WO2022257833A1

WO2022257833A1 - Intermediate of substituted phenylpropyl pyridine derivative and preparation method for intermediate

Info

Publication number: WO2022257833A1
Application number: PCT/CN2022/096632
Authority: WO
Inventors: 朱卫星; 刘强; 郝旭辉; 陈永刚; 李少博; 曾振亚; 赵志明
Original assignee: 上海海雁医药科技有限公司; 扬子江药业集团有限公司
Priority date: 2021-06-07
Filing date: 2022-06-01
Publication date: 2022-12-15

Abstract

The present application relates to an intermediate of a phenylpropyl pyridine derivative and a preparation method for the intermediate. The intermediate is a compound as represented by formula (I) or a pharmaceutically acceptable salt thereof.

Description

Substituted phenylpropenylpyridine derivative intermediate and preparation method thereof

Cross References to Related Applications

This application claims the priority of the Chinese patent application submitted to the China Patent Office on June 7, 2021, with the application number 202110632353.3, and the title of the invention is "Substituted phenylpropenylpyridine derivative intermediate and its preparation method". The entire contents are incorporated by reference in this application.

technical field

The application relates to the field of organic chemical synthesis, in particular to an intermediate of substituted phenylpropenylpyridine derivatives and a preparation method of the intermediate.

technical background

Programmed cell death-1 (PD-1), a member of the CD28 superfamily, delivers negative signals when interacting with its two ligands, PD-L1 or PD-L2. PD-1 and its ligands are ubiquitously expressed and exert a wider range of immunomodulatory roles in T cell activation and tolerance than other CD28 members. PD-1 and its ligands are involved in attenuating infectious and tumor immunity, and promoting chronic infection and tumor progression. The biological importance of PD-1 and its ligands suggests the therapeutic possibility of manipulation of the PD-1 pathway for various human diseases.

At present, many patents have reported a variety of different types of PD-1 or PD-L1 inhibitors, such as the PD-1 inhibitors with inhibitory activity of the compound represented by formula (II), the effect is particularly remarkable.

The preparation method of this type of compound is to use compound 18a as a key intermediate, introduce cyano and amine groups through compound 18a, wherein, cyano is a key group that affects the activity of compounds shown in formula (II), and amine is used to construct benzene And [d] oxazole ring. The synthetic method of compound 18a is:

Due to the presence of both cyano and nitro groups on the benzene ring of compound 18a-1 (i.e. (R)-1-(3-cyano-4-hydroxy-5-nitrobenzyl)pyrrolidine-3-carboxylate) , so in the process of reducing the nitro group to an amine group, the cyano group is also easily reduced, and it is found in the process research that the by-product produced by the reduction reaction has the same polarity as the target compound 18a and is difficult to separate, so the compound 18a is used as an intermediate, The method for preparing the compound represented by formula (II) is difficult to apply in industrial scale-up.

Therefore, it is necessary to develop new intermediates and synthetic routes to prepare compounds shown in formula (II) to meet the needs of industrial production.

Contents of the invention

According to various embodiments of the present application, an intermediate of a substituted phenylpropenylpyridine derivative and a preparation method thereof are provided.

The first aspect of the present application provides an intermediate, which is a compound represented by formula (I) or a salt thereof:

in,

R ₁ and R ₂ are each independently hydrogen, cyano, acetyl, hydroxyl, carboxyl, nitro, halogen (preferably Cl, F), C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, NR _a0 R _b0 , -CONR _a0 R _b0 , -SO ₂ NR _a0 R _b0 , -SO ₂ C _1-6 alkyl, phenyl, 5 to 6-membered heteroaryl, C _3-6 cycloalkyl or 3-6 membered saturated monoheterocycle, wherein the phenyl, 5-6 membered heteroaryl, C _3-6 cycloalkyl, 3-6 membered The saturated monoheterocycle is unsubstituted or replaced by 1, 2 or 3 independently selected from acetyl, hydroxyl, cyano, carboxyl, nitro, halogen, C _1-3 alkyl, halogenated C _1-3 alkane Substituents of radical, C _1-3 alkoxy, halogenated C _1-3 alkoxy, C _3-6 cycloalkyl, NR _a1 R _b1 , -CONR _a1 R _b1 , -SO ₂ NR _a1 R _b1 ;

R _G1 is -CHO or -CH(OR _G10 )(OR _G20 ); wherein R _G10 and R _G20 are each independently a C _1-6 alkyl group, or R _G10 and R _G20 form a 5-membered group together with the attached oxygen atom Or 6-membered saturated monoheterocycle;

R ₃ and R _a are each independently hydrogen, hydroxyl, cyano, nitro, acetyl, carboxyl, halogen (preferably Cl, F), hydroxymethyl, hydroxyethyl, cyanomethyl, cyanoethyl , C _1-6 alkyl, C _1-6 alkoxy, halogenated C _1-6 alkyl, halogenated C _1-6 alkoxy, -NR _a0 R _b0 , C _3-6 cycloalkyl, - CONR _a0 R _b0 or -SO ₂ NR _a0 R _b0 ;

R _Gb is hydrogen or a hydroxyl protecting group;

R _a0 , R _b0 , R _a1 , and R _b1 are each independently hydrogen, C _1-3 alkyl or halogenated C _1-3 alkyl.

In some embodiments, R ₁ and R ₂ are each independently hydrogen, cyano, hydroxyl, nitro, halogen (preferably Cl, F), C _1-6 alkyl (preferably C ₁₄ alkyl), C _1-6 alkoxy (preferably C _1-4 alkoxy), halogenated C _1-6 alkyl (preferably halogenated C _1-4 alkyl), halogenated C _1-6 alkoxy.

In some embodiments, _one of R and R is an electron _- withdrawing group and one is an electron-donating group.

In some embodiments, one of R ₁ and R ₂ is C _1-6 alkoxy, and one is halogenated C _1-6 alkyl.

In some embodiments, one of R ₁ and R ₂ is C _1-6 alkoxy, and one is fluoro C _1-6 alkyl.

In some embodiments, R ₁ is trifluoromethyl and R ₂ is methoxy.

In some embodiments, R _G1 is -CHO.

In some embodiments, R ₃ and R _a are each independently: hydroxyl, cyano, nitro, acetyl, carboxyl, F, Cl, hydroxymethyl, hydroxyethyl, cyanomethyl, cyanoethyl , C _1-3 alkyl, halogenated C _1-3 alkyl, halogenated C _1-3 alkoxy, -NR _a0 R _b0 , C _3-6 cycloalkyl, -CONR _a0 R _b0 , -SO ₂ NR _a0 R _b0 ; wherein R _a0 and R _b0 are each independently hydrogen or C _1-3 alkyl.

In some embodiments, R ₃ and R _a are each independently C _1-6 alkyl (preferably C _1-3 alkyl).

In some embodiments, R ₃ and R _a are each independently methyl or ethyl.

In some embodiments, the hydroxyl protecting group is selected from the group consisting of: trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, benzyl, p-methoxybenzyl group, trityl, benzoyl, p-nitrobenzoyl, acetyl, and p-toluenesulfonyl.

In some embodiments, the compound shown in formula (I) is the compound shown in formula (I-1):

In some embodiments, the compound shown in formula (I) is the compound shown in formula (I-2):

By adopting the compound shown in formula (I) as the key intermediate, the compound shown in formula (II) can be obtained in high yield through simple reactions such as reductive amination and oxidation, the reaction conditions are easy to control, and the post-treatment is simple; and the formula (I ) The compound shown in ) is simple to synthesize, has wide sources of raw materials, convenient post-treatment, and is suitable for industrial production and application.

The second aspect of the present application provides a method for preparing the intermediate shown in the first aspect, comprising the following steps:

S100: Coupling the compound represented by formula (I-A) with the compound represented by formula (I-B) to prepare the compound represented by formula (I); optionally, salt-forming the compound represented by formula (I) Reaction, the salt of compound shown in formula (I) is prepared.

Among them, R _Ga and R _G2 are a pair of groups capable of coupling reaction.

In some embodiments, R _Ga and R _G2 are a pair of groups capable of Suzuki coupling reaction.

In some embodiments, one of R _Ga and R _G2 is halogen, and the other is (HO) ₂ B- or borate (including pinacol borate).

In some embodiments, R _Ga is Br, Cl or I; R _G2 is (HO) ₂ B- or boronate (including pinacol borate).

In some embodiments, R _G2 is Br, Cl or I; R _Ga is (HO) ₂ B- or a boronate group (including pinacol borate group).

In some embodiments, the compound of Formula (I-A) is:

In some embodiments, the compound of formula (I-B) is:

In some embodiments, step S100 includes the following steps:

S110: Mix and react the compound represented by formula (I-A), the compound represented by formula (I-B), solvent, catalyst and base to prepare the compound represented by formula (I).

