阅读说明：本技术 一种3-（取代苯基）氧杂环丁烷-3-羧酸及其中间体的制备方法及应用 (Preparation method and application of 3- (substituted phenyl) oxetane-3-carboxylic acid and intermediate thereof ) 是由 练华文 张�杰 刘贵华 于 2019-04-28 设计创作，主要内容包括：以3-氧杂环丁酮(化合物II)为起始原料,在碱性条件下与膦酰基三乙酸三乙酯经过Wittig反应得到化合物III；化合物III与硼酸化合物IV发生偶联反应得到化合物V；化合物V酯基经过还原生成化合物VI；化合物VI的羟基与磺酰氯/磺酸酐发生亲核取代反应生成化合物VII；化合物VI的羟基与卤代试剂反应生成化合物VIII；化合物VII或化合物VIII经过消除反应生成化合物IX；最后化合物IX双键经过氧化生成3-(取代苯基)氧杂环丁烷-3-羧酸(化合物I)。本方法操作简便、收率较高,总收率可达35％,可以实现大规模生产。(Taking 3-oxetanone (compound II) as an initial raw material, and carrying out Wittig reaction with triethyl phosphonotriacetate under an alkaline condition to obtain a compound III; carrying out coupling reaction on the compound III and a boric acid compound IV to obtain a compound V; reducing the ester group of the compound V to generate a compound VI; the hydroxyl of the compound VI and sulfonyl chloride/sulfonic anhydride carry out nucleophilic substitution reaction to generate a compound VII; reacting hydroxyl of the compound VI with a halogenating reagent to generate a compound VIII; carrying out elimination reaction on the compound VII or the compound VIII to generate a compound IX; finally, the double bond of compound IX is oxidized to form 3- (substituted phenyl) oxetane-3-carboxylic acid (compound I). The method has simple and convenient operation and high yield, the total yield can reach 35 percent, and large-scale production can be realized.)

1. A compound of structural formula (IX):

wherein: r₁Hydrogen, C1-C3 straight chain alkyl, halogen, trifluoromethyl or C1-C3 straight chain alkoxy.

2. A process for the preparation of compound I from compound IX according to claim 1, comprising:

wherein: r₁Hydrogen, C1-C3 straight chain alkyl, halogen, trifluoromethyl or C1-C3 straight chain alkoxy.

3. A process for the preparation of compound IX according to claim 1, comprising:

wherein: r₁Hydrogen, C1-C3 straight-chain alkyl, halogen, trifluoromethyl or C1-C3 straight-chain alkoxy; r₂Is methylsulfonyl, ethylsulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl; r₃Is chlorine, bromine or iodine.

4. A process for the preparation of compound IX according to claim 3, characterized in that:

wherein: r₁Hydrogen, C1-C3 straight-chain alkyl, halogen, trifluoromethyl or C1-C3 straight-chain alkoxy; r₂Is methylsulfonyl, ethylsulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl; r₃Is chlorine, bromine or iodine.

5. The process according to claim 4, wherein compound I is prepared from compound II, wherein:

wherein: r₁Hydrogen, C1-C3 straight-chain alkyl, halogen, trifluoromethyl or C1-C3 straight-chain alkoxy; r ₂Is methylSulfonyl, ethylsulfonyl-p-toluenesulfonyl, or trifluoromethanesulfonyl; r₃Is chlorine, bromine or iodine.

6. The production method according to claim 4 or claim 5, characterized in that: in the step of preparing the compound III from the compound II, the base 1 is potassium tert-butoxide, sodium hydride, 1, 8-diazabicycloundecen-7-ene, sodium methoxide or sodium ethoxide; the molar ratio of the compound II, the alkali 1 and the phosphono triethyl triacetate is 1: 0.8-3; the reaction temperature is in the range of-20 to 50 ℃.

