CN112616314A

CN112616314A - Process for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt, intermediates therefor and process for the preparation of intermediates

Info

Publication number: CN112616314A
Application number: CN201980055467.7A
Authority: CN
Inventors: 朴恩婷; 李元一; 朴相昱; 金甫贞; 丁藇熙; 金澈佑; 慎祥允; 赵民龙; 孙世一
Original assignee: Dae Won Pharmaceutical Co ltd
Current assignee: Dae Won Pharmaceutical Co ltd; Daewon Pharm Co Ltd
Priority date: 2018-08-24
Filing date: 2019-08-23
Publication date: 2021-04-06
Also published as: KR102001835B1; WO2020040614A1

Abstract

The present invention provides a process for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt, intermediates useful therefor and a process for the preparation of said intermediates. The preparation process of the present invention is carried out in a convergent synthesis, in which the main moieties of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt are synthesized separately and then coupled. Therefore, the related substances can be easily controlled, and the preparation time can be shortened, resulting in an improvement in the productivity of the compound and an increase in the yield of the final compound.

Description

Process for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt, intermediates therefor and process for the preparation of intermediates

Technical Field

The present invention relates to a process for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt, intermediates used therefor and a process for the preparation of said intermediates.

Background

(3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt is useful as an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibits the intracellular synthesis of cholesterol, and thus is useful as a lipid-lowering agent or a cholesterol-lowering agent.

Korean patent registration No. 10-1329113 describes a method for preparing (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxy-heptanoic acid hemicalcium salt as shown in the following reaction scheme.

Further, korean patent registration No. 10-1329113 describes a preparation method of compound 2 as a starting material in example 1, and also states that compound 2 is prepared according to the methods described in the papers of [ j.med.chem.,41,26, (1998), 5297-. The method is shown in the following reaction formula.

However, according to this production method, it is difficult to remove the main relevant substances, and also difficult to perform purification because a solid cannot be produced due to the use of a dihydropyranyl (THP) protecting group. In addition, the substituents are sequentially synthesized one by one, and thus when any problem occurs in an intermediate step, the synthesis needs to be started again from the beginning, resulting in a long process time. In addition, not only the reagents become expensive, but also the overall yield becomes poor. Therefore, the conventional production method has a problem that it is not suitable for mass synthesis.

Accordingly, the present inventors have devised a method for efficiently synthesizing (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt in a convergent synthesis manner, in which the main moieties of the compound are synthesized separately and then coupled (instead of the sequential synthesis method as conventional above), the reaction intermediates are synthesized as a solid by using a protecting group, and the main relevant substances are easily controlled, thereby completing the present invention.

[ related art reference ]

[ patent document ]

Korean registered patent publication No. 10-1329113

[ non-patent document ]

J.Med.Chem.,41,26,(1998),5297-5309

Tetrahedron Lett.,43,30,(2002),5353

Detailed Description

Technical problem

It is an object of the present invention to provide a novel process for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt which effectively solves the drawbacks of the prior sequential synthesis processes.

It is another object of the present invention to provide intermediates useful in the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt and processes for the preparation thereof.

Technical scheme

In order to solve the above problems, the present invention can provide a process for producing (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt, an intermediate for use therein, and a process for producing the intermediate.

Hereinafter, each item of the present invention will be described in detail.

(3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl]-pyridine Pyrrol-1-yl]Preparation method of (E) -3, 5-dihydroxyheptanoic acid hemicalcium salt

The present invention provides a novel process for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt.

According to a specific embodiment of the present invention, it is possible to prepare (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt by a preparation method comprising the following steps.

There may be provided a process for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt comprising the steps of:

(1a) reacting a compound of the following chemical formula a-1 with a compound of the following chemical formula B to prepare a compound of the following chemical formula C;

(1b) deprotecting the compound of chemical formula C to produce a compound of chemical formula D below;

(1c) reacting the compound of chemical formula D with a compound of chemical formula E below to prepare a compound of chemical formula F-1 below;

(1d) preparing a compound of the following chemical formula G from the compound of the chemical formula F-1; and (1e) preparing a compound of the following chemical formula 1 from the compound of the chemical formula G:

[ chemical formula A-1]

[ chemical formula B ]

[ chemical formula C ]

[ chemical formula D ]

[ chemical formula E ]

[ chemical formula F-1]

[ chemical formula G ]

[ chemical formula 1]

In the above-mentioned chemical formula, the metal oxide,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₁And R₂Each independently is C₁-C₆Alkyl groups, or combine with each other to form a five-to seven-membered ring,

R₃、R₄and R₅Each independently is C₁-C₆Alkyl or C₆-C₁₂An aryl group, a heteroaryl group,

R₆、R₇and R₈Each independently is H, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or C₆-C₁₂Aryl { the C₆-C₁₂At least one H in the aryl radical may be replaced by C₁-C₆Alkoxy substitution },

R₉is C₁-C₆Alkyl or C₆-C₁₂Aryl radical, and

r is C₁-C₆An alkyl group.

Specifically, the P may be tetrahydropyranyl, methoxymethyl, methoxyethyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, trityl, methoxyphenyldiphenylmethyl, bis (methoxyphenyl) phenylmethyl, benzyl, P-methoxybenzyl, dimethoxybenzyl, benzoyl or t-butoxycarbonyl, but is not limited thereto.

In the present specification, "C" or "C" is used_x-C_y"may refer to functional groups having x or more and y or less carbon atoms.

In the present specification, X described in the chemical formula may refer to a halogen atom. For example, X can be F, Cl, Br, and the like.

The step (1a) may be a step of alkylating an active methylene compound, and may be performed under basic conditions.

In the present specification, "alkylation" may be a reaction in which a hydrogen atom of an organic compound is substituted with an alkyl group. The alkyl group may be substituted by C_nH_2n+1And (4) showing. Alkylation may be carried out as a nucleophilic reaction or an electrophilic reaction.

Examples of the base may include lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, 1, 8-diazabicyclo (5.4.0) undec-7-ene (DBU), N-Diisopropylethylamine (DIPEA), Triethanolamine (TEA), pyridine, sodium hydride, potassium tert-butoxide (K [ OC (CH) C)₃)₃]) And the like, they may be used alone or in combination of two or more, but are not limited thereto. Further, the step (1a) may be carried out in a solvent that can be used for the alkylation reaction of the active methylene compound, and examples of the solvent may include toluene, xylene, benzene, methylene chloride, butanol, tetrahydrofuran, ethyl acetate, propanol, cyclohexanone, diethyl ether, dioxane, ethanol, methanol, pyridine, acetone, acetonitrile, N-dimethylformamide, dimethyl sulfoxide, an aqueous solution thereof, and the like, which may be used alone or in combination of two or more thereof, but are not limited thereto. Further, the step (1a) may be performed under a temperature condition of 20 to 30 ℃, or may be performed by heating or refluxing at 50 to 60 ℃ depending on the solvent.

Step (1b) may be a step of removing a hydroxyl protecting group of the compound of formula C, and may be performed under acidic conditions.

In the present specification, a "protecting group" may be a group that selectively reacts with a specific functional group to modify the functional group, thereby protecting the functional group in the reaction step. For example, in the preparation method of the compound of chemical formula 1, a compound containing a protecting group may become an intermediate.

Examples of the acid may include formic acid, acetic acid, sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, chromic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid (TFA), and the like, wherein these aqueous solutions may be used alone or in combination of two or more, but are not limited thereto. Further, step (1b) may be carried out in a solvent which can be used for the deprotection reaction of the hydroxyl protecting group, and specifically may be carried out under the conditions of methanol, ethanol, tetrahydrofuran, 1, 4-dioxane, water, or the like. Further, the step (1b) may be performed under a temperature condition of 20 ℃ to 40 ℃.

In the present specification, "deprotection" may be a reaction of removing an introduced protecting group and recovering a protected functional group. For example, a hydroxyl group can be recovered by deprotecting a hydroxyl protecting group.

Step (1c) may be a step of coupling the compound of formula D with the compound of formula E to form an azole ring.

In the present specification, "coupling" may be a reaction of forming a new covalent bond by a reaction between organic compounds. For example, for coupling, a 1, 4-dicarbonyl compound and a primary amine may undergo a condensation reaction to form an enamine, and the enamine formed may continue to undergo an intramolecular condensation reaction with the carbonyl group to restore aromaticity, thereby forming an azole ring.

Step (1c) may be carried out in a solvent that can be used for pyrrole cyclization reaction, and specifically methanol, diethyl ether, ethyl acetate, tetrahydrofuran, toluene, heptane, cyclohexane, hexane, and the like may be used alone or in combination of two or more, but are not limited thereto. Further, the step (1c) may be performed under a temperature condition of 20 ℃ to 30 ℃, or may be performed by heating at 80 ℃ to 90 ℃ depending on the solvent. The reaction may be performed under acidic conditions, and usable acids may include pivalic acid, toluene-4-sulfonic acid, and the like, but are not limited thereto.

Step (1d) may be a step of removing the acetal protecting group of the diol in the compound of formula F-1, and may be performed under acidic conditions. In the present invention, in the step of removing the acetal protecting group, the acetal may be converted into a hemiacetal under acidic conditions, and the hemiacetal may be removed to recover a hydroxyl group. Further, the acid may include hydrochloric acid, bromic acid, iodic acid, sulfuric acid, acetic acid, trifluoroacetic acid, and the like, which may be used alone or in combination of two or more, but is not limited thereto. Further, step (1d) may be carried out in a solvent that can be used for the deprotection reaction of the glycol protecting group, and specifically, methanol, tetrahydrofuran or a mixture thereof may be used, but is not limited thereto. Further, the step (1d) may be performed under a temperature condition of 20 ℃ to 30 ℃.

Step (1e) may be a step of preparing a final product, which is (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt, by hydrolyzing the compound of formula G under basic conditions and adding a source of calcium ions thereto.

In the present specification, "hydrolysis under alkaline conditions" may be a hydrolysis reaction carried out in the presence of a base. For example, the hydrolysis reaction may be a decomposition reaction essentially caused by the action of water molecules during the chemical reaction.

In one embodiment, the hydrolysis reaction may be performed under alkaline conditions using sodium hydroxide, potassium hydroxide, or an aqueous solution thereof, which may be used alone or in combination of two or more, but is not limited thereto. Further, the hydrolysis reaction may be carried out in a solvent that can be used for the basic hydrolysis reaction of the ester, and specifically, methanol, tetrahydrofuran, water, and the like may be used alone or in combination of two or more, but are not limited thereto. In addition, the hydrolysis reaction may be performed under a temperature condition of 0 ℃ to 30 ℃.

Meanwhile, the reaction for preparing the hemicalcium salt may use a calcium ion source. Examples of the calcium ion source may include calcium acetate, calcium chloride, calcium carbonate, tricalcium phosphate, calcium citrate malate, calcium lactate, calcium gluconate, calcium hydroxide, calcium oxalate, calcium fluoride, calcium sulfate, aqueous solutions thereof, and the like, which may be used alone or in combination of two or more, but are not limited thereto.

