CN111423319B

CN111423319B - Preparation method of loxoprofen

Info

Publication number: CN111423319B
Application number: CN202010391255.0A
Authority: CN
Inventors: 毛宇成; 潘仙华; 陈宇; 黎鸿艺
Original assignee: Shanghai Institute of Technology
Current assignee: Shanghai Institute of Technology
Priority date: 2020-05-11
Filing date: 2020-05-11
Publication date: 2022-11-04
Anticipated expiration: 2040-05-11
Also published as: CN111423319A

Abstract

The invention discloses a novel method for preparing loxoprofen (I). The reaction process is as follows: the compound (VII) and the compound (VIII) are subjected to condensation reaction to obtain an Intermediate (IX), the Intermediate (IX) is subjected to hydrogenation reduction reaction in a mixed solvent of acid and alcohol to obtain an intermediate (X), and the intermediate (X) is subjected to hydrolysis reaction to obtain loxoprofen (I).

Description

Preparation method of loxoprofen

Technical Field

The invention relates to a novel method for preparing loxoprofen (I).

Background

Loxoprofen Sodium (II), 2- [4- (2-oxocyclopentane-1-ylmethyl) phenyl ] Sodium propionate dihydrate, is a phenylpropionic acid nonsteroidal anti-inflammatory drug, and is used for relieving pain and inflammation of diseases such as chronic rheumatic arthritis, osteoarthritis, scapulohumeral periarthritis and the like and for relieving pain and inflammation after tooth extraction or operation. Developed by Sanko corporation of Japan (now the first Sanko Co., ltd.). The trade name is Lesong (Rifampicin).

The main commercial route for the preparation of loxoprofen sodium is currently reported by japan, ltd, and the following routes are described in detail in patent US 4161538A and j.med. Chem,1984,27, 212:

route one:

the route firstly carries out condensation reaction on a compound (III) and cyclopentanone formate (IV) under the action of alkali to form a compound (V), and then the compound (V) is refluxed in a hydrobromic acid/acetic acid solution to carry out ester group hydrolysis and decarboxylation reaction to form loxoprofen (I). Salifying the compound (I) to obtain loxoprofen sodium (II). The biggest problem with this route is that compound (v) needs to be hydrolyzed and decarboxylated in large amounts of very corrosive hydrobromic acid and under reflux. The main reason is that the carboxylic ester on the cyclopentanone segment in the compound (V) is not easily hydrolyzed due to steric hindrance, and the hydrolysis must be promoted at high temperature and strong acid. However, at such strong acidity and high temperatures, the product is easily carbonized, resulting in a very dark compound color. In addition, hydrobromic acid is very corrosive to equipment and is not environment-friendly, which limits the practical application of the method.

And a second route:

the route forms the loxoprofen (I) by the sequential reactions of condensation, hydrolysis and the like of the compound (III) and the enamine compound (VI). However, the biggest problem of this route is that the compound (VI) has poor activity and the reaction with the compound (III) has low conversion rate, resulting in low yield of the whole route.

In addition, the compound (III) is required to be used as a starting material in both the first route and the second route, but the synthesis route of the compound (III) is long and the process is complicated. The synthesis of compound (III) can be found in Chinese patent CN 101412670A.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a novel synthetic method of loxoprofen (I). The method has the advantages of simple operation, low cost, environmental protection and the like, and is suitable for industrial production.

In order to achieve the above object, the present invention provides a method for preparing loxoprofen, comprising the steps of:

(1) Carrying out condensation reaction on the compound (VII) and the compound (VIII) to obtain an Intermediate (IX),

(2) The Intermediate (IX) is subjected to hydrogenation reduction reaction in a mixed solvent of acid and alcohol to obtain an intermediate (X),

(3) The intermediate (X) is hydrolyzed to obtain the loxoprofen (I),

in the reaction for obtaining the Intermediate (IX) by the condensation reaction of the compound (VII) and the compound (VIII), a Lewis acid catalyst is added, and the Lewis acid catalyst is selected from the following: aluminum trichloride, ferric trichloride and zinc dichloride.

In the above reaction for obtaining the Intermediate (IX) by condensation reaction of the compound (VII) with the compound (VIII), the solvent used is selected from: dichloromethane, trichloromethane, dichloroethane.

In the reaction for obtaining the intermediate (X) from the Intermediate (IX) by the hydrogenation reduction reaction in the mixed solvent of an acid and an alcohol, a palladium-carbon catalyst is used.