7. The production method according to claim 4 or claim 5, characterized in that: in the step of preparing the compound V from the compound III and the compound IV, the catalyst is selected from (1, 5-cyclooctadiene) chlororhodium (I) dimer, palladium acetate or bis (ethylene) chlororhodium dimer, preferably (1, 5-cyclooctadiene) chlororhodium (I) dimer; the base 2 is selected from potassium carbonate, cesium carbonate or sodium carbonate; the molar ratio of the compound III to the compound IV to the base 2 is in the range of: 1: 0.8-3: 0.5-3; the reaction temperature is in the range of-10 ℃ to 80 ℃.

8. The production method according to claim 4 or claim 5, characterized in that: in the step of preparing the compound VI from the compound V, lithium aluminum hydride, sodium borohydride, lithium borohydride or potassium borohydride is used as a reducing agent; the molar ratio of the compound V to the reducing agent is 1: 0.5-1: 2; the reaction temperature is-30-60 ℃, and preferably 0-20 ℃.

9. The production method according to claim 4 or claim 5, characterized in that: in the step of preparing the compound VII from the compound VI, sulfonyl chloride is selected from methylsulfonyl chloride, ethylsulfonyl chloride or p-methylbenzenesulfonyl chloride; the sulfonic anhydride is methyl sulfonic anhydride or trifluoromethanesulfonic anhydride; the base 3 is selected from sodium hydroxide, potassium hydroxide, triethylamine, N-diisopropylethylamine, sodium carbonate or potassium carbonate; the molar ratio of the compound VI to the sulfonyl chloride/sulfonic anhydride is 1: 0.8-1: 2; the reaction temperature is-10-40 ℃, and preferably 20-30 ℃.

10. The production method according to claim 4 or claim 5, characterized in that: in the step of preparing the compound VIII from the compound VI, the halogenating reagent is liquid bromine, iodine or carbon tetrachloride; the molar ratio of the compound VI to the halogenated reagent to the triphenylphosphine is 1: 1-5: 1-2; the reaction temperature range is-10 ℃ to 50 ℃.

11. The production method according to claim 4 or claim 5, characterized in that: in the step of preparing the compound IX from the compound VII or the compound VIII, the base 4 is selected from potassium tert-butoxide, potassium tert-amylate, sodium hydride, 1, 8-diazabicycloundecen-7-ene, potassium hydroxide or sodium hydroxide.

12. The method of claim 11, wherein: in the step of preparing the compound IX from the compound VII or the compound VIII, the molar ratio of the compound VII or the compound VIII to the base 4 is 1: 1-1: 2; the reaction temperature is 10-70 ℃, preferably 10-25 ℃.

13. The production method according to claim 2 or claim 5, characterized in that: in the step of preparing compound I from compound IX, the oxidizing agent is selected from sodium periodate, potassium permanganate or ozone, preferably sodium periodate;

when the oxidant is sodium periodate, ruthenium trichloride is required to be added in the reaction;

when the oxidant is ozone, sodium hypochlorite, sodium dihydrogen phosphate and 2-methyl-2-butylene are required to be added for the reaction.

Technical Field

The invention relates to the field of synthesis of pharmaceutical intermediates, in particular to a preparation method and application of 3- (substituted phenyl) oxetane-3-carboxylic acid and an intermediate thereof.

Background

Since oxetane can be taken as a metabolically stable tert-butyl bioisostere, the distribution coefficient of molecular ester water of the drug can be changed to improve the utilization rate of the drug, and oxetane is a molecular building block widely applied in the research and development of new drugs. Among them, 3-carboxylic acid-oxetane derivatives are a very important drug intermediate with wide application, and patent WO2019031618a1 discloses compound X, which has good biological activity and can be used as cytochrome P450CYP4F2 inhibitor, and the molecule of compound X contains 3-carboxylic acid-oxetane molecular fragment. In recent years, introduction of an aromatic ring at the 3-position of a 3-carboxylic acid-oxetane derivative has been a great concern to chemists.

Patent WO2013025733a1 discloses the following synthetic route:

reagents and conditions: (a) triethyl phosphonoacetate, sodium ethoxide, DMF, room temperature, overnight, yield: 37 percent; (b) LiAlH₄THF, room temperature-60 ℃, 2h, yield: 60 percent; (c) ethyl carbonate, KOH and EtOH, the yield is 14 percent at the temperature of 110-200 ℃; (d) jones reagent, acetone, yield: 97 percent.

The method reports the reaction of ethyl 4-bromobenzoate (compound X) with triethyl phosphonoacetate under the action of sodium ethoxide to give compound XI; the ester of compound X is reduced to produce compound XII; the compound XII is subjected to ring closure to obtain an oxetane compound XIII; finally, the compound I-1 is prepared by the oxidation reaction of hydroxymethyl under the action of Jones reagent. The yield of the third step of the route is very low, only 14%, the post-treatment is complicated, the purification and the separation are difficult, and the method is not suitable for large-scale production.

Disclosure of Invention

The purpose of the invention is as follows: the invention aims to overcome the defects in the prior art and provides a preparation method of 3- (substituted phenyl) oxetane-3-carboxylic acid and an intermediate thereof, which has the advantages of simple and convenient operation, high yield and 35% of total yield and can realize the rapid preparation in a laboratory.

In one aspect, the present invention discloses compounds of structural formula (IX):

wherein: r₁Is hydrogen,C1-C3 straight chain alkyl, halogen, trifluoromethyl or C1-C3 straight chain alkoxy.

In another aspect, the invention discloses a method of preparing compound I from compound IX, comprising:

wherein: r₁Hydrogen, C1-C3 straight chain alkyl, halogen, trifluoromethyl or C1-C3 straight chain alkoxy.

In another aspect, the present invention discloses a method for preparing compound IX, comprising:

wherein: r₁Hydrogen, C1-C3 straight-chain alkyl, halogen, trifluoromethyl or C1-C3 straight-chain alkoxy; r₂Is methylsulfonyl, ethylsulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl; r₃Is chlorine, bromine or iodine.

Preferably, the preparation of compound IX is characterized by:

wherein: r₁Hydrogen, C1-C3 straight-chain alkyl, halogen, trifluoromethyl or C1-C3 straight-chain alkoxy; r₂Is methylsulfonyl, ethylsulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl; (ii) a R₃Is chlorine, bromine or iodine;

preferably, compound I is prepared from compound II, characterized in that:

wherein: r₁Hydrogen, C1-C3 straight-chain alkyl, halogen, trifluoromethyl or C1-C3 straight-chain alkoxy; r ₂Is methylsulfonyl, ethylsulfonyl, pTosyl or triflyl; r₃Is chlorine, bromine or iodine;

preferably, in the step of preparing compound III from compound II, the base 1 is potassium tert-butoxide, sodium hydride, 1, 8-diazabicycloundecen-7-ene, sodium methoxide or sodium ethoxide; the molar ratio of the compound II, the alkali 1 and the phosphono triethyl triacetate is 1: 0.8-3; the reaction temperature is in the range of-20 to 50 ℃;

preferably, in the step of preparing the compound V from the compound III and the compound IV, the catalyst is selected from (1, 5-cyclooctadiene) chlororhodium (I) dimer, palladium acetate or bis (ethylene) chlororhodium (I) dimer, preferably (1, 5-cyclooctadiene) chlororhodium (I) dimer; the base 2 is selected from potassium carbonate, cesium carbonate or sodium carbonate; the molar ratio of the compound III to the compound IV to the base 2 is in the range of: 1: 0.8-3: 0.5-3; the reaction temperature is in the range of-10 to 80 ℃;

preferably, in the step of preparing the compound VI from the compound V, the reducing agent is lithium aluminum hydride, sodium borohydride, lithium borohydride or potassium borohydride; the molar ratio of the compound V to the reducing agent is 1: 0.5-1: 2; the reaction temperature is-30-60 ℃, and preferably 0-20 ℃;

preferably, in the step of preparing the compound VII from the compound VI, the sulfonyl chloride is methylsulfonyl chloride, ethylsulfonyl chloride or p-methylbenzenesulfonyl chloride; the sulfonic anhydride is methyl sulfonic anhydride or trifluoromethanesulfonic anhydride; the base 3 is selected from sodium hydroxide, potassium hydroxide, triethylamine, N-diisopropylethylamine, sodium carbonate or potassium carbonate; in the step of preparing the compound VII from the compound VI, the molar ratio of the compound VI to sulfonyl chloride/sulfonic anhydride is 1: 0.8-1: 2, preferably 1: 1.1; the reaction temperature is in the range of-10 to 40 ℃, and preferably 20 to 30 ℃;

Preferably, the halogenating agent is liquid bromine, iodine or carbon tetrachloride; the molar ratio of the compound VI to the halogenated reagent to the triphenylphosphine is 1: 1-5: 1-2; the reaction temperature is in the range of-10 to 50 ℃;

preferably, in the step of preparing the compound IX from the compound VII or the compound VIII, the base 4 is selected from potassium tert-butoxide, potassium tert-amylate, sodium hydride, 1, 8-diazabicycloundecen-7-ene, potassium hydroxide or sodium hydroxide;

preferably, in the step of preparing the compound IX from the compound VII or the compound VIII, the molar ratio of the compound VII or the compound VIII to the base 3 is 1: 1-1: 2; the reaction temperature is 10-70 ℃, and preferably 10-25 ℃;

preferably, it is characterized in that: in the step of preparing the compound I from the compound IX, the catalyst is selected from ruthenium trichloride; the oxidant is selected from sodium periodate, potassium permanganate or ozone, preferably sodium periodate; when the oxidant is sodium periodate, ruthenium trichloride is required to be added; when the oxidant is ozone, sodium hypochlorite and sodium dihydrogen phosphate 2-methyl-2-butylene are needed in the reaction.

Taking 3-oxetanone (compound II) as an initial raw material, and carrying out Wittig reaction with triethyl phosphonotriacetate under an alkaline condition to obtain a compound III; carrying out coupling reaction on the compound III and a boric acid compound IV to obtain a compound V; reducing the ester group of the compound V to generate a compound VI; the hydroxyl of the compound VI and sulfonyl chloride/sulfonic anhydride carry out nucleophilic substitution reaction to generate a compound VII; reacting hydroxyl of the compound VI with a halogenating reagent to generate a compound VIII; carrying out elimination reaction on the compound VII or the compound VIII to generate a compound IX; finally, the double bond of compound IX is oxidized to form 3- (substituted phenyl) oxetane-3-carboxylic acid (compound I).

Advantageous effects

Taking 3-oxetanone (compound II) as an initial raw material, and carrying out Wittig reaction with triethyl phosphonotriacetate under an alkaline condition to obtain a compound III; carrying out coupling reaction on the compound III and a boric acid compound IV to obtain a compound V; reducing the ester group of the compound V to generate a compound VI; the hydroxyl of the compound VI and sulfonyl chloride/sulfonic anhydride carry out nucleophilic substitution reaction to generate a compound VII; reacting hydroxyl of the compound VI with a halogenating reagent to generate a compound VIII; carrying out elimination reaction on the compound VII or the compound VIII to generate a compound IX; finally, the double bond of compound IX is oxidized to form 3- (substituted phenyl) oxetane-3-carboxylic acid (compound I). The method has the advantages of mild reaction conditions, simple and convenient operation, stable process, high yield, total yield up to 35 percent and suitability for large-scale production.

Compound XVIII is disclosed in WO2013025733a1, and compound I-1 can be used to prepare compound XVIII:

the following synthetic route can be used:

compound XVIII is a lysophosphatidic acid (LPA) receptor antagonist.

Abbreviations for the reagents referred to in the specification are as follows:

DBU: 1, 8-diazabicycloundec-7-ene;

LAH: lithium aluminum hydride;

MeOH: methanol;

EtOH: ethanol;

THF: tetrahydrofuran;

DCM: dichloromethane;

DMSO, DMSO: dimethyl sulfoxide;

TEA: triethylamine;

DIPEA: n, N-diisopropylethylamine.

Detailed Description

The present invention will be further illustrated by the following specific examples, which are carried out on the premise of the technical scheme of the present invention, and it should be understood that these examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.