In some embodiments, in step S110, the molar ratio of the compound represented by formula (I-A) to the compound represented by formula (I-B) is about (1-1.2):1.

In some embodiments, in step S110, the solvent is selected from: toluene, xylene, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, diethyl ether, dichloromethane, chloroform, 1,2-di Ethyl chloride, ethyl acetate, acetonitrile, dimethylsulfoxide, N,N-dimethylformamide, methanol, ethanol, propanol, isopropanol, butanol, water, and combinations thereof.

In some embodiments, the solvent is a mixed solvent composed of 1,4-dioxane and water; further, the volume ratio of 1,4-dioxane and water is about (2-5):1.

In some embodiments, in step S110, the catalyst is a palladium catalyst; further, the palladium catalyst is selected from the group consisting of: palladium carbon, tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ), tetrakis(tri Phenylphosphino)palladium (Pd(PPh ₃ ) ₄ ), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl ₂ ), palladium acetate, dichloro Bis(triphenylphosphine)palladium, palladium trifluoroacetate, triphenylphosphinepalladium acetate, bis(triphenylmethylphosphine)palladium dichloride, 1,2-bis(diphenylphosphino)ethane dichloride Palladium chloride and combinations thereof. Further, the catalyst is Pd(dppf)Cl ₂ .

In some embodiments, in step S110, the base is an inorganic base or an organic base; further, the base is selected from: triethylamine, diisopropylethylamine, tributylamine, sodium methoxide, sodium ethoxide, potassium ethoxide , sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, 1,8-diazabicyclo[5,4,0]-7-undecene (DBU), sodium hydroxide, potassium hydroxide, carbonic acid Sodium, potassium carbonate, N-methylmorpholine, pyridine and combinations thereof. Further, the base is potassium carbonate or sodium carbonate.

In some embodiments, in step S110, the reaction temperature is about 60°C to about 150°C; further, the reaction temperature is about 80°C to about 120°C; further, the reaction temperature is about 90°C to about 110°C.

In some embodiments, the step of preparing the compound shown in formula (I-A) is also included:

S121: reacting the compound represented by the formula (IA-5) with 1,1-dichloromethyl ether to prepare the compound represented by the formula (IA-4) in which R _G1 is an aldehyde group;

Wherein Y is a halogen;

S122: Optionally, for the protecting group on the aldehyde group on the compound represented by the formula ( _IA -4) _where R _G1 is an aldehyde group, the formula ( _IA- 4) the compound shown;

S123: reacting the compound shown in formula (I-A-4) and the compound shown in formula (I-A-3) to prepare the compound shown in formula (I-A-2);

Wherein M is a boronic acid group or a borate ester group; and

S124: reacting the compound represented by formula (I-A-2) with the compound represented by formula (I-A-1) to prepare the compound represented by formula (I-A).

Understandably, step S122 can be omitted when the compound represented by formula (IA-4) in which R _G1 is an aldehyde group is used in the subsequent steps. In addition, in step S122, methods known in the art for protecting aldehyde groups can be used, which are not specifically limited here, and should be understood as being within the protection scope of the present application. In some embodiments, the aldehyde group protected by a protecting group is -CH(OR _G10 )(OR _G20 ); wherein R _G10 and R _G20 are as defined in the specification.

In some embodiments, in the compound represented by formula (I-A-5), Y is Br.

In some embodiments, Y is I in the compound represented by formula (I-A-1).

In some embodiments, M is

In some embodiments, step S121 includes the following steps: mixing the compound represented by formula (IA-5), 1,1-dichloromethyl ether and a solvent (preferably DCM), in an inert gas atmosphere, the temperature is about -60 Under the condition of below ℃ (preferably about -80 ℃ to about -60 ℃), add TiCl ₄ , carry out the reaction after the dropwise addition, after the reaction is completed, _quench the reaction, post-treatment, and obtain the formula ( IA-4) shown compound.

Further, the molar ratio of the compound represented by formula (I-A-5) to 1,1-dichloromethyl ether is about 1:(1.8-2.2); further, the molar ratio is about 1:2.

Further, the molar ratio of the compound represented by formula (IA-5) to TiCl ₄ is about 1:(2.5-3.5); further, the molar ratio is about 1:3.

Further, step S121 also includes a post-processing step, the post-processing includes: extracting, obtaining an organic phase, drying and concentrating to obtain a crude product, stirring the crude product with petroleum ether, solids are precipitated, collecting the solid by filtration, and drying.

In some embodiments, step S123 includes the following steps: compound shown in formula (I-A-4), compound shown in formula (I-A-3), solvent (preferably aprotic solvent, more preferably toluene), catalyst, ligand Mix body and alkali, react under inert gas (preferably carry out lock reaction under the condition of about 90°C to about 100°C), after the reaction, carry out post-treatment to prepare the compound shown in formula (I-A-2).

Further, the catalyst may be a catalyst suitable for this type of reaction well known in the art, such as a palladium catalyst. In yet other embodiments, the catalyst is Pd ₂ (dba) ₃ ; the ligand is tri-tert-butylphosphine tetrafluoroborate.

Further, the molar ratio of the compound represented by formula (I-A-4) to the compound represented by formula (I-A-3) is about 1:(1.1-1.3).

In some embodiments, step S124 includes the following steps: mixing the compound shown in formula (I-A-2), the compound shown in formula (I-A-1), catalyst, base and solvent, reacting under an inert gas atmosphere, after the reaction Post-treatment is carried out to obtain the compound represented by formula (I-A).

Further, in step S124, the solvent can be a conventional inert solvent known in the art, and in some embodiments, the solvent is a combination of 1,4-dioxane and water; further, 1,4-dioxane The volume ratio with water is about (2-4):1.

Further, in step S124, the molar ratio of the compound represented by formula (I-A-2) to the compound represented by formula (I-A-1) is about 1:(1.1-1.3).

Further, in step S124, the catalyst may be a catalyst well known in the art and suitable for this type of reaction, such as a palladium catalyst. In yet other embodiments, the catalyst is Pd(dppf)Cl ₂ .

Further, step S124 also includes a post-processing step. Post-processing includes: concentrating the reaction solution to obtain a concentrate, adding ethyl acetate, ultrasonically dispersing, filtering, collecting the filtrate, concentrating, and repeatedly using an organic solvent (preferably petroleum ether and The combination of ethyl acetate, more preferably the volume ratio of petroleum ether and ethyl acetate is about 8-12:1) is subjected to beating treatment, filtered, and the solid is collected and dried.

In some embodiments, in step S100, the following steps are also included:

S130: Using the compound shown in the formula (I-B-1) to prepare the compound shown in the formula (I-B):

Wherein, X is Br, Cl or I, and the definitions of other groups are as above, and will not be repeated here.

In some embodiments, step S130 includes the following steps: mixing the compound represented by formula (IB-1), solvent, Zn(CN) ₂ , and catalyst, refluxing under an inert gas atmosphere, and post-processing to obtain formula (IB) Compounds shown.

In some embodiments, the solvent in step S130 is a mixed solvent of THF and water; further, the volume ratio of THF and water is about (0.8-1.2):1.

In some embodiments, the reaction temperature in step S130 is about 60°C to about 150°C; further, the reaction temperature is about 80°C to about 120°C; further, the reaction temperature is about 90°C to about 110°C.

In some embodiments, preparing the compound represented by formula (I-B-1) comprises the following steps:

S131: Nitrate the compound represented by formula (I-B-7) to prepare the compound represented by formula (I-B-6);

Wherein R _c is C _1-6 alkyl; X is Br, Cl or I;

S132: performing a reduction reaction on the compound represented by the formula (I-B-6) to prepare the compound represented by the formula (I-B-4);

S133: reacting the compound shown in formula (I-B-4) with the compound shown in formula (I-B-5) to prepare the compound shown in formula (I-B-3);

Wherein Y is a halogen;

S134: performing a reduction reaction on the compound represented by formula (I-B-3) to prepare the compound represented by formula (I-B-2);

S135: Optionally, for the protecting group on the hydroxyl group on the compound shown in formula (IB-2), prepare the compound shown in formula (IB-1) in which R _Gb is a hydroxyl protecting group and R _Ga is a halogen;

S136: Optionally, the compound shown in formula (IB-2) is reacted with boric acid or boric acid ester to obtain the formula (IB-1) in which R _Ga is a boric acid group or a boric acid ester group and R _Gb is hydrogen compound.

It can be understood that step S135 and step S136 can be optionally carried out according to the structure of the compound used in the specific reaction, and the compound shown in formula (I-B-2) can be used to directly carry out the next step reaction without going through the hydroxyl protecting group reaction, or through the above Carry out next step reaction after hydroxyl protecting group reaction. Y in the compound represented by formula (I-B-2) can also be optionally converted into a boronic acid group or a borate ester group according to specific reaction needs. As long as the choice between step S135 and step S136 is not contrary to the purpose of the invention of the present application, there is no special limitation here, and it should be understood that all are within the protection scope of the present application.

