Procaterol hydrochloride nitrosamine impurity as well as preparation method and application thereof

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a procaterol hydrochloride nitrosamine synthesis method and application, and the procaterol hydrochloride nitrosamine impurity synthesis method comprises the following process steps: procaterol hydrochloride, sodium nitrite and acid are subjected to a reaction in a first solvent to generate a procaterol hydrochloride nitrosamine impurity, the procaterol hydrochloride nitrosamine impurity obtained in the invention can be used as a standard substance for detecting the content of the nitrosamine impurity in procaterol hydrochloride granules, and has a high application value.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis, and particularly relates to a procaterol nitrosamine hydrochloride impurity and a preparation method and application thereof. Background Art

[0002] Procaterol hydrochloride is an adrenergic β2 receptor agonist developed by Otsuka Pharmaceutical Co., Ltd. It is highly selective for bronchial β2 receptors and has a strong and lasting bronchodilator effect. It also has multiple mechanisms of action, such as anti-inflammatory and anti-allergic, antitussive, and promotion of ciliary beating, which can comprehensively relieve the symptoms of cough, sputum, and wheezing. It is suitable for common respiratory diseases such as asthma, chronic cough, cough variant asthma, chronic obstructive pulmonary disease, and respiratory infections with increased bronchial reactivity. Since the tablet was launched in Japan in December 1980, it has been available in a variety of dosage forms, including tablets, oral solutions, syrups, dry syrups, granules, inhalation powder sprays, inhalation aerosols, and inhalation solutions.

[0003] Nitrosamine compounds are highly potent genotoxic agents in several animals, and some are classified as possible human carcinogens by the International Agency for Research on Cancer (IARC). They are referred to as "cohort of concern" compounds in the ICH Industry Guideline M7 (R1) "Evaluation and Control of DNA-Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk" (March 2018). In recent years, the international drug regulatory agency FDA has issued the "Control of Nitrosamine Impurities in Human Drugs", which clarifies the causes of nitrosamine production and control strategies. EMA has issued the "Classification Method for the Carcinogenic Potency of N-Nitrosamines", which clarifies the basis for the carcinogenic classification of nitrosamines and the limit requirements. Therefore, quality control of nitrosamine impurities in drugs is the key to ensuring the safety and effectiveness of drugs. The chemical structure of Procaterol hydrochloride contains a secondary amine structure, and the excipients of the preparation may introduce the risk of nitrite and nitrite (such as microcrystalline cellulose, etc.), which meets the conditions for the production of nitrosamines and has the risk of producing nitrosamine impurities. It is necessary to increase the study of nitrosamine impurities in Procaterol hydrochloride preparations.

[0004] Therefore, in the review of new drugs for Procaterol hydrochloride, the monitoring requirements for nitrosamine impurities in Procaterol hydrochloride are also clearly put forward.

[0005] The impurity of Procaterol nitrosamine hydrochloride represented by formula (I) of the present invention and its synthesis method have not been reported.

[0006] After evaluation, the nitrosamine impurities in the Procaterol hydrochloride of the present invention are produced by the reaction of Procaterol hydrochloride with the impurity sodium nitrite introduced as an excipient. The presence of nitrosamine impurities will increase the toxic side effects of Procaterol hydrochloride, and long-term use will increase the carcinogenicity rate. Since 2018, several drugs including angiotensin II receptor blockers (ARBs), ranitidine, nizatidine and metformin have been found to contain unacceptable levels of nitrosamines.

[0007] Therefore, the nitrosamine impurities in Procaterol hydrochloride and the synthesis method thereof of the present invention are provided to provide a cheap and readily available reference substance for the quality control of various dosage forms of Procaterol hydrochloride, and to provide important guidance for safe drug use. Summary of the invention

[0008] Aiming at the problem that there is no corresponding standard product for nitrosamine impurities in existing Procaterol hydrochloride preparations, the present invention provides a synthesis method and application of Procaterol nitrosamine impurities.

