CN118047774A

CN118047774A - Method for preparing non-neridrone and intermediate thereof

Info

Publication number: CN118047774A
Application number: CN202410126945.1A
Authority: CN
Inventors: 赵楠; 靳家玉; 胡文军; 李成刚
Original assignee: Jiangsu Puxin Pharmaceutical Co ltd; Jiangxi Desino Pharmaceutical Co ltd; Shanghai Desano Pharmaceuticals Investment Co ltd; Shanghai Desano Chemical Pharmaceutical Co Ltd
Current assignee: Jiangsu Puxin Pharmaceutical Co ltd; Jiangxi Desino Pharmaceutical Co ltd; Shanghai Desano Pharmaceuticals Investment Co ltd; Shanghai Desano Chemical Pharmaceutical Co Ltd
Priority date: 2024-01-30
Filing date: 2024-01-30
Publication date: 2024-05-17

Abstract

The invention provides a novel non-nereirenone intermediate (a compound shown in a formula I), which is used for preparing the non-nereirenone, so that palladium-carbon hydrogenation reduction which is not suitable for industrial production can be avoided, expensive reagents and special equipment are not needed, and the energy consumption is low; the reaction condition is mild, the impurity generation is less, the process is stable, the product purity is high, and the method is suitable for large-scale industrial production.

Description

Method for preparing 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

Non-nelidane (finerenone, trade name Kerendia) is a third generation non-steroidal mineralocorticoid receptor antagonist approved by the FDA in 2021 developed by bayer for use in patients with chronic kidney disease combined with type 2 diabetes and heart failure to reduce the risk of reduced renal function, renal failure, cardiovascular death, non-fatal heart attacks and hospitalization for heart failure, and is a once-a-day oral drug. Non-nefarnesone inhibits the binding of aldosterone to mineralocorticoid receptor, thereby blocking the over-activation of MR and its mediated sodium reabsorption. The medicine has high efficacy and selectivity, and can obviously improve kidney and cardiovascular functions of patients with chronic kidney disease accompanied by type II diabetes. The chemical name is: (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2, 8-dimethyl-1, 4-dihydro-1, 6-naphthyridine-3-carboxamide having the structural formula:

one synthetic route for non-nelidane is as follows:

In the methods disclosed in patent US20100136142, US10059707 and the like, chiral columns are adopted to split the non-neridone racemate, so that the method is not suitable for industrial production.

Patent US2021163474 uses tartrate to split the valoneracemate, but the scheme of the last step of splitting causes a lot of material waste.

The patent CN114605410 adds the catalyst S2O82-/ZrO 2/gamma-Al 2O3 to the non-nefardone racemate for transformation, and then splits the mixture by using tartaric acid.

Patent WO2021074078 adopts a resolving agent to resolve the intermediate, but the resolving agent gives an intermediate diastereomeric salt with ee value less than 80% and needs further purification. The process has low resolution efficiency, more steps and long time consumption, and needs to stir for 2 times overnight.

In addition, the carboxyl protecting groups in the above route are all nitrile ethyl groups, the nitrile ethyl groups can generate equivalent byproducts of acrylonitrile in the deprotection process, and the acrylonitrile is extremely toxic, is easy to volatilize and highly flammable, has great potential safety hazard and is not suitable for industrial production.

Patent CN115340539 is to solve the problems of low resolution efficiency and low ee value of intermediates and products in the prior art, replace the protecting group cyanoethyl in the above process with benzyl, split the intermediates to obtain single configuration intermediates, and then deprotect and ammonify to obtain the non-neridone. The enantiomer mixture is separated by the tartrate, the de value of the intermediate diastereomer salt is more than 98.5%, the ee value of the intermediate after the dissociation can be more than 99.5%, and the ee value of the final product non-nelidane can be more than 99.8%. Firstly, in the resolution step, the intermediates with two configurations can form salts with a resolving agent, the process is very unstable during crystallization, and sometimes the unwanted R-configuration compounds can be separated out together, so that the resolution effect is affected. Secondly, since the benzyl is difficult to remove, high-pressure hydrogenation under the catalysis of expensive palladium-carbon is needed in the step of debenzylation, special high-pressure resistant equipment is needed, and potential safety hazards exist. In addition, in the process of debenzylation, because the reaction conditions are relatively severe, more impurities are generated, such as excessive reduction impurities, decarboxylation impurities generated at high temperature and the like, and the subsequent purification and the purity of the product are greatly influenced.