In some embodiments, _Rc is methyl, ethyl, n-propyl, isopropyl, or tert-butyl.

In some embodiments, step S131 includes the following steps: mixing the compound represented by formula (I-B-7), acetic acid, and nitric acid for reaction, and post-processing after the reaction to obtain the compound represented by formula (I-B-6).

Further, in step S131, the reaction temperature is lower than about 40°C; further, the reaction temperature is about 15 to about 35°C.

In some embodiments, iron powder is used in step S132 to reduce the nitro group in the compound represented by formula (I-B-6).

Further, step S132 includes the following steps: mixing the compound represented by formula (IB-6), NH ₄ Cl and a solvent (preferably a mixed solvent of tetrahydrofuran and water, further, the volume ratio of tetrahydrofuran and water is about 8-12: 1) mixing, reacting, and post-processing to obtain the compound shown in formula (IB-4).

Further, in step S132, react at about 15°C to about 35°C for about 20 minutes to about 40 minutes, and then raise the temperature to about 55°C to about 60°C for about 1 hour to about 2 hours.

In some embodiments, step S133 includes the following steps: mixing the compound represented by formula (I-B-4), the compound represented by formula (I-B-5) and a solvent, stirring for about 18h to about 24h, concentrating to obtain a concentrate, and An organic solvent is added to the concentrate, and then DDQ is added for reaction. After the reaction is complete, the compound is washed to obtain the compound shown in formula (I-B-3).

In some embodiments, in step S134, lithium aluminum tetrahydrogen is used to reduce the compound represented by formula (I-B-3).

Further, step S134 includes the following steps: dissolving the compound represented by formula (I-B-3) in a solvent, adding lithium aluminum tetrahydrogen at a temperature below about -10°C, and performing the reaction, and quenching the reaction after the reaction is completed , post-treatment to obtain the compound shown in formula (I-B-2).

In some embodiments, step S136 includes the following steps: mixing the compound represented by formula (IB-2), boric acid or boric acid ester, solvent, catalyst (preferably Pd(dppf)Cl ₂ ), and acetate, and reacting , After the reaction, the post-treatment makes R _Ga a boronic acid group or a borate ester group, and R _Gb a compound shown in the formula (IB-1) of hydrogen.

The reaction conditions of each step of the preparation method of the compound represented by the above formula (I) are relatively mild, the yield is high, and most of the steps can reach the target purity through simple purification treatment, which is especially suitable for industrial production applications.

The third aspect of the present application provides a method for preparing the compound represented by the formula (II), including the step of preparing the compound represented by the formula (II) using the intermediate described in the first aspect of the present application;

Where R _a , R ₃ , R ₁ , and R ₂ are defined as above, and will not be repeated here;

A ring and B ring are each independently a 4-6 membered saturated nitrogen-containing monoheterocycle;

R ₀₁ and R ₀₂ are independently hydroxyl, carboxyl or -C(O)OC _1-3 alkyl;

m and n are 0, 1, 2 or 3 each independently.

In some embodiments, Ring A and Ring B are each independently a 5-membered nitrogen-containing monoheterocycle.

In some embodiments, Ring A and Ring B are each independently a 6-membered nitrogen-containing monoheterocycle.

In some embodiments, Ring A is a tetrahydropyrrole ring.

In some embodiments, Ring B is a tetrahydropyrrole ring.

In some embodiments,

each independently selected from any of the following groups:

In some embodiments, it also includes the step of preparing an intermediate by using the method described in the second aspect of the application.

In some embodiments, the preparation method of the compound represented by formula (II) comprises the following steps:

S210: Reductive amination of the compound represented by formula (I) in which R _G1 is an aldehyde group and the compound represented by formula (a) or its salt, to obtain the compound represented by formula (IA); or the compound represented by R _G1 is -CH (OR _G10 ) (OR _G20 ) After the compound shown in the formula (I) of (OR G20 ) removes the formaldehyde protecting group, carry out reductive amination reaction with the compound shown in the formula (a) or its salt, make the compound shown in the formula (IA);

S220: Oxidize the compound shown in formula (IA) where R _Gb is hydrogen to prepare the compound shown in formula (IB); or remove the hydroxyl protecting group from the compound shown in formula (IA) where R _Gb is a hydroxyl protecting group In addition to the reaction, the oxidation reaction is carried out to obtain the compound shown in the formula (IB); and

S230: performing reductive amination reaction on the compound represented by formula (IB) and the compound represented by formula (b) or its salt, to prepare the compound represented by formula (II);

Understandably, the method for deprotecting the aldehyde group in step S210 and the method for deprotecting the hydroxyl group in step S220 are not particularly limited, and methods well known in the art can be used, as long as they do not conflict with the purpose of the invention of the present application. It should be understood that all are within the protection scope of the present application.

In some embodiments, step S210 includes the following steps: mixing the compound represented by formula (I), the compound represented by formula (a) or a salt thereof, and a solvent (preferably an alcoholic solvent, more preferably anhydrous methanol), and About 10°C-about 30°C (preferably about 18°C-about 22°C) for about 60min-about 120min, then add NaBH ₃ CN, at about 10°C-about 30°C (preferably about 18°C-about 22°C) ) under the conditions of the reaction, after the reaction, post-treatment, the compound shown in the formula (IA) is obtained.

In some embodiments, step S210 includes the following steps: mixing the compound represented by formula (I), a solvent (preferably dichloromethane), and adding a mixture of a compound represented by formula (a) or a salt thereof, and a solvent (preferably methanol) , react at about 10°C-about 50°C (preferably about 35°C-about 45°C) for about 60min-about 120min, then add NaBH at about 5°C-about 25°C (preferably about 10°C-about 20°C) (OAc) ₃ , react under the condition of about 10°C-about 30°C (preferably about 20°C-about 25°C), after the reaction, post-treatment to prepare the compound represented by formula (IA).

Further, the molar ratio of the compound represented by formula (I) to the compound represented by formula (a) or its salt is about 1: (1.8-2.2); further, the molar ratio is about 1:2.

Further, the molar ratio of the compound represented by formula (I) to NaBH ₃ CN or NaBH(OAc) ₃ is about (1-1.2):1.

Further, step S210 also includes a purification step of the compound represented by formula (IA).

Further, the purification step includes: mixing the crude compound represented by formula (IA), an acid (preferably phosphoric acid), and a solvent (preferably ethyl acetate), and reacting at about 20°C to about 30°C for about 1h - about 3h to obtain the salt of the compound shown in the formula (IA); then the salt of the compound shown in the formula (IA), a solvent (preferably a mixed solvent of dichloromethane and methanol) mixed, at about 0 ° C to about 30 ° C ( Add alkali (preferably 10% potassium carbonate aqueous solution) under the condition of preferably about 10°C to about 20°C) for stirring, and post-treatment to obtain the refined product of the compound represented by formula (IA).

Further, the salt of the compound represented by the formula (IA) is a phosphate salt of the compound represented by the formula (IA).

In some embodiments, the compound shown in formula (IA) is the compound shown in formula (IA-1):

In some embodiments, step S220 includes the following steps: dissolving the compound represented by formula (IA) in a solvent (preferably the solvent is THF), adding IBX, and performing the reaction (preferably, the reaction temperature is about 45° C. to about 65° C.), After the reaction, after treatment, the compound shown in formula (IB) is obtained.

In some embodiments, step S220 includes the following steps: mixing and stirring IBX and a solvent (preferably a mixed solvent of DMSO and ethyl acetate) (preferably at a temperature of about 20° C. to about 30° C.), at about 0° C. to about 15 The compound represented by the formula (IA) is added under the condition of ℃ for reaction, and after the reaction is completed, the compound represented by the formula (IB) is obtained by post-processing.

Further, in step S220, the molar ratio of the compound represented by formula (IA) to IBX is about 1:(3-8).

Further, step S220 also includes a purification step of the compound represented by formula (IB).

Further, the purification step includes: mixing the crude compound represented by formula (IB), acid (preferably phosphoric acid), solvent (preferably ethyl acetate), and reacting at about 20°C to about 30°C for about 1h-about 3h to obtain the salt of the compound shown in formula (IB); then the salt of the compound shown in formula (IB), solvent (preferably a mixed solvent of ethyl acetate and methanol) mixed, at about 0 ℃ to about 30 ℃ (Preferably about 20°C to about 25°C), add alkali (preferably 10% potassium carbonate aqueous solution) for stirring, and post-treatment to obtain the refined product of the compound represented by formula (IB).

Further, the salt of the compound represented by the formula (IB) is a phosphate salt of the compound represented by the formula (IB).