Further, the reaction for preparing the hemicalcium salt may be carried out in a solvent that can be used for the reaction for preparing the salt, and specifically, methanol, tetrahydrofuran, water, and the like may be used alone or in combination of two or more, but not limited thereto. In addition, the hydrolysis reaction may be performed under a temperature condition of 20 ℃ to 30 ℃.

In the present invention, the preparation method including the steps (1a) to (1e) can be summarized in the following reaction formula 1.

[ reaction formula 1]

In the present invention, P may be R₆R₇R₈In the case of C-, a production method comprising the steps (1a) to (1e) is used, but not limited thereto.

According to another embodiment of the present invention, it is possible to prepare (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt by a preparation method comprising the steps of:

(2a) reacting a compound of the following chemical formula a-1 with a compound of the following chemical formula B to prepare a compound of the following chemical formula C;

(2b) reacting the compound of chemical formula C with a compound of chemical formula E below to prepare a compound of chemical formula F-2 below;

(2c) deprotecting the compound of formula F-2 to produce a compound of formula G below; and

(2d) preparing a compound of the following chemical formula 1 from the compound of the chemical formula G:

[ chemical formula A-1]

[ chemical formula B ]

[ chemical formula C ]

[ chemical formula E ]

[ chemical formula F-2]

[ chemical formula G ]

[ chemical formula 1]

In the above-mentioned chemical formula, the metal oxide,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂Aryl radical, and

r is C₁-C₆An alkyl group.

Step (2a) may be substantially the same as step (1 a). Therefore, any redundant detailed description will be omitted.

Step (2b) may be a step of coupling the compound of formula C with the compound of formula E while maintaining a hydroxyl protecting group of the compound of formula C, thereby forming an azole ring. Further, step (2b) may be carried out in a solvent that can be used for pyrrole cyclization reaction, and methanol, diethyl ether, ethyl acetate, tetrahydrofuran, toluene, heptane, cyclohexane, hexane, etc. may be used alone or in combination of two or more, but are not limited thereto. Further, the step (2b) may be performed under a temperature condition of 20 ℃ to 30 ℃, or may be performed by heating at 80 ℃ to 90 ℃ depending on the solvent.

Step (2c) may be a step of simultaneously removing a hydroxyl protecting group and a diol protecting group from the compound of formula F-2, and may be performed under acidic conditions. Further, examples of the acid may include formic acid, acetic acid, sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, chromic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, and the like, wherein these aqueous solutions may be used alone or in combination of two or more, but are not limited thereto. Further, step (2c) may be carried out in a solvent that can be used for the deprotection reaction of a hydroxyl protecting group or a glycol protecting group, and specifically, methanol, tetrahydrofuran, water, or the like may be used alone or in combination of two or more, but is not limited thereto. Further, step (2c) may be performed at 20 ℃ to 30 ℃.

Step (2d) may be substantially the same as step (1 e). Therefore, any redundant detailed description will be omitted.

In the present invention, the preparation method including the steps (2a) to (2d) can be summarized in the following reaction formula 2.

[ reaction formula 2]

In the present invention, P may be R₃R₄R₅In the case of Si-, a preparation method including the steps (2a) to (2d) is used, but not limited thereto.

According to yet another embodiment of the present invention, it is possible to prepare (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt by a preparation method comprising the steps of:

(3a) reacting a compound of the following chemical formula a-2 with a compound of the following chemical formula B to prepare a compound of the following chemical formula D;

(3b) reacting the compound of chemical formula D with a compound of chemical formula E below to prepare a compound of chemical formula F-1 below;

(3c) preparing a compound of the following chemical formula G from the compound of the chemical formula F-1; and

(3d) preparing a compound of the following chemical formula 1 from the compound of the chemical formula G:

[ chemical formula A-2]

[ chemical formula B ]

[ chemical formula D ]

[ chemical formula E ]

[ chemical formula F-1]

[ chemical formula G ]

[ chemical formula 1]

In the above formula, R is C₁-C₆An alkyl group.

The step (3a) may be a step of alkylating an active methylene compound, and is performed under basic conditions. In this case, step (3a) may be performed in substantially the same manner as described in step (1 a). Therefore, any redundant detailed description will be omitted.

The step (3b) may be a step of coupling the compound of formula D with the compound of formula E to form an azole ring. Step (3b) may be carried out in substantially the same manner as the pyrrole cyclization reaction described in step (1 c). Therefore, any redundant detailed description will be omitted.

Step (3c) may be a step of removing the acetal protecting group of diol from the compound of formula F-1, and may be performed under acidic conditions. In this case, step (3c) may be performed in substantially the same manner as step (1 d). Therefore, any redundant detailed description will be omitted.

Step (3d) may be a step of preparing a final product, which is (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt, by hydrolyzing the compound of formula G under basic conditions and adding a source of calcium ions thereto. Step (3d) may be performed in substantially the same manner as step (1 e). Therefore, any redundant detailed description will be omitted.

In the present invention, the preparation method including the steps (3a) to (3d) can be summarized in the following reaction formula 3.

[ reaction formula 3]

Compounds of formula A and methods for preparing the same

The present invention can provide a compound which is useful as an intermediate for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt and is represented by chemical formula a-1:

[ chemical formula A-1]

In the above-mentioned chemical formula, the metal oxide,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₆、R₇and R₈Each independently is H, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or C₆-C₁₂Aryl { the C₆-C₁₂At least one H in the aryl radical may be replaced by C₁-C₆Alkoxy substituted }, and

R₉is C₁-C₆Alkyl or C₆-C₁₂And (4) an aryl group.

The P may be tetrahydropyranyl, methoxymethyl, methoxyethyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, trityl, methoxyphenyldiphenylmethyl, bis (methoxyphenyl) phenylmethyl, benzyl, P-methoxybenzyl, dimethoxybenzyl, benzoyl or t-butoxycarbonyl, but is not limited thereto.

In addition, the present invention may provide a method for preparing the compound represented by the chemical formula A-1. Specifically, the compound represented by the formula a-1 may be prepared according to a preparation method comprising the steps of:

(SA-1) reacting a compound of the following chemical formula a-1 with P-X to prepare a compound of the following chemical formula a-2;

(SA-2) preparing a compound of the following chemical formula a-3 from the compound of the chemical formula a-2; and

(SA-3) reacting the compound of chemical formula a-3 with a compound of the following chemical formula a-4 to prepare a compound of the following chemical formula a-1:

[ chemical formula a-1]

[ chemical formula a-2]

[ chemical formula a-3]

[ chemical formula a-4]

[ chemical formula A-1]

In the above-mentioned chemical formula, the metal oxide,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂An aryl group, a heteroaryl group,

R₁₀is C₁-C₆Alkyl radical, and

x is halogen.

In the present invention, the preparation method of the compound of formula A-1 can be summarized in the following reaction formula 4.

[ reaction formula 4]

According to the reaction formula 4, the compound of chemical formula a-2 may be prepared by protecting the compound of chemical formula a-1, i.e., 4-nitrobenzyl alcohol, as a starting material with a protecting group (P), and the compound of chemical formula a-3 may be prepared by reducing the nitro group contained in the compound of chemical formula a-2 to aniline, and then the compound of chemical formula A-1 may be prepared by a cross-coupling reaction with the compound of chemical formula a-4.

In the present specification, "cross-coupling" may be a coupling reaction that occurs between different compounds.

Further, the present invention can provide a compound which is useful as an intermediate for preparing (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt and is represented by chemical formula A-2.

[ chemical formula A-2]

In addition, the present invention may provide a method for preparing the compound represented by the chemical formula a-2. Specifically, the compound represented by the chemical formula a-2 may be prepared according to a preparation method comprising the steps of:

(SA-2) preparing a compound of the following chemical formula a-3 from the compound of the chemical formula a-2;

(SA-3) reacting the compound of chemical formula a-3 with a compound of chemical formula a-4 below to prepare a compound of chemical formula a-1 below; and

(SA-4) deprotecting the compound of formula a-1 to produce a compound of formula a-2 below:

[ chemical formula a-1]

[ chemical formula a-2]

[ chemical formula a-3]

[ chemical formula a-4]

[ chemical formula A-1]

[ chemical formula A-2]

In the above-mentioned chemical formula, the metal oxide,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₁And R₂Each independently of the otherGround is C₁-C₆Alkyl groups, or combine with each other to form a five-to seven-membered ring,

R₉is C₁-C₆Alkyl or C₆-C₁₂An aryl group, a heteroaryl group,

R₁₀is C₁-C₆Alkyl radical, and

x is halogen.

In the present invention, the preparation method of the compound of formula a-2 can be summarized in the following reaction formula 5.

[ reaction formula 5]

According to the reaction formula 5, the compound of chemical formula a-1 may be prepared by substantially the same procedure as described in the reaction formula 4, and then the compound of chemical formula a-2 may be prepared by deprotection reaction of a hydroxyl group.

Process for the preparation of compounds of formula B

The present invention can provide a process for producing { 2-bromo-1- (4-fluorophenyl) -2-phenyleth-1-one }, which is useful as an intermediate for producing (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt, and is represented by the following chemical formula B.

[ chemical formula B ]

Specifically, the compound represented by the formula B may be prepared according to a preparation method comprising the steps of:

(SB-1) reacting a compound of the following chemical formula b-1 with a compound of the following chemical formula b-2 to prepare a compound of the following chemical formula b-3; and

(SB-2) brominating the compound of chemical formula B-3 to prepare a compound of chemical formula B below.

[ chemical formula b-1]

[ chemical formula b-2]

[ chemical formula b-3]

[ chemical formula B ]

In the present invention, the preparation method of the compound of formula B can be summarized in the following reaction formula 6.

[ reaction formula 6]

According to the reaction formula 6, the compound of formula B-1, which is a starting material, fluorobenzene and the compound of formula B-2 may be subjected to a friedel-crafts acylation reaction to prepare a compound of formula B-3, and then may be subjected to a bromination reaction to prepare a compound of formula B.

In the present specification, the "friedel-crafts acylation reaction" may be a reaction of introducing a carbonyl group into an aromatic compound or an aromatic compound derivative by Electrophilic Aromatic Substitution (EAS) reaction with an acid chloride compound under lewis acid conditions.

In the present specification, the "bromination reaction" may be a reaction by passing a halogen compound (Br) to be introduced under acidic or basic conditions₂) Reaction to introduce a Br group alpha to the ketone.

Compounds of formula C or D and methods of making the same

The present invention can provide compounds useful as intermediates in the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt and represented by chemical formula C:

[ chemical formula C ]

In the above-mentioned chemical formula, the metal oxide,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂And (4) an aryl group.

In addition, the present invention may provide a method for preparing the compound represented by chemical formula C. Specifically, the compound represented by chemical formula C may be prepared according to a preparation method including the step of reacting a compound of chemical formula a-1 with a compound of chemical formula B to prepare a compound of chemical formula C:

[ chemical formula A-1]

[ chemical formula B ]

[ chemical formula C ]

In the above-mentioned chemical formula, the metal oxide,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂And (4) an aryl group.

In the present invention, the preparation method of the compound of formula C can be summarized in the following reaction formula 7.

