Nefopam hydrochloride new impurity and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical chemistry preparation, in particular to a nefopam hydrochloride impurity and a preparation method thereof. The new nefopam hydrochloride impurity and the preparation method thereof are disclosed for the first time, and the prepared new nefopam hydrochloride impurity is high in liquid phase purity and can be directly used as a reference substance for quality research of nefopam hydrochloride. The impurity enlarges the impurity spectrum of nefopam hydrochloride stability research, promotes the improvement of the quality standard of nefopam hydrochloride, and realizes more strict quality control of nefopam hydrochloride bulk drugs and preparations, thereby ensuring the safety of nefopam hydrochloride bulk drugs and preparations.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical preparation, and in particular to a new impurity of nefopam hydrochloride and a preparation method thereof. Background Art

[0002] Nefopam hydrochloride is a new type of non-narcotic receptor agonist analgesic. It does not have the characteristics of non-steroidal anti-inflammatory drugs. It can increase the pain threshold. Its action is not blocked by naloxone. Its analgesic effect is stronger than aspirin. It takes effect slowly but lasts longer. It is not tolerant or addictive. In addition, it has antipyretic, local anesthetic and anti-inflammatory effects. It can slow down the increase in capillary permeability in the early stage of inflammation and inhibit the proliferation of inflammatory edema, exudation and granulation tissue caused by inflammation. It has no inhibitory effect on the circulatory system and its inhibitory effect on respiration is also relatively mild. Therefore, it has a wide range of clinical applications and has a good effect on postoperative analgesia, cancer pain, acute traumatic pain, acute gastritis pain, visceral smooth muscle colic caused by biliary ascariasis, etc. and other moderate and severe pain.

[0003] Nefopam hydrochloride is a white crystalline powder, odorless. Its English name is Nefopam, and its Chinese chemical name is 5-methyl-1-phenyl-3,4,5,6-tetrahydro-1H-2,5-oxazolidinone hydrochloride. Its CAS registration number is 23327-57-3, and its molecular formula is C 17 H 19 NO·HCl, molecular weight 289.80, slightly soluble in water and slightly soluble in ethanol.

[0004] The present invention technicians found a large unknown impurity in the process of synthesizing Nefopam. The present inventors searched all the impurities about Nefopam hydrochloride in the current literature and pharmacopoeia and found that they were inconsistent with the impurity information. Therefore, it is necessary to conduct a detailed study on the chemical structure, preparation method, etc. of Nefopam hydrochloride impurities, which is not only the key to improving the quality of Nefopam hydrochloride drugs, but also a reliable control for solving the process impurities or degradation impurities generated in the synthesis process of Nefopam hydrochloride, which has very important practical significance. Summary of the invention

[0005] The present invention discloses for the first time a new impurity of Nefopam hydrochloride and a preparation method thereof. The Nefopam hydrochloride impurity is discovered and separated for the first time, and a preparation method of the impurity is provided. The present invention solves the problem that the prior art still has incomplete research on the impurities of Nefopam hydrochloride, expands the impurity spectrum of Nefopam hydrochloride, and promotes the improvement of the quality standard of Nefopam hydrochloride.

[0006] First, the structure of the new impurity in Nefopam hydrochloride was determined by liquid chromatography-mass spectrometry (LC-MS), and the impurity was not included in any official pharmacopoeia or literature reports. The provided new impurity in Nefopam hydrochloride, i.e., the compound of formula I (4-methyl-1-phenyl-3,4-dihydrobenzo[c]oxirane-5(1H)-one), has the following chemical structure:

[0007]

[0008] The present invention provides a method for preparing a compound of formula I, and the specific synthetic route is as follows:

[0009]

[0010] Step 1: Acid chloride reaction and amination reaction

[0011] The o-benzoylbenzoic acid (SM1) and the acyl chloride reagent are stirred and reacted in the presence of a solvent, and the supernatant is separated to obtain acyl chloride liquid A, and the acyl chloride liquid A is subjected to an amination reaction with an aminating agent (N-methylethanolamine) and a catalyst (triethylamine), and the mixture is washed with water and concentrated to obtain an intermediate 1.

[0012] Step 2: Reduction reaction

[0013] First, add intermediate 1 and reaction solvent into a reaction vessel, stir, and then add reducing agent in small amounts for multiple times for reduction. After the reaction is completed, add ice water dropwise to quench the reaction. Stand and separate, collect the organic phase, wash with water, and concentrate to obtain intermediate 2.