[0009] In order to achieve the above-mentioned purpose of the present invention, the following technical scheme is adopted:

[0010] The first object of the present invention is to provide a nitrosamine impurity compound of Procaterol hydrochloride, wherein the nitrosamine impurity compound is N-((1R, 2S)-1-hydroxy-1-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)butane-2-yl)-N-isopropylnitrosamide, and the structural formula is shown in formula (I):

[0011]

[0012] The second object of the present invention is to provide a method for preparing the aforementioned nitrosamine impurity compound, comprising the following steps:

[0013] Procaterol hydrochloride is taken as a raw material, and water, nitrite and acid are added to react to obtain the nitrosamine impurity compound of Procaterol hydrochloride represented by formula (I).

[0014] The structural formula of Procaterol hydrochloride is:

[0015] Furthermore, the nitrite is sodium nitrite or potassium nitrite.

[0016] Furthermore, the acid is hydrochloric acid or phosphoric acid.

[0017] Furthermore, the mass percentage concentration of the acid is no more than 40%.

[0018] Furthermore, the molar ratio of the raw material to the nitrite is 1:0.5-1:1.5; the molar ratio of the raw material to the acid is 1:30.0-1:100.0.

[0019] Furthermore, the reaction temperature is 20-30°C.

[0020] Furthermore, the reaction time is 10-16 hours.

[0021] The third object of the present invention is to provide the use of the aforementioned nitrosamine impurity compound of Procaterol hydrochloride as an impurity reference substance in the quality control of Procaterol hydrochloride.

[0022] Beneficial effects of the technical solution of the present invention

[0023] The present invention provides a method for synthesizing the nitrosamine impurity of Procaterol hydrochloride, wherein Procaterol hydrochloride and sodium nitrite are reacted under the action of hydrochloric acid or phosphoric acid to generate the nitrosamine impurity of Procaterol hydrochloride. Currently, there is no other report on the synthesis of the nitrosamine impurity of Procaterol hydrochloride. The synthesis method has high reaction selectivity and simple operation. The synthesis method of the present invention can finally obtain the nitrosamine impurity of Procaterol hydrochloride with a purity of more than 95% and high quality. The obtained product can be directly used as an impurity reference substance for monitoring the content of nitrosamine impurities in Procaterol hydrochloride preparations, and has high application value. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 , hydrogen spectrum of nitrosamine impurities in Procaterol hydrochloride;

[0025] Figure 2 , mass spectrum of nitrosamine impurities in Procaterol hydrochloride;

[0026] Figure 3 , HPLC chart of nitrosamine impurities of Procaterol hydrochloride;

[0027] Figure 4 , 1 .0eq sodium nitrite in central control HPLC;

[0028] Figure 5 , in-process control mass spectrometry of nitrosamine impurities in Procaterol hydrochloride;

[0029] Figure 6 , 10 eq sodium nitrite reaction control HPLC chart;

[0030] Figure 7 , mass spectrum of nitrosation of Procaterol hydrochloride;

[0031] Figure 8 , 42.5% phosphoric acid reaction control HPLC;

[0032] Fig. 9 , HPLC and mass spectrometry of the reaction with ethyl acetate as solvent;

[0033] Fig.10 , two HPLC and mass spectrometry of the reaction with methyl chloride as solvent;

[0034] Fig.11 , Four HPLC and mass spectrometry of the reaction with hydrofuran as solvent;

[0035] Fig.12 , reaction control HPLC and mass spectrometry of the acetic acid treatment group;

[0036] Fig.13 , reaction control HPLC and mass spectrum of the 50℃ reaction group. DETAILED DESCRIPTION

[0037] The present invention is further explained below with reference to the examples, but the examples do not limit the present invention in any form.