[ reaction formula 7]

According to the reaction formula 7, the compound of chemical formula C may be obtained by simply coupling the compound of chemical formula a-1 with the compound of chemical formula B under basic conditions. In this case, for the basic condition, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, 1, 8-diazabicyclo (5.4.0) undec-7-ene (DBU), N-Diisopropylethylamine (DIPEA), Triethanolamine (TEA), pyridine, sodium hydride, potassium tert-butoxide (K [ OC (CH)₃)₃]) Etc. may be used alone or in combination of two or more, but are not limited thereto.

The present invention can provide a compound which is useful as an intermediate for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt and is represented by chemical formula D.

[ chemical formula D ]

In addition, the present invention may provide a method for preparing the compound represented by chemical formula D. Specifically, the compound represented by chemical formula D may be prepared according to a preparation method including a step of reacting a compound of chemical formula a-2 below with a compound of chemical formula B below to prepare a compound of chemical formula D below.

[ chemical formula A-2]

[ chemical formula B ]

[ chemical formula D ]

In the present invention, the preparation method of the compound of formula D can be summarized in the following reaction formula 8.

[ reaction formula 8]

According to the reaction formula 8, the compound of chemical formula D may be prepared by substantially the same reaction as described in the reaction formula 7, except that the compound of chemical formula a-2 is used instead of the compound of chemical formula a-1 in the reaction formula 7.

Compounds of formula F and methods for preparing the same

The present invention can provide a compound which is useful as an intermediate for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt and is represented by the chemical formula F-2:

[ chemical formula F-2]

In the above-mentioned chemical formula, the metal oxide,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂Aryl radical, and

r is C₁-C₆An alkyl group.

In addition, the present invention may provide a method for preparing the compound represented by the chemical formula F-2. Specifically, the compound represented by the chemical formula F-2 may be prepared according to a preparation method including the step of reacting a compound of the following chemical formula C with a compound of the following chemical formula E to prepare a compound of the following chemical formula F-2:

[ chemical formula C ]

[ chemical formula E ]

[ chemical formula F-2]

In the above-mentioned chemical formula, the metal oxide,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂Aryl radical, and

r is C₁-C₆An alkyl group.

In the present invention, the preparation method of the compound of formula F-2 can be summarized in the following reaction formula 9.

[ reaction formula 9]

According to the reaction formula 9, an intermolecular condensation reaction between the compound of formula C and the compound of formula E may occur through a coupling reaction, and intramolecular condensation reactions may occur continuously to prepare the compound of formula F-2 including a pyrrole ring.

Further, the present invention can provide a process for producing a compound which is useful as an intermediate for producing (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt and is represented by the chemical formula F-1:

[ chemical formula F-1]

In the above formula, R is C₁-C₆An alkyl group.

Specifically, the compound represented by the chemical formula F-1 may be prepared according to a preparation method including a step of reacting a compound of the following chemical formula D with a compound of the chemical formula E to prepare a compound of the following chemical formula F-1. In this case, in this step, the compound of formula F-1 of the solid phase may be obtained by using a mixed solvent in which a first solvent selected from the group consisting of ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, acetone, methanol, ethanol and isopropanol is mixed with a second solvent selected from the group consisting of hexane, pentane, heptane, water and petroleum ether, but not limited thereto.

[ chemical formula D ]

[ chemical formula E ]

[ chemical formula F-1]

In the above formula, R is C₁-C₆An alkyl group.

The mixed solvent (first solvent/second solvent) may include any one selected from the following: ethyl acetate/hexane; ethyl acetate/pentane; ethyl acetate/heptane; dichloromethane/hexane; dichloromethane/pentane; dichloromethane/heptane; chloroform/pentane; chloroform/heptane; tetrahydrofuran/hexane; tetrahydrofuran/pentane; tetrahydrofuran/heptane; acetone/water; acetone/hexane; acetone/pentane; acetone/heptane; acetone/petroleum ether; methanol/water; ethanol/water; and isopropanol/water, preferably tetrahydrofuran/heptane, but not limited thereto.

The compound of formula F-1 may be prepared by substantially the same procedure as described in the reaction formula 9, except that the compound of formula D is used instead of the compound of formula C in the reaction formula 9.

Process for the preparation of compounds of formula G

The present invention can provide a process for the preparation of a compound useful as an intermediate for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt and represented by the formula G.

The method may include the step of preparing a compound of the following chemical formula G from a compound of the following chemical formula F-1 or a compound of the following chemical formula F-2:

[ chemical formula F-1]

[ chemical formula F-2]

[ chemical formula G ]

In the above-mentioned chemical formula, the metal oxide,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂Aryl radical, and

r is C₁-C₆An alkyl group.

In the present invention, there may be provided a method for preparing the compound of formula G, wherein the compound of formula G may be prepared by using the compound of formula F-1 or the compound of formula F-2, but may be obtained in a solid phase by using a mixed solvent in which a first solvent selected from the group consisting of ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, acetone, methanol, ethanol and isopropanol is mixed with a second solvent selected from the group consisting of hexane, pentane, heptane, water and petroleum ether. For example, a mixed solvent (first solvent/second solvent) may be used as any one combination selected from the following: ethyl acetate/hexane; ethyl acetate/pentane; ethyl acetate/heptane; dichloromethane/hexane; dichloromethane/pentane; dichloromethane/heptane; chloroform/pentane; chloroform/heptane; tetrahydrofuran/hexane; tetrahydrofuran/pentane; tetrahydrofuran/heptane; acetone/water; acetone/hexane; acetone/pentane; acetone/heptane; acetone/petroleum ether; methanol/water; ethanol/water; and isopropanol/water, but is not limited thereto.

The compound of formula G may be prepared by the following steps: the compound of formula F-1 or F-2 is subjected to a deprotection reaction under acidic conditions, thereby deprotecting both the hydroxyl group and the diol.

Advantageous effects

According to the present invention, the preparation method of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt can be performed in a convergent synthesis manner in which each main structural part of the compound is synthesized separately and coupled, and thus has an advantage in that it is easy to control the main relevant substances as compared with the sequential synthesis manner disclosed in conventional documents. In addition, the present invention can reduce preparation time by reducing the risk factors inherent in sequential synthesis pathways, such as having to return to the first pathway and recombine upon failure of an intermediate synthesis.

Further, the novel intermediate used in the production method of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt can be purified by curing with the use of a protecting group such as trityl group, and can be synthesized stably in high yield, thereby increasing the yield of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid hemicalcium salt.

Best mode for carrying out the invention

Hereinafter, the present invention will be described in detail by preferred embodiments for better understanding of the present invention. However, the following embodiments are provided only for the purpose of illustrating the present invention, and thus the present invention is not limited thereto.

Furthermore, AvanceII 500 using Brucker's was measured at 500MHz¹H-NMR。

Example 1

Hereinafter, the present invention will be described in more detail by specific embodiments. Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Unless clearly defined in the present application, terms such as those defined in commonly used dictionaries are to be interpreted as having the same meaning as a contextual meaning in the related art and are not to be interpreted as having an ideal or excessively formal meaning.

Example 1: preparation of 4-methyl-3-oxo-N- (4- ((trityloxy) methyl) phenyl) pentanamide

Step 1: preparation of ((4-nitrobenzyl) oxy) methyl-claw) triphenyl

4-Nitro-benzyl alcohol (109g) and trityl chloride (198g) were dissolved in CH₂Cl₂(1.5L). Triethylamine (TEA, 115g) was added to the reaction solution, stirred at 20 ℃ to 30 ℃ for four hours, and washed with distilled water (0.5L) and brine (0.5L). The extracted organic layer was concentrated under reduced pressure, followed by addition of anhydrous ethanol (0.25L) and stirring at 20 ℃ to 30 ℃ for one hour, and then at 0 ℃ to 5 ℃ for two hours. At this time, the resulting solid was filtered, washed with anhydrous ethanol (0.1L), and dried under vacuum at 55 ℃ to 60 ℃ for 12 hours to obtain the title compound.

225g of solid (yield 80%);

¹H NMR(500MHz,DMSO-d₆):δ8.21(d,J＝9.0Hz,2H),7.65(d,J＝9.0Hz,2H),7.44(d,J＝7.5Hz,6H),7.37(t,J＝7.5Hz,6H),7.29(t,J＝7.5Hz,3H),4.28(s,2H).

step 2: preparation of 4- ((trityloxy) methyl) aniline

The (((4-nitrobenzyl) oxy) methyl claw) triphenyl (203g) obtained in step 1 and zinc powder (174.5g) were added to methanol (2L) and cooled to 0 ℃ to 5 ℃. Ammonium formate (213.5g) was added to the reaction solution and refluxed for two hours. The reaction solution was cooled to 20 ℃ to 25 ℃, filtered through celite, and charged with CH₂Cl₂(0.5L) wash to remove zinc. The resulting filtrate was concentrated under reduced pressure, followed by addition of CH₂Cl₂(0.8L) and stirred until the resulting mixture was sufficiently dissolved. The resulting solution was taken up in saturated NaHCO₃The aqueous solution (1L), distilled water (0.5L) and brine (0.5L) were washed, and the organic layer was concentrated under reduced pressure. Isopropanol (IPA, 0.25L) and ethyl acetate (EA, 0.15L) were added to the resulting solid, stirred at 55 ℃ to 60 ℃ for one hour, then at 20 ℃ to 30 ℃ for one hour, then at 0 ℃ to 5 ℃ for two hours. The resulting solid was filtered and washed with IPA (0.2L). The resulting product was dried under vacuum at 50 ℃ to 55 ℃ for 12 hours to obtain the title compound.

Solid 149g (yield 80%);

¹H NMR(500MHz,DMSO-d₆):δ7.42(d,J＝7.5Hz,6H),7.35(t,J＝7.5Hz,6H),7.27(t,J＝7.5Hz,3H),6.96(d,J＝8.5Hz,2H),6.54(d,J＝8.5Hz,2H),5.03(NH₂,br s,2H),3.85(s,2H),MH+366.

and step 3: preparation of 4-methyl-3-oxo-N- (4- ((trityloxy) methyl) phenyl) pentanamide

The 4- ((trityloxy) methyl) aniline obtained in step 2 (134g) was dissolved in toluene (1.3L). Methyl 4-methyl-3-oxopentanoate (53g, 1 eq) and ethylenediamine (2.48ml, 0.1 eq) were added to the reaction solution. The resulting solution was then refluxed under stirring for 40 hours under a Dean-Stark trap. The resulting reaction solution was cooled to 20 ℃ and washed with distilled water (0.5L) and brine (0.5L). The organic layer was concentrated under reduced pressure to obtain the title compound.

192g of oil (110%, assuming a yield of 70%).

Example 1-1: preparation of 4-methyl-3-oxo-N- (4- ((trityloxy) methyl) phenyl) pentanamide

Step 1: preparation of ((4-nitrobenzyl) oxy) methyl-claw) triphenyl

The title compound was obtained by substantially the same method as shown in step 1 of example 1.

