 preparation of Compounds of formula II
8.7g of the white solid compound of formula IIa-3 obtained in example 4-3 was added to 87ml of water, the pH was adjusted to 8.0 to 8.5 using saturated sodium phosphate, stirred at room temperature for 11 hours, and 4.9g of a white solid (compound of formula II) was obtained by filtration and separation, the yield was 99.0%, the purity was 99.8% and the ee value was 99.5%. MS: m/z=510 [ m+1 ]] + 。
Examples 5-4 preparation of Compounds of formula II
8.9g of the white solid compound of formula IIa-4 obtained in example 4-4 are added to 89ml of water, the pH is adjusted to 8.0 to 8.5 using saturated sodium phosphate, stirring is carried out at room temperature for 11h, 4.7g of white solid (compound of formula II) is obtained by filtration and separation, the yield is 97.9%, the purity is 99.5% and the ee value is 99.6%. MS: m/z=510 [ m+1 ]] + 。
EXAMPLES 5-5 preparation of Compounds of formula II
9.0g of the white solid compound of formula IIa-5 obtained in example 4-5 was added to 90ml of water, the pH was adjusted to 8.0 to 8.5 using saturated sodium phosphate, stirred at room temperature for 11 hours, and 4.7g of a white solid (compound of formula II) was isolated by filtration, the yield was 95.9%, the purity was 99.6%, and the ee value was 99.7%. MS: m/z=510 [ m+1 ]] + 。
EXAMPLES 5-6 preparation of Compounds of formula II
8.5g of the white solid compound of formula IIa-6 obtained in examples 4-6 are added to 85ml of water, the pH is adjusted to 8.0 to 8.5 using saturated sodium phosphate, stirring is carried out at room temperature for 11h, 4.5g of white solid (compound of formula II) is obtained by filtration and separation, the yield is 95.7%, the purity is 99.8% and the ee value is 99.5%. MS: m/z=510 [ m+1 ]] + 。
Example 6-1 preparation of Finerenone
At room temperature (about 20 DEG C) To the autoclave was added the compound of formula II (10.0 g,19.64 mmol), 1, 8-diazabicyclo [5.4.0]]Undec-7-ene (5.96 g,39.28 mmol), N, N-Dimethylacetamide (DMAC) (80 ml) was introduced with NH 3 The autoclave is closed until the pressure in the autoclave is 0.4-0.5Mpa, the autoclave is heated to 80 ℃ and stirred for reaction for 20h. Subsequently, the reaction solution was cooled to 50 ℃, then the solvent DMAC was distilled off under reduced pressure, ethanol (100 ml) was added and heated to reflux for 2 hours, the solvent was distilled off under normal pressure to 30ml, the temperature was slowly lowered to 0 ℃ (8 h) and stirred at that temperature for 3 hours, the filtration was separated, and vacuum drying was carried out at 40 ℃ for 16 hours to obtain 6.15g of a white solid, namely, a raw material drug of non-nelidaton, with a yield of 82.8% and a purity of 99.5%.
1 H NMR(400MHz,[D6]DMSO):δ＝1.05(t,3H),2.12(s,3H),2.18(s,3H),3.82(s,3H),3.96–4.06(m,2H),5.37(s,1H),6.49–6.86(2H),7.15(d,1H),7.28(d,1H),7.37(d,1H),7.55(s,1H),7.68(s,1H)。MS：m/z＝379[M+1] + 。
Example 6-2 preparation of Finerenone
/>
The compound of formula II (10.0 g,19.64 mmol), 1, 8-diazabicyclo [5.4.0] is charged to the autoclave at room temperature (about 20 ℃)]Undec-7-ene (7.5 g,50.00 mmol), N, N-Dimethylacetamide (DMAC) (100 ml) was introduced with NH 3 The autoclave is closed until the pressure in the autoclave is 0.3-0.4Mpa, the autoclave is heated to 90 ℃ and stirred for reaction for 18h. Subsequently, the reaction solution was cooled to 50 ℃, then the solvent DMAC was distilled off under reduced pressure, ethanol (120 ml) was added and heated to reflux for 2 hours, the solvent was distilled off under normal pressure to 35ml, the temperature was slowly lowered to 0 ℃ (8 h) and stirred at that temperature for 3 hours, the filtration was separated, and vacuum drying was carried out at 40 ℃ for 16 hours to obtain 6.13g of a white solid, namely, a crude drug of non-nelidaton, with a yield of 82.5% and a purity of 99.5%.