[0038] Example 1

[0039] Preparation of Procaterol Nitrosamine Hydrochloride:

[0040]

[0041] 500 mg of Procaterol hydrochloride (1.0 eq), 105 mg of sodium nitrite (1.0 eq) and 50 mL of 1 mol / L (3% w / w, 33.3 eq) hydrochloric acid aqueous solution were added to the reaction bottle and kept at 28°C for 15 h. The raw material was detected by HPLC until <5.0% (HPLC chart is shown in Figure 4 , mass spectrum see Figure 5 ), after the reaction was completed, 300 mg of brown-red solid was directly purified by column, i.e., the product containing the nitrosamine impurity compound of Procaterol hydrochloride represented by formula (I) with a purity of more than 95% (HPLC chart see Figure 3 ), yield 63.58%, MS (m / z): 320 [M+H] + (Mass spectrum see Figure 2 ), 1 H-NMR (400MHz, DMSO) δ10.46 (s, 1H), δ8.36 (s, 1H), δ7.85-7.82 (d, J = 12.0Hz, 1H), δ6.69-6.62 (m, 2H ), δ5.04(s,1H), δ3.06(s,1H), δ1.64(s,1H), δ1.44(s,1H), δ1.26-1.20(m,6H), δ0.71(s,3H), (See the hydrogen spectrum Figure 1 ).

[0042] Example 2

[0043] Preparation of Procaterol Nitrosamine Hydrochloride:

[0044] 600 mg of Procaterol hydrochloride (1.0 eq), 126 mg of sodium nitrite (1.0 eq) and 60 mL of 28.3% phosphoric acid aqueous solution (96.25 eq) were added to a reaction bottle, and the mixture was kept at 21° C. for 15 h. After the reaction was completed, 420 mg of a brown-red solid was directly purified by column purification, i.e., a product containing nitrosamine impurity compounds of Procaterol hydrochloride represented by formula (I), with a purity of more than 95% and a yield of 73.68%.

[0045] Comparative Example 1

[0046] Preparation of Procaterol Nitrosamine Hydrochloride:

[0047] 500 mg of Procaterol hydrochloride (1.0 eq), 105 mg of sodium nitrite (1.0 eq) and 33.6 mL of 42.5% phosphoric acid aqueous solution (96.25 eq) were added to a reaction bottle, and the mixture was kept at 21° C. for 15 h. After the reaction was completed, the mixture was directly purified by column to obtain 180 mg of a brown-red solid, i.e., a product containing a nitrosamine impurity compound of Procaterol hydrochloride represented by formula (I), with a purity of more than 95%, but the yield was reduced to 38.89%.

[0048] It can be seen that when the phosphoric acid feed concentration is greater than 40%, the amount of nitrosamine produced by Procaterol hydrochloride decreases, while the amount of oxidized impurities in Procaterol hydrochloride increases (see HPLC chart). Figure 8 ).

[0049] Comparative Example 2

[0050] Preparation of Procaterol Nitrosamine Hydrochloride:

[0051] 20 mg of Procaterol hydrochloride (1.0 eq), 70 mg of sodium nitrite (1.7 eq) and 2 mL of 1 mol / L hydrochloric acid aqueous solution (33.3 eq) were added to a reaction flask, and the mixture was kept at 28° C. for 15 h. HPLC detection was performed until the raw material content was <5.0%. After the reaction was completed, the mixture was directly purified by column to obtain 10 mg of a brown-red solid with a yield of 53.7%.

[0052] It can be seen that when the equivalent amount of sodium nitrite added increases, the nitration impurities of Procaterol hydrochloride increase, while the nitrosamine impurities of Procaterol hydrochloride decrease.

[0053] Comparative Example 3

[0054] Preparation of Procaterol Nitrosamine Hydrochloride:

[0055] 20 mg of Procaterol hydrochloride (1.0 eq), 85 mg of sodium nitrite (1.0 eq), 2 mL of 1 mol / L hydrochloric acid (33.3 eq) and ethyl acetate were added to a reaction flask and kept at 28°C for 15 h. HPLC detection was performed until the raw material was less than 5.0%, and no nitrosamine impurity of Procaterol hydrochloride was generated at the end of the reaction. (HPLC chart and mass spectrum are shown in Fig. 9 ).