In view of this, there is a need in the art to develop a process for preparing non-nereirenone that has good resolution effect, stable process, simple operation, low cost, and suitability for industrial production.

Disclosure of Invention

The invention aims to provide a preparation method of non-nereirenone, which has the advantages of good resolution effect, stable process, simple and convenient operation, low cost and suitability for industrial production.

In a first aspect of the present invention there is provided a process for the preparation of a compound of formula I comprising the steps of:

(1) Resolving the racemic compound of the formula II by using a resolving agent shown in a formula IIIa compound or a formula IIIb compound to obtain a compound of the formula I.

In another preferred embodiment, the resolving agent in step (1) is a compound of formula iiia, step (1) comprising:

(1 a-1) salifying a racemic compound of formula II with a compound of formula IIIa, and separating to obtain a salt shown as the compound of formula IVa;

(1 a-2) treating the salt of the compound of formula IVa obtained in step 1 with a base to obtain the compound of formula I.

In another preferred embodiment, the resolving agent in step (1) is a compound of formula IIIb, step (1) comprising:

(1 b-1) reacting a racemic compound of formula II with a compound of formula IIIb to form a salt, and removing the salt represented by the compound IVb to obtain a compound of formula I.

Wherein Ar is unsubstituted or substituted C6-C14 aryl or unsubstituted or substituted C5-C14 heteroaryl containing 1 to 3 groups selected from O, N and S, wherein said substitution is substituted with one or more groups selected from the group consisting of: C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, nitro, cyano, carboxyl, hydroxyl, and amido.

In another preferred embodiment, ar is an unsubstituted or substituted phenyl group.

In another preferred embodiment, ar has the structure shown in formula V:

Wherein each R ₁、R₂、R₃、R₄、R₅ is independently selected from the group consisting of: hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, phenoxy, nitro, cyano, amido.

In another preferred embodiment, four substituents in R ₁、R₂、R₃、R₄、R₅ are hydrogen and one substituent is other than hydrogen, preferably R3 is other than 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 R, R '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 heterocyclic ring containing 1-2 nitrogen atoms.

In another preferred embodiment Ar is an unsubstituted or substituted C10-C14 polycyclic aryl group, such as naphthyl, anthracenyl.

In another preferred embodiment Ar is an unsubstituted or substituted C5-C10 heteroaryl group, such as piperidinyl, piperazinyl, quinolinyl.

In another preferred embodiment, ar is selected from the group consisting of:

Wherein represents the connection point.

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, in step 1, the molar ratio of the compound of formula II to the compound of formula IIIa is 1:0.4-1.2, preferably 1:0.5-0.6, more preferably 1:0.51-0.55.

In another preferred embodiment, in step 1, the molar ratio of the compound of formula II to the compound of formula IIIb is 1:0.4-1.2, preferably 1:0.5-0.6, more preferably 1:0.51-0.55.

In another preferred embodiment, in step1, the resolving agent is a compound of formula IIIa.

In another preferred example, in steps 1a-1 and 1b-1, the salification reaction is performed in an organic solvent or a mixed solvent of an organic solvent and water, wherein the organic solvent is selected from ethanol, methanol, isopropanol, 1-propanol, 1-pentanol, acetone, 2-butanone, methyl isobutyl ketone, acetic acid, ethyl acetate, isoamyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, dioxane, or a combination thereof.

In another preferred embodiment, in steps 1a-1 and 1b-1, the salification reaction also independently has one or more of the following features:

(a) The concentration of the compound of formula II in the solvent is 0.1-0.3mmol/mL, preferably 0.10-0.15 mmol/mL;

(b) The salification reaction is carried out at 40-100 ℃, preferably 60-80 ℃;

(c) The reaction time of the salification reaction is 1-4h, preferably 2h.

In another preferred embodiment, the separation described in step 1a-1 is a filtration separation or a centrifugation separation, preferably a filtration separation.

In another preferred embodiment, in step 1a-1, the separating comprises: cooling the reaction system to 20-90 deg.c, preferably 30-60 deg.c or 40-50 deg.c, separating out, filtering and separating out.

In another preferred embodiment, in step 1a-2, the base is an inorganic base or an organic base. Wherein the inorganic base is selected from ammonia water, potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium phosphate, sodium phosphate, ammonium carbonate, lithium carbonate, potassium carbonate, sodium carbonate, ammonium bicarbonate, sodium bicarbonate or potassium bicarbonate, preferably potassium hydroxide, sodium hydroxide, potassium phosphate or sodium phosphate; the organic base is selected from triethylamine, imidazole, N-methylimidazole, pyridine or DBU.

