CN115850052A - Preparation method of loxoprofen ring-opening impurity - Google Patents

Abstract

The invention relates to a brand-new preparation method of loxoprofen ring-opening impurities, which comprises the following steps: 1) The loxoprofen and methanol are subjected to esterification reaction to obtain a compound B; 2) Carrying out Baeyer-Villiger rearrangement reaction on the compound B and an oxidant to insert oxygen atoms at the electron-rich end of a carbonyl group to obtain a compound C, and 3) carrying out ring opening on the compound C under the strong alkali condition to obtain an alcoholic hydroxyl intermediate state, and oxidizing the alcoholic hydroxyl intermediate state into ketone by using the oxidant to obtain ring-opened impurities. The invention avoids using explosive and supervision reagents, has the advantages of easily obtained reaction raw materials, short steps, high yield, simple purification and less three wastes, can be produced in large scale, and can meet the requirement of the market on the impurity standard substance or the reference substance by short-time single operation.

Description

Preparation method of loxoprofen ring-opening impurity

Technical Field

The invention relates to a preparation method of loxoprofen ring-opening impurities, belonging to the field of pharmaceutical raw materials or the field of impurity standard products and reference products.

Background

Loxoprofen Sodium (Loxoprofen Sodium) dihydrate with the chemical name of 2- [4- (2-oxocyclopentane-1-ylmethyl) phenyl ] Sodium propionate belongs to the phenylpropionic acid nonsteroidal anti-inflammatory drug, is firstly developed by three co-products of Japan, is the first variety of non-steroidal anti-inflammatory drugs to be sold in Japan at present, is collected by the prescription of the Japanese medical administration, and is imported in China. The product is listed in one of the national product development and recommended trial varieties in nine five and 2010, and the structural formula of the product is as follows:

loxoprofen sodium

The pharmacopoeia of each country does not specify known impurities with respect to the quality standards of loxoprofen sodium, and the japanese pharmacopoeia controls the relevant substances by a Thin Layer Chromatography (TLC) technique. Improving the quality of clinical medication and reducing side effects, and is the direction of efforts of pharmaceutical workers. With the continuous development of the analysis technology, the loxoprofen quality standard is continuously upgraded, the detection of related substances is gradually replaced by a High Performance Liquid Chromatography (HPLC), and a loxoprofen sodium process impurity reference substance or a degraded impurity reference substance is required for perfecting the loxoprofen sodium quality standard.

The compound shown in the structural formula (I) is Loxoprofen sodium ring-opening impurity, is a process impurity in the synthetic process of Loxoprofen sodium, is also the largest impurity in the original preparation (Loxoprofen), and can be increased in Loxoprofen sodium raw material medicine and preparation stability experiments, so that qualified impurity compounds are required to be used as reference substances or standard substances in daily inspection of Loxoprofen sodium raw material medicines and preparations, and the market demand is strong.

Through retrieval, the synthesis of the impurity (I) is described in a few documents, and most of the currently disclosed synthetic routes involve synthetic raw materials which are easy to prepare virus or expensive. Chinese patent CN201710441698 discloses one of the synthetic routes

The intermediate 2 is synthesized by using urotropine which is a chemical easy to explode under supervision, the intermediate 4 is synthesized by using 1-morpholine-1-cyclopentene 3 with higher price, the supervision solvents chloroform and toluene are used in the whole synthesis route, the operation steps are too complicated, and the final product is purified by using column chromatography.

Disclosure of Invention

Object of the Invention

The invention aims to provide a novel, efficient and simple preparation method of the doxofine ring-opening impurity (I). And qualified impurity standard products or reference products are provided for loxoprofen sodium bulk drug manufacturing enterprises and preparation manufacturing enterprises.

Technical scheme

The preparation method of the loxoprofen ring-opening impurity I is characterized in that the synthetic route is as follows:

the method comprises the following steps:

s1: synthesis of Compound B:

the loxoprofen and the methanol are subjected to esterification reaction at room temperature under acidic catalysis, and the loxoprofen and the methanol are concentrated to be dry or to obtain a compound B after TLC detection reaction; the ratio of loxoprofen (a) to methanol is 1; the acid used is a methanolic hydrogen chloride solution, concentrated sulfuric acid, trimethylchlorosilane, p-toluenesulfonic acid, or the like, and a methanolic hydrogen chloride solution is preferable.