In some embodiments, the compound shown in formula (IB) is the compound shown in formula (IB-1):

In some embodiments, step S230 includes the following steps: mixing the compound represented by formula (IB), the compound represented by formula (b) or its salt with a solvent, adding NaBH(OAc) ₃ , and performing the reaction. After the reaction, treatment to obtain the compound shown in formula (II).

In some embodiments, step S230 includes the following steps: the compound represented by formula (IB), the compound represented by formula (b) or a salt thereof, a base (preferably N,N-diisopropylethylamine) and a solvent ( The preferred solvent is a mixed solvent of anhydrous methanol and dichloromethane), and NaBH(OAc) ₃ is added for reaction. After the reaction, post-treatment is performed to obtain the compound represented by formula (II).

Further, the molar ratio of the compound represented by formula (IB) to the compound represented by formula (b) or its salt is about 1:(1.1-1.8); further, the molar ratio is about 1:(1.3-1.6).

Further, the molar ratio of the compound represented by formula (b) or its salt to the base is about 1:(1.1-1.8); further, the molar ratio is about 1:(1.3-1.6).

Further, step S230 also includes a purification step of the compound represented by formula (II).

Further, the purification step includes: mixing the crude compound represented by formula (II), acid (preferably oxalic acid), solvent (preferably ethyl acetate), and reacting at about 20°C to about 30°C for about 1h-about 3h to obtain the salt of the compound shown in formula (II); then the salt of the compound shown in formula (II), solvent (preferably a mixed solvent of ethyl acetate and methanol) mixed, at about 0 ℃ to about 30 ℃ (Preferably about 10°C to about 20°C), add alkali (preferably 10% potassium carbonate aqueous solution) for stirring, and post-treatment to obtain the refined product of the compound represented by formula (II).

Further, the purification step may include: heating and stirring the salt of the compound represented by formula (II), a solvent (preferably a mixed solvent of acetone and anhydrous methanol) (preferably at a temperature of about 50°C to about 60°C) , and then cooled and stirred (preferably at a temperature of about 0° C. to about 10° C.), and post-processed to obtain the refined product of the salt of the compound represented by formula (II).

Further, the salt of the compound represented by the formula (II) is the oxalate of the compound represented by the formula (II).

Understandably, after the compound represented by formula (II) is obtained, conventional reactions in this field can also be used, such as: hydrolysis, esterification, etc. to adjust R ₀₁ and R ₀₂ , which are not specifically limited here, and can be selected according to the structure of the target product That is, it should be understood that all are within the protection scope of the present application.

The preparation method of the compound shown in the above-mentioned formula (II) adopts the compound shown in the formula (I) as a key intermediate, and the compound shown in the formula (II) can be obtained in high yield through simple reactions such as reductive amination and oxidation, and the reaction The conditions are easy to control and the post-treatment is simple, which overcomes the disadvantages of low yield and difficult separation and purification in traditional methods, and is especially suitable for industrial production applications.

It should be understood that within the scope of the present application, the above-mentioned technical features of the present application and the technical features specifically described in the following (such as embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, we will not repeat them here.

Detailed ways

The examples of the present application provide an intermediate of a substituted phenylpropenylpyridine derivative and a preparation method thereof, and the intermediate can be used to prepare an immunomodulator of PD-1/PD-L1. The general formula adopts the compound shown in formula (I) as the key intermediate to effectively avoid the problem that the cyano group on the benzene ring of the starting material is easily reduced, and the by-products are difficult to effectively separate, which is more suitable for the needs of industrial production, and the preparation of the present application The starting material of the method is simple and easy to obtain, the operation is simple and convenient, the environment is friendly, the cost is reduced, and the scale-up production of the final product is easier.

Definition of Terms

As used herein, "alkyl" refers to straight and branched saturated aliphatic hydrocarbon groups, C _1-10 alkyl is an alkyl group containing 1 to 10 carbon atoms, preferably C _1-6 alkyl, more preferably is C _1-4 alkyl, more preferably C _1-3 alkyl, similarly defined; non-limiting examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl base, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethyl Butyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylbutyl Amylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethyl Pentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl Hexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethyl Pentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethyl Hexyl, 2,2-diethylhexyl, and various branched isomers thereof are more preferable.

As used herein, "cycloalkyl" and "cycloalkyl ring" are used interchangeably and both refer to a saturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon group which may be fused with an aryl or heteroaryl group. Cycloalkyl rings can be optionally substituted. In certain embodiments, cycloalkyl rings contain one or more carbonyl groups, such as oxo groups. "C _3-8 cycloalkyl" refers to a monocyclic cycloalkyl group with 3 to 8 carbon atoms, non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc. In some embodiments, cycloalkyl is C _3-6 cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, "alkoxy" refers to -O-alkyl, wherein alkyl is as defined above. It is preferably C _1-6 alkoxy, more preferably C _1-3 alkoxy. Non-limiting examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, pentoxy, and the like.

As used herein, "halogen" refers to fluorine, chlorine, bromine or iodine.

"Halo" refers to a group in which one or more (eg 1, 2, 3, 4 or 5) hydrogens are replaced by a halogen.

For example, "haloalkyl" refers to an alkyl group substituted with one or more (eg, 1, 2, 3, 4, or 5) halogens, wherein alkyl is as defined above. It is preferably a halogenated C _1-8 alkyl group, more preferably a halogenated C _1-6 alkyl group, and more preferably a halogenated C _1-3 alkyl group. Examples of haloalkyl include, but are not limited to, monochloromethyl, dichloromethyl, trichloromethyl, monochloroethyl, 1,2-dichloroethyl, trichloroethyl, monobromoethyl, monochloroethyl, Fluoromethyl, difluoromethyl, trifluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc.

As another example, "haloalkoxy" means that alkoxy is substituted by one or more (such as 1, 2, 3, 4 or 5) halogens, wherein the definition of alkoxy is as above. It is preferably a halogenated C _1-8 alkoxy group, more preferably a halogenated C _1-6 alkoxy group, and more preferably a halogenated C _1-3 alkoxy group. Haloalkoxy includes, but is not limited to, trifluoromethoxy, trifluoroethoxy, monofluoromethoxy, monofluoroethoxy, difluoromethoxy, difluoroethoxy, and the like.

"Heteroaryl" and "heteroaryl ring" are used interchangeably and both refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system having ring carbon atoms and ring heteroatoms (e.g., having A group of shared 6 or 10 π electrons) where each heteroatom is independently selected from nitrogen, oxygen and sulfur. In this application, heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. Heteroaryl rings can be optionally substituted. "5 to 10 membered heteroaryl" refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms. "5 to 6 membered heteroaryl" means a monocyclic heteroaryl group having 5 to 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms, non-limiting examples include thienyl, furan base, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 ,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadi Azolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazine base. "Heteroatom" means nitrogen, oxygen or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.

"Saturated monoheterocyclic ring" means that 1, 2 or 3 ring carbon atoms in a saturated monocyclic ring are replaced by heteroatoms selected from nitrogen, oxygen or S(O) _t (where t is an integer from 0 to 2), but Ring moieties excluding -OO-, -OS- or -SS-, the remaining ring atoms are carbon. The "3- to 6-membered saturated monoheterocyclic ring" has 3 to 6 ring atoms, of which 1, 2 or 3 ring atoms are the above-mentioned heteroatoms. Preference is given to 5- to 6-membered saturated monoheterocyclic rings having 5 to 6 ring atoms, of which 1 or 2 ring atoms are the above-mentioned heteroatoms. Non-limiting examples of saturated monoheterocyclic rings include propylene oxide rings, azetidine rings, oxetane rings, tetrahydrofuran rings, tetrahydrothiophene rings, tetrahydropyrrole rings, piperidine rings, pyrroline rings , oxazolidine ring, piperazine ring, dioxolane, dioxane, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, tetrahydropyran ring, nitrogen Heterocyclobutane-2-one ring, oxetane-2-one ring, pyrrolidin-2-one ring, pyrrolidine-2,5-dione ring, piperidin-2-one ring, dihydro Furan-2(3H)-one ring, dihydrofuran-2,5-dione ring, tetrahydro-2H-pyran-2-one ring, piperazin-2-one ring, morpholin-3-one ring Wait.

"Amino" means NH ₂ , "cyano" means CN, "nitro" means NO ₂ , "benzyl" means -CH ₂ -phenyl, "oxo" means =O, "carboxy" means -C (O)OH, "acetyl" refers to -C(O)CH ₃ , "hydroxymethyl" refers to -CH ₂ OH, "hydroxyethyl" refers to -CH ₂ CH ₂ OH or -CHOHCH ₃ , "hydroxyl" refers to -OH, "cyanomethyl" refers to -CH ₂ CN, and "cyanoethyl" refers to -CH ₂ CH ₂ CN.

As used herein, non-limiting examples of "boronate" include (CH3O) _2B- , ₍ _CH3CH2O ₎ _2B- , pinacol borate,

Wait.