MS：m/z＝379[M+1] + 。
EXAMPLE 7 preparation of Compounds of formula I
At room temperature (about 20 ℃ C.), the compound of formula II (9.0 g,17.68 mmol) and THF (105 ml) were added to the reaction vessel, cooled to 0 ℃ C., stirred for 10min, acetic acid (18 ml) and CuCl were added in this order 2 (2.40 g,17.68 mmol) and Zn powder (11.56 g,176.8 mmol) were reacted at 0℃with stirring for 5h. The mother liquor was isolated by filtration, a solution of NaOH (11.90 g,297.68 mmol) in water (105 ml) was added and stirred at 0deg.C for 1h, the solution was separated by washing with methyl tert-butyl ether (MTBE) (105 ml) 2 times, the lower aqueous phase was taken off and washed with further ethyl acetate (105 ml), the pH of the lower aqueous phase was adjusted to 5.5-6.5 using 10% hydrochloric acid and stirred at 0deg.C for 1h, isolated by filtration and dried under vacuum at 40deg.C for 16h to give 6.37g of a white solid with a yield of 94.9% and a purity of 98.6%.
EXAMPLE 8Finerenone preparation
To the reaction vessel was added the compound of formula I (10.0 g,26.39 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (6.05 g,31.64 mmol), 1-hydroxybenzotriazole (4.28 g,31.64 mmol), THF (150 ml), NH at room temperature (about 20 ℃) 3 3 times of replacement, NH 3 The balloon is supplied with ammonia, the temperature is raised to 50 ℃ and the reaction is stirred for 8 hours. Cooling to room temperature, evaporating the solvent under reduced pressure, adding a mixture of ethanol and water (ethanol: water=1:9, 100 ml), stirring at room temperature for 3h, filtering, separating, and vacuum drying at 40 ℃ for 16h to obtain a solid. The resulting solid was added to ethanol (30 ml), stirred at 0℃for 12h, isolated by filtration, dried under vacuum at 40℃for 16h, then ethanol (180 ml) was added to the solid, heated to reflux and stirred for 1h, the solvent was distilled off to 25ml and then slowly cooled to 0℃for 8h and stirred at 0℃for 2h, isolated by filtration, dried under vacuum at 40℃for 16h to give 8.8g of a white crystalline powder with a yield of 88% and a purity of 99.89%. 1 H NMR(400MHz,[D 6 ]DMSO):δ＝1.05(t,3H),2.12(s,3H),2.18(s,3H),3.82(s,3H),3.96–4.06(m,2H),5.37(s,1H),6.49–6.86(2H),7.15(d,1H),7.28(d,1H),7.37(d,1H),7.55(s,1H),7.68(s,1H)。MS：m/z＝379[M+1] + 。
EXAMPLE 9 preparation of Finerenone
At room temperature (about 20 ℃ C.), the compound of formula II (9.0 g,17.68 mmol) and THF (105 ml) were added to the reaction vessel, cooled to 0 ℃ C., stirred for 10min, acetic acid (2 ml) and CuCl were added in this order 2 (2.40 g,17.68 mmol), zn powder (11.56 g,176.8 mmol), stirring at 0deg.C for 5h, filtering to obtain mother liquor, adding 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (4.06 g,21.22 mmol), 1-hydroxybenzotriazole (2.86 g,21.22 mmol), NH to the mother liquor 3 3 times of replacement, NH 3 The balloon is supplied with ammonia, the temperature is raised to 50 ℃ and the reaction is stirred for 8 hours. Cooling to room temperature, evaporating the solvent under reduced pressure, adding a mixture of ethanol and water (ethanol: water=1:9, 90 ml), stirring at room temperature for 3h, filtering, separating, and vacuum drying at 40 ℃ for 16h to obtain a solid. The solid obtained was added to ethanol (30 ml), stirred at 0℃for 12h, isolated by filtration and dried under vacuum at 40℃for 16h, added to ethanol (180 ml) and heated to reflux and stirred for 1h, the solvent was distilled off to 25ml and then slowly cooled to 0℃and stirred for 2h, filtered off and dried under vacuum at 40℃for 16h to give 5.7g of a white crystalline powder with a two-step yield of 85% and a purity of 99.89%.
1 H NMR(400MHz,[D6]DMSO):δ＝1.05(t,3H),2.12(s,3H),2.18(s,3H),3.82(s,3H),3.96–4.06(m,2H),5.37(s,1H),6.49–6.86(2H),7.15(d,1H),7.28(d,1H),7.37(d,1H),7.55(s,1H),7.68(s,1H)。
MS：m/z＝379[M+1] + 。
All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims (12)

