阅读说明：本技术 一种卡格列净中间体的合成方法 (Synthesis method of canagliflozin intermediate ) 是由 何燕 封娜 王元有 于 2019-11-14 设计创作，主要内容包括：本发明公开了一种卡格列净中间体的合成方法。该方法以4-溴甲苯和5-溴乙酰丙酸乙酯为起始原料,在三氯化铝催化下,经傅-克反应得到化合物3；化合物3在碱性条件下进行水解反应,得到化合物4；化合物4与二甲亚砜进行反应生产酰氯,然后在三氯化铝催化下,与氟苯发生傅克酰基化反应得到化合物5；化合物5在150～200℃下,采用三硫化二磷硫代进行环合,得到2-(4-氟苯基)-5-[(5-溴-2-甲基苯基)甲基]噻吩。该合成方法的原料简单,操作步骤简单,产品的纯度高、收率高,适宜于工业化生产。<Image he="274" wi="700" file="DDA0002272998490000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a synthetic method of a canagliflozin intermediate. The method takes 4-bromotoluene and 5-bromolevulinic acid ethyl ester as initial raw materials, and a compound 3 is obtained through Friedel-crafts reaction under the catalysis of aluminum trichloride; carrying out hydrolysis reaction on the compound 3 under an alkaline condition to obtain a compound 4; reacting the compound 4 with dimethyl sulfoxide to produce acyl chloride, and then performing Friedel-crafts acylation reaction on the acyl chloride and fluorobenzene under the catalysis of aluminum trichloride to obtain a compound 5; cyclizing the compound 5 by adopting diphosphorus trisulfide at the temperature of 150-200 ℃ to obtain 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl]Thiophene. The synthesis method has the advantages of simple raw materials, simple operation steps, high product purity and high yield, and is suitable for industrial production.)

1. A synthetic method of a canagliflozin intermediate is characterized in that the canagliflozin intermediate is 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene, and the synthetic method comprises the following steps:

1) 4-bromotoluene and 5-bromolevulinic acid ethyl ester are used as initial raw materials, and a compound 3 is obtained through Friedel-crafts reaction under the catalysis of aluminum trichloride;

2) carrying out hydrolysis reaction on the compound 3 under an alkaline condition to obtain a compound 4;

3) reacting the compound 4 with dimethyl sulfoxide to produce acyl chloride, and then performing Friedel-crafts acylation reaction on the acyl chloride and fluorobenzene under the catalysis of aluminum trichloride to obtain a compound 5;

4) cyclizing the compound 5 by adopting diphosphorus trisulfide at the temperature of 150-200 ℃ to obtain 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene;

the compound 3 is:

the compound 5 is

2. The method for synthesizing the canagliflozin intermediate as claimed in claim 1, wherein the molar ratio of the ethyl 5-bromolevulinate, the 4-bromotoluene and the aluminum trichloride in the step 1) is 1: 1-1.5: 2 to 4.

3. The method for synthesizing the canagliflozin intermediate as claimed in claim 1, wherein the hydrolysis in the step 2) is carried out by adding water and an inorganic base, wherein the addition amount of the water is 20-30% of the volume of the organic solvent used.

4. The method for synthesizing a canagliflozin intermediate as claimed in claim 3, wherein the inorganic base is sodium hydroxide or potassium hydroxide.

5. The method for synthesizing the canagliflozin intermediate as claimed in claim 1, wherein the molar ratio of the compound 4, the thionyl chloride, the fluorobenzene and the aluminum trichloride in the step 3) is 1: 2-5: 1-1.5: 2 to 4.

6. The method for synthesizing the canagliflozin intermediate as claimed in claim 1, wherein the molar ratio of the compound 5 to the phosphorus trisulfide in the step 4) is 1: 2 to 5.

7. A process for the synthesis of a canagliflozin intermediate as claimed in any one of claims 1 to 6, characterised by comprising the steps of:

1) adding solvents of dichloromethane, 5-bromoethyl levulinate and aluminum trichloride into a reaction container, cooling to-10 ℃, dropwise adding 4-bromotoluene, reacting for 0.5-2.0 hours at a constant temperature after dropwise adding, heating to a normal temperature, reacting for 4-8 hours at a constant temperature, and performing post-treatment to obtain a compound 3;

2) dissolving the compound 3 in an organic solvent methanol, adding water, adding solid sodium hydroxide, heating to 35-40 ℃, reacting for 1-3 hours under the condition of heat preservation, and carrying out post-treatment to obtain a compound 4;

3) adding the compound 4 and dichloromethane into a reaction container, dropwise adding thionyl chloride, heating, carrying out reflux reaction for 3-5 hours, and concentrating under reduced pressure until the mixture is dry; then, re-dissolving by using dichloromethane, adding aluminum trichloride, cooling to-10 ℃, starting to slowly dropwise add fluorobenzene, carrying out heat preservation reaction for 1-2 hours after dropwise adding is finished, then heating to room temperature, carrying out heat preservation reaction for 4-8 hours, and carrying out post-treatment after the reaction is finished to obtain a compound 5;

4) by ring closure

Dissolving the compound 5 in diphenyl ether, adding phosphorus trisulfide, heating to 150-200 ℃, and reacting for 1-3 hours while keeping the temperature; after post-treatment, 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene is obtained.

Technical Field

The invention relates to a method for synthesizing a canagliflozin intermediate, namely 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene, and belongs to the technical field of medicines.

Background

Canagliflozin (canagliflozin) is a sodium-glucose cotransporter 2(SGLT-2) inhibitor commonly developed by the american fast-growing drug and the japanese honda mitsubishi drug, which was approved by the FDA for marketing in 5 months of 2013 under the trade name of Invokana. The composition is used for improving the blood sugar control of the type II diabetes adult patients, can effectively reduce the blood sugar level of the type 2 diabetes adult patients, and has higher safety.

2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene is a key intermediate in the synthesis process of canagliflozin, and the structural formula of the intermediate is as follows:

the currently used synthetic routes for the compound are: friedel-crafts reaction is carried out on 2- (4-fluorophenyl) thiophene and 5-bromo-2-chloro-benzoyl chloride or 5-bromo-2-chloro-benzoyl chloride, and then 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene is obtained through carbonyl reduction, wherein the reaction equation is shown as follows. WO2012160218, CN104892566A and CN107556287A all adopt the above routes. In the above route, 2- (4-fluorophenyl) thiophene needs to be synthesized first, and the preparation method of 2- (4-fluorophenyl) thiophene is complicated.

Other suture routes are the looping method, such as the method adopted by CN102115468A, etc. The method is characterized in that 1- (5-bromo-2-methylphenyl) -2-chloroacetone and 3-chloro-3- (4-fluorophenyl) -2-acrolein react under the action of a vulcanizing agent, and then a target product is generated through carbonyl reduction. The 3-chloro-3- (4-fluorophenyl) -2-acrolein used in the reaction has problems of difficulty in storage (easy oxidation in air) and low yield.

Disclosure of Invention

The invention overcomes the defects of the prior art and provides a novel synthetic method of a canagliflozin intermediate, namely 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene. The synthesis method has the advantages of simple raw materials, simple operation steps, high product purity and high yield, and is suitable for industrial production.

The technical scheme of the invention is as follows: a synthetic method of a canagliflozin intermediate (2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene) is characterized by comprising the following steps:

1) 4-bromotoluene (compound 1) and 5-bromoethyl levulinate (compound 2) are taken as initial raw materials, and 5- (5-bromo-2-methylphenyl) -4-ethyl levulinate (compound 3) is obtained through Friedel-crafts reaction under the catalysis of aluminum trichloride;

2) hydrolyzing the compound 3 under alkaline conditions to obtain 5- (5-bromo-2-methylphenyl) -4-levulinic acid (compound 4);

3) reacting the compound 4 with dimethyl sulfoxide to produce acyl chloride, and then carrying out Friedel-crafts acylation reaction on the acyl chloride and fluorobenzene under the catalysis of aluminum trichloride to obtain 5- (5-bromo-2-methylphenyl) -1- (4-fluorophenyl) pentane-1, 4-diketone (a compound 5);

4) and (3) cyclizing the compound 5 by adopting diphosphorus trisulfide at the temperature of 150-200 ℃ to obtain 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene.

The synthetic route is shown below.

Preferably, the molar ratio of the ethyl 5-bromolevulinate, the 4-bromotoluene and the aluminum trichloride in the step 1) is 1: 1-1.5: 2 to 4.

Preferably, water and inorganic base (sodium hydroxide, potassium hydroxide and the like) are added in the step 2) for hydrolysis, and the addition amount of the water is 20-30% of that of the organic solvent (such as methanol).

Preferably, the molar ratio of the compound 4, the thionyl chloride, the fluorobenzene and the aluminum trichloride in the step 3) is 1: 2-5: 1-1.5: 2 to 4.

Preferably, the molar ratio of the compound 5 in the step 4) to the phosphorus trisulfide is 1: 2 to 5.

The method comprises the following specific steps:

1) adding solvents of dichloromethane, 5-bromoethyl levulinate and aluminum trichloride into a reaction container, cooling to-10 ℃, dropwise adding 4-bromotoluene, reacting for 0.5-2.0 hours at a constant temperature after dropwise adding, heating to a normal temperature, reacting for 4-8 hours at a constant temperature, and performing post-treatment to obtain a compound 3;

2) dissolving the compound 3 in an organic solvent methanol, adding water, adding solid sodium hydroxide, heating to 35-40 ℃, reacting for 1-3 hours under the condition of heat preservation, and carrying out post-treatment to obtain a compound 4;

3) adding the compound 4 and dichloromethane into a reaction container, dropwise adding thionyl chloride, heating, carrying out reflux reaction for 3-5 hours, and concentrating under reduced pressure until the mixture is dry; then, re-dissolving by using dichloromethane, adding aluminum trichloride, cooling to-10 ℃, starting to slowly dropwise add fluorobenzene, carrying out heat preservation reaction for 1-2 hours after dropwise adding is finished, then heating to room temperature, carrying out heat preservation reaction for 4-8 hours, and carrying out post-treatment after the reaction is finished to obtain a compound 5;

4) by ring closure

Dissolving the compound 5 in diphenyl ether, adding phosphorus trisulfide, heating to 150-200 ℃, and reacting for 1-3 hours while keeping the temperature; after post-treatment, 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene is obtained.

The invention has the beneficial effects that: the invention provides a novel synthetic method of a canagliflozin intermediate, namely 2- (4-fluorophenyl) -5- [ (5-bromo-2-methylphenyl) methyl ] thiophene. The synthesis method has the advantages of simple raw materials, simple operation steps, high product purity and high yield, and is suitable for industrial production.

Detailed Description