In another preferred embodiment, in step 1a-2, the base may be used in anhydrous form or in the form of its hydrate.

In another preferred embodiment, the alkali treatment step of step 1a-2 is performed in water, an organic solvent, or a mixture of an organic solvent and water, wherein the organic solvent is selected from the group consisting of ethanol, methanol, isopropanol, 1-propanol, 1-pentanol, acetone, 2-butanone, methyl isobutyl ketone, acetic acid, ethyl acetate, isoamyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, dioxane, or a combination thereof.

In another preferred embodiment, in step 1a-2, the alkali treatment is performed in an aqueous alkali solution.

In another preferred embodiment, in step 1a-2, the pH of the alkaline treatment step is 7-12, preferably 7.5-10, preferably 7.5-8.5.

In another preferred embodiment, in step 1a-2, the alkali treatment further has one or more of the following features:

(a) The concentration of the salt shown in the formula IVa compound in a solvent is 0.05-0.20mmol/mL;

(b) The alkali treatment is carried out at the temperature of 5-30 ℃;

(c) The reaction time of the alkali treatment is 0.5 to 4 hours, preferably 2 hours.

In another preferred embodiment, step 1b-1 comprises the steps of: cooling and crystallizing (such as 30-90 ℃ or 50-65 ℃) the reaction liquid of the salifying reaction, filtering, concentrating the filtrate to remove the reaction solvent, separating the solution in water and an organic solvent to obtain an organic phase, removing the organic solvent, and crystallizing in the crystallization solvent to obtain the compound of the formula I.

In another preferred embodiment, the organic solvent is selected from the group consisting of acetone, 2-butanone, methyl isobutyl ketone, acetic acid, ethyl acetate, isoamyl acetate, n-heptane, methylene chloride, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, dioxane, or a combination thereof.

In another preferred embodiment, the crystallization solvent is selected from the group consisting of: acetone, 2-butanone, methyl isobutyl ketone, ethyl acetate, n-heptane, methylene chloride, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, or dioxane, or combinations thereof.

In another preferred embodiment, the crystallization includes crystallization in a crystallization solvent under reflux with stirring and then cooling (e.g., 10-25 ℃).

In another preferred embodiment, the method further comprises the steps of:

i) Reacting the compound II-1 with the compound II-2 to obtain a compound II-3;

II) reacting compound II-3 with compound II-4 to give compound II-5;

iii) Reacting the compound II-5 with triethyl orthoformate to obtain a compound of formula II;

The reaction formula is as follows:

in a second aspect of the present invention, there is provided a process for preparing non-nelidane, the process comprising the steps of:

(s 1) providing a compound of formula II;

(s 2) taking a compound of formula II as a raw material, and carrying out resolution to prepare the compound of formula I, wherein the method for preparing the compound of formula I is as described in the first aspect of the invention;

(s 3) removing p-methoxybenzyl from the compound shown in the formula I to obtain a compound shown in the formula I-1; removing p-methoxybenzyl group using an acid, wherein the acid is selected from the group consisting of: trifluoroacetic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid;

(s 4) ammonifying the compound shown in the formula I-1 to obtain non-netilone;

The reaction formula is as follows:

in another preferred embodiment, in step s3, the acid addition salt corresponding to the compound of formula I-1 is obtained when the p-methoxybenzyl group is removed using an acid and used directly in the next reaction.

In another preferred embodiment, in step s3, p-methoxybenzyl is removed using trifluoroacetic acid.

In another preferred embodiment, in step s3, the molar ratio of the compound of formula I to the reagent for removing p-methoxybenzyl is 1:0.5-5.0, preferably 1:2.0 to 4.0, more preferably 1:3.0.

In another preferred embodiment, in step s3, the reaction is performed in an organic solvent, wherein the organic solvent is selected from the group consisting of ethanol, methanol, isopropanol, 1-propanol, 1-pentanol, acetone, 2-butanone, methyl isobutyl ketone, acetic acid, ethyl acetate, isoamyl acetate, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, or dioxane, or a combination thereof. Preferably dichloromethane, methanol, acetic acid, or a combination thereof.

In another preferred embodiment, in step s3, the reaction further has one or more of the following features:

(a) The concentration of the compound of formula I in the organic solvent is 0.1-0.5mmol/mL, preferably 0.30-0.40mmol/mL;

(b) The reaction is carried out at a temperature of 5-40 ℃, preferably 10-20 ℃;

(c) The reaction time of the reaction is 1-4h, preferably 2h;

(d) The reaction further comprises: after the reaction is finished, adding an organic solvent for crystallization, wherein the organic solvent is selected from the group consisting of: n-heptane, methylene chloride, methyl tertiary ether, toluene, or a combination thereof.