1. A process for the preparation of a compound of formula II, comprising the steps of:
1) Reacting a racemic compound of formula III with a compound of formula IX to form a salt, and separating to obtain a salt of a compound of formula IIa;
2) Treating the salt of the compound of formula IIa obtained in step 1) with a base to obtain a compound of formula II,
the reaction formula is as follows:
wherein Ar in the compound of formula IX is unsubstituted or substituted C 6 -C 14 An aromatic or heteroaromatic group, wherein said substitution means substitution with a group selected from the group consisting of: c (C) 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, halogen, nitro, cyano, carboxyl, hydroxyl, amide,
wherein in the compound of formula IIIRepresenting the racemic structure.
2. The method of claim 1, wherein Ar is a compound having the structure shown in formula X:
wherein R is 1 、R 2 、R 3 、R 4 、R 5 Each independently is hydrogen, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Haloalkyl, C 1 -C 3 Alkoxy, phenoxy, nitro, cyano, amido,
wherein, represents the connection point.
3. The method of claim 2, wherein Ar is selected from the group consisting of:
wherein, represents the connection point.
4. The method of claim 1, wherein step 1) has one or more of the following features:
the molar ratio of the compound of formula III to the compound of formula IX is from 1:0.4 to 1.2, preferably from 1:0.6 to 1.2, more preferably 1:1,
the salification reaction is carried out in an organic solvent or a mixed solvent of water and the organic solvent, wherein the organic solvent is selected from ethanol, methanol, isopropanol, n-butanol, sec-butanol, ethylene glycol dimethyl ether, acetone, ethyl acetate or a combination thereof; and
the salt forming reaction temperature is 50-70 ℃ and the time is 1-3 hours.
5. The method according to claim 1, wherein the alkali treatment in step 2) comprises the steps of: dissolving the compound of the formula IIa obtained in the step 1) in a solvent, regulating the pH value of the obtained solution to 7.5-9.5 by using alkali, stirring for 8-18h at room temperature, filtering and separating to obtain the compound of the formula II,
preferably, the base is selected from potassium hydroxide, potassium phosphate or sodium phosphate, or a combination thereof, and/or
Preferably, the solvent in which the compound of formula IIa is dissolved is an organic solvent or a mixture of water and an organic solvent, wherein the organic solvent is selected from ethanol, methanol, isopropanol, n-butanol, sec-butanol, or a combination thereof.
6. A process for the preparation of a compound of formula III, comprising the steps of:
(a) The compound of formula VI reacts with the compound of formula VII to obtain a compound of formula V-1 and a compound of formula V-2, wherein the reaction formula is as follows:
(b) The compound of formula IV is obtained by reacting a mixture of a compound of formula V-1 and a compound of formula V-2 with a compound of formula VIII, wherein the reaction formula is as follows:
wherein in formula IVThe term "racemic structure" is used to refer to a racemic structure,
(c) The compound of formula IV is subjected to ethyl esterification to obtain a compound of formula III, wherein the reaction formula is as follows:
wherein in formula IIIRepresenting the racemic structure.
7. The method of claim 6, wherein the process comprises the steps of,
in step a), the compound of formula VI is reacted with a compound of formula VII in the presence of 0.05 to 0.15 equivalent of piperidine and 0.05 to 0.15 equivalent of acetic acid at a temperature of 10 to 50℃to obtain a mixture of a compound of formula V-1 and a compound of formula V-2, preferably the solvent used for the reaction is selected from methanol, ethanol, isopropanol, n-butanol, sec-butanol, dichloromethane or a combination thereof; and/or
In step b), the reaction temperature is 75-130 ℃, preferably, the solvent used in the reaction is selected from isopropanol, n-butanol, sec-butanol or a combination thereof; and/or
In the step c), the esterification reaction uses triethyl orthoformate as an esterifying agent, the reaction temperature is 80-120 ℃ and the reaction time is 4-8 h in the presence of acid,
preferably, the solvent used in the ethylation reaction is selected from the group consisting of N, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a combination thereof.
8. A method for preparing non-nelidane, which is characterized by comprising the following steps:
(i) Providing a compound of formula III;
(ii) Taking a compound of formula III as a raw material, and obtaining a compound of formula II through resolution, wherein the compound of formula II is obtained according to the preparation method of any one of claims 1 to 5;
(iii) Ammonification of the compound of formula II gives the non-neridone, the reaction formula is as follows:
wherein in formula IIIRepresenting the racemic structure.
9. The method for preparing non-nelidamide according to claim 8, wherein the ammonification process in the step (iii) is: heating the solution of the compound of the formula II for 15-25 h at 60-100 ℃ in the presence of an organic base catalyst in an ammonia atmosphere to generate non-neridone,
preferably, the organic base catalyst is selected from 1, 8-diazabicyclo [5.4.0] undec-7-ene, triethylamine, N-diisopropylethylamine, piperidine, N-methylmorpholine, or a combination thereof, and/or
Preferably, the solvent used to dissolve the compound of formula II is selected from N, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, or a combination thereof.
10. A method for preparing non-nelidane, which is characterized by comprising the following steps:
s1 provides a compound of formula III;
s2 takes a compound of a formula III as a raw material, and a compound of a formula II is obtained through resolution, wherein the compound of the formula II is obtained according to the preparation method of any one of claims 1 to 5;
s3, hydrolyzing the compound shown in the formula II to obtain a compound shown in the formula I:
the S4 compound of the formula I is aminated to obtain the non-neridrone,
the reaction formula is as follows:
wherein in formula IIIRepresenting the racemic structure.
11. The process for preparing non-nelidane according to claim 10, wherein,
in the step S3, the hydrolysis process of the compound of the formula II is to dissolve the compound of the formula II in a solvent to obtain a solution of 15 to 20 equivalents of acetic acid and 1 to 1.5 equivalents of CuCl 2 Reacting for 3-8 h at-5-10 ℃ in the presence of 8-15 equivalent Zn powder to obtain the compound shown in the formula I,
preferably, the solvent used to dissolve the compound of formula II is selected from tetrahydrofuran, 2-methyltetrahydrofuran, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, or a combination thereof;
and/or
In the step S4, the ammoniation process of the compound of the formula I is to dissolve the compound of the formula I in a solvent, heat the obtained solution for 5 to 10 hours at the temperature of 40 to 70 ℃ in the presence of 1 to 2 equivalents of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 1 to 2 equivalents of 1-hydroxybenzotriazole in an ammonia atmosphere to generate the non-nefardone,
preferably, the solvent used to dissolve the compound of formula I is selected from tetrahydrofuran, N-dimethylacetamide, N-dimethylformamide, dimethylsulfoxide, or a combination thereof;
and/or
Step S3 and step S4 are carried out in a one-pot mode.
12. A non-nelidamide intermediate, characterized in that it has the following structure:
wherein Ar is as defined in claim 1,
wherein, in the formula IV and the formula III,representing the racemic structure.
CN202310567956.9A 2023-05-19 2023-05-19 Preparation method of non-neridrone and intermediate thereof Pending CN116715663A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202310567956.9A CN116715663A (en) 2023-05-19 2023-05-19 Preparation method of non-neridrone and intermediate thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202310567956.9A CN116715663A (en) 2023-05-19 2023-05-19 Preparation method of non-neridrone and intermediate thereof

Publications (1)

Publication Number Publication Date
CN116715663A true CN116715663A (en) 2023-09-08

Family

ID=87874291

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310567956.9A Pending CN116715663A (en) 2023-05-19 2023-05-19 Preparation method of non-neridrone and intermediate thereof

Country Status (1)

Country Link
CN (1) CN116715663A (en)

Similar Documents

Publication Publication Date Title
CN115340539B (en) Process for preparing non-nereirenone and intermediates thereof
CN115340540A (en) Process for preparing non-neferone and intermediates thereof
US6133454A (en) Method for preparing a substituted perhydroisoindole
AU731835B2 (en) Method of manufacturing sertindole
CN111233866B (en) Process for the preparation of tofacitinib or a salt thereof
CN116715663A (en) Preparation method of non-neridrone and intermediate thereof
US6248891B1 (en) Synthesis of acridine derivative multidrug-resistant inhibitors
WO2011001976A1 (en) Method for producing threo-3-(3,4-dihydroxyphenyl)-l-serine
TW202210486A (en) Method for preparing glp-1 receptor agonist
JP4190879B2 (en) A novel intermediate for the production of theanine
WO2011116491A1 (en) Preparation method for nortropine benzilate and its salts and intermediates used in said method
CN118047782A (en) Process for preparing intermediate of ponatinib
CN113121414B (en) Synthesis method of trelagliptin intermediate
JPS60181058A (en) Cyanomethyl-(2-cyano-ethyl)- (3-hydroxy-propyl)-amine and manufacture, 1-(3-hydroxy-propyl)-1,4-diazpam and manufacture of 1,4-bis-(3-(3,4,5-trimethoxy- benzoyloxy)-propyl)-diazepam
JP4022953B2 (en) Process for producing 2,2-bis (3-amino-4-hydroxyphenyl) propane
KR102201609B1 (en) Process for Preparing Naldemedine
JPH072742A (en) New production method of 4-amino-3-methyl-n-ethyl-n-(beta-hydroxyethyl)aniline sulfuric acid salt
CN117756801A (en) Preparation method of non-neridrone
CN116675692A (en) Synthesis method of low-impurity linagliptin
CN116804011A (en) Method for preparing non-nereirenone intermediate by racemate resolution
CN116969831A (en) Monetalol intermediate and preparation method thereof
JP2005533037A (en) Process for preparing (S) -tetrahydro-α- (1-methylethyl) -2-oxo-1 (2H) -pyrimidineacetic acid
CN117229216A (en) Preparation method of entecavir intermediate
JP4634168B2 (en) Theanine production method
KR20020032589A (en) Preparation of Halogenated Primary Amines

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination