A preparation method of verapamil hydrochloride

Abstract

The present invention discloses a preparation method of verapamil hydrochloride. The method comprises the following steps: reacting compound II with compound III under strong alkaline conditions to obtain verapamil IV, and regenerating verapamil IV by methylating the generated O-demethyl impurity and N-demethyl impurity by adding a methylation reagent, or acylating it by adding an acylating reagent, and the acylating impurity is easily removed in the subsequent preparation process. Either of the above two methods can obtain verapamil hydrochloride I with high purity and high yield.

Description

Technical Field

[0001] The present invention relates to the field of drug synthesis, and particularly to a preparation method of verapamil hydrochloride. Background Art

[0002] Verapamil hydrochloride belongs to arylalkylamine calcium channel antagonists. The original research company is Knoll, and it was launched in Germany in 1963 under the trade name Isoptin.

[0003] Verapamil hydrochloride is a commonly used drug for cardiovascular system diseases. Its main effects are to reduce the oxygen consumption of myocardial cells, lower the heart load, dilate blood vessels, and increase blood flow. Verapamil hydrochloride also has a certain blood pressure lowering effect, and its blood pressure lowering mechanism is to lower blood pressure by reducing peripheral resistance. In addition, verapamil has a good anti-arrhythmic effect, especially for supraventricular arrhythmias. It can delay conduction and play an anti-arrhythmic role. Verapamil hydrochloride can be used to treat angina pectoris, including variant angina pectoris, unstable angina pectoris, and chronic stable angina pectoris; it can be used in combination with digoxin to treat arrhythmias, especially suitable for arrhythmias of atrial fibrillation and atrial flutter; it can be used to prevent paroxysmal supraventricular tachycardia; due to its blood pressure lowering effect, it can also be used to treat hypertension. In short, verapamil is a commonly used drug in the cardiovascular system, with the effects of dilating blood vessels and increasing myocardial oxygen supply, and can be used to treat hypertension, angina pectoris, and arrhythmias.

[0004] Patents US3261859 and US4418017 reported the preparation method of verapamil. During the preparation of verapamil, a series of O-demethylated and N-demethylated verapamil derivatives will be produced. These impurities are not easily removed during the process, resulting in a relatively low purity of the obtained verapamil. It needs to be refined multiple times, which seriously affects the yield and increases the production cost.

[0005] Patent WO2016181292 reported a method for removing O-demethylated and N-demethylated verapamil derivatives. This patent acylates by adding acetic anhydride or acetyl chloride, and the acylates can be effectively removed during the subsequent salt formation process, thereby improving the yield.

[0006] Therefore, developing a process that can efficiently remove impurities of O-demethylated and N-demethylated verapamil derivatives is the key to improving the yield and reducing the cost, and is crucial for commercial production. Summary of the Invention

[0007] The object of the present invention is to provide a new method for preparing verapamil hydrochloride to overcome the defects existing in the prior art. The verapamil hydrochloride prepared by using this method has simple operation and good product quality, reduces the cost and is easy to realize commercial production.

[0008] The main technical solution of the present invention is as follows:

[0009] 1. A preparation method of verapamil hydrochloride I,

[0010]

[0011] The method comprises the following operations:

[0012] 1) Under strong alkaline conditions, compound II and compound III are coupled in an organic solvent to obtain verapamil IV, and then a methylation reagent is added continuously;

[0013] 2) Verapamil hydrochloride I is obtained under the action of isopropyl alcohol hydrochloride.

[0014] The preparation method of verapamil hydrochloride I described above is characterized in that: in step 1)

[0015] The strong base reagent used is potassium hydroxide or sodium amide, and sodium amide is preferably used.

[0016] The organic solvent used is toluene;

[0017] The reaction temperature is 80 - 120 °C, and 110 - 120 °C is preferably used;

[0018] The reaction time is 1 - 3 hours.

[0019] The preparation method of verapamil hydrochloride I described above is characterized in that: in step 1)

[0020] The methylation reagent used is dimethyl sulfate or methyl iodide, and dimethyl sulfate is preferably used;

[0021] The usage amount of the methylation reagent is 0.01 - 0.1 eq, and 0.03 - 0.06 eq is preferably used;

[0022] The reaction temperature is 10 - 70 °C, and 50 - 60 °C is preferably used;

[0023] The reaction time is 1 - 3 hours.

[0024] The preparation method of verapamil hydrochloride I described above is characterized in that: the reaction temperature used in step 2) is 0 - 40 °C, and 20 - 30 °C is preferably used.

[0025] Beneficial effects

[0026] 1. In the preparation method proposed by the invention, the key operation lies in the preparation of Compound IV. After the reaction between Compound II and Compound III is completed under the action of a strong base, by adding a methylation reagent such as dimethyl sulfate or methyl iodide, it reacts with the O-demethyl and N-demethyl verapamil derivatives impurities to regenerate verapamil IV;

[0027] In the prior art (WO2016181292), the O-demethyl and N-demethyl verapamil derivatives impurities are acylated by adding an acylating reagent such as acetic anhydride or acetyl chloride, and the acylates can be effectively removed during the subsequent salt formation process.

[0028] The present invention adopts a different design concept from the prior art (WO2016181292). Both of the above two methods can remove the demethyl impurities and reduce the number of purification steps, but the present invention has the remarkable effects of higher yield and cost reduction.

[0029] 2. Compared with the verapamil hydrochloride prepared by the prior art, the preparation method proposed by the present invention not only has high product quality and high yield, but also has simpler post-treatment and is suitable for commercial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 It is the HPLC chromatogram of verapamil hydrochloride in Example 1

[0031] Figure 2 It is the HPLC chromatogram of verapamil hydrochloride in Example 2

[0032] Figure 3 It is the HPLC chromatogram of verapamil hydrochloride in Comparative Example 1

[0033] Figure 4 It is the HPLC chromatogram of verapamil hydrochloride in Comparative Example 2 DETAILED DESCRIPTION OF THE INVENTION

[0034] The following provides a detailed description of the embodiments of the present invention. These embodiments are implemented on the premise of the technical solution of the present invention, and detailed implementation methods and specific operation processes are given. However, the protection scope of the present invention is not limited to the following embodiments.

[0035] Example 1

[0036] Preparation of Compound IV:

[0037]

[0038] At room temperature, compound III (109.6 g, 0.5 mol) was added to 200 mL of toluene. After stirring to dissolve, sodium amide (29.3 g, 0.75 mol) was added. The temperature was raised to 60 - 70 °C and stirring was continued for 0.5 h. Then the temperature was further raised to 110 - 120 °C, and compound II (135.9 g, 0.5 mol) was added to a 500 mL toluene solution. After the reaction was completed, the reaction mixture was cooled to 50 - 60 °C, dimethyl sulfate (3.2 g, 0.025 mol) was added, and stirring was continued for 2 h. Then the temperature was lowered to 20 - 30 °C, water was added, and the organic phase was separated by liquid separation. The organic phase was washed with a dilute acid solution and water to obtain a toluene solution of compound IV, which was directly used for the next reaction without separation.

[0039] Preparation of Compound I

[0040]

[0041] At room temperature, 4% hydrochloric acid (1000 ml) was added to the above toluene solution of compound IV, stirred well, separated by liquid separation, the aqueous phase was extracted with dichloromethane, concentrated, acetone was added, crystallization occurred, and after filtration and drying, 190.5 g of verapamil hydrochloride I was obtained, with a yield of 77.6% and an HPLC purity of 99.95%.

[0042] Example 2

[0043] Preparation of Compound IV:

[0044] At room temperature, compound III (109.6 g, 0.5 mol) was added to 200 mL of toluene. After stirring to dissolve, sodium amide (29.3 g, 0.75 mol) was added. The temperature was raised to 60 - 70 °C and stirring was continued for 0.5 h. Then the temperature was further raised to 110 - 120 °C, and compound II (135.9 g, 0.5 mol) was added to a 500 mL toluene solution. After the reaction was completed, the temperature was lowered to 20 - 30 °C, methyl iodide (3.5 g, 0.025 mol) was added, and stirring was continued for 2 h. Water was added, and the organic phase was separated by liquid separation. The organic phase was washed with a dilute acid solution and water to obtain a toluene solution of compound IV, which was directly used for the next reaction without separation.

[0045] Preparation of Compound I

[0046] At room temperature, 4% hydrochloric acid (1000 ml) was added to the above toluene solution of compound IV, stirred well, separated by liquid separation, the aqueous phase was extracted with dichloromethane, concentrated, acetone was added, crystallization occurred, and after filtration and drying, 179.3 g of verapamil hydrochloride I was obtained, with a yield of 73.0% and an HPLC purity of 99.85%.

[0047] In Comparative Example 1, an acylating agent was added

[0048] Preparation of Compound IV:

[0049] At room temperature, compound III (109.6 g, 0.5 mol) was added to 200 mL of toluene. After stirring to dissolve, sodium amide (29.3 g, 0.75 mol) was added. The temperature was raised to 60 - 70 °C and stirring was continued for 0.5 h. Then the temperature was further raised to 110 - 120 °C, and compound II (135.9 g, 0.5 mol) was added to a 500 ml toluene solution. After the reaction was completed, water was added. The organic phase was separated by liquid separation, washed with saturated brine, a small amount of solvent was distilled off to remove water, acetic anhydride (4.6 g, 0.05 mol) was added, and stirring was continued for 2 hours. The organic phase was washed with water to obtain a toluene solution of compound IV, which was directly used for the next reaction without separation.

[0050] Preparation of Compound I

[0051] At room temperature, 4% hydrochloric acid (1000 ml) was added to the above toluene solution of compound IV. After sufficient stirring, liquid separation was carried out. The aqueous phase was extracted with dichloromethane, concentrated, acetone was added, crystallization occurred, and after filtration and drying, 155.3 g of verapamil hydrochloride I was obtained, with a yield of 63.3% and an HPLC purity of 99.81%.

[0052] Comparative Example 2 Without Methylating Agent

[0053] Preparation of Compound IV:

[0054] At room temperature, compound III (109.6 g, 0.5 mol) was added to 200 mL of toluene. After stirring to dissolve, sodium amide (29.3 g, 0.75 mol) was added. The temperature was raised to 60 - 70 °C and stirring was continued for 0.5 h. Then the temperature was further raised to 110 - 120 °C, and compound II (135.9 g, 0.5 mol) was added to a 500 ml toluene solution. After the reaction was completed, the temperature was lowered to 20 - 30 °C, water was added. The organic phase was separated by liquid separation, washed with saturated brine to obtain a toluene solution of compound IV, which was directly used for the next reaction without separation.

[0055] Preparation of Compound I

[0056] At room temperature, 4% hydrochloric acid (1000 ml) was added to the above toluene solution of compound IV. After sufficient stirring, liquid separation was carried out. The aqueous phase was extracted with dichloromethane, concentrated, acetone was added, crystallization occurred, and after filtration and drying, 161.3 g of verapamil hydrochloride I was obtained, with a yield of 65.7% and an HPLC purity of 98.90% (lower than the specified 99.7% and requiring multiple refinements).

[0057] Compared with the method of adding methylating agents such as dimethyl sulfate or iodomethane, or acylating agents such as acetic anhydride or acetyl chloride, the purity of the product obtained by the method without adding the above reagents is significantly reduced, and further purification is required. To obtain a product that meets the quality standards, a large amount of yield needs to be sacrificed, thus significantly increasing the cost.

Claims

1. A preparation method of verapamil hydrochloride I: The method comprises: a. Under strong alkaline conditions, coupling the compound II with the compound III in an organic solvent: Thereby obtaining verapamil IV, adding a methylation reagent, and the methylation reagent is dimethyl sulfate or methyl iodide: b. Obtaining verapamil hydrochloride I from the compound IV under the action of hydrochloric acid:

2. The preparation method of verapamil hydrochloride I according to claim 1, characterized in that in the step a, the strong base reagent used is potassium hydroxide or sodium amide; the organic solvent used is toluene; the reaction temperature is 80 - 120 °C.

3. The preparation method of verapamil hydrochloride I according to claim 1, characterized in that in the step a, the usage amount of the methylation reagent is 0.01 - 0.1 eq; the reaction temperature is 10 - 70 °C.

4. For the preparation method of verapamil hydrochloride I according to claim 1, the use of the methylation reagent is to methylate the O-demethylated impurity and N-demethylated impurity generated in the step a to regenerate verapamil IV.

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