225g of solid (yield 80%);

step 2: preparation of 4- ((trityloxy) methyl) aniline

The (((4-nitrobenzyl) oxy) methyl-tolyl) triphenyl (40g) obtained in step 1 and zinc powder (53.04g) were added to methanol (0.2L), and stirred at 20 ℃ to 25 ℃. Ammonium chloride (27.04g) was added to the reaction solution, and refluxed for five hours. The reaction solution was filtered and washed with CH₂Cl₂(0.1L) washing. Subjecting the obtained product toThe filtrate was concentrated under reduced pressure, followed by addition of isopropanol (0.1L) and dissolution at 55 ℃ to 60 ℃, stirring for one hour at 30 ℃ to 40 ℃, cooling to 10 ℃ to 15 ℃, stirring for one hour, and filtration. The resulting solid was filtered and washed with IPA (0.02L). The resulting product was dried under vacuum at 50 ℃ to 55 ℃ for 12 hours to obtain the title compound.

Solid 32.3g (yield 87%);

The title compound was obtained by substantially the same method as shown in step 3 of example 1.

Example 2: n- (4- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) -4-methyl-3-oxopentane Preparation of amides

Step 1: preparation of tert-butyldimethyl ((4-nitrobenzyl) oxy) silane

After 4-nitrobenzyl alcohol (300mg, 1.96mmol) was dissolved in tetrahydrofuran (THF, 4ml), the resulting solution was stirred at room temperature. TEA (0.82ml, 5.88mmol) and tert-butyldimethylsilyl chloride (TBDMSCl, 1M in THF, 4.8ml, 4.80mmol) were added to the reaction solution, and stirred at the same temperature for 95 hours. Then, EA was added to the reaction solution, diluted, washed several times with distilled water, and then added with MgSO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.

520mg of a colorless oil (yield 99%);

¹H NMR(500MHz,DMSO-d₆):δ8.22(d,J＝8.5Hz,2H),7.58(d,J＝8.5Hz,2H),4.86(s,2H),0.92(s,9H),0.10(s,6H),MH+268.

step 2: preparation of 4- (((tert-butyldimethylsilyl) oxy) methyl) aniline

Tert-butyldimethyl ((4-nitrobenzyl) oxy) silane (100mg) obtained in step 1 was diluted with MeOH (8ml) and stirred at room temperature. Zinc powder (150mg, 2.24mmol) and ammonium formate (94mg, 1.50mmol) were added to the reaction solution and refluxed for one hour. Then, the reaction solution was cooled and filtered through celite to remove zinc. The filtrate was concentrated under reduced pressure, diluted with EA, washed several times with distilled water, and then added with MgSO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.

40mg (yield 46%) of a colorless oil;

¹H NMR(500MHz,DMSO-d₆):δ6.94(d,J＝8.0Hz,2H),6.50(d,J＝8.0Hz,2H),4.96(NH₂,br s,2H),4.49(s,2H),0.87(s,9H),0.03(s,6H),MH+238.

and step 3: n- (4- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) -4-methyl-3-oxovaleryl Preparation of amines

The 4- (((tert-butyldimethylsilyl) oxy) methyl) aniline obtained in step 2 (500mg) was diluted with toluene (10.5ml) and stirred at room temperature, followed by adding TEA (90ul, 0.63mmol) and methyl 4-methyl-3-oxopentanoate (0.34ml, 2.32mmol) to the reaction solution and heating at 110 ℃ to 120 ℃ for 2.5 hours. The resulting solution was then cooled and saturated NaHCO was used₃The aqueous solution, brine and distilled water were washed by adding MgSO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.

668mg of light brown gel (91% yield);

¹H NMR(500MHz,DMSO-d₆):δ10.03(NH,br s,1H),7.53(d,J＝8.5Hz,2H),7.23(d,J＝8.5Hz,2H),4.64(s,2H),3.60(s,2H),2.75(sep,J＝7.0Hz,1H),1.05(d,J＝7.0Hz,6H),0.89(s,9H),0.06(s,6H),MH+350.

example 3: n- (4- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) -4-methyl-3-oxopentane Preparation of amides

Step 1: (in situ) preparation of 4- (((tert-butyldimethylsilyl) oxy) methyl) aniline

After 4-nitrobenzyl alcohol (1000mg, 6.53mmol) was dissolved in THF (13ml), the resulting solution was stirred at room temperature. TEA (1.9ml, 13.6mmol) and t-butyldimethylsilyl chloride (TBDMSCl, 1M in THF, 10.4ml, 10.4mmol) were added to the reaction solution, and stirred at the same temperature for 40 hours. Then, EA was added to the reaction solution, diluted, washed several times with distilled water, and then added with MgSO₄The extracted organic layer was dried and filtered under reduced pressure. The resulting filtrate was concentrated under reduced pressure, diluted with MeOH (65ml), and stirred at room temperature. Zinc powder (2560mg, 39.2mmol) and ammonium formate (1650mg, 26.1mmol) were added to the reaction solution and refluxed for 4.5 hours. Then, the reaction solution was cooled and filtered through celite to remove zinc. The resulting filtrate was concentrated under reduced pressure, diluted with EA and saturated NaHCO₃The aqueous solution and brine were washed several times by addition of MgSO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.

954mg of light brown oil (yield 62%);

¹H NMR(500MHz,DMSO-d₆):δ6.94(d,J＝8.0Hz,2H),6.51(d,J＝8.0Hz,2H),4.95(NH₂,br s,2H),4.49(s,2H),0.87(s,9H),0.03(s,6H),MH+238.

step 2: n- (4- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) -4-methyl-3-oxovaleryl Preparation of amines

The 4- (((tert-butyldimethylsilyl) oxy) methyl) aniline obtained in step 1 (500mg) was diluted with toluene (10.5ml) and stirred at room temperature, followed by addition of TEA (90ml, 0.63mmol) and methyl 4-methyl-3-oxopentanoate (0.34ml, 2.32mmol) to the reaction solution,and heated at 110 to 120 ℃ for 2.5 hours. The resulting solution was then cooled and saturated NaHCO was used₃The aqueous solution, brine and distilled water were washed by adding MgSO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.

668mg of light brown gel (91% yield);

example 4: preparation of N- (4- (((4-methoxybenzyl) oxy) methyl) phenyl) -4-methyl-3-oxopentanamide Prepare for

Step 1: preparation of 1-methoxy-4- (((4-nitrobenzyl) oxy) methyl) benzene

After 4-nitrobenzyl alcohol (1g, 6.53mmol) was dissolved in THF (22ml), the resulting solution was stirred at room temperature. TEA (4.6ml, 32.65mmol) and p-methoxybenzyl chloride (PMBCl, 2.7ml, 19.59mmol) were added to the reaction solution and stirred at 65 ℃ for 14 h. Then, EA was added to the reaction solution, diluted, and NaHCO₃(aqueous solution) and distilled water were washed several times. By adding MgSO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.

680mg of pale yellow oil (40% yield);

¹H NMR(500MHz,DMSO-d₆):δ8.22(d,J＝9.0Hz,2H),7.61(d,J＝9.0Hz,2H),7.30(d,J＝8.5Hz,2H),6.93(d,J＝8.5Hz,2H),4.64(s,2H),4.51(s,2H),3.75(s,3H).

step 2: preparation of 4- (((4-methoxybenzyl) oxy) methyl) aniline

1-methoxy-4- (((4-nitrobenzyl) oxy) methyl) benzene obtained in step 1 (680mg, 2.49mmol) was diluted with MeOH (25ml) and stirred at room temperature. Zinc powder (980mg, 14.93mmol) and ammonium formate (630mg, 9.95mmol) were added to the reaction solution and refluxed at 65 ℃ for 1.5 hours. Then, the reaction solution was cooled and filtered through celite to remove zinc. The filtrate was concentrated under reduced pressure, diluted with EA and with NaHCO₃(aqueous solution) and distilled water were washed several times. By adding MgSO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure to obtain the title compound.

600mg of yellow oil (yield 99%);

¹H NMR(500MHz,DMSO-d₆):δ7.23(d,J＝9.0Hz,2H),6.97(d,J＝8.5Hz,2H),6.90(d,J＝8.5Hz,2H),6.52(d,J＝8.5Hz,2H),5.04(br s,2H),4.35(s,2H),4.27(s,2H),3.74(s,3H),MH+244.

and step 3: preparation of N- (4- (((4-methoxybenzyl) oxy) methyl) phenyl) -4-methyl-3-oxopentanamide

The 4- (((4-methoxybenzyl) oxy) methyl) aniline obtained in step 2 (600mg, 2.47mmol) was diluted with toluene (25ml) and stirred at room temperature. TEA (0.1ml, 0.81mmol) and methyl 4-methyl-3-oxopentanoate (0.4ml, 2.71mmol) were added to the reaction solution and refluxed at 110 ℃ for six hours. The reaction solution was cooled, diluted with EA and NaHCO₃(aqueous solution) and distilled water were washed several times. By adding MgSO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.

620mg of orange oil (yield 70%);

¹H NMR(500MHz,DMSO-d₆):δ10.07(br s,1H),7.55(d,J＝8.5Hz,2H),7.27(d,J＝8.5Hz,2H),7.26(d,J＝8.5Hz,2H),6.91(d,J＝8.5Hz,2H),4.42(s,4H),3.74(s,3H),3.61(s,2H),2.75(sep,J＝7.0Hz,1H),1.05(d,J＝7.0Hz,6H),MH+356.

example 5: n- (4- (((4-methoxyphenyl) diphenylmethoxy) methyl) phenyl) -4-methyl-3-oxopentane Preparation of amides

Step 1:preparation of ((4-methoxyphenyl) ((4-nitrobenzyl) oxy) methylene) diphenyl

The title compound was prepared by the same procedure (room temperature, 20 hours) except that methoxyphenyl-diphenylmethane-1-ylchloride was used instead of tert-butyldimethylsilyl chloride in step 1 of example 2.

White solid (yield 68%);

¹H NMR(500MHz,DMSO-d₆):δ8.21(d,J＝9.0Hz,2H),7.65(d,J＝9.0Hz,2H),7.45(d,J＝7.0Hz,4H),7.36(t,J＝7.5Hz,4H),7.30(d,J＝9.0Hz,2H),7.27(t,J＝7.5Hz,2H),6.93(d,J＝9.0Hz,2H),4.27(s,2H).

step 2: preparation of 4- (((4-methoxyphenyl) diphenylmethoxy) methyl) aniline

The title compound was obtained (room temperature, 15.5 hours) by the same procedure except that ((4-methoxyphenyl) ((4-nitrobenzyl) oxy) methylene) diphenyl was used instead of tert-butyldimethyl ((4-nitrobenzyl) oxy) silane in step 2 of example 2.

Colorless crystals (yield 73%);

¹H NMR(500MHz,DMSO-d₆):δ7.42(d,J＝7.5Hz,4H),7.34(t,J＝7.5Hz,4H),7.28(d,J＝8.5Hz,2H),7.25(t,J＝7.5Hz,2H),6.96(d,J＝8.0Hz,2H),6.92(d,J＝9.0Hz,2H),6.54(d,J＝8.0Hz,2H),5.04(NH₂,br s,2H),3.84(s,2H),3.74(s,3H),MH+396.

and step 3: n- (4- (((4-methoxyphenyl) diphenylmethoxy) methyl) phenyl) -4-methyl-3-oxovaleryl Preparation of amines

The title compound was prepared by the same procedure except that 4- (((4-methoxyphenyl) diphenylmethoxy) methyl) aniline was used instead of 4- ((trityloxy) methyl) aniline in step 3 of example 1.