The present application will be further elaborated below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. For the experimental methods without specific conditions indicated in the following examples, usually follow the conventional conditions or the conditions suggested by the manufacturer. Percentages and parts are by weight unless otherwise indicated. Unless otherwise defined, terms used herein have the same meanings as those skilled in the art are familiar with. In addition, any methods and materials similar or equivalent to those described can be applied to this application.

Reagents and Instruments

¹ HNMR: Bruker AVANCE-400 nuclear magnetic analyzer, the internal standard is tetramethylsilane (TMS).

LC-MS: Agilent 1290HPLC System/6130/6150MS liquid mass spectrometer (manufacturer: Agilent), column Waters BEH/CHS, 50×2.1mm, 1.7μm.

HPLC analysis adopts Agilent 1260 Infinity HPLC, OpenLAB CDS Chemstation workstation, chromatographic column XBridge C18 4.6*250mm, ID 5μm column, detector DAD.

Adopt ISCO Combiflash-Rf75 or Rf200 automatic column passing instrument, Agela 4g, 12g, 20g, 40g, 80g, 120g disposable silica gel column.

Known starting materials can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc) and Darui Chemicals, etc. company.

Unless otherwise specified, the reactions in the examples were carried out under a nitrogen atmosphere or an argon atmosphere.

As used herein, room temperature means from about 20°C to about 25°C.

As used herein, DCM is dichloromethane, _TiCl4 is titanium tetrachloride, DIPEA is N,N _- diisopropylethylamine, _H2O is water, K2CO3 is potassium carbonate, _HNO3 is nitric _acid , NH ₄ Cl is ammonium chloride, THF is tetrahydrofuran, DDQ is 2,3-dichloro-5,6-dicyanobenzoquinone, PE is petroleum ether, Zn(CN) ₂ is zinc cyanide, t-Bu-XPhos –Pd-G3 is methanesulfonic acid (2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1 '-biphenyl-2-yl)palladium(II), EA is ethyl acetate, _NaBH3CN is sodium cyanoborohydride, MeOH is methanol, IBX is 2-iodoxybenzoic acid, NaBH(OAc) ₃ is tris Sodium acetoxyborohydride, NaOH is sodium hydroxide, DMSO is dimethyl sulfoxide, and NaCl is sodium chloride.

Example 1

Preparation of (E)-4-(3-bromo-2-methylstyryl)-2-methoxy-5-(trifluoromethyl)benzaldehyde (1d)

Step 1: Dissolve 1a (200g, 784mmol) and 1,1-dichloromethyl ether (180g, 142mL, 1568mmol) in ultra-dry DCM (800mL), replace the reaction system with argon twice, under the protection of argon , the temperature of the reaction system was lowered to -78°C. After the temperature stabilized, TiCl ₄ (446g, 259mL, 2352mmol) was added dropwise to the reaction system through a constant pressure dropping funnel, and the reaction was stirred at -78°C for 2 hours after the drop was completed. , LC-MS monitoring until the raw material is consumed completely. Keep at -78°C, slowly add 1500mL saturated ammonium chloride aqueous solution to quench the reaction, add 1500mL water to dissolve until clear, extract with dichloromethane (1200mL*4), wash the organic phase with saturated brine (500mL), add the organic phase without Sodium sulfate water (300g) was stirred for 10 minutes, and the filtrate was obtained by filtration. The crude product concentrated under reduced pressure was stirred with 250mL petroleum ether for 30 minutes, and the white solid was filtered and spin-dried to obtain 1b (175g, 73% yield). LC-MS: 92% purity (Sig=254nm), MS m/z (ESI): 283[M+1] ⁺ .

Step 2: Place 1b (43.6g, 142mmol), vinyl borate pinacol ester (28g, 184mmol) in a sealed tube, add toluene 100mL, then add DIPEA (183mg, 1.42mmol), Pd ₂ (dba) ₃ (1.3g, 1.42mmol) and tri-tert-butylphosphine tetrafluoroborate (53g, 184mmol), under the protection of N ₂ , react at 95°C for 2 hrs. The reaction solution was dissolved and diluted with 120 mL of DCM solvent, transferred to a round bottom flask, and spin-dried. The crude product is mixed with petroleum ether: dichloromethane = 7:1 (120mL) to stir and beat the crude product for 0.5 hours, filter the solution after beating, and scrape the filter cake again with petroleum ether: dichloromethane = 7:1 (120mL) was repeatedly beaten 5 times until the solid filter cake was detected by LCMS until there were substantially no borate and boric acid products. Concentrate and spin dry all the filtrates and combine them together, add petroleum ether (3000mL) and stir evenly, disperse for 30 minutes, filter with suction, wash the filter cake with petroleum ether (120mL*2) until the filter cake is a uniform light yellow solid , the product 1c (40 g, 69% yield) was obtained as a pale yellow solid after drying. LC-MS: 87% purity (Sig=254nm) MS m/z (ESI): 357[M+1] ⁺ .

Step 3: Dissolve the crude product 1c (119g, 290mmol) and 1-bromo-3-iodo-2-methylbenzene (107g, 362mmol) in dioxane (1020mL) and H ₂ O (340mL), add Pd (dppf)Cl ₂ (26.5g, 36.2mmol) and K ₂ CO ₃ (65g, 470mmol), the reaction system was replaced with argon three times, under the protection of argon, heated to 100°C, and stirred for 2hr. The reaction solution was lowered to room temperature, and directly concentrated to obtain an oily substance. The oily substance was added to ethyl acetate (3 L), uniformly dispersed and ultrasonically filtered, filtered with diatomaceous earth (600 g), the filter cake was washed with ethyl acetate until colorless, and the filtrate was concentrated to Dry, add 2000mL of petroleum ether/ethyl acetate (10:1) prepared in advance for beating operation, after beating for 10 minutes, the system is uniformly dispersed, filter, filter cake with petroleum ether/ethyl acetate (10:1) 400mL was repeatedly washed and drained, and the solid was dried on a water pump to obtain a white solid 1d (120g, 92% yield). LC-MS: 89% purity (Sig=254nm), MS m/z (ESI): 399[M+1] ⁺ .

5-(Hydroxymethyl)-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxabororan-2-yl)phenyl ) Preparation of benzo [d] oxazole-7-carbonitrile (7)

Step 1: Control the temperature of the reaction solution below 40°C, add HNO ₃ (147mL, 65-68% wt, 2.25mol) dropwise to 1 (300g, 1.6mol) of acetic acid (500mL) mixture within 1 hour while stirring. After dropping, continue to maintain room temperature and stir the reaction for 2 hr. The reaction solution was slowly poured into cold water (3L), and the filter cake was washed with cold water (500mL*4) to obtain a yellow solid crude product, which was spread on an enamel dish and dried at room temperature overnight to obtain a yellow solid 2 (350g, 93% yield). LC-MS: 98% purity (Sig=254nm), MS m/z (ESI): 230[M-1] ^- .

Step 2: During stirring, add reduced iron powder (50g, 893mmol) to 880mL mixture of 2 (100g, 424mmol) and NH ₄ Cl (48g, 906mmol) in THF/H ₂ O (10:1), and stir at room temperature The reaction was carried out for 30 minutes, and the temperature was raised to 55-60° C. to continue the reaction for 1.5 hours. After cooling down, the reaction mixture was diluted with THF (100 mL) to terminate the reaction, stirred at 60°C for 5 minutes, filtered through diatomaceous earth (300 g), and the filtrate was concentrated to obtain crude black solid 3 (155 g, containing iron and NH ₄ Cl). MS m/z (ESI): 202 [M+1] ⁺ .

Step 3: The crude product 3 (253 g) and 3-bromo-2-methylbenzaldehyde (100 g, 502 mmol) were dissolved in THF (1 L), and stirred at room temperature for 20 hr. Concentrate to dryness, add DCM (1 L), slowly add DDQ (114 g, 502 mmol) in batches, maintain room temperature, and stir for 2.5-3 hr. The reaction solution was diluted with DCM (3L), filtered with diatomaceous earth (500g), and the filter cake was washed repeatedly with DCM (4L) until no product was found. 775 mL was stirred for 30 minutes, filtered, and the filter residue was spin-dried to obtain product 4 (144 g, 70% yield). LC-MS: 93% purity (Sig=254nm), MS m/z (ESI): 380[M+1] ⁺ .

Step 4: Compound 4 (50 g, 123 mmol) was dissolved in THF (500 mL), and lithium aluminum tetrahydrogen (10 g, 263 mmol) was added in batches at -20°C, and stirred at -20°C for 10 minutes. Add water (10mL) dropwise to the reaction solution, add 20% sodium hydroxide aqueous solution dropwise until the pH value is 8-9, add ethyl acetate (300mL), add anhydrous sodium sulfate (50g), stir for 10 minutes, filter, and concentrate the filtrate Dry to obtain product 5 (47g, containing non-UV-absorbing salt). MS m/z (ESI): 352 [M+1] ⁺ .