S2: synthesis of Compound C:

dissolving the compound B in an organic solvent, adding an oxidizing reagent at room temperature to perform Baeyer-Villiger oxidation reaction under the oxidation action of the oxidizing reagent to generate a compound C, adding a 20% sodium bicarbonate solution in batches after TLC detection reaction is finished to neutralize the solution until the pH is =7-8, extracting with ethyl acetate, washing, drying, concentrating, and performing column chromatography to obtain the compound C; the organic solvent is dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran, preferably dichloromethane; the oxidant is m-chloroperoxybenzoic acid, peracetic acid, hydrogen peroxide and the like, preferably m-chloroperoxybenzoic acid; the ratio of compound B to oxidant is 1 to 1.5, preferably 1:1.2.

s3: synthesis of Ring-opened impurity I:

dissolving the compound C in an organic solvent, adding alkali in batches at a certain room temperature, after TLC detection reaction is finished, concentrating under reduced pressure to remove the solvent, regulating pH =4-5 by hydrochloric acid (1M), extracting by dichloromethane, washing, drying and filtering, adding an oxidant in batches into clear liquid at room temperature, after TLC monitoring reaction is finished, adding water for dilution, filtering to remove white solid, drying filtrate, filtering by quickly padding crude silica gel once, concentrating the filtrate to dryness, and pulping methyl-tert-ether and n-heptane (1V, 3V) to obtain a pure product, namely, an open-ring impurity I.

The organic solvent is tetrahydrofuran, 2-first-grade tetrahydrofuran, methanol and the like, preferably tetrahydrofuran;

the reaction temperature is 20-80 ℃, preferably 40-60 ℃;

the ratio of compound C to oxidant is 1 to 1, preferably 1:1.1;

the oxidant is DMP, IBX, ac ₂ o/DMF, activated manganese dioxide, and the like, preferably DMP;

the ratio of compound C to base is 1 to 1:5;

the alkali is lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., preferably sodium hydroxide.

Advantageous effects

1. The invention adopts a brand new design concept, accidentally discovers that the carboxyl of loxoprofen is subjected to oxidation rearrangement reaction under the protection of methyl esterification and under the action of an oxidant at normal temperature, five-membered cyclic ketone is changed into a six-membered lactone ring, and the six-membered lactone is subjected to hydrolytic ring opening to obtain the impurity (I).

2. The impurity has triple attributes of process impurities, bulk drugs and preparation degradation maximum impurities, is a scarce impurity in the market, and is expensive. The impurity standard substance or the reference substance prepared by the preparation method has important significance for controlling the quality of the raw material medicine and the preparation of the loxoprofen sodium.

Detailed Description

Example 1

The method comprises the following steps: loxoprofen (3.00g, 21.2mmol) was weighed out, dissolved in 30ml of methanol, and 1ml of methanolic hydrogen chloride solution (4M) was added thereto, followed by stirring at room temperature overnight. TLC monitored the reaction was complete. Concentration gave compound B as a yellow oil (3.30 g, 100% yield).

Step two: compound B (2.95g, 11.3mmol) was weighed out, dissolved in 150ml of dichloromethane, metachloroperoxybenzoic acid (85%, 4.60g,22.7 mmol) was added portionwise. The reaction was stirred at room temperature for 1.5h and monitored by TLC for completion. The mixture was neutralized to PH =7-8 by addition of 20% sodium bicarbonate solution, extracted with ethyl acetate (50ml × 3), washed, dried, concentrated and purified by column chromatography (PE: EA = 2).

Step three: compound C (2.10g, 7.61mmol) was weighed, dissolved in 40ml of tetrahydrofuran, and 40ml of water was added thereto, followed by addition of sodium hydroxide (1.52g, 38.0mmol) in portions. Reacting at 50 ℃ for 2h, and monitoring by TLC. The reaction mixture was concentrated under reduced pressure, the aqueous phase was adjusted to pH =4-5 with hydrochloric acid (1M), extracted with dichloromethane (50ml. Times.3), washed with water, dried over anhydrous sodium sulfate, and Dess-Martin oxidant (DMP, 2.80g, 6.64mmol) was added to the clear solution in portions at room temperature. After the reaction is completed, stirring is carried out for 40min. Diluting the reaction solution by adding 30ml of water to generate a large amount of white precipitate, filtering the reaction solution, collecting filtrate, extracting and layering the filtrate, collecting an organic phase, drying by using anhydrous sodium sulfate, filtering by using quick pad crude silica gel (30g, 100-200 meshes) once, concentrating and drying the filtrate, adding methyl tert-ether (5 ml) and n-heptane (15 ml) and pulping to obtain white solid ring-opening impurity I (500 mg, yield 40.7%).

ESI-MS(m/z):278.1；

¹ HNMR(400MHz,DMSO)δ12.16(s,1H),7.20(dd,J＝3.6,0.8Hz,4H),3.69(s,2H),3.67(m,1H),2.53(m,2H),2.20(m,2H),1.68(m,2H),1.35(d,J＝0.8,1H).

Example 2

The method comprises the following steps: after 2ml of thionyl chloride was added to 220ml of methanol by a syringe and stirred for 15min, loxoprofen (21.7g, 88.1mmol) was weighed and dissolved by stirring, and stirred at room temperature overnight. TLC monitored the reaction was complete. Concentration gave compound B as a yellow oil (22.5 g, 98.2% yield).

Step two: compound B (22.5g, 0.086 mol) was weighed out and dissolved in 400ml of methylene chloride. m-CPBA (85%, 35.1g, 0.17mol) was added in portions, the reaction was stirred at room temperature for 1.5h, and the completion of the reaction was monitored by TLC. The mixture was neutralized to PH =7-8 by addition of 20% sodium bicarbonate solution, extracted with ethyl acetate (500ml × 3), washed, dried, concentrated to dryness, and then purified by column chromatography (PE: EA = 2).

Step three: compound C (18.7g, 0.068mol) was weighed, dissolved in 120ml of tetrahydrofuran and 120ml of water, and then sodium hydroxide (13.6g, 0.34mol) was added in portions. Reaction at 50 ℃ for 2h and TLC to monitor that the starting material has reacted to completion. The reaction solution is decompressed and concentrated, the aqueous phase is adjusted to pH =4-5 by hydrochloric acid (1M), dichloromethane (250ml x 3) is used for extraction, water washing and anhydrous sodium sulfate drying are carried out, dess-Martin oxidant (43.1g, 102mmol) is added into the clear solution in batches at room temperature, stirring is carried out for 40min, TLC is carried out for monitoring reaction, the raw materials are completely reacted, the reaction solution is diluted by 300ml of water to generate a large amount of white precipitate, the upper reaction solution is filtered, filtrate is collected, filtrate is extracted and layered, an organic phase is collected, anhydrous sodium sulfate is dried, rapid pad crude silica gel (150g, 100-200 meshes) is filtered once, and methyl tert-ether (60 ml) and n-heptane (180 ml) are added after the filtrate is concentrated to be dried, and ring-opening impurity I (7.44 g, yield is 39.5%) of white solid is beaten.

ESI-MS(m/z):278.1；

¹ HNMR(400MHz,DMSO)δ12.16(s,1H),7.20(dd,J＝3.6,0.8Hz,4H),3.72(s,2H),3.67(m,1H),2.53(m,2H),2.20(m,2H),1.68(m,2H),1.35(d,J＝0.8,1H)。

Claims (4)

1. A preparation method of loxoprofen ring-opening impurities is characterized by comprising the following steps: the method is realized by the following steps:

the method comprises the following steps:

s1: synthesis of Compound B:

the loxoprofen A and methanol are subjected to esterification reaction at room temperature under acidic catalysis to obtain a compound B;

s2: synthesis of Compound C:

dissolving the compound B in an organic solvent, adding an oxidizing reagent at room temperature to perform Baeyer-Villiger oxidation reaction under the oxidation action of the oxidizing reagent to generate a compound C, and adding an alkali solution to neutralize until the pH =7-8 to obtain the compound C;

s3: synthesis of Ring-opened impurity I:

dissolving compound C in organic solvent, adding alkali in batches, removing solvent by vacuum concentration, adjusting pH to be =4-5 by using 1M hydrochloric acid, extracting with dichloromethane, washing, drying, filtering, and adding oxidant in batches to clear liquid at room temperature to obtain ring-opening impurity I.

2. The method for preparing the loxoprofen ring-opening impurity according to claim 1, wherein the mass-to-volume ratio of loxoprofen a to methanol in step S1 is 1; the acid used is methanol hydrogen chloride solution, concentrated sulfuric acid, trimethylchlorosilane and p-toluenesulfonic acid.

3. The method for preparing the loxoprofen open-ring impurity according to claim 1, wherein the step S2 is performed by

The organic solvent is dichloromethane, chloroform, 1, 2-dichloroethane, tetrahydrofuran;

the oxidant is m-chloroperoxybenzoic acid, peracetic acid and hydrogen peroxide;

the molar ratio of the compound B to the oxidant is 1-1;

the base is a 20% sodium bicarbonate solution.

4. The method for preparing loxoprofen open-ring impurities according to claim 1,

in the step S3, the organic solvent is tetrahydrofuran, 2-first-grade tetrahydrofuran and methanol; the reaction temperature is 20-80 ℃; the mass ratio of the compound C to the oxidant is 1; the oxidant is DMP, IBX and Ac ₂ o/DMF, activated manganese dioxide; the molar ratio of the compound C to the base is 1; the alkali is lithium hydroxide, sodium hydroxide or potassium hydroxide.