Example 6: n- (4- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) phenyl) -4-methyl-3-oxo Preparation of pentanamides

Step 1: preparation of 4, 4' - (((4-nitrobenzyl) oxy) (phenyl) methylene) bis (methoxybenzene)

The title compound was prepared (room temperature, 15.5 hours) by the same procedure except that 4, 4' - (chloro (phenyl) methylene) bis (methoxybenzene) was used instead of tert-butyldimethylsilyl chloride in step 1 of example 2.

White solid (yield 79%);

¹H NMR(500MHz,DMSO-d₆)δ8.21(d,J＝9.0Hz,2H),7.65(d,J＝8.5Hz,2H),7.59(d,J＝7.0Hz,2H),7.34(t,J＝7.5Hz,2H),7.31(d,J＝9.0Hz,4H),7.25(t,J＝7.5Hz,1H),6.92(d,J＝9.0Hz,4H),4.26(s,2H).

step 2: preparation of 4- ((di (4-methoxyphenyl) (phenyl) methoxy) methyl) aniline

The title compound was obtained by the same procedure except for using 4, 4' - (((4-nitrobenzyl) oxy) (phenyl) methylene) bis (methoxybenzene) instead of tert-butyldimethyl ((4-nitrobenzyl) oxy) silane in step 2 of example 2.

Colorless gel (yield 84%);

¹H NMR(500MHz,DMSO-d₆):δ7.41(d,J＝9.0Hz,2H),7.32(t,J＝7.5Hz,2H),7.28(d,J＝9.0Hz,4H),7.22(t,J＝7.5Hz,1H),6.96(d,J＝8.5Hz,2H),6.91(d,J＝9.0Hz,4H),6.53(d,J＝8.5Hz,2H),5.03(NH₂,br s,2H),3.83(s,2H),3.74(s,6H),MH+426.

and step 3: n- (4- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) phenyl) -4-methyl-3-oxopentane Preparation of amides

The title compound was prepared by the same procedure except that 4- ((bis (4-methoxyphenyl) (phenyl) methoxy) methyl) aniline was used instead of 4- ((trityloxy) methyl) aniline in step 3 of example 1.

Example 7: n- (4- (((tert-butyldiphenylsilyl) oxy) methyl) phenyl) -4-methyl-3-oxopentane Preparation of amides

Step 1: preparation of tert-butyl ((4-nitrobenzyl) oxy) diphenylsilane

In this step, tert-butyl ((4-nitrobenzyl) oxy) diphenylsilane was obtained (room temperature, 67 hours) by conducting the process through the same method as shown in step 1 of example 2, except that tert-butyldiphenylsilyl chloride (TBDPS-Cl) was used instead of TBDMS-Cl.

White solid (yield 81%);

¹H NMR(500MHz,DMSO-d₆):δ8.24(d,J＝9.0Hz,2H),7.66-7.65(m,3H),7.64-7.63(m,3H),7.50-7.48(m,1H),7.47(t,J＝3.0Hz,1H),7.44-7.42(m,4H),4.92(s,2H),1.06(s,9H).

step 2: preparation of 4- (((tert-butyldiphenylsilyl) oxy) methyl) aniline

The process was carried out by the same method as shown in step 2 of example 2 to prepare 4- (((tert-butyldiphenylsilyl) oxy) methyl) aniline.

And step 3: n- (4- (((tert-butyldiphenylsilyl) oxy) methyl) phenyl) -4-methyl-3-oxovaleryl Preparation of amines

The process was carried out by the same method as shown in step 3 of example 2 to prepare N- (4- (((tert-butyldiphenylsilyl) oxy) methyl) phenyl) -4-methyl-3-oxovaleramide.

Example 8: preparation of 2-bromo-1- (4-fluorophenyl) -2-phenyleth-1-one

Step 1: preparation of 1- (4-fluorophenyl) -2-phenyleth-1-one

Fluorobenzene (216g, 8 eq.) and AlCl₃(75g, 1.2 eq) was cooled to 0 ℃ to 5 ℃ followed by the slow dropwise addition of 2-phenylacetyl chloride (62ml, 1 eq) and stirred at the same temperature for one hour. 2N HCl (0.28L) was added to the reaction solution and saturated NaHCO₃Aqueous (0.11L), distilled (0.11L) and brine (0.11L). The organic layer was concentrated under reduced pressure, followed by addition of IPA (0.26L) andthe reaction was stirred at 55 ℃ to 60 ℃ for one hour, at 20 ℃ to 30 ℃ for one hour, and at 0 ℃ to 5 ℃ for two hours to give a solid. The resulting solid was filtered, washed with IPA (0.06L), and dried under vacuum at 50 ℃ to 55 ℃ for 12 hours to obtain the title compound.

Solid 80g (yield 70%);

¹H NMR(500MHz,DMSO-d₆):δ8.15-8.11(m,2H),7.39-7.34(m,2H),7.33-7.30(m,2H),7.27-7.21(m,3H),4.39(s,2H),MH+215.

step 2: preparation of 2-bromo-1- (4-fluorophenyl) -2-phenyleth-1-one

1- (4-fluorophenyl) -2-phenyleth-1-one (144g, 1 eq) was obtained in step 1 and dissolved in CH₂Cl₂(1.4L), HBr (2.88ml, 0.01 eq) was then added dropwise to the reaction solution and cooled to 0 ℃ to 5 ℃. Adding Br₂(34.56ml, 2 equiv.) with CH₂Cl₂(0.29L) and added dropwise to the solution of 1- (4-fluorophenyl) -2-phenyleth-1-one. Then, 5% Na was added₂SO₃(0.29L) was added to the reaction solution, and stirred at 20 ℃ to 25 ℃ for one hour. Separation of CH₂Cl₂Layer by mixing with 5% Na₂SO₃(0.29L) further washed twice. Add 5% NaHCO₃(0.29L) and stirred at 20 ℃ to 25 ℃ for one hour. Separation of CH₂Cl₂The layer was washed with 5% NaCl (0.29L). MgSO (MgSO)₄(30g) Added to the organic layer, dried, and filtered. The resulting filtrate was concentrated under reduced pressure, followed by addition of hexane (0.4L), stirring at 20 to 30 ℃ for one hour, and stirring at 0 to 5 ℃ for two hours, to give a solid. The resulting solid was filtered, washed with hexane (0.2L), and dried under vacuum at 25 ℃ to 30 ℃ for 12 hours to obtain the title compound.

184g of solid (yield 93%);

¹H NMR(500MHz,DMSO-d₆):δ8.18-8.14(m,2H),7.55-7.53(m,2H),7.40-7.31(m,5H),7.18(s,1H).

example 9: 2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -4-methyl-3-oxo-N-(4- ((triphenyl) Preparation of methyloxy) methyl) phenyl) pentanamide

The 4-methyl-3-oxo-N- (4- ((trityloxy) methyl) phenyl) pentanamide (52.6g) obtained in example 1 was diluted with acetone (0.5L), followed by addition of K₂CO₃(31.2g, 2 equivalents) and stirred at 20 ℃ to 30 ℃. 2-bromo-1- (4-fluorophenyl) -2-phenyleth-1-one (33.1g, 1 eq) obtained in example 8 was added to the reaction solution, and stirred at the same temperature for 18 hours and refluxed for three hours. After completion of the reaction, K was filtered off₂CO₃Using CH together₂Cl₂(0.1L) washing. Then, the reaction solution was washed with distilled water (0.1L) and brine (0.1L), and concentrated under reduced pressure. MeOH (0.15L) was added to the resulting concentrate, stirred at 55 ℃ to 60 ℃ for one hour, and at 20 ℃ to 30 ℃ for two hours to give a solid. The resulting solid was filtered, washed with MeOH (20ml), and dried under vacuum at 50 ℃ to 55 ℃ for 12 hours to obtain the title compound.

Solid 33g (yield 42%);

¹H NMR(500MHz,DMSO-d₆):δ10.21(NH,br s,1H),8.14-8.12(m,2H),7.41(d,J＝7.5Hz,6H),7.37-7.34(m,8H),7.31-7.25(m,9H),7.23-7.20(m,2H),7.15(t,J＝7.5Hz,1H),5.43(d,J＝11.0Hz,1H),4.87(d,J＝11.0Hz,1H),3.96(s,2H),2.91(sep,J＝7.0Hz,1H),1.17(d,J＝7.0Hz,3H),0.94(d,J＝7.0Hz,3H).

example 9-1: 2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -4-methyl-3-oxo-N- (4- ((Tris-phenyl) Preparation of Phenylmethyloxy) methyl) phenyl) pentanamide

The 4-methyl-3-oxo-N- (4- ((trityloxy) methyl) phenyl) pentanamide (43.0g) obtained in example 1 was diluted with 5% acetone (0.25L) and dissolved by stirring at room temperature for 20 minutes. Addition of K₂CO₃(19.17g, 1.56 eq) and stirred for 10 minutes. 2-bromo-1- (4-fluorophenyl) -2-phenyleth-1-one (29.98g, 1.1 eq) obtained in example 8 was added to the reaction solution, and stirred at 25 ℃ to 35 ℃ for 12 hours. After completion of the reaction, purified water (0.2) was added5L), stirred for one hour, and the resulting solid was filtered. The resultant product was washed with a mixed solution of purified water and methanol. Methanol (0.41L) was added to the as-triturated solid, refluxed at 60 ℃ to 65 ℃ for one hour, cooled to 20 ℃ to 30 ℃, and stirred for one hour to give a solid. The resulting solid was filtered, washed with MeOH (30ml), and dried under vacuum at 60 ℃ to 65 ℃ for 12 hours to obtain the title compound.

Solid 42.2g (yield 68%);

example 10: n- (4- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) -2- (2- (4-fluorobenzene) Preparation of yl) -2-oxo-1-phenylethyl) -4-methyl-3-oxopentanamide

N- (4- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) -4-methyl-3-oxopentanamide obtained in example 2 (605mg, 1.73mmol) was diluted with acetone (6.5ml), followed by addition of K₂CO₃(620mg, 4.50mmol) and stirred at room temperature. 2-bromo-1- (4-fluorophenyl) -2-phenyleth-1-one (530mg, 1.78mmol), obtained in example 8 and diluted with acetone (2ml), was added to the reaction solution. The resulting solution was further stirred at the same temperature for 66 hours, and filtered under reduced pressure to remove K therefrom₂CO₃. The resulting filtrate was concentrated under reduced pressure, diluted with EA, washed several times with brine, then by addition of Na₂SO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.

381mg of white solid (yield 39%);

¹H NMR(500MHz,DMSO-d₆):δ10.16(NH,br s,1H),8.14-8.11(m,2H),7.35(d,J＝8.0Hz,2H),7.29(t,J＝8.5Hz,2H),7.25(d,J＝8.5Hz,2H),7.23(d,J＝8.0Hz,2H),7.16-7.14(m,3H),5.42(d,J＝11.0Hz,1H),4.86(d,J＝11.0Hz,1H),4.59(s,2H),2.90(sep,J＝7.0Hz,1H),1.16(d,J＝7.0Hz,3H),0.93(d,J＝7.0Hz,3H),0.87(s,9H),0.04(s,6H),MH+562.

example 11: 2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -N- (4- (((4-methoxybenzyl) oxy) Group) methyl) phenyl) -4-methyl-3-oxopentanamide preparation

N- (4- (((4-methoxybenzyl) oxy) methyl) phenyl) -4-methyl-3-oxopentanamide obtained in example 4 (620mg, 1.74mmol) was diluted with acetone (5.8ml) and stirred at room temperature. Make K₂CO₃(626ml, 4.54mmol) was dissolved in the reaction solution, and then 2-bromo-1- (4-fluorophenyl) -2-phenyleth-1-one (510mg, 1.74mmol) obtained in example 8 was diluted with acetone (2ml), added dropwise, and stirred at room temperature for 31 hours. Then, EA was added to the resulting solution, diluted, and washed several times with brine. By adding MgSO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.

630mg of yellow oil (yield 64%);

¹H NMR(500MHz,DMSO-d₆):δ10.19(br s,1H),8.14-8.11(m,2H),7.36(d,J＝7.5Hz,2H),7.31-7.29(m,3H),7.27(d,J＝2.5Hz,2H),7.24(d,J＝9.0Hz,4H),7.20(t,J＝9.0Hz,3H),7.14(t,J＝7.5Hz,1H),6.90(d,J＝9.0Hz,2H),5.43(d,J＝11.0Hz,1H),4.87(d,J＝11.0Hz,1H),4.39(s,2H),4.37(s,2H),3.74(s,3H),2.90(sep,J＝7.0Hz,1H),1.16(d,J＝7.0Hz,3H),0.94(d,J＝7.0Hz,3H),MH+568.

example 12: 2- ((4R,6R) -6- (2- (3- ((4- (((tert-butyldimethylsilyl) oxy) methyl) benzene) Yl) carbamoyl) -5- (4-fluorophenyl) -2-isopropyl-4-phenyl-1H-pyrrol-1-yl) ethyl) -2, 2-dimethyl-1, 3- Preparation of dioxan-4-yl) acetic acid tert-butyl ester

The N- (4- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) -2- (2- (4-fluorobenzene) obtained in example 10 was reacted with toluene to obtain a reaction mixtureThe yl) -2-oxo-1-phenylethyl) -4-methyl-3-oxopentanamide (258mg) was dissolved in heptane/THF/toluene (6ml/1.5ml/1.5ml), followed by addition of tert-butyl 2- ((4R,6R) -6- (2-aminoethyl) -2, 2-dimethyl-1, 3-dioxan-4-yl) acetate (190mg, 0.69mmol) and pivalic acid (47mg, 0.46mmol) and heating at 90 ℃ for 20.5 h. The reaction solution cooled at room temperature was diluted with EA and saturated NaHCO₃Aqueous solution, brine and distilled water. By adding Na₂SO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.

190mg of a yellow solid (yield 52%);

¹H NMR(500MHz,DMSO-d₆):δ9.78(NH,br s,1H),7.47(d,J＝8.5Hz,2H),7.28-7.23(m,2H),7.20(d,J＝9.0Hz,2H),7.15(d,J＝8.5Hz,2H),7.08-7.07(m,4H),7.02-6.98(m,1H),4.61(s,2H),4.13-4.08(m,1H),3.95-3.89(m,1H),3.80-3.74(m,2H),3.21(sep,J＝7.0Hz,1H),2.30(dd,J＝15.0Hz,5.0Hz,1H),2.17(dd,J＝15.0Hz,8.0Hz,1H),1.63-1.50(m,2H),1.38(s,9H),1.38-1.31(m,1H),1.36(d,J＝7.0Hz,6H),1.31(s,3H),1.17(s,3H),0.94-0.89(m,1H),0.89(s,9H),0.06(s,6H).

example 13: 2- ((4R,6R) -6- (2- (2- (4-fluorophenyl) -5-isopropyl-4- ((4- (((4-methoxybenzyl) Yl) oxy) methyl) phenyl) carbamoyl) -3-phenyl-1H-pyrrol-1-yl) ethyl) -2, 2-dimethyl-1, 3-dioxanes Hexane-4-yl) acetic acid tert-butyl ester preparation

2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -N- (4- (((4-methoxybenzyl) oxy) methyl) phenyl) -4-methyl-3-oxopentanamide (630mg, 1.11mmol) obtained in example 11 was diluted with heptane/THF/toluene (16ml/4ml/3ml) and stirred at room temperature. Pivalic acid (170mg, 1.66mmol) was dissolved in the reaction solution. Tert-butyl 2- ((4R,6R) -6- (2-aminoethyl) -2, 2-dimethyl-1, 3-dioxan-4-yl) acetate (455mg, 1.66mmol) was diluted with toluene (1ml) and added dropwise to the reaction solution. Then, the reaction solution was refluxed at 95 ℃ for 32 hours, and then the resulting reaction solution was diluted by adding EA,with NaHCO₃(aqueous solution), distilled water and brine were washed several times. By adding MgSO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.

350mg of pale yellow oil (yield 40%);

¹H NMR(500MHz,DMSO-d₆):δ9.81(s,1H),7.49(d,J＝8.5Hz,2H),7.27-7.25(m,4H),7.24-7.18(m,4H),7.08-7.07(m,4H),7.00-6.98(m,1H),6.92-6.89(m,2H),4.40(s,2H),4.38(s,2H),4.13-4.07(m,1H),3.95-3.88(m,1H),3.80-3.75(m,2H),3.74(s,3H),3.24-3.18(m,1H),2.30(dd,J＝15.5Hz,5.0Hz,1H),2.17(dd,J＝15.5Hz,3.0Hz,1H),1.62-1.50(m,2H),1.38(s,9H),1.37(s,3H),1.35(s,3H),1.34-1.32(m,1H),1.31(s,3H),1.17(s,3H),0.92(q,J＝12.5Hz,1H),MH+805.

example 14: (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylaminomethyl) Yl) carbonyl]-pyrrol-1-yl]Preparation of (E) -3, 5-dihydroxyheptanoic acid hemicalcium salt

Step 1: (3R,5R) -7- (2- (4-fluorophenyl) -4- ((4- (hydroxymethyl) phenyl) carbamoyl) -5-isopropyl- Preparation of 3-phenyl-1H-pyrrol-1-yl) -3, 5-dihydroxyheptylic acid tert-butyl ester

Tert-butyl 2- ((4R,6R) -6- (2- (3- ((4- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) carbamoyl) -5- (4-fluorophenyl) -2-isopropyl-4-phenyl-1H-pyrrol-1-yl) ethyl) -2, 2-dimethyl-1, 3-dioxan-4-yl) acetate (170mg) obtained in example 12 was dissolved in THF (5ml), followed by addition of 1N aqueous HCl (5ml) and stirring at room temperature for 17.5 hours. EA was added to the reaction solution, diluted, and washed several times with distilled water. By adding Na₂SO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the title compound.

79mg of a white solid (yield 58%);

¹H NMR(500MHz,DMSO-d₆):δ9.72(NH,br s,1H),7.45(d,J＝8.5Hz,2H),7.26-7.23(m,2H),7.19(d,J＝9.0Hz,2H),7.16(d,J＝8.0Hz,2H),7.08-7.06(m,4H),7.02-6.98(m,1H),5.03(OH,t,J＝5.5Hz,1H),4.66(OH,d,J＝5.5Hz,1H),4.60(OH,d,J＝5.5Hz,1H),4.39(d,J＝5.5Hz,2H),3.96-3.90(m,1H),3.84-3.74(m,2H),3.55-3.49(m,1H),3.23(sep,J＝7.0Hz,1H),2.24(dd,J＝14.8Hz,7.5Hz,1H),2.18(dd,J＝14.8Hz,7.5Hz,1H),1.65-1.59(m,1H),1.56-1.49(m,1H),1.45-1.38(m,1H),1.38(s,9H),1.37(d,J＝7.0Hz,6H),1.32-1.27(m,1H),MH+645

step 2: (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl Base of]-pyrrol-1-yl]Preparation of (E) -3, 5-dihydroxyheptanoic acid hemicalcium salt

Tert-butyl (3R,5R) -7- (2- (4-fluorophenyl) -4- ((4- (hydroxymethyl) phenyl) carbamoyl) -5-isopropyl-3-phenyl-1H-pyrrol-1-yl) -3, 5-dihydroxyheptanoate obtained in step 1 in a mixture of MeOH and THF in a 1:1 (volume) ratio was cooled to 0 ℃ and NaOH pellets were added. The reaction solution was then stirred at ambient temperature. At the end of the ester hydrolysis, the solvent was removed, the residue was subsequently dissolved in water and the aqueous layer was washed with diethyl ether. Then, an aqueous solution (1M) of calcium acetate (0.55 eq) was added dropwise to an aqueous solution of the sodium salt of (3R,5R) -7- [2- (4-fluorophenyl) -4- (4-hydroxymethyl-phenylamino) carbonyl) -5-isopropyl-3-phenyl-pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid. A white precipitate was obtained, filtered, washed with copious amounts of water, and dried in vacuo to afford the title compound.

White solid (yield 63.4%);

¹H NMR(DMSO-d₆):δ1.22-1.62(m,11H),1.98(dd,J＝15Hz,8.1Hz,1H),2.06-2.16(m,1H),3.25-3.37(m,2H),3.57(br s,2H),3.80(br s,1H),4.43(s,2H),7.03-7.28(m,12H),7.50(d,J＝6H,2H),9.80(s,1H).

MS (positive ion mode) m/z 589 (acid +1).

Example 15: (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylaminomethyl) Yl) carbonyl]-pyrrol-1-yl]Preparation of (E) -3, 5-dihydroxyheptanoic acid hemicalcium salt

Step 1: 2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -N- (4- (hydroxymethyl) phenyl) -4-methyl-3- Preparation of oxovaleramides

2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -4-methyl-3-oxo-N- (4- ((trityloxy) methyl) phenyl) pentanamide (270g) obtained in example 9 was dissolved in CH₂Cl₂(5.4L) and MeOH (1.35L), followed by addition of TFA (300ml) and stirring at 30 deg.C to 35 deg.C for two hours. The reaction solution was cooled to 20 ℃ and saturated NaHCO was used₃Aqueous (3L), distilled (3L) and brine (3L). The organic layer was concentrated under reduced pressure and toluene (1.08L) was added. The resulting solution was stirred at 55 ℃ to 60 ℃ for 30 minutes, followed by addition of heptane (1.62L) and further stirring. The reaction solution was stirred at 55 ℃ to 60 ℃ for one hour, at 20 ℃ to 30 ℃ for one hour, and at 0 ℃ to 5 ℃ for two hours to give a solid. The resulting solid was filtered and washed with heptane (0.4L). The resulting product was dried under vacuum at 50 ℃ to 55 ℃ for 12 hours to obtain the title compound.