Step 5: Under nitrogen protection, compound 5 (47g) and biboronic acid pinacol ester (37g, 146mmol) were dissolved in dioxane (550mL), and Pd(dppf)Cl ₂ (4.88g, 6.7mmol) was added ) and potassium acetate (32.6g, 333mmol), reacted at 100°C for 3hr. After filtration, the filtrate was concentrated to dryness to obtain crude product 6 (45 g, 72% yield). LC-MS: 94% purity (Sig=254nm), MS m/z (ESI): 400[M+1] ⁺ .

Step 6: 6 (80g, 188mmol) was uniformly dissolved in a mixture of THF (480mL) and H ₂ O (480mL), the mixture was in a uniform dissolved state, and then Zn(CN) ₂ (71g, 600mmol), t-Bu-XPhos–Pd-G3 (32g, 40mmol) was added to the reaction system. After argon replacement for 3 times, the reaction was stirred at 100°C for 20hr. After the reaction was cooled to room temperature, the reaction solution was carried out with THF (1500mL). Dilute, filter the insoluble solid on diatomaceous earth, wash the filter cake with THF until no product remains, further concentrate the obtained filtrate, and when the organic solvent in the system is spin-dried, slowly pour out the remaining water inside, THF was added to the system several times, concentrated and spin-dried to remove water, until the product was in the form of uniform solid particles, and dried to obtain a brown solid 7 (50 g, 65% yield). LC-MS: 95% purity (Sig=254nm), MS m/z (ESI): 391 [M+1] ⁺ .

(R)-1-((7-cyano-2-(3'-((E)-4-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-5-methoxy Base-2-(trifluoromethyl)styryl)-2,2'-dimethyl-[1,1'-biphenyl]-3-yl)benzo[d]oxazol-5-yl) Preparation of methyl)pyrrolidine-3-carboxylic acid (12)

Step 1: Dissolve 1d (117g, 262mmol), 7 (98g, 239mmol) in a mixture of Dioxane (1000mL) and H ₂ O (300mL), and add Pd(dppf)Cl ₂ (4.8 g, 6.5mmol) and K ₂ CO ₃ (58.5g, 424mmol), the reaction system was replaced with argon three times, and the reaction glass bottle was heated to 100°C in an oil bath under the protection of argon, and the reaction was stirred for 2hr. After the reaction liquid is cooled to room temperature, remove the organic solvent, add dichloromethane (3L) and water (1.5L) for extraction, extract the aqueous phase with dichloromethane (800mL*2), combine the organic phases, and dry over anhydrous sodium sulfate , and the organic phase was spin-dried to obtain a brown solid crude product. COMBI-FLASH column separation (120g, PE:EA:DCM=10:1:1 to PE:EA:DCM=2:1:0.2) gave brown solid 8 (102g, 59% yield). LC-MS: 80% purity (Sig=254nm), MS m/z (ESI): 583[M+1] ⁺ .

Step 2: Dissolve the brown solid 8 (87g, 120mmol) by ultrasound, and disperse it evenly in anhydrous methanol (800mL), add (R)-3-pyrrolidinol (20.9g, 240mmol) and then sonicate again to ensure a uniform reaction system , after stirring at 20°C for 90 minutes, NaBH ₃ CN (6.8mg, 108mmol) was added in 4 times, and the stirring reaction was continued at 20°C for 12hr. (120g, 1-10% MeOH/DCM) to obtain light yellow solid 9 (63g, 75% yield) after separation and purification. LC-MS: 93% purity (Sig=254nm), MS m/z (ESI): 654[M+1] ⁺ .

Step 3: 9 (50g, 71mmol) was uniformly dissolved in anhydrous THF (500mL), and IBX (86g, 306mmol) was added in batches. After the addition, the reaction oil bath was heated to 55°C, and the reaction was carried out at 55°C. Stir at ℃ for 2.5 hr. After the reaction solution was cooled to room temperature, the reaction system was diluted with THF (1500 mL), the insoluble solid was filtered off on diatoms, and the filter cake was washed with THF (300 mL*4) until no product was found. After the filtrate was spin-dried again, it was dissolved in DCM (2500 mL), then stirred with saturated aqueous sodium bicarbonate (800 mL), and the organic phase was separated and washed again with saturated aqueous sodium bicarbonate (500 mL*2) until no IBX remained. The organic phase was dried with anhydrous sodium sulfate, filtered and spin-dried to obtain the crude product 10 (50 g, 86% yield). LC-MS: 80% purity (Sig=254nm), MS m/z (ESI): 652[M+1] ⁺ .

Step 4: Dissolve 10 (25g, 30.7mmol) uniformly in anhydrous DMF (125mL), add (R)-3-pyrrolidinecarboxylic acid methyl ester hydrochloride (7.62g, 46.0mmol) and then sonicate again To ensure the uniformity of the reaction system, after the reaction was stirred at 24°C for 2hr, NaBH(OAc) ₃ (10.57g, 49.87mmol) was slowly added to the reaction system in batches, stirred at room temperature at 24°C for 2hr and then heated to At 40°C, NaBH(OAc) ₃ (8.1 g, 38.4 mmol) was added in portions, and the reaction was continued at 40°C for 0.5 hr. The reaction solution was cooled to room temperature, diluted with DCM (500 mL), and saturated sodium bicarbonate solution was added dropwise with stirring until no bubbles occurred. Stand and separate the layers, extract the aqueous phase with DCM (800mL*3) until there is no product in the aqueous phase, combine the organic phases, dry over anhydrous sodium sulfate, filter, and spin the filtrate to obtain a brown solid, which is separated through a silica gel column (DCM : MeOH=500:1 to 100:4) to obtain brown solid 11 (18g, 73% yield). LC-MS: 95% purity (Sig=254nm), MS m/z (ESI): 383[1/2M+1] ⁺ .

Step 5: 11 (18g, 22.4mmol) was uniformly dissolved in THF (360mL) under stirring, and after cooling to 0°C, the NaOH aqueous solution (3.3M, 72mL) cooled to 0°C was gradually Add it dropwise to the reaction solution, keep stirring at 0°C for 0.5hr after dropping, then gradually rise to room temperature (24°C), and continue to stir and react for 8hr. After cooling the reaction solution to 0°C, slowly add hydrochloric acid solution (2M) dropwise under stirring until the reaction solution becomes weakly acidic (PH=5-6), then use saturated sodium bicarbonate solution until the reaction solution is weakly alkaline (PH=5-6). 8-9), let stand to separate the layers, and extract the aqueous phase with dichloromethane/methanol (10:1) (400mL*3) until there is no product in the aqueous phase. The organic phases were combined, dried by adding anhydrous sodium sulfate, filtered, and concentrated to obtain a crude brown solid. The crude product was separated and purified by liquid phase preparation to obtain the final product 12 (10.5 g, 62% yield). LC-MS: 99.3% purity (Sig=254nm), MS m/z (ESI): 751.4 [M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.13(dd, J=6.1,1.7Hz,1H),8.08(d,J=1.2Hz,1H),7.85(d,J=1.2Hz,1H) ,7.68–7.59(m,3H),7.52(t,J=7.7Hz,1H),7.48(s,1H),7.38(d,J=6.6Hz,1H),7.34(t,J=7.7Hz, 1H), 7.23(dd, J＝15.8, 2.2Hz, 1H), 7.12(d, J＝7.1Hz, 1H), 4.21–4.16(m, 1H), 3.93(s, 3H), 3.78–3.68(m ,3H),3.66–3.58(m,3H),2.92(dt,J＝15.1,7.7Hz,1H),2.76–2.60(m,4H),2.56–2.49(m,2H),2.40–2.38(m ,4H),2.11(s,3H),2.06–1.88(m,3H),1.60–1.49(m,1H).

Example 2

Step 1: Add 8 (5.0kg) and dichloromethane (66.0kg) into the reactor, start stirring, and add (R)-3-pyrrolidinol (1.0kg)-methanol (9.9kg) solution. After the addition was completed, under nitrogen protection, the temperature was raised to reflux (about 40° C.), and the reaction was kept for 1.5 hours. The temperature of the reaction solution was lowered to 10-20° C., and sodium triacetoxyborohydride (4.6 kg) was added in batches. After the addition, the temperature was raised to 20-25°C, and the reaction was kept for 1 hour. Add 10% potassium carbonate solution dropwise to pH = 9-10 while keeping warm, stir for 1 hour, and let stand to separate layers. The aqueous layer was extracted with dichloromethane (33.0 kg), and the organic phases were combined. The organic phase was washed with 10% sodium chloride solution (25.0 kg*2). The collected organic phase was dried over anhydrous sodium sulfate (5.0 kg). After suction filtration, the filtrate was concentrated under reduced pressure by rotary evaporator until there was no liquid drop, and the crude product 9 was obtained, MS m/z (ESI): 654[M+1] ⁺ .

Step 2: Add ethyl acetate (67.5kg) and 9 crude products into the reaction kettle, stir for 30min, and filter with diatomaceous earth (2kg). The filtrate was transferred to a reaction kettle, and phosphoric acid (1.48kg)-ethyl acetate (22.5kg) solution was added dropwise at 20-30°C. After the dropping was complete, it was stirred at 20-30°C for 1h. Shake off the filter, put the filter cake in a vacuum dryer, and dry it at 45°C to 50°C. Obtain 9-1 (6.47kg, quantitative yield, purity 99.1%)

Step 3: Add dichloromethane (85.0kg) to the reaction kettle, start stirring anhydrous methanol (25.6kg), and add 9-1 (6.39kg) to dissolve. Use 10% potassium carbonate solution at 10-20°C to adjust the pH of the reaction solution to 8-9, and let it stand to separate into layers. The aqueous phase was extracted with dichloromethane (25.6kg*2), the organic phases were combined, and 10% sodium chloride (32.0kg) was added to the organic phase for washing, left to stand, and separated into layers. The collected organic phase was dried over anhydrous sodium sulfate (6.39 kg). After filtration, the filtrate was concentrated by rotary evaporator under reduced pressure until there was no liquid drop to obtain 9 fine product, MS m/z (ESI): 654[M+1] ⁺ .

Step 4: Add dimethyl sulfoxide (38.1kg), ethyl acetate (9.6kg) and IBX (12.78kg) into the reactor, stir at 20-30°C for 4.5h, then cool down to 0-5°C. Dissolve the above materials (9 fine products) with dimethyl sulfoxide (16.0kg) and add them dropwise to the reaction system at 0-5°C. After dropping, control the temperature at 0-10°C, stir for 1 hour, then raise the temperature to 10-15°C and stir for 2 hours . Cool down to 0-10°C, add isopropyl acetate (51.1kg), stir for 10min, add dropwise 10% sodium hydroxide solution to adjust pH=9~10, add dropwise 10% sodium thiosulfate solution (35.1kg), After dropping, stir for 1h. Suction filtration (pad with diatomaceous earth), the filtrate was allowed to stand to separate layers, the aqueous phase was extracted with isopropyl acetate (51.1 kg), the organic phases were combined, and the organic phase was washed with saturated sodium chloride solution (32 kg). Let stand to layer. The collected organic phase was dried over anhydrous sodium sulfate (6.5 kg). After filtration, the filtrate was concentrated by rotary evaporation under reduced pressure until there were no droplets. 10 crude product was obtained, MS m/z (ESI): 652[M+1] ⁺ .

Step 5: Add ethyl acetate (67.1kg) and the above-mentioned materials (10 crude products) into the reaction kettle, and start stirring. Add phosphoric acid (1.09kg)-ethyl acetate (22.4kg) solution dropwise at 20-30°C, and stir for 1h after the addition is complete. Shake the filter and dry the filter cake under vacuum at 45-50°C. 10-1 was obtained (5.5kg, yield 86%, purity 98.5%).

Step 6: Add ethyl acetate (32.7kg) and anhydrous methanol (16.4kg) to the reaction kettle, start stirring, add 10-1 (5.45kg), and stir to dissolve. Control the temperature at 20-25°C, add 10% potassium carbonate solution dropwise, adjust the pH of the reaction solution to 8-9, and let it stand to separate into layers. The aqueous phase was extracted with ethyl acetate (32.7 kg). The organic phases were combined, and purified water (32.7 kg) was added to the organic phase, stirred and washed, and allowed to stand to separate layers. The collected organic phase was dried over anhydrous sodium sulfate (5.5 kg). After filtration, the filtrate was concentrated under reduced pressure until there was no liquid droplet, and the refined material 10 was obtained, MS m/z (ESI): 652[M+1] ⁺ .

Step 7: Add methanol (7.0kg) and (R)-3-pyrrolidine carboxylic acid methyl ester hydrochloride (1.67kg) into the reactor, start stirring, add N,N-diisopropylethylamine (1.74kg ), stirred for 1h. Add dichloromethane (58.3kg) and the above 10 refined products into the reaction kettle. After the addition is complete, under nitrogen protection, the reaction solution is heated to reflux (about 40°C), kept for 2 hours, and then cooled to 10-20°C. Concentrate under reduced pressure until there is no liquid drop. The residue was dissolved with dichloromethane (58.3 kg) and added to the reaction kettle; stirring was started, and sodium triacetoxyborohydride (2.86 kg) was added in batches. After the addition is complete, keep the reaction at 20-25°C for 1h. Control the temperature at 10-20°C, add 10% potassium carbonate solution dropwise to adjust the pH of the system to 9-10, stir for 30 minutes, let stand to separate layers, and extract the aqueous phase with dichloromethane (58.3kg). The organic phases were combined, washed with 10% NaCl (38.7kg*2), and allowed to stand for separation. The organic phase was dried over anhydrous sodium sulfate (5.5 kg). After suction filtration, the filtrate was concentrated under reduced pressure until there was no liquid drop to obtain 11 crude product, MS m/z (ESI): 383[1/2M+1] ⁺ .

Step 8: Add ethyl acetate (58.3kg) and the above-mentioned materials (11 crude products) into the reaction kettle, start stirring, and dissolve until clarified. Add dropwise oxalic acid (1.23kg)-ethyl acetate (19.4kg) solution at 20-30°C. Continue to stir for 1 hour after dropping, shake off the filter, put the filter cake in a vacuum dryer, and dry at 45°C to 50°C.

Add the above solid into the reaction kettle, start stirring with acetone (73.0kg) and anhydrous methanol (29.0kg), raise the temperature to 50-60°C, and stir for 2h. Slowly lower the temperature to 0-10°C and keep stirring for 2 hours. Centrifugal filter. The filter cake was placed in a vacuum dryer and dried at 45°C to 50°C to obtain 11-1 (5.40kg, yield 79%, purity 98.6%).

Step 9: Add ethyl acetate (53.5kg) and anhydrous methanol (26.8kg) to the reaction kettle to start stirring, add 11-1 (5.35kg), control the temperature at 10-20°C and adjust the system with 10% potassium carbonate solution pH=9~10, let stand to separate. The aqueous phase was extracted with ethyl acetate (53.5 kg), the layers were separated after standing, and the organic phases were combined. Add 10% sodium chloride (53.5kg) to the organic phase, stir and wash; let stand to separate layers. The collected organic phase was dried over anhydrous sodium sulfate (5.4 kg). After filtration, the filtrate was concentrated under reduced pressure until there was no liquid drop, and the collected material (11 fine products), MS m/z (ESI): 383[1/2M+1] ⁺ . .

Step 10: Add tetrahydrofuran (96.3kg) and the above materials (11 refined products) into the reaction kettle. Nitrogen protection, control the temperature at 15-25°C, add dropwise 1M lithium hydroxide solution (182g lithium hydroxide plus 7.9kg water), after dropping, control the temperature at 15-25°C, and stir for 5h. Add dropwise oxalic acid (3.43kg)-tetrahydrofuran (8.6kg) solution, and stir for 4 hours after dropping. Shake the filter, place the filter cake in a vacuum dryer, and dry at 45°C to 50°C to obtain 12-1.

Step 11: Add dichloromethane (74.9kg) into the reaction kettle, start stirring with anhydrous methanol (10.7kg), and add the above 12-1. Control the temperature at 10-20°C and add dropwise 10% potassium bicarbonate solution to adjust the pH of the system to 7.7-7.9, and continue stirring for 6 hours. Static separation, the aqueous phase was extracted with dichloromethane (37.5kg), static separation, the organic phase was combined, the organic phase was washed with 10% sodium chloride solution (26.8kg*2), static separation, the organic phase Dry over anhydrous sodium sulfate (5.4 kg). After suction filtration, the filtrate was concentrated to about 5 L.

The concentrated solution was put on a silica gel column, eluted with dichloromethane-methanol, and the eluent was concentrated to dryness under reduced pressure to obtain 12 refined products (3.0kg, yield 70%, purity 98%), MS m/z (ESI): 751.4[ M+1]. ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.13(dd, J=6.1,1.7Hz,1H),8.08(d,J=1.2Hz,1H),7.85(d,J=1.2Hz,1H) ,7.68–7.59(m,3H),7.52(t,J=7.7Hz,1H),7.48(s,1H),7.38(d,J=6.6Hz,1H),7.34(t,J=7.7Hz, 1H), 7.23(dd, J＝15.8, 2.2Hz, 1H), 7.12(d, J＝7.1Hz, 1H), 4.21–4.16(m, 1H), 3.93(s, 3H), 3.78–3.68(m ,3H),3.66–3.58(m,3H),2.92(dt,J＝15.1,7.7Hz,1H),2.76–2.60(m,4H),2.56–2.49(m,2H),2.40–2.38(m ,4H),2.11(s,3H),2.06–1.88(m,3H),1.60–1.49(m,1H).

All documents mentioned in this application are incorporated by reference in this application as if each individual document were individually indicated to be incorporated by reference. In addition, it should be understood that after reading the above teaching content of the application, those skilled in the art can make various changes or modifications to the application, and these equivalent forms also fall within the scope defined by the appended claims of the application.

Claims

An intermediate, which is a compound or a salt thereof shown in formula (I):

in,

R 1 and R 2 are each independently hydrogen, cyano, acetyl, hydroxyl, carboxyl, nitro, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl , Halogenated C 1-6 alkoxy, NR a0 R b0 , -CONR a0 R b0 , -SO 2 NR a0 R b0 , -SO 2 C 1-6 alkyl, phenyl, 5 to 6-membered heteroaryl, C 3-6 cycloalkyl or 3 to 6 membered saturated monoheterocycle, wherein the phenyl, 5 to 6 membered heteroaryl, C 3-6 cycloalkyl, 3 to 6 membered saturated monoheterocycle are unsubstituted or by 1, 2 or 3 independently selected from acetyl, hydroxyl, cyano, carboxyl, nitro, halogen, C 1-3 alkyl, halogenated C 1-3 alkyl, C 1-3 alkane Oxygen, halogenated C 1-3 alkoxy, C 3-6 cycloalkyl, NR a1 R b1 , -CONR a1 R b1 , -SO 2 NR a1 R b1 are substituted by substituents;

R G1 is -CHO or -CH(OR G10 )(OR G20 ); wherein R G10 and R G20 are each independently a C 1-6 alkyl group, or R G10 and R G20 form a 5-membered group together with the attached oxygen atom Or 6-membered saturated monoheterocycle;

R 3 and R a are each independently hydrogen, hydroxyl, cyano, nitro, acetyl, carboxyl, halogen, hydroxymethyl, hydroxyethyl, cyanomethyl, cyanoethyl, C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, -NR a0 R b0 , C 3-6 cycloalkyl, -CONR a0 R b0 or -SO 2 NR a0 R b0 ;

R Gb is hydrogen or a hydroxyl protecting group;

R a0 , R b0 , R a1 , and R b1 are each independently hydrogen, C 1-3 alkyl or halogenated C 1-3 alkyl.
The intermediate according to claim 1, wherein the compound shown in the formula (I) is a compound shown in the formula (I-1):
The intermediate according to claim 1, wherein the compound shown in the formula (I) is a compound shown in the formula (I-2):
The intermediate according to claim 1, wherein R 3 and R a are each independently hydroxyl, cyano, nitro, acetyl, carboxyl, F, Cl, hydroxymethyl, hydroxyethyl, cyanomethyl , cyanoethyl, C 1-3 alkyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a0 R b0 , C 3-6 cycloalkyl, -CONR a0 R b0 , -SO 2 NR a0 R b0 ; wherein R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
The intermediate according to claim 1, wherein the hydroxyl protecting group is selected from: trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl , benzyl, p-methoxybenzyl, trityl, benzoyl, p-nitrobenzoyl, acetyl, and p-toluenesulfonyl.
A preparation method of the intermediate described in any one of claims 1-5, comprising the following steps:

The compound shown in the formula (I-A) is coupled with the compound shown in the formula (I-B) to obtain the compound shown in the formula (I);

Optionally, the compound represented by formula (I) is subjected to a salt-forming reaction to prepare a salt of the compound represented by formula (I);

Among them, R Ga and R G2 are a pair of groups capable of coupling reaction.
The preparation method according to claim 6, wherein R Ga and R G2 are a pair of groups that can undergo Suzuki coupling reaction.
The preparation method according to claim 6, wherein one of R Ga and R G2 is a halogen, and the other is (HO) 2 B- or a borate ester group.
The preparation method according to claim 6, wherein R Ga is Br, Cl or I; R G2 is (HO) 2 B- or a borate ester group; or

R G2 is Br, Cl or I; R Ga is (HO) 2 B- or a borate ester group.
The preparation method according to any one of claims 6-9, further comprising the step of preparing the compound shown in formula (I-A):

Wherein, Y is a halogen, and M is a boronic acid group or a borate ester group;

The compound shown in formula (IA-5) is reacted with 1,1-dichloromethyl ether to prepare the compound shown in formula (IA-4) in which R G1 is an aldehyde group;

Optionally, for the protecting group on the aldehyde group of the compound shown in the formula ( IA -4) in which R G1 is an aldehyde group, the formula ( IA- 4) the compound shown;

Reacting the compound shown in formula (I-A-4) and the compound shown in formula (I-A-3) to prepare the compound shown in formula (I-A-2); and

The compound represented by formula (I-A-2) is reacted with the compound represented by formula (I-A-1) to prepare the compound represented by formula (I-A).
The preparation method according to any one of claims 6-9, further comprising the step of preparing the compound shown in the formula (I-B) using the compound shown in the formula (I-B-1):

Wherein, X is Br, Cl or I.
The preparation method according to claim 11, further comprising the step of preparing the compound shown in the formula (I-B-1):

Wherein, Y is halogen; R c is C 1-6 alkyl;

Reaction of the compound shown in the formula (I-B-4) and the compound shown in the formula (I-B-5) to prepare the compound shown in the formula (I-B-3);

The compound shown in the formula (I-B-3) is subjected to a reduction reaction to obtain the compound shown in the formula (I-B-2);

Optionally, for the protecting group on the hydroxyl group on the compound shown in formula (IB-2), prepare the compound shown in formula (IB-1) that R Gb is a hydroxyl protecting group and R Ga is a halogen;

Optionally, the compound represented by formula (IB-2) is reacted with boronic acid or borate to prepare the compound represented by formula (IB-1) in which R Ga is boronic acid group or borate ester group and R Gb is hydrogen.
The preparation method according to claim 12, wherein, also comprising the step of preparing the compound shown in the formula (I-B-4):

Nitrating the compound shown in formula (I-B-7) to prepare the compound shown in formula (I-B-6); and

The compound represented by the formula (I-B-6) is subjected to a reduction reaction to obtain the compound represented by the formula (I-B-4).
The preparation method according to any one of claims 6-9, wherein the compound of formula (I-A) is:
The preparation method according to any one of claims 6-9, wherein the compound of formula (I-B) is:
A preparation method of the intermediate described in any one of claims 1-5, comprising the following steps:

Wherein, X is Br, Cl or I; R Ga , R G2 are a pair of groups that can undergo coupling reactions;

Adopt the compound shown in formula (I-B-1) to prepare the compound shown in formula (I-B);

Carrying out a coupling reaction between the compound shown in formula (I-B) and the compound shown in formula (I-A) to obtain the compound shown in formula (I);

Optionally, the compound represented by formula (I) is subjected to a salt-forming reaction to prepare a salt of the compound represented by formula (I).
A method for preparing a compound represented by formula (II), comprising the step of preparing the compound represented by formula (II) using the intermediate described in any one of claims 1-5;

Wherein R a , R 3 , R 1 , R 2 are as defined in claim 1;

A ring and B ring are each independently a 4-6 membered saturated nitrogen-containing monoheterocycle;

R 01 and R 02 are independently hydroxyl, carboxyl or -C(O)OC 1-3 alkyl;

m and n are 0, 1, 2 or 3 each independently.
The preparation method according to claim 17, further comprising the step of preparing the intermediate by the preparation method according to any one of claims 6-16.
The preparation method according to claim 17, wherein, comprising the following steps:

R G1 is the compound shown in formula (I) of aldehyde group and the compound shown in formula (a) or its salt is carried out reductive amination reaction, makes the compound shown in formula (IA); Or R G1 is-CH(OR G10 ) (OR G20 ) After the compound shown in the formula (I) of (OR G20 ) removes the formaldehyde protecting group, carry out reductive amination reaction with the compound shown in the formula (a) or its salt, and prepare the compound shown in the formula (IA);

The compound shown in formula (IA) that R Gb is hydrogen is carried out oxidation reaction, the compound shown in formula (IB) is prepared; Or the compound shown in formula (IA) that R Gb is hydroxyl protecting group is carried out the removal reaction , then carry out oxidation reaction, make the compound shown in formula (IB); And

Carry out reductive amination reaction with the compound shown in formula (IB) and the compound shown in formula (b) or its salt, make the compound shown in formula (II);
The preparation method according to claim 17, wherein R G1 is -CHO; R Gb is hydrogen.
The preparation method according to any one of claims 17-20, wherein, ring A and ring B are tetrahydropyrrole rings.
The preparation method according to any one of claims 17-20, wherein,
each independently selected from any of the following groups: