Method for preparing azetidinone compound and intermediate of azetidinone compound

Patent metadata

Field	Value
Publication number	US-10364219-B2
Application number	US-201715835649-A
Country	US
Kind code	B2
Filing date	Dec 8, 2017
Priority date	Jun 9, 2014
Publication date	Jul 30, 2019
Grant date	Jul 30, 2019

Abstract

Disclosed is a new method for preparing an azetidinone compound represented by formula (I). The carboxylic ketoester represented by formula (II) serves as the raw material and is subjected to Grignard addition, stereoselective dehydration, ester group reduction, hydroxyl group protection, addition with imine after condensation with a chiral auxiliary, cyclization and deprotection to obtain the compound represented by formula (I). The present invention has advantages of easily available raw material, a few synthetic steps, simple operation, high yield, good stereoselectivity and low cost, and can be used for industrial production.

First claim

The invention claimed is:

1. A method for preparing the compound represented by formula (I),

comprising the following steps:
(a) reacting the compound of formula V with a hydroxyl protectant to obtain the compound of formula VI:

wherein R 2 is an alcoholic hydroxyl protecting group;
(b) converting the carboxylic acid of formula VI into mixed anhydride or acyl halide, then reacting with (S)-4-phenyl-2-oxazolidone of formula VII which is used as a chiral auxiliary to obtain a derivative of oxazolidone of formula VIII:

wherein the carboxylic acid of formular VI is reacted with an acylating agent to produce mixed anhydride; or the carboxylic acid of formula VI is reacted with phosphorus trihalide, phosphorus pentahalide, dichlorosulfane (SOCl 2 ), oxalyl chloride((COCl) 2 ) or phosgene (COCl 2 ) to produce acyl halide; X is chlorine or bromine;
or the above step (a) and step (b) can be carried out in one step, the compound of formula VIII can be prepared from the compound of formula V through a one-pot method with the following specific steps:
(ab) reacting the compound of formula V with a hydroxyl protecting agent to obtain the compound of formula VI, further converting the carboxylic acid of formula VI into mixed anhydride or acyl halide without separation and purification, then reacting with (S)-4-phenyl-2-oxazolidone of formula VII which is used as a chiral auxiliary to obtain a derivative of oxazolidone of formula VIII:

wherein R 2 is an alcoholic hydroxyl protecting group; and
wherein the carboxylic acid of formula VI is reacted with an acylating agent to produce mixed anhydride; or the carboxylic acid of formula VI is reacted with phosphorus trihalide, phosphorus pentahalide, dichlorosulfane (SOCl 2 ), oxalyl chloride((COCl) 2 ) or phosgene (COCl 2 ) to produce acyl halide; X is chlorine or bromine;
(c) under the presence of Lewis acids (titanium tetrachloride (TiCl 4 ) and tetraisopropyl titanate) and tertiary amine, reacting the oxazolidone derivative of formula VIII with an imine of formula IX to obtain an addition product of formula XI:

wherein R 2 and R 3 are all hydroxyl protecting groups, which can be the same or different;
(d) cyclizing the addition product of formula XI with N,O-bis(trimethylsilyl)acetamide (BSA) and tetrabutylammonium fluoride (TBAF) to obtain the β-lactams of formula XII, XIII and XIV:

and
(e) obtaining the compound of formula (I) via the deprotection of the mixture of the compounds of formula XII, XIII and XIV obtained in step (d):

2. The method according to claim 1 , further comprising the following step before step (a) or (ab):
(a′) carrying out a Grignard addition selectively to the ketone of formula II with 4-fluorophenyl magnesium halide to obtain the tertiary alcohol of formula III:

wherein, R 1 is C 1 -C 6 alkyl; X is a halogen;

(a″) under the action of a dehydrating agent, the tertiary alcohol of formula III is dehydrated stereoselectively to obtain the (Z)-α,β-unsaturated ester of formula IV:

wherein R 1 is C 1 -C 6 alkyl; and

(a″′) under the action of a reducing agent, the ester of formula IV is reduced selectively to the alcohol of formula V:

wherein R 1 is C 1 -C 6 alkyl.

3. The method according to claim 1 , wherein in step (a) or (ab), the alcoholic hydroxyl protecting group R 2 is selected from acetyl, or benzoyl that is unsubstituted or substituted by halogen, alkyl or nitro; the molar ratio of the compound V to the hydroxyl protecting agent in step (a) is 1:1.0˜3.0, or the molar ratio of the compound V to the hydroxyl protecting agent in step (ab) is 1:1.0˜3.0; and the solvent of the reaction in step (a) or the solvent of the reaction of synthesizing compound of formula VI from the compound of formula V in step (ab) is selected from N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethylsulfoxide (DMSO), 1,3-dimethylpropyleneurea (DMPU) or hexamethylphosphoramide (HMPA).

4. The method according to claim 1 , wherein in step (b) or step (ab), the acylating agent used for forming the mixed anhydride is selected from pivaloyl chloride, 3-nitrobenzoyl chloride or isobutyl chloroformate; and in step (b), the molar ratio of the compound of formula VI to the acylating agent is 1:1.0˜2.0, preferably, and the molar ratio of the compound of formula VI to (S)-4-phenyl-2-oxazolidone is 1:0.5˜1.5; or in step (ab), the molar ratio of the compound of formula V to the acylating agent is 1:1.0˜2.0, and the molar ratio of the compound of formula V to (S)-4-phenyl-2-oxazolidone is 1:0.5˜1.5.

5. The method according to claim 1 , wherein in step (c),
R 2 is defined as in claim 3 ;
R 3 is selected from acetyl, or benzoyl that is unsubstituted or substituted by halogen, alkyl or nitro;
the tertiary amine is diisopropylethylamine (DIPEA);
the molar ratio of the compound of formula VIII to the imine of formula IX is 1:1.0˜2.0;
the reaction temperature is controlled between −90° C.˜0° C.; and
after the completion of the reaction in the step (c), a post-processing quenching reaction is carried out, and alcohols, acids or mixed liquids of acids diluted by organic solvents are used in the post-processing quenching reaction; wherein the alcohols are selected from methanol, ethanol, propanol, isopropanol, or tertiary butanol; wherein the acids are inorganic acids or organic acids, wherein the inorganic acids are selected from the group consisting of hydrochloric acid, sulfuric acid, nitric acid, and hydrobromic acid, and the organic acids are selected from the group consisting of formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, maleic acid and tartaric acid.

6. The method according to claim 1 , wherein in step (d), the solvent of the reaction is selected from acetonitrile or toluene; the molar ratio of the compound of formula XI to N,O-bis(trimethylsilyl)acetamide (BSA) is 1:1.0˜5.0; and the molar ratio of the compound of formula XI to tetrabutylammonium fluoride trihydrate (TBAF) is 1:0.1˜0.5.

7. The method according to claim 1 , wherein in step (e), the solvent used for the deprotection of the mixture of the compounds of formula XII, XIII and XIV is selected from tetrahydrofuran or acetone; the alkali is selected from aqueous lithium hydroxide, aqueous sodium hydroxide or aqueous potassium hydroxide; and the molar ratio of the alkali to the compound of formula XI in step (d) is 3.0˜5.0:1.

8. The method according to claim 2 , wherein in step (a′), the molar ratio of the compound of

Assignees

• Zhejiang Hisun Pharm Co Ltd

Inventors

• Bai Hua
• Zhao Xuyang
• Zhang Yuncai
• Li Xufei
• Zhang Yong
• Xu Dezhou
• Zhang Li
• Xu Xiaojie
• Zhu Qifeng
• Wang Xiaoming
• Yang Zhiqing
• Zhong Zehua
• Zhang Jian

Classifications

• C07D205/08 Primary

  with one oxygen atom directly attached in position 2, e.g. beta-lactams · CPC title

• C07C69/732

  of unsaturated hydroxy carboxylic acids · CPC title

• C07C67/343

  by increase in the number of carbon atoms · CPC title

• C07C67/30

  by modifying the acid moiety of the ester, such modification not being an introduction of an ester group · CPC title

• C07C59/56

  containing halogen · CPC title