157.5g of solid (yield 90%);

¹H NMR(500MHz,DMSO-d₆):δ10.12(NH,br s,1H),8.14-8.11(m,2H),7.35(d,J＝7.0Hz,2H),7.30(t,J＝7.5Hz,2H),7.25-7.21(m,4H),7.16-7.12(m,3H),5.41(d,J＝11.0Hz,1H),5.06(OH,t,J＝5.5Hz,1H),4.85(d,J＝11.0Hz,1H),4.38(d,J＝5.5Hz,2H),2.90(sep,J＝7.0Hz,1H),1.16(d,J＝7.0Hz,3H),0.94(d,J＝7.0Hz,3H),MH+448.

step 2: 2- ((4R,6R) -6- (2- (2- (4-fluorophenyl) -4- ((4- (hydroxymethyl) phenyl) carbamoyl) -5-iso Process for preparation of propyl-3-phenyl-1H-pyrrol-1-yl) ethyl) -2, 2-dimethyl-1, 3-dioxan-4-yl) acetic acid tert-butyl ester Preparation of

To the mixture was added 2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -N- (4- (hydroxymethyl) phenyl) -4-methyl-3-oxovaleramide obtained in step 1 (140g, 1 eq), tert-butyl 2- ((4R,6R) -6- (2-aminoethyl) -2, 2-dimethyl-1, 3-dioxan-4-yl) acetate (128g, 1.5 eq) and pivalic acid (33g, 1.03 eq)heptane/toluene/THF (1.18L/0.42L) in a mixed solvent. The reaction solution was refluxed overnight under a Dean-Stark trap to remove water. The reaction solution was cooled to 20 ℃ and concentrated under reduced pressure, followed by CH₂Cl₂(1.4L) was added to the resulting concentrate and stirred. Will CH₂Cl₂The layer was washed twice with distilled water (0.7L). Make CH₂Cl₂The layer was concentrated under reduced pressure, followed by addition of IPA (1.86L) and stirring until the resulting mixture was sufficiently dissolved. The reaction solution was further stirred at 60 ℃ to 65 ℃ for one hour. Distilled water (0.56L) was added, cooled to 20 ℃ to 30 ℃, stirred at 20 ℃ to 30 ℃ for two hours, and stirred at 0 ℃ to 5 ℃ for one hour to give a solid. The resulting solid was filtered, washed with IPA (0.14L) and distilled water (0.14L), and dried under vacuum at 50 ℃ to 55 ℃ for 12 hours to obtain the title compound.

150g (70%) of solid;

¹H NMR(500MHz,DMSO-d₆):δ9.74(NH,br s,1H),7.45(d,J＝8.5Hz,2H),7.27-7.24(m,2H),7.21-7.15(m,4H),7.08-7.07(m,4H),7.02-6.98(m,1H),5.03(OH,t,J＝5.5Hz,1H),4.39(d,J＝5.5Hz,2H),4.13-4.08(m,1H),3.95-3.89(m,1H),3.80-3.74(m,2H),3.21(sep,J＝7.0Hz,1H),2.30(dd,J＝15.0Hz,5.0Hz,1H),2.17(dd,J＝15.0Hz,8.0Hz,1H),1.63-1.50(m,2H),1.40-1.33(m,1H),1.38(s,9H),1.36(d,J＝7.0Hz,6H),1.31(s,3H),1.17(s,3H),0.92(q,J＝12.0Hz,1H),MH+685.

and step 3: (3R,5R) -7- (2- (4-fluorophenyl) -4- ((4- (hydroxymethyl) phenyl) carbamoyl) -5-isopropyl- Preparation of 3-phenyl-1H-pyrrol-1-yl) -3, 5-dihydroxyheptylic acid tert-butyl ester

Tert-butyl 2- ((4R,6R) -6- (2- (3- ((4- (((tert-butyldimethylsilyl) oxy) methyl) phenyl) carbamoyl) -5- (4-fluorophenyl) -2-isopropyl-4-phenyl-1H-pyrrol-1-yl) ethyl) -2, 2-dimethyl-1, 3-dioxan-4-yl) acetate (5g) obtained in step 2 was dissolved in methanol (37ml) and THF (37ml), followed by addition of 1N aqueous HCl (37ml) and stirring at room temperature for two hours. EA was added to the reaction solution, diluted, and washed several times with distilled water and brine. By adding Na₂SO₄The extracted organic layer was dried and filtered under reduced pressure. The resulting filtrate was concentrated under reduced pressure, followed by addition of EA and hexane, and purification by recrystallization to obtain the title compound.

4.6g of white solid (quantitative yield);

¹H NMR(500MHz,CDCl₃):7.24-7.14(m,9H),7.06(d,J＝8.5Hz,2H),6.99(t,J＝8.5Hz,2H),6.87(br s,1H),4.57(s,2H),4.45-4.08(m,2H),3.96-3.90(m,1H),3.75-3.71(m,1H),3.58(sep,J＝7.0Hz,1H),2.32(d,J＝6.5Hz,2H),1.73-1.65(m,1H),1.64-1.58(m,1H),1.54(d,J＝7.0Hz,6H),1.45(s,9H),1.27-1.22(m,2H),MH+645.

and 4, step 4: (3R,5R) -7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- ((4-hydroxymethylphenylamino) carbonyl Base of]Preparation of (E) -pyrrol-1-yl) -3, 5-dihydroxyheptanoic acid hemicalcium salt

Tert-butyl (3R,5R) -7- (2- (4-fluorophenyl) -4- ((4- (hydroxymethyl) phenyl) carbamoyl) -5-isopropyl-3-phenyl-1H-pyrrol-1-yl) -3, 5-dihydroxyheptoate (4.19g) obtained in step 3 was dissolved in MeOH (65ml) and THF (65ml) and stirred under ice bath. NaOH pellets (5 equivalents, 1.3g) were added and stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure, followed by addition of distilled water (44ml) until the resulting solid was completely dissolved. The reaction solution was concentrated under reduced pressure, followed by addition of distilled water (430ml) until the resulting solid was sufficiently dissolved. Slowly add 1M Ca (OAc) dropwise₂Aqueous solution (3.6ml) and stirred at room temperature for 15.5 hours. The resulting solid was filtered under reduced pressure and washed several times with distilled water, followed by drying the filtered solid in an oven.

White solid 2.98g (yield 76%);

¹H NMR(500MHz,DMSO-d₆)δ9.78(br s,1H),7.46(d,J＝8.5Hz,2H),7.26-7.23(m,2H),7.19(t,J＝9.0Hz,2H),7.15(d,J＝8.5Hz,2H),7.09-7.05(m,4H),7.02-6.98(m,1H),6.41(br s,1H),5.04(t,J＝5.5Hz,1H),4.75(br s,1H),4.39(d,J＝5.5Hz,2H),3.98-3.91(m,1H),3.79-3.69(m,2H),3.55-3.50(m,1H),3.22(sep,J＝7.0Hz,1H),2.03(dd,J＝15.0Hz,4.0Hz,1H),1.90(dd,J＝15.0Hz,8.0Hz,1H),1.63-1.57(m,1H),1.54-1.47(m,1H),1.41-1.36(m,1H) 1.37(d, J ═ 7.0Hz,6H),1.23-1.16(m,1H), MH + (acid +1)589.

Example 16: (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylaminomethyl) Yl) carbonyl]-pyrrol-1-yl]Preparation of (E) -3, 5-dihydroxyheptanoic acid hemicalcium salt

2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -N- (4- (((4-methoxybenzyl) oxy) methyl) phenyl) -4-methyl-3-oxopentanamide (18.6mg, 0.03mmol) obtained in example 11 was added dropwise to TFA (0.2ml, 2.62mmol) and stirred at room temperature for 44 hours. EA was added to the reaction solution, diluted, and washed several times with brine. By adding MgSO₄The extracted organic layer was dried and filtered under reduced pressure. The obtained filtrate was concentrated under reduced pressure to obtain the title compound. The title compound was obtained in 9% yield as confirmed by LC/mass spectrometry (LC/mass).

MH+448。

The title compound was obtained by the same method as shown in step 2 of example 15.

150g of solid (yield 70%);

The title compound was obtained by the same method as shown in step 3 of example 15.

White solid (96% yield);

The title compound was prepared by the same method as shown in step 4 of example 15.

White solid (yield 76%);

¹H NMR(500MHz,DMSO-d₆)δ9.78(br s,1H),7.46(d,J＝8.5Hz,2H),7.26-7.23(m,2H),7.19(t,J＝9.0Hz,2H),7.15(d,J＝8.5Hz,2H),7.09-7.05(m,4H),7.02-6.98(m,1H),6.41(br s,1H),5.04(t,J＝5.5Hz,1H),4.75(br s,1H),4.39(d,J＝5.5Hz,2H),3.98-3.91(m,1H),3.79-3.69(m,2H),3.55-3.50(m,1H),3.22(sep,J＝7.0Hz,1H),2.03(dd,J＝15.0Hz,4.0Hz,1H),1.90(dd,J＝15.0Hz,8.0Hz,1H),1.63-1.57(m,1H),1.54-1.47(m,1H),1.41-1.36(m,1H)

1.37(d, J ═ 7.0Hz,6H),1.23-1.16(m,1H), MH + (acid +1)589.

Example 17: (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylaminomethyl) Yl) carbonyl]-pyrrol-1-yl]Preparation of (E) -3, 5-dihydroxyheptanoic acid hemicalcium salt

Step 1: preparation of N- (4- (hydroxymethyl) phenyl) -4-methyl-3-oxopentanamide

4-methyl-3-oxo-N- (4- ((trityloxy) methyl) phenyl) pentanamide (350.6g, 0.734mol), obtained in step 3 of example 1, was added to THF (1L). c-HCl (223.0g, 2.202mol, 3 eq.) was added slowly and stirred at room temperature for two hours. The reaction was concentrated and purified water (300g) and CH were added₂Cl₂(500g) In that respect A45% KOH aqueous solution (166g) was added to adjust the pH of the reaction solution to 12.0-12.5. The resulting solution was stirred at room temperature for one hour. The resulting mixture was allowed to stand, from which the organic (lower) layer was separated and discarded. Adding c-HCl aqueous solution to the aqueous layer to adjust the pH of the reaction solution to 5.0-6.0, and adding CH₂Cl₂(300g) Extraction is carried out. Will CH₂Cl₂The layer was washed with purified water, and the organic layer was concentrated. Toluene was added to the reaction solution and stirred for two hours. The resulting solid was filtered, washed with toluene, and dried under vacuum at 45 ℃ to 50 ℃ for 12 hours.