In another preferred embodiment, in step s4, the ammoniation is carried out under conventional acid amine condensation reaction conditions.

In another preferred embodiment, in step s4, the ammoniation is performed in the presence of a condensing agent, a catalyst, a nitrogen source, wherein the condensing agent is selected from condensing agents commonly used in acid amine condensation reactions, such as: 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI), N, N '-Carbonyldiimidazole (CDI), N, N-Dicyclohexylcarbodiimide (DCC), CBMIT, N, N, N', N '-tetramethyl-O- (7-azabenzotriazol-1-yl) hexafluoro-phosphate urea (HATU), 1-propylphosphoric anhydride (T3P), N, N' -Diisopropylcarbodiimide (DIC), or chloroformates of formula VI,

Wherein R6 is a C1-C10 alkyl group.

The ammonia source is selected from: ammonia, ammonia water, ammonium chloride, ammonium bicarbonate, ammonium carbonate, hexamethyldisilazane, ammonium acetate, ammonium formate, formamide, and ammonium carbamate.

The catalyst is selected from the group consisting of: 4- (dimethylamino) pyridine, N-diisopropylethylamine, triethylamine, or 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU).

In another preferred embodiment, in step (s 1), the method further comprises the steps of:

i) Reacting the compound II-1 with the compound II-2 to obtain a compound II-3;

II) reacting compound II-3 with compound II-4 to give compound II-5;

The reaction formula is as follows:

Wherein the wavy line is denoted as a racemic structure.

In a third aspect of the invention there is provided a diastereomeric salt, or a pharmaceutically acceptable salt thereof, of the formula:

wherein Ar is as defined in the first aspect of the invention.

In another preferred embodiment, the diastereomeric salt is IVa.

In another preferred embodiment, the diastereomeric salt has an ee (enantiomeric excess) value of greater than or equal to 98%, greater than or equal to 99%, greater than or equal to 99.5% or greater than or equal to 99.8%.

In a fourth aspect of the present invention, there is provided a non-nefarnesone intermediate which is a compound of formula II or an isomer or pharmaceutically acceptable salt thereof

In another preferred embodiment, the intermediate is a racemic compound of formula II.

In another preferred embodiment, the intermediate is the (S) -isomer of the compound of formula II, i.e., the compound of formula I

In another preferred embodiment, the ee value of the intermediate is not less than 98%, not less than 99%, not less than 99.5% or not less than 99.8%.

In a fifth aspect of the invention there is provided the use of a diastereomeric salt according to the third aspect of the invention, or a pharmaceutically acceptable salt thereof, and a compound of formula II according to the fourth aspect of the invention, or an enantiomer thereof, or a pharmaceutically acceptable salt thereof, as an intermediate in the preparation of a non-nefarnesone.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Drawings

FIG. 1 is a table of HPLC spectra peaks for compound I-1 prepared in example 5.

FIG. 2 is a table of HPLC spectrogram peaks for compound I-1 sample prepared in comparative example 1.

Detailed Description

The inventor of the present invention has studied extensively and intensively, and found a preparation method of non-nereidone suitable for industrial production unexpectedly, in particular, the inventor found a new non-nereidone intermediate, and after nitrile ethyl/benzyl is replaced by specific p-methoxybenzyl in the existing technology, not only can the intermediate with high ee value be obtained, but also the p-methoxybenzyl of the present invention is easier to remove, does not need palladium carbon hydrogenation reduction, and can remove the protecting group at normal temperature and normal pressure only by using trifluoroacetic acid. In addition, the inventors have found that after the resolution step is performed by reducing the amount of the resolving agent to about 0.5 equivalent, the resolving agent can selectively form a salt with the compound of formula II in a single configuration, thereby being easier to separate from the compound of the enantiomer (non-salt form), having better resolution effect and being capable of effectively saving the resolving agent and the preparation cost. The method has the advantages of simple operation, mild condition, no need of special reagent and equipment and no need of expensive reagent, and the purity of the non-neridrone prepared by the method is more than 99.9%, the ee value can reach 100%, thus being very suitable for industrial production. On this basis, the inventors completed the present invention.

Definition of the definition

The following are definitions of terms used in the present specification. Unless otherwise indicated, the initial definition of a group or term provided herein applies to the group or term in this specification, either alone or as part of another group.

As used herein, the term "comprising" or "including" can be open, semi-closed, and closed. In other words, the term also includes "consisting essentially of …", or "consisting of …".

The prefix "Cu-v" means that the following groups have u to v carbon atoms, e.g. "C1-6" may be C1, C2, C3, C4, C5 or C6. For example, "C1-6 alkyl" means that the alkyl group has 1 to 6 carbon atoms.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine, iodine.

The term "alkyl" refers to a straight or branched chain unsubstituted hydrocarbon group having 1 to 10 carbon atoms (i.e., C1-10 alkyl), preferably 1 to 6 carbon atoms (i.e., C1-6 alkyl), more preferably 1 to 3 carbon atoms (i.e., C1-3 alkyl). Examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-methylpentyl, and the like.

The terms "aromatic ring" and "aryl" refer to aromatic carbocyclic groups having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl has 6 to 14 ring carbon atoms (i.e., C6-14 aryl), 6 to 12 carbon ring atoms (i.e., C6-12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Aryl groups include bicyclic groups that include in the group a ring fused to a saturated or partially unsaturated aromatic ring, or an aromatic carbocyclic or heterocyclic ring. Typically aryl groups include, but are not limited to, the following groups: benzene, naphthalene, anthracene, biphenyl, 1, 2-dihydronaphthalene, 1,2,3, 4-tetrahydronaphthalene, and the like. The "aryl" category includes aryl ring structures fused to cycloalkyl, heterocycloalkyl, and heteroaryl rings.

The term "heteroaryl" or "heteroaromatic ring" refers to a heteroaromatic system containing one or more heteroatoms selected from oxygen, nitrogen, sulfur, silicon, boron and phosphorus, including monocyclic, bicyclic or polycyclic fused systems. Heteroaryl groups may be optionally substituted with one or more substituents described herein. As used herein, heteroaryl groups can have 5 to 14 ring atoms (i.e., 5-14 membered heteroaryl), 5 to 12 ring atoms (i.e., 5-12 membered heteroaryl), 5 to 10 ring atoms (i.e., 5-10 membered heteroaryl), 5 to 8 ring atoms (i.e., 3-8 membered heteroaryl), or 5 to 6 ring atoms (i.e., 5-6 membered heteroaryl). Heteroaryl groups may have 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, wherein the ring heteroatoms are independently selected from oxygen, nitrogen, sulfur, silicon, boron, and phosphorus. Examples of "heteroaryl" include, but are not limited to, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, pyrazinyl, imidazopyridyl, benzofuranyl, pyrimidinyl, triazolyl, tetrazolyl, furanyl, thienyl, thiazolyl, quinolinyl, isoquinolinyl, indolyl, and the like.

The term "substituted" means that one or more hydrogen atoms in a particular group is replaced by any of the substituents mentioned in the specification of the present invention. Unless otherwise specified, the term "substituted" means that 1 or more (e.g., 2, 3, or 4) hydrogens on the group are optionally independently replaced with a group selected from the group consisting of: C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, nitro, cyano, carboxyl, hydroxyl, and amido.

Compounds of formula II and process for their preparation

The invention provides a racemized compound of formula II and a preparation method thereof, and the racemized compound is used as a key intermediate for preparing non-nefarnesone, has the advantages of mild reaction conditions, high yield, high product purity and the like, and is very suitable for industrial production of the non-nefarnesone.

A process for the preparation of a compound of formula ii comprising the steps of:

i) Reacting the compound II-1 with the compound II-2 to obtain a compound II-3;

II) reacting compound II-3 with compound II-4 to give compound II-5;

The reaction formula is as follows:

compounds of formula I and process for their preparation

The present invention also provides a process for preparing a compound of formula I from a compound of formula II, comprising the steps of:

In another preferred embodiment, ar is selected from the group consisting of:

Wherein represents the connection point.

Preferably, in step 1, the molar ratio of the compound of formula ii to the compound of formula iiia is 1:0.4-1.2, preferably 1:0.5-0.6, more preferably 1:0.51-0.55. Alternatively, the molar ratio of S-configuration compound (formula I compound) to formula IIIa in the compound of formula II is 1:1-1.2, more preferably 1:1-1.1.

Preferably, in step 1, the molar ratio of the compound of formula II to the compound of formula IIIb is 1:0.4-1.2, preferably 1:0.5-0.6, more preferably 1:0.51-0.55. Alternatively, the molar ratio of the R-configuration compound to the IIIb compound in the compound of formula II is 1:1-1.2, more preferably 1:1-1.1.

In another preferred embodiment, in step 1, the resolving agent is a compound of formula IIIa. Particularly, when the resolving agent is a compound of formula IIIa, the compound of formula IIIa can form salt with a required compound of formula II of S configuration selectively and preferentially, but is not easy to form salt with a compound of formula II of R configuration, so when the molar ratio of the compound of formula IIIa to the racemized compound of formula II is about 0.5 (such as 0.5-0.6), the compound of formula II of S configuration can be converted into salt, and the salt is obtained through crystallization, filtration and separation; at this time, the compound of formula II in R configuration does not form salt yet, is not easy to crystallize, remains in the filtrate, is easy to separate from crystals obtained by crystallization, and avoids split salt eutectoid of the compound of formula II in two configurations. Surprisingly, with about half the amount of compound resolving agent of formula IIIa, a high yield of resolved salt of S-configuration formula II can be obtained, and the product ee (. Gtoreq.99.5%) is rather higher than when a sufficient amount of resolving agent is used.

In fact, when the ee value in the compounds of the formula II does not meet the desired requirements (e.g.an ee value of 90%, an ee value of 50% or an ee value of 0), further resolution can be carried out using the process according to the invention.

Diastereomeric resolution salts

The invention also provides a diastereomeric salt or a pharmaceutically acceptable salt thereof, which is shown in the following formula:

wherein Ar is as defined in the first aspect of the invention.

In another preferred embodiment, the diastereomeric salt is IVa.

The invention also provides the (S) -isomer of the compounds of formula II, i.e. the compounds of formula I

Preparation method of non-nereirenone

The present invention also provides a novel process for preparing non-nelidane, comprising the steps of:

(s 1) providing a compound of formula II;

(s 4) ammonifying the compound shown in the formula I-1 to obtain non-netilone;

The reaction formula is as follows:

the compound of the formula II uses a specific p-methoxybenzyl protecting group, and experiments show that the protecting group can be removed under an acidic condition at normal temperature, compared with the benzyl protecting group which is removed by hydrogenation reduction of palladium carbon in the prior art, the compound of the formula II does not need expensive reagents and special equipment, has low energy consumption, mild reaction conditions, less impurity generation, stable process and high product purity (the purity is more than or equal to 98 percent and even more than or equal to 99 percent), and is very suitable for large-scale industrial production.

The advantages of the invention include:

1. The invention adopts the specific methoxybenzyl as the protecting group, so that the step of removing the protecting group avoids palladium-carbon hydrogenation reduction which is not suitable for industrial production, expensive reagents and special equipment are not needed, and the energy consumption is low;

2. The reaction condition of the deprotection step is mild, the deprotection can be carried out at room temperature and normal pressure, less impurities are generated, the purity of the product is higher, and the quality is controllable;

3. The consumption of resolving agent is reduced, on one hand, the cost is reduced, and on the other hand, the resolving effect and the process stability are improved;

4. The ee value of the intermediate compound I can reach more than 99.8%, and the ee value of the final product non-nefardone can reach more than 99.9%.

The invention will be further illustrated with reference to specific examples. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. 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.

Example 1

Preparation of Compound II

Compound II-1 (150.0 g,0.93 mol) was dissolved in isopropyl alcohol (750 mL), acetic acid (1.68 g,0.028 mol), piperidine (2.38 g,0.028 mol) and compound II-2 (227.35 g,1.02 mol) were added, reacted at 50℃and after the reaction was completed, the temperature was lowered to 15℃and stirred for 0.5h, filtered, and the cake was dried under reduced pressure at 45℃to give 319.30g of compound II-3 in a molar yield of 93.89%.

Compound II-3 (320 g,0.88 mol) and compound II-4 (119.59 g,0.96 mol) were dissolved in DMF (1280 mL), warmed to 120℃and incubated for 8h. Concentrating the reaction system under reduced pressure until no fraction is present, cooling to 60 ℃, adding ethanol (1600 mL) for refluxing for 0.5h, cooling to 20 ℃, stirring for 2h, filtering, and drying the filter cake under reduced pressure at 50 ℃ to obtain 345.89g of the compound II-5 with a molar yield of 83.76%.

Compound II-5 (200.0 g,0.42 mol) was dissolved in DMF (500 mL), warmed to 115℃and reacted with triethyl orthoformate (138.30 g) and concentrated sulfuric acid (10.20 g, diluted with 100mL of LDMF) at 115℃with 600mL of water added after the completion of the reaction, cooled to room temperature and stirred for over 0.5h, filtered, and the filter cake was dried under reduced pressure at 45℃to give 188.27g of Compound II in 88.85% molar yield.

Example 2

Preparation of Compound Iva-1

Compound II (5.00 g,10.0 mmol) and compound IIIa-1 (1.97 g,5.5 mmol) were added to a mixed solvent of acetic acid (25 mL) and ethyl acetate (50 mL), heated to 65℃for reaction, cooled to 50℃for crystallization for 2 hours, cooled to 25℃for filtration, the filter cake was rinsed with ethyl acetate, and the filter cake was dried under reduced pressure at 45℃to give 4.20g of compound Iva-1 (97.83% of theory) with ee value of 99.5%.

Example 3

Preparation of Compound I

To compound Iva-1 (10.0 g,11.7 mmol) was added water (100 mL), stirred for 0.5h, dropwise added 20% aqueous sodium hydroxide solution, the aqueous phase PH adjusted to 9, stirred for 2h, filtered, rinsed once with water (20 mL), and the filter cake dried to give 5.49g of compound I in a molar yield of 94.28%, ee value of 99.8%, purity of 99.7%.

Example 4

Preparation of Compound I

Compound II (5.00 g,10.0 mmol) and compound IIIb-1 (2.12 g,5.5 mmol) were added to isoamyl acetate (90 mL), heated to 100 ℃ for reaction, cooled to 80 ℃ for crystallization for 2 hours, cooled to 60 ℃ for filtration, the filtrate was concentrated under reduced pressure until no fraction was distilled off, water (50 mL) and methylene chloride (50 mL) were added, stirred for 0.5h, separated, the organic phase was washed once with water (50 mL), the organic phase was concentrated under reduced pressure until no fraction was distilled off, ethyl acetate (30 mL) was added, stirred for 2h under reflux, cooled to 20 ℃ for crystallization for 2h, filtration, and cake drying gave 4.49g of compound I with a molar yield of 89.80%, an ee value of 99.2% and a purity of 99.5%.

Example 5

Preparation of Compound I-1

Compound I (5.0 g,10.0 mmol) was dissolved in dichloromethane (30 mL), trifluoroacetic acid (3.42 g,30.0 mmol) was added, the mixture was stirred at 15℃for 2h, the HPLC purity of the reaction solution was measured, the content of the target compound I-1 was 98.0%, and the HPLC spectrum was shown in FIG. 1; adding 20mL of water, stirring for 1h, separating, taking an organic phase, cooling to about 5 ℃, dropwise adding n-heptane (90 mL), and continuously stirring for 2h for crystallization after the dropwise adding is finished; filtration, washing the filter cake once with a mixed solvent (5 mL) of dichloromethane and n-heptane (1:3), and drying the filter cake gave 3.72g of compound I-1 in 97.96% molar yield, 99.6% ee and 99.1% purity.

Example 6

Finerenone preparation

Compound I-1 (10 g,26.4 mmol) and N, N' -carbonyldiimidazole (5.1 g,31.5 mmol) were dissolved in acetonitrile (50 mL) and reacted at 0-10℃for 1h; 4-dimethylaminopyridine (0.32 g,2.62 mmol) and 25% ammonia (73.90 g,527.1 mmol) were added, heated to reflux, reacted for 2h, cooled to 45 ℃, water (100 mL) was added dropwise, cooled to room temperature after the dropwise addition, filtered, and the filter cake was rinsed twice with water (10 mL each time); absolute ethyl alcohol (40 mL) is added into the filter cake, reflux is carried out for 0.5h, the temperature is reduced to 0-5 ℃, filtration is carried out, the filter cake is dried, 8.95g of product is obtained, the molar yield is 89.72%, the purity is 99.9%, and the ee value is 100%.

Comparative example 1

Preparation of Compound I-1 (catalyzed by palladium on carbon)

Compound I (5.0 g,10.0 mmol) was dissolved in tetrahydrofuran (50 mL), 5% palladium on carbon (0.29 g) was added, argon was substituted 3 times, hydrogen pressure was 0.5Mpa, reacted at room temperature for 3 hours, HPLC purity of the reaction solution was measured, content of target compound I-1 was 89.6%, and HPLC profile was shown in fig. 2; filtering palladium carbon, concentrating the filtrate under reduced pressure until no fraction is distilled out; adding dichloromethane (30 mL) and water (20 mL) into the concentrated solution, stirring for 1h, separating, taking an organic phase, cooling to about 5 ℃, dropwise adding n-heptane (90 mL), and continuing stirring for 2h for crystallization after the dropwise adding is finished; filtration, washing the filter cake once with a mixed solvent (5 mL) of dichloromethane and n-heptane (1:3), and drying the filter cake gave 3.63g of Compound I-1 in a molar yield of 95.59%, ee value of 99.4% and purity of 92.8%.

Comparative example 2

Preparation of Compound I-1 (starting from benzyl-protected Compound V)

Compound V (5.0 g,10.6 mmol) was dissolved in dichloromethane (30 mL), 3 equivalents of the acid in the following table were added, the reaction was stirred at 15℃and after 2h the reaction was observed as a spot-on-plate:

The acid used	Reaction conditions
		Trifluoroacetic acid	Almost no product is produced
Sulfuric acid	A small amount of product is produced, but the impurity is large and more
		Hydrochloric acid	A small amount of product is produced, but the impurity is large and more

Comparative example 3

Preparation of Compound Iva-1 (Using 1.1 equivalents of resolving agent)

Compound II (5.00 g,10.0 mmol) and compound IIIa-1 (3.94 g,11.0 mmol) were added to a mixed solvent of acetic acid (25 mL) and ethyl acetate (50 mL), heated to 65℃for reaction, cooled to 50℃for crystallization for 2 hours at a constant temperature, cooled to 25℃for filtration, the filter cake was rinsed with ethyl acetate, and the filter cake was dried under reduced pressure at 45℃to give 4.48g of compound Iva-1 (104.35% of theory) with an ee value of 97.5%.

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

1. A process for preparing a compound of formula I comprising the steps of:

(1) Resolving the racemic compound of the formula II by using a resolving agent shown in a formula IIIa compound or a formula IIIb compound to obtain a compound of the formula I;

Wherein the resolving agent in step (1) is a compound of formula IIIa, step (1) comprising:

(1 a-2) treating the salt shown in the compound of the formula IVa obtained in the step 1 with alkali to obtain a compound of the formula I; or alternatively

The resolving agent in the step (1) is a compound of formula IIIb, and the step (1) comprises:

(1 b-1) reacting a racemic compound of formula II with a compound of formula IIIb to form a salt, and removing the salt represented by the compound IVb to obtain a compound of formula I;

wherein Ar is unsubstituted or substituted C6-C14 aryl or unsubstituted or substituted C5-C14 heteroaryl containing 1 to 3 groups selected from O, N and S, wherein said substitution is substituted with one or more groups selected from the group consisting of:

C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, halogen, nitro, cyano, carboxyl, hydroxyl, and amido.

2. The method of claim 1, wherein Ar has a structure as shown in formula V:

3. The method of claim 1, wherein Ar is selected from the group consisting of:

Wherein represents the connection point.

4. The method of claim 1, wherein in step 1 the molar ratio of the compound of formula ii to the compound of formula iiia is 1:0.4-1.2, preferably 1:0.5-0.6, more preferably 1:0.51-0.55.

5. The method of claim 1, wherein in step 1, the molar ratio of the compound of formula ii to the compound of formula IIIb is 1:0.4-1.2, preferably 1:0.5-0.6, more preferably 1:0.51-0.55.

6. The method of claim 4, wherein in step 1, the resolving agent is a compound of formula IIIa.

7. A process for preparing non-nelidane, the process comprising the steps of:

(s 1) providing a compound of formula II;

(s 2) starting from a compound of formula II, and preparing a compound of formula I by resolution, wherein the process for preparing the compound of formula I is as described in claim 1;

(s 3) removing p-methoxybenzyl from the compound shown in the formula I to obtain a compound shown in the formula I-1; wherein p-methoxybenzyl is removed using an acid, wherein the acid is selected from the group consisting of: trifluoroacetic acid, methanesulfonic acid, sulfuric acid, hydrochloric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid;

(s 4) ammonifying the compound shown in the formula I-1 to obtain non-netilone;

The reaction formula is as follows:

8. A diastereomeric salt or a pharmaceutically acceptable salt thereof, of the formula:

Wherein Ar is as defined in claim 1.

9. A non-nefarnesone intermediate is a compound or a pharmaceutically acceptable salt thereof

Wherein formula II is racemate.

10. Use of a diastereomeric salt according to claim 8, or a pharmaceutically acceptable salt thereof, or a compound of formula II according to claim 9, or an enantiomer thereof, or a pharmaceutically acceptable salt thereof, as an intermediate in the preparation of non-nefarnesone.