[0056] It can be seen that when the solvent is changed to ethyl acetate, the nitrosamine impurity of Procaterol hydrochloride cannot be generated.

[0057] Comparative Example 4

[0058] Compared with Comparative Example 3, except that the solvent was replaced with dichloromethane, the rest was the same.

[0059] The results also showed that when the solvent was changed to dichloromethane, the impurity of Procaterol nitrosamine hydrochloride could not be generated. (HPLC chart and mass spectrum see Fig.10 ).

[0060] Comparative Example 5

[0061] Compared with Comparative Example 3, except that the solvent was replaced with tetrahydrofuran, the rest was the same.

[0062] The results also showed that when the solvent was changed to tetrahydrofuran, no nitrosamine hydrochloride impurity of Procaterol could be generated. (HPLC chart and mass spectrum see Fig.11 ).

[0063] Comparative Example 6

[0064] 20 mg of Procaterol hydrochloride (1.0 eq), 70 mg of sodium nitrite (1.0 eq) and 1.2 mL of 10.0% acetic acid (33.3 eq) or 0.9 mL of 10% formic acid aqueous solution (33.3 eq) were added to a reaction bottle, and the mixture was kept at 28° C. for 15 h. HPLC detection was performed until the raw material content was <5.0%, and no nitrosamine impurity of Procaterol hydrochloride was generated at the end of the reaction.

[0065] The results showed that when the acid type was changed, the nitrosamine impurity of Procaterol hydrochloride could not be generated. (HPLC chart and mass spectrum of the acetic acid treatment group are shown in Fig.12 ).

[0066] Comparative Example 7

[0067] 20 mg of Procaterol hydrochloride (1.0 eq), 70 mg of sodium nitrite (1.0 eq) and 2 mL of 1 mol / L hydrochloric acid aqueous solution (33.3 eq) were added to a reaction flask, and the mixture was kept at 50° C. for 15 h. HPLC detection was performed until the raw material content was <5.0%. After the reaction was completed, the mixture was directly purified by column to obtain 5 mg of a brown-red solid with a yield of 26.8%.

[0068] It can be seen that when the reaction temperature increases, the amount of impurity 3 in Procaterol hydrochloride increases, while the amount of nitrosamine impurity in Procaterol hydrochloride decreases (see HPLC graph and mass spectrum). Fig.13 ).

[0069] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A nitrosamine impurity compound of Procaterol hydrochloride, characterized in that: The nitrosamine impurity compound is N-((1R, 2S)-1-hydroxy-1-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)butane-2-yl)-N-isopropylnitrosoamide, the structural formula is shown in formula (I):

2. The method for preparing the nitrosamine impurity compound according to claim 1, characterized in that: The steps include: Procaterol hydrochloride is taken as a raw material, and water, nitrite and acid are added to react to obtain the nitrosamine impurity compound of Procaterol hydrochloride represented by formula (I).

3. The method for preparing the nitrosamine impurity compound according to claim 2, characterized in that: The nitrite is sodium nitrite or potassium nitrite.

4. The method for preparing the nitrosamine impurity compound according to claim 2, characterized in that: The acid is hydrochloric acid or phosphoric acid.

5. The method for preparing the nitrosamine impurity compound according to claim 2, characterized in that: The mass percentage concentration of the acid is no more than 40%.

6. The method for preparing the nitrosamine impurity compound according to claim 2, characterized in that: The molar ratio of the raw material to the nitrite is 1:0.5-1:1.5; the molar ratio of the raw material to the acid is 1:30.0-1:100.

0.

7. The method for preparing the nitrosamine impurity compound according to claim 2, characterized in that: The reaction temperature is 20-30°C.

8. The method for preparing the nitrosamine impurity compound according to claim 2, characterized in that: The reaction time is 10-16h.

9. Use of the nitrosamine impurity compound of Procaterol hydrochloride according to claim 1 as an impurity reference substance in the quality control of Procaterol hydrochloride.

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