The yield is 50%;

¹H NMR(500MHz,DMSO-d₆)δ10.01(NH,br s,1H),7.51(d,J＝8.5Hz,2H),7.24(d,J＝8.5Hz,2H),5.09(OH,t,J＝5.5Hz,1H),4.43(d,J＝5.5Hz,2H),3.60(s,2H),2.75(sep,J＝7.0Hz,1H),1.05(d,J＝7.0Hz,6H),MH+236.

step 2: 2- (2- (4-fluorophenyl) -2-oxo-1-phenylethyl) -N- (4- (hydroxymethyl) phenyl) -4-methyl-3- Preparation of oxovaleramides

N- (4- (hydroxymethyl) phenyl) -4-methyl-3-oxopentanamide obtained in step 1 (200.0g, 0.850mol), 2-bromo-1- (4-fluorophenyl) -2-phenyleth-1-one obtained in example 8 (249.2g, 0.850mol), K₂CO₃(352.4g, 2.55mol, 3 equiv.) and KI (14.1g, 0.085mol, 0.1 equiv.) were added to acetone (3L). The reaction mixture was stirred at room temperature for 42 hours and concentrated, followed by addition of purified water (2L) and EA (3L) and stirring at room temperature for 30 minutes. The resulting mixture was allowed to stand, from which the aqueous (lower) layer was separated and discarded. ConcentratingThe organic layer was crystallized from toluene and heptane. The resulting solid was filtered, washed with toluene, and dried under vacuum at 45 ℃ to 50 ℃ for 12 hours.

Yield: 40 percent;

and step 3: 2- ((4R,6R) -6- (2- (2- (4-fluoromethyl) -4- ((4- (hydroxymethyl) phenyl) carbamoyl) -5-iso Process for preparation of propyl-3-phenyl-1H-pyrrol-1-yl) ethyl) -2, 2-dimethyl-1, 3-dioxan-4-yl) acetic acid tert-butyl ester Preparation of

The title compound was prepared by the same method as shown in step 2 of example 15.

And 4, step 4: (3R,5R) -7- (2- (4-fluorophenyl) -4- ((4- (hydroxymethyl) phenyl) carbamoyl) -5-isopropyl- Preparation of 3-phenyl-1H-pyrrol-1-yl) -3, 5-dihydroxyheptylic acid tert-butyl ester

The title compound was prepared by the same method as shown in step 3 of example 15.

¹H NMR(500MHz,CDCl₃):7.24-7.14(m,9H),7.06(d,J＝8.5Hz,2H),6.99(t,J＝8.5Hz,2H),6.87(br s,1H),4.57(s,2H),4.45-4.08(m,2H),3.96-3.90(m,1H),3.75-3.71(m,1H),3.58(sep,J＝7.0Hz,1H),2.32(d,J＝6.5Hz,2H),1.73-1.65(m,1H),1.64-1.58(m,1H),1.54(d,J＝7.0Hz,6H),1.45(s,9H),1.27-1.22(m,2H),MH+645

And 5: (3R,5R) -7- (2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- ((4-hydroxymethylphenylamino) carbonyl Preparation of yl) -pyrrol-1-yl) -3, 5-dihydroxyheptanoic acid hemicalcium salt

¹H NMR(500MHz,DMSO-d₆) δ 9.78(br s,1H),7.46(d, J ═ 8.5Hz,2H),7.26-7.23(m,2H),7.19(t, J ═ 9.0Hz,2H),7.15(d, J ═ 8.5Hz,2H),7.09-7.05(m,4H),7.02-6.98(m,1H),6.41(br s,1H),5.04(t, J ═ 5.5Hz,1H),4.75(br s,1H),4.39(d, J ═ 5.5Hz,2H),3.98-3.91(m,1H),3.79-3.69(m,2H),3.55-3.50(m,1H),3.22(sep, J ═ 7.0, 1H), 7.03 (m,1H),1.54 (1H), 7.54, 1H), 7.54 (1H, 1H), 7.54, 1H, 7.7, 7, 7.7.7, 1H, 7, 1H, 7, 1H, 7, 6H) 1.23-1.16(m,1H), MH + (acid +1)589.

The present invention has been described with reference to preferred exemplary embodiments thereof, but it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the present invention as described in the scope of the appended patent claims.

Claims

1. A process for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid, hemicalcium salt, said process comprising:

(1d) deprotecting the compound of formula F-1 to produce a compound of formula G below; and

(1e) preparing a compound of the following chemical formula 1 from the compound of the chemical formula G:

[ chemical formula A-1]

[ chemical formula B ]

[ chemical formula C ]

[ chemical formula D ]

[ chemical formula E ]

[ chemical formula F-1]

[ chemical formula G ]

[ chemical formula 1]

Wherein the content of the first and second substances,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂Aryl radical, and

r is C₁-C₆An alkyl group.

2. The method of claim 1, wherein P is R₆R₇R₈C-。

3. A process for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid, hemicalcium salt, said process comprising:

[ chemical formula A-1]

[ chemical formula B ]

[ chemical formula C ]

[ chemical formula E ]

[ chemical formula F-2]

[ chemical formula G ]

[ chemical formula 1]

Wherein the content of the first and second substances,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂Aryl radical, and

r is C₁-C₆An alkyl group.

4. The method of claim 3, wherein P is R₃R₄R₅Si-。

5. A process for the preparation of (3R,5R) -7- [2- (4-fluorophenyl) -5-isopropyl-3-phenyl-4- [ (4-hydroxymethylphenylamino) carbonyl ] -pyrrol-1-yl ] -3, 5-dihydroxyheptanoic acid, hemicalcium salt, said process comprising:

(3c) deprotecting the compound of formula F-1 to produce a compound of formula G below; and

[ chemical formula A-2]

[ chemical formula B ]

[ chemical formula D ]

[ chemical formula E ]

[ chemical formula F-1]

[ chemical formula G ]

[ chemical formula 1]

Wherein R is C₁-C₆An alkyl group.

6. A compound represented by the following chemical formula A-1:

[ chemical formula A-1]

Wherein the content of the first and second substances,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂And (4) an aryl group.

7. The compound of claim 6, wherein P is tetrahydropyranyl, methoxymethyl, methoxyethyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, trityl, methoxyphenyldiphenylmethyl, bis (methoxyphenyl) phenylmethyl, benzyl, P-methoxybenzyl, dimethoxybenzyl, or benzoyl.

8. A process for preparing a compound represented by formula a-1, the process comprising:

[ chemical formula a-1]

[ chemical formula a-2]

[ chemical formula a-3]

[ chemical formula a-4]

[ chemical formula A-1]

Wherein the content of the first and second substances,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₆、R₇and R₈Each is independentStanding on the ground is H, C₁-C₆Alkyl radical, C₁-C₆Alkoxy or C₆-C₁₂Aryl { the C₆-C₁₂At least one H in the aryl radical may be replaced by C₁-C₆Alkoxy substitution },

R₉is C₁-C₆Alkyl or C₆-C₁₂An aryl group, a heteroaryl group,

R₁₀is C₁-C₆An alkyl group; and is

X is halogen.

9. A compound represented by the following chemical formula a-2:

[ chemical formula A-2]

10. A process for preparing a compound represented by formula a-2, the process comprising:

[ chemical formula a-1]

[ chemical formula a-2]

[ chemical formula a-3]

[ chemical formula a-4]

[ chemical formula A-1]

[ chemical formula A-2]

Wherein the content of the first and second substances,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂An aryl group, a heteroaryl group,

R₁₀is C₁-C₆Alkyl radical, and

x is halogen.

11. A compound represented by the following chemical formula C:

[ chemical formula C ]

Wherein the content of the first and second substances,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂And (4) an aryl group.

12. A process for preparing a compound represented by formula C, the process comprising:

reacting a compound of the following chemical formula a-1 with a compound of the following chemical formula B to prepare a compound of the following chemical formula C:

[ chemical formula A-1]

[ chemical formula B ]

[ chemical formula C ]

Wherein the content of the first and second substances,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂And (4) an aryl group.

13. A compound represented by the following chemical formula D:

[ chemical formula D ]

14. A process for preparing a compound represented by formula D, the process comprising:

reacting a compound of the following chemical formula a-2 with a compound of the following chemical formula B to prepare a compound of the following chemical formula D:

[ chemical formula A-2]

[ chemical formula B ]

[ chemical formula D ]

15. A compound represented by the following chemical formula F-2:

[ chemical formula F-2]

Wherein the content of the first and second substances,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂Aryl radical, and

r is C₁-C₆An alkyl group.

16. A process for preparing a compound represented by formula F-2, the process comprising:

reacting a compound of the following chemical formula C with a compound of the following chemical formula E to prepare a compound of the following chemical formula F-2:

[ chemical formula C ]

[ chemical formula E ]

[ chemical formula F-2]

Wherein the content of the first and second substances,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂Aryl radical, and

r is C₁-C₆An alkyl group.

17. A process for preparing a compound represented by formula F-1, the process comprising:

reacting a compound of the following chemical formula D with a compound of the following chemical formula E to prepare a compound of the following chemical formula F-1,

wherein the compound of formula F-1 in a solid phase is obtained by using a mixed solvent in which a first solvent selected from the group consisting of ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, acetone, methanol, ethanol and isopropanol is mixed with a second solvent selected from the group consisting of hexane, pentane, heptane, water and petroleum ether:

[ chemical formula D ]

[ chemical formula E ]

[ chemical formula F-1]

Wherein R is C₁-C₆An alkyl group.

18. The method according to claim 17, wherein the mixed solvent (first solvent/second solvent) is any one selected from the group consisting of: ethyl acetate/hexane; ethyl acetate/pentane; ethyl acetate/heptane; dichloromethane/hexane; dichloromethane/pentane; dichloromethane/heptane; chloroform/pentane; chloroform/heptane; tetrahydrofuran/hexane; tetrahydrofuran/pentane; tetrahydrofuran/heptane; acetone/water; acetone/hexane; acetone/pentane; acetone/heptane; acetone/petroleum ether; methanol/water; ethanol/water; and isopropanol/water.

19. A process for preparing a compound represented by formula G, the process comprising:

preparing a compound of the following chemical formula G from the compound of the following chemical formula F-1 or the compound of the following chemical formula F-2,

wherein the compound of formula G in a solid phase is obtained by using a mixed solvent in which a first solvent selected from the group consisting of ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, acetone, methanol, ethanol and isopropanol is mixed with a second solvent selected from the group consisting of hexane, pentane, heptane, water and petroleum ether:

[ chemical formula F-1]

[ chemical formula F-2]

[ chemical formula G ]

Wherein the content of the first and second substances,

p is R₁-O-R₂-、R₃R₄R₅Si-、R₆R₇R₈C-or R₉-C(＝O)-，

R₉is C₁-C₆Alkyl or C₆-C₁₂Aryl radical, and

r is C₁-C₆An alkyl group.

20. The method according to claim 19, wherein the mixed solvent (first solvent/second solvent) is any one selected from the group consisting of: ethyl acetate/hexane; ethyl acetate/pentane; ethyl acetate/heptane; dichloromethane/hexane; dichloromethane/pentane; dichloromethane/heptane; chloroform/pentane; chloroform/heptane; tetrahydrofuran/hexane; tetrahydrofuran/pentane; tetrahydrofuran/heptane; acetone/water; acetone/hexane; acetone/pentane; acetone/heptane; acetone/petroleum ether; methanol/water; ethanol/water; and isopropanol/water.