In the above reaction of obtaining the intermediate (X) from the Intermediate (IX) by the hydrogenation reduction reaction in a mixed solvent of an acid and an alcohol, it is necessary to use a mixture of two solvents. One solvent is an acid, the acid used being selected from: formic acid, acetic acid, propionic acid. Another solvent is an alcohol, the alcohol used being selected from: methanol, ethanol, isopropanol.

We have found that the Intermediate (IX) reacts more difficultly in the conventional hydrogen/palladium on carbon system. The reason for this is that the carbonyl group ortho to the phenyl group is first reduced to a hydroxyl function. However, further conversion of the hydroxyl functionality to methylene requires means such as high temperature and pressure to complete the reduction. However, at a relatively high temperature and a relatively high pressure, the carbonyl group of cyclopentanone is also reduced to some extent to form cyclopentanol compounds and cyclopentane compounds (XI-A-D), respectively. The combination of these compounds in compound (X) results in poor separation of these compounds from compound (X) due to their very similar polarity to each other, resulting in low purity of compound (X) (generally not more than 98.5% purity). These impurities are carried over into the subsequent product and also bring about considerable troubles in the purification of the subsequent product.

In the research, it is found that the addition of a certain proportion of acid, such as acetic acid, to a conventional alcohol solvent, such as ethanol, such as an alcohol, can promote the hydrogenation reduction reaction, and the reaction can successfully reduce the carbonyl group at the benzyl position to methylene at normal temperature and pressure. Under such mild conditions, the carbonyl group of cyclopentanone is not changed at all.

The above-mentioned reaction for obtaining the intermediate (X) from the Intermediate (IX) by the hydrogenation reduction reaction in the mixed solvent of an acid and an alcohol is carried out substantially as follows:

adding the Intermediate (IX), palladium carbon, an acid solvent and an alcohol solvent into a reaction bottle, and then introducing hydrogen into the reaction bottle at normal temperature and normal pressure to stir the mixture for 1 to 24 hours. And filtering to remove the palladium carbon. The solvent was distilled off under reduced pressure, and the obtained oily substance was used in the next reaction without purification.

In the hydrolysis reaction of intermediate (X) to obtain loxoprofen (I), the hydrolysis decarboxylation is carried out by acid catalysis, and the acid is selected from: hydrochloric acid, sulfuric acid.

The reaction for obtaining loxoprofen (i) from the intermediate (x) after hydrolysis is carried out in a mixed solvent of water and acetic acid at a volume ratio of water to acetic acid of 1 to 1.

The operation of the above-mentioned reaction for obtaining loxoprofen (i) by hydrolysis reaction of the intermediate (x) is roughly as follows:

adding the intermediate (X), acid and a mixed solvent of water and acetic acid into a reaction flask, and reacting for 1-20h at a proper temperature. After the reaction, dichloromethane and water were added, and the organic phase was obtained by liquid separation. And (3) distilling under reduced pressure to remove the solvent, and recrystallizing the obtained oily substance by using a mixed solvent of ethyl acetate and petroleum ether to obtain the loxoprofen (I).

The reaction formula is shown as follows:

compared with the prior art, the invention has the beneficial effects that:

the method has the advantages that: since only one sterically unhindered ester group needs to be hydrolyzed and decarboxylation does not need to occur, the reaction system can be carried out under a relatively mild strong acid, such as hydrochloric acid, or a less volatile acid, such as sulfuric acid, and only a small amount of strong acid (0.5 to 2 equivalents) is needed. Therefore, a large amount of volatile and strong corrosive hydrobromic acid is avoided, the whole reaction is overlong, no carbonization phenomenon occurs, the color of a reaction system is light, and the corrosivity to equipment is weak; II, secondly: the hydrogenation reaction can be carried out under mild conditions, and impurities are few; thirdly, the method comprises the following steps: the used initial raw materials are simple and easy to obtain, and the method is more favorable for industrial production.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.

Example 1

The embodiment provides a preparation method of loxoprofen, which comprises the following specific steps:

step 1: synthesis of intermediate (ix):

55g of the compound (VIII), 300mL of methylene chloride and 70g of anhydrous aluminum trichloride were charged into a reaction flask, and 50mL of a methylene chloride solution of 53.5g of the compound (VII) prepared according to example IV was slowly dropped into the reaction flask while controlling the internal temperature to about 0 ℃; then raising the temperature to 40 ℃ and stirring for 12h until no obvious gas is discharged; after cooling, 750mL of 4N hydrochloric acid aqueous solution is slowly added into the reaction system under the temperature of 0-5 ℃; then heating to 25 ℃, and continuing stirring for 1h; separating the liquid and separating an organic phase; the aqueous phase was extracted once with 100mL dichloromethane and the organic phases were combined; washing the organic phase with 500mL of saturated sodium bicarbonate aqueous solution and 500mL of water respectively, drying the separated organic phase with anhydrous magnesium sulfate, concentrating under reduced pressure to obtain a light yellow oily substance, namely an Intermediate (IX), and directly using the Intermediate (IX) in the next step without purification;

wherein, the preparation of the compound (VII) specifically comprises the following steps:

50g cyclopentanone methyl formate and 15g sodium hydroxide in 250mL water were added to the reaction flask, followed by stirring at room temperature for 20 hours; after cooling to 0 ℃, dropwise adding concentrated hydrochloric acid until the PH of the system is 2; adding 250mL of methyl tert-butyl ether for extraction, and washing the obtained organic phase with 250mL of saturated saline solution; the organic layer obtained by liquid separation was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain a yellow oil; mixing the oily substance with 50g of thionyl chloride at 0 ℃, then gradually heating to 70 ℃ and stirring for 12 hours; removing excessive thionyl chloride under reduced pressure to obtain 53.5g of light yellow oily matter, namely the compound (VII), which is directly used for the next reaction;

step 2: synthesis of intermediate (X)

The crude pale yellow oil obtained in the previous step was dissolved in 0.75L of isopropanol and 0.75L of acetic acid and then transferred to a 3L reaction flask; then 10g of palladium-carbon is added, the system is fully replaced by nitrogen-hydrogen, hydrogen is introduced, and the reaction is carried out for 15 hours at normal temperature and normal pressure; filtering to remove palladium carbon, concentrating under reduced pressure to obtain light yellow oily substance, namely an intermediate (X), and directly using the intermediate (X) in the next step without purification;

and step 3: synthesis of loxoprofen (I)

The crude pale yellow oil obtained in the previous step was dissolved in 1L of acetic acid and 0.5L of water, and 20g of concentrated sulfuric acid was added with stirring, followed by heating to 90 ℃ and reacting for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 1L of methylene chloride and 1L of water were added thereto, and after sufficient stirring, a methylene chloride solution was obtained by liquid separation. After the solvent was distilled off under reduced pressure, the obtained oily substance was recrystallized from a mixed solvent of 40mL of ethyl acetate and 320mL of petroleum ether, cooled and filtered, and the solid obtained after the filtration was dried, 55.1g of an off-white solid was obtained by pouring out, the yield was 66.8% (starting from compound (VIII)), and the purity was 99.58%. ¹ H-NMR(400MHz,CDCl ₃ )δ:1.50(d,J＝7.6Hz,3H),1.56～1.60(m,1H),1.65～1.80(m,1H),1.90～2.00(m,1H),2.05～2.18(m,2H),2.28～2.40(m,2H),2.52(dd,J＝9.2,13.6Hz,1H),3.12(dd,J＝3.6,13.6Hz,1H),3.72(q,J＝7.2Hz,1H),7.12(d,J＝8.4Hz,2H),7.21(d,J＝8.4Hz,2H),11.40(br,1H)。

Claims

1. A method for preparing loxoprofen, comprising:

(1) The condensation reaction of compound (VII) with compound (VIII) to give Intermediate (IX), the reaction for preparing Intermediate (IX) requires the addition of a Lewis acid catalyst selected from the group consisting of: aluminum trichloride, ferric trichloride, zinc dichloride,

(2) The Intermediate (IX) is subjected to a hydrogenation reduction reaction in a mixed solvent of an acid and an alcohol to give an intermediate (X), and the intermediate (X) is prepared by using a palladium-carbon catalyst and H ₂ And the reaction of the step is carried out at normal temperature and normal pressure,

(3) The intermediate (X) is hydrolyzed to obtain the loxoprofen (I),

2. the process according to claim 1, wherein the reaction to prepare Intermediate (IX) is carried out in a suitable solvent selected from the group consisting of dichloromethane, trichloromethane and dichloroethane.

3. The process according to claim 1, wherein the reaction for preparing the intermediate (X) requires a mixture of two solvents; one solvent is an acid, the acid used being selected from: formic acid, acetic acid, propionic acid; another solvent is an alcohol, the alcohol used being selected from: methanol, ethanol, isopropanol.

4. The process according to claim 1, wherein the loxoprofen (I) is prepared by hydrolysis decarboxylation under the catalysis of an acid selected from the group consisting of: hydrochloric acid, sulfuric acid.

5. The process according to claim 1, wherein the reaction for producing loxoprofen (I) is carried out in a mixed solvent of water and acetic acid at a volume ratio of 1.