[0014] Step 3: Cyclization reaction

[0015] First, add the reaction solvent, intermediate 2 and cyclizing agent into the reaction container, raise the temperature to reflux and separate the water, wash once with 20% sodium hydroxide solution and wash twice with water after the reaction is completed, concentrate to remove toluene, add acetone, cool to 0-5°C for crystallization, and centrifuge and dry to obtain the compound of formula I.

[0016] The above synthesis method is further carried out,

[0017] The acyl chloride reagent in step 1 is phosphorus trichloride, thionyl chloride, phosgene, solid phosgene or phosphorus pentachloride; more preferably phosphorus trichloride.

[0018] The reducing agent in step 2 is stannous chloride, lithium aluminum hydride, potassium borohydride, or sodium borohydride; more preferably potassium borohydride.

[0019] The cyclizing agent in step 3 is p-toluenesulfonic acid monohydrate or hydrobromic acid; p-toluenesulfonic acid monohydrate is more preferred.

[0020] The above synthesis method is further carried out,

[0021] The reaction solvent in step 1 is tetrahydrofuran or dichloromethane; dichloromethane is more preferred.

[0022] The reaction solvent in step 2 is tetrahydrofuran, methanol or ethanol; tetrahydrofuran is more preferred.

[0023] The reaction solvent in step 3 is toluene, n-butanol, or xylene; more preferably toluene.

[0024] The above synthesis method is further carried out,

[0025] In step 1, the molar ratio of the raw material SM1: phosphorus trichloride: N-methylethanolamine: triethylamine is 1:0.4-1:1-1.6:1-1.6; more preferably 1:0.5:1.1:1.1.

[0026] In step 2, the molar ratio of the intermediate 1 to potassium borohydride is 1:1-2, and more preferably 1:1.1.

[0027] In step 3, the molar ratio of the intermediate 2 to p-toluenesulfonic acid monohydrate is 1:1.1-2, and more preferably 1:1.2.

[0028] The above synthesis method is further carried out,

[0029] The reaction time of the acyl chloride reaction in step 1 is not less than 3 hours, preferably 4-8 hours, and the reaction temperature is 25-35° C. The reaction time of the amination reaction is not less than 4 hours, preferably 6-10 hours, and the reaction temperature is 20-30° C.

[0030] The reduction reaction time in step 2 is not less than 1 hour, preferably 1-3 hours; the reaction temperature is 25-35°C.

[0031] The reaction time of the cyclization reaction in step 3 is not less than 4 hours, preferably 4-10 hours; the reaction temperature is 105-110°C.

[0032] The above synthesis method is further carried out,

[0033] In step 1, the weight ratio of the raw material SM1 to the reaction solvent volume is 1:4-8; the further preferred ratio is 1:4.

[0034] The weight ratio of the intermediate 1 in step 2 to the volume of the reaction solvent is 1:3-6; the more preferred ratio is 1:3.

[0035] The weight ratio of the intermediate 2 in step 3 to the reaction solvent volume is 1:4-8; the more preferred ratio is 1:5.

[0036] The reagents and raw materials used in the present invention can be obtained commercially.

[0037] The impurity preparation process used in the present invention is simple, the reaction conditions are mild and controllable, and the product has high yield and high purity.

[0038] The present invention discloses for the first time a new impurity of Nefopam hydrochloride (compound of formula I) and a preparation method thereof. Through LC-MS / MS identification and reaction mechanism analysis, the structures of these impurities are firstly inferred, and then directional synthesis is carried out through chemical synthesis means. The synthesized target compound is analyzed to confirm the structure of the compound. The new impurity of Nefopam hydrochloride with high purity can be accurately identified and prepared in large quantities, providing a good foundation for the quality research of Nefopam hydrochloride products, effectively ensuring and controlling the quality of Nefopam hydrochloride, having important application value for the quality research of Nefopam hydrochloride raw materials and preparation research, and providing important guiding significance for safe drug use. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 The HPLC test results of the prepared intermediate compound are shown;

[0040] Figure 2 The HPLC test results of the prepared intermediate compound II are shown;

[0041] Figure 3 The HPLC test results of the prepared compound containing impurities of formula (I) are shown; DETAILED DESCRIPTION

[0042] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be understood as limiting the present invention.

[0043] The synthesis process of the compound of formula I (4-methyl-1-phenyl-3,4-dihydrobenzo[c]oxirane-5(1H)-one) is as follows:

[0044]

[0045] Example 1: Preparation of Compounds of Formula I

[0046] Step 1: 100g of o-benzoylbenzoic acid (SM1) and 30.35g of phosphorus trichloride are reacted in the presence of 400ml of dichloromethane solvent at a reaction temperature of 25-35°C, stirred for reaction for 4h, and the supernatant is separated to obtain acyl chloride liquid A; acyl chloride liquid A is subjected to amination reaction with 36.52g of N-methylethanolamine and 49.20g of triethylamine at a reaction temperature of 20-30°C for 6 hours, the reaction liquid is washed once with 400ml of water, and the organic phase is concentrated under vacuum conditions at 40°C (-0.08MPa) until no obvious liquid flows out to obtain 78.0g of off-white solid, the yield is 67.36%, and the HPLC purity is 93.594% (HPLC normalization method, Figure 1 ).

[0047] Step 2: First add 75.0g of intermediate 1 and 225ml of tetrahydrofuran solution into the reaction bottle, stir at 25-35°C, and then add 20.93g of potassium borohydride (slowly added in four times) for reduction. After 2 hours of reaction, slowly add 200ml of ice water to quench the reaction. Let stand for 30 minutes, separate and collect the organic phase, wash once with 200ml of water, and concentrate the organic phase at 40°C under vacuum (-0.08MPa) until no obvious liquid flows out to obtain 52g of off-white solid (intermediate 2), with a yield of 68.85% and an HPLC purity of 99.043% (HPLC normalization method, Figure 2 ).

[0048] Step 3: First, add 250 ml of toluene solution, 50 g of intermediate 2 and 40.14 g of p-toluenesulfonic acid monohydrate to the reaction bottle, heat to 105-110 ° C, reflux and separate water for 6 hours, wash once with 150 ml of 20% sodium hydroxide solution after the reaction is completed, separate and collect the organic phase, and then wash twice with 150 ml of water. The organic phase is concentrated under 80 ° C vacuum conditions (-0.08 MPa) to remove toluene until no obvious liquid flows out, add 100 ml of acetone, cool to 0-5 ° C crystallization for 2 hours, centrifuge at 60 ° C vacuum (-0.08 MPa) and dry to obtain 35.6 g of white solid (Formula I compound), the yield is 75.99%, and the HPLC purity is 98.872% (HPLC normalization method, Figure 3 ).

[0049] ESI-MS (m / z): 268.2043 [M+H] + .

[0050] 1 H-NMR (D2O, 400 MHz): 7.96 (d, 1H), 7.63 (m, 1H), 7.54 (m, 1H), 7.30-7.38 (m, 6H), 5.41 (s, 1H), 3.72 (t, 2H), 3.47 (s, 3H), 3.39 (t, 2H). Example 2: Preparation of the compound of formula I

[0051] Step 1: 100g of o-benzoylbenzoic acid (SM1) and 24.27g of phosphorus trichloride are reacted in the presence of 400ml of dichloromethane solvent at a reaction temperature of 25-35°C, stirred for 6h, and the supernatant is separated to obtain acyl chloride liquid A; acyl chloride liquid A is subjected to amination reaction with 36.52g of N-methylethanolamine and 49.20g of triethylamine at a reaction temperature of 20-30°C for 6 hours, the reaction solution is washed once with 400ml of water, and the organic phase is concentrated under vacuum conditions at 40°C (-0.08MPa) until no obvious liquid flows out to obtain 73.0g of an off-white solid with a yield of 63.04% and an HPLC purity of 92.411% (HPLC normalization method).

[0052] Step 2: First, add 75.0g of intermediate 1 and 225ml of tetrahydrofuran solution to the reaction bottle, stir at 25-35°C, and then add 11.02g of sodium borohydride (slowly added twice) for reduction. After reacting for 2 hours, slowly add 200ml of ice water to quench the reaction. Let stand for 30min, separate and collect the organic phase, wash it once with 200ml of water, and concentrate the organic phase under 40°C vacuum conditions (-0.08MPa) until no obvious liquid flows out, to obtain 50g of off-white solid (intermediate 2), the yield is 66.20%, and the HPLC purity is 93.558% (HPLC normalization method).

[0053] Step 3: First, add 250 ml of toluene solution, 50 g of intermediate 2 and 36.67 g of p-toluenesulfonic acid monohydrate into the reaction bottle, heat to 105-110 ° C, reflux and separate water for 4 hours, wash once with 150 ml of 20% sodium hydroxide solution after the reaction is completed, separate and collect the organic phase, and then wash twice with 150 ml of water. The organic phase is concentrated under 80 ° C vacuum conditions (-0.08 MPa) to remove toluene until no obvious liquid flows out, add 100 ml of acetone, cool to 0-5 ° C for crystallization for 2 hours, centrifuge at 60 ° C vacuum (-0.08 MPa) and dry to obtain 29.7 g of a white solid (compound of formula I), with a yield of 63.39% and an HPLC purity of 95.352% (HPLC normalization method).

[0054] See implementation case 1 for mass spectrometry and NMR data.

[0055] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. An impurity of nefopam hydrochloride, the structural formula of which is as follows:

2. A method for preparing an impurity of Nefopam hydrochloride according to claim 1, characterized in that The following steps are used to prepare it, and the synthetic route is as follows: Step 1: Acid chloride reaction and amination reaction The o-benzoylbenzoic acid (SM1) and the acyl chloride reagent are stirred and reacted in the presence of a solvent, and the supernatant is separated to obtain acyl chloride liquid A. The acyl chloride liquid A is stirred and mixed with an aminating agent (N-methylethanolamine) and a catalyst (triethylamine) to carry out an amination reaction, and the mixture is washed with water and concentrated to obtain an intermediate 1. Step 2: Reduction reaction First, add intermediate 1 and reaction solvent into a reaction vessel, stir, and then add reducing agent in small amounts for multiple times for reduction. After the reaction is completed, add ice water dropwise to quench the reaction. Stand and separate, collect the organic phase, wash with water, and concentrate to obtain intermediate 2. Step 3: Cyclization reaction First, add the reaction solvent, intermediate 2 and cyclizing agent into the reaction container, raise the temperature to reflux and separate the water, wash once with 20% sodium hydroxide solution and wash twice with water after the reaction is completed, concentrate to remove toluene, add acetone, cool to 0-5°C for crystallization, and centrifuge and dry to obtain the compound of formula I.

3. The method for preparing impurities of Nefopam hydrochloride according to claim 2, characterized in that: The acyl chloride reagent in step 1 is one of phosphorus trichloride, thionyl chloride, phosgene, solid phosgene or phosphorus pentachloride. The reducing agent in step 2 is one of stannous chloride, lithium aluminum hydride, potassium borohydride and sodium borohydride. The cyclizing agent in step 3 is one of p-toluenesulfonic acid monohydrate and hydrobromic acid.

4. The method for preparing impurities of Nefopam hydrochloride according to claim 2, characterized in that The reaction solvent in step 1 is one of tetrahydrofuran and dichloromethane. The reaction solvent in step 2 is one of tetrahydrofuran, methanol and ethanol. The reaction solvent in step 3 is one of toluene, n-butanol and xylene.

5. The method for preparing impurities of Nefopam hydrochloride according to claim 2, characterized in that In step 1, the molar ratio of the raw material SM1: phosphorus trichloride: N-methylethanolamine: triethylamine is 1: 0.4-1: 1-1.6: 1-1.

6. In step 2, the molar ratio of the intermediate 1 to potassium borohydride is 1: 1-2. In step 3, the molar ratio of the intermediate 2 to p-toluenesulfonic acid monohydrate is 1: 1.1-2.

6. The method for preparing impurities of Nefopam hydrochloride according to claim 2, characterized in that The reaction time of the acyl chloride reaction in step 1 is not less than 3 hours, preferably 4-8 hours, and the reaction temperature is 25-35°C. The reaction time of the amination reaction is not less than 4 hours, preferably 6-10 hours, and the reaction temperature is 20-30°C. The reaction time of the reduction reaction in step 2 is not less than 1 hour, preferably 1-3 hours, and the reaction temperature is 25-35°C. The reaction time of the cyclization reaction in step 3 is not less than 4 hours, preferably 4-10 hours, and the reaction temperature is 105-110°C.

7. The method for preparing impurities of Nefopam hydrochloride according to claim 2, characterized in that The weight ratio of the raw material SM1 in step 1 to the volume ratio of the reaction solvent is 1:4-8. The weight ratio of the intermediate 1 in step 2 to the volume ratio of the reaction solvent is 1:3-6. The weight ratio of the intermediate 2 in step 3 to the volume ratio of the reaction solvent is 1:4-8.

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