A kind of synthetic method of ranitidine hydrochloride impurity A

Abstract

The invention discloses a method for synthesizing a ranitidine hydrochloride impurity A. The method comprises taking 2-[(5-dimethylaminomethylfurfuryl]thioethylamine and 1,1-dimethylthio-2-nitroethyleneamine as raw materials, reacting in a solvent until no bubbles emerge, and purifying the mixture after the reaction to obtain the ranitidine hydrochloride impurity A. The invention discloses a method for synthesizing a ranitidine hydrochloride impurity A. The ranitidine hydrochloride impurity A is synthesized by taking 2-[(5-dimethylaminomethylfurfuryl]thioethylamine and 1,1-dimethylthio-2-nitroethyleneamine as raw materials. The synthetic conditions are mild and controllable, the operation is simple and convenient, and the ranitidine hydrochloride impurity A is suitable for industrial production. The synthesized ranitidine hydrochloride impurity A has a high yield and excellent purity, can meet the need of being used as an impurity control, and fills the gap of the industry in lacking impurity standard products for finished product detection.

Description

Technical Field

[0001] The invention relates to the technical field of organic chemical synthesis, and in particular to a method for synthesizing impurity A of ranitidine hydrochloride. Background Art

[0002] Ranitidine hydrochloride is an H2 receptor antagonist with wide clinical application and good efficacy. It can inhibit basal gastric acid secretion and gastric acid secretion after stimulation, and can also inhibit the secretion of pepsin. It is mainly used to treat benign gastric ulcer, duodenal ulcer, postoperative ulcer, reflux esophagitis, Zollinger-Ellison syndrome, etc.

[0003] As a clinical drug, ranitidine hydrochloride has strict requirements on the content control of impurities. Among them, ranitidine hydrochloride impurity A is one of the impurities of ranitidine hydrochloride, and its chemical name is: N,N'-bis[2-[[[5-[(dimethylamino)methyl]furan-2-]methyl]thio]ethyl]-2-nitroethylene-1,1-diamine.

[0004] Currently, the industry is still blank in the synthesis of impurity A in ranitidine hydrochloride. There is a lack of impurity standards for finished product testing, and its chromatographic characteristics cannot be effectively determined. As a result, ranitidine hydrochloride cannot be distinguished from other impurities during impurity identification, and its content cannot be determined. Summary of the invention

[0005] The present invention provides a method for synthesizing ranitidine hydrochloride impurity A, thereby solving the problem in the prior art that the ranitidine hydrochloride impurity A in ranitidine hydrochloride cannot be effectively identified by liquid chromatography and its content cannot be confirmed.

[0006] In order to solve the above technical problems, the present invention provides a method for synthesizing impurity A of ranitidine hydrochloride, and the reaction process is as follows:

[0007]

[0008] In a preferred embodiment of the present invention, 2-[(5-dimethylaminomethylfurfuryl]thioethylamine and 1,1-dimethylthio-2-nitroethyleneamine are used as raw materials, reacted in a solvent until no bubbles emerge, and purified after the reaction to obtain the ranitidine hydrochloride impurity A.

[0009] In a preferred embodiment of the present invention, the mass ratio of the 2-[(5-dimethylaminomethylfurfuryl]thioethylamine to 1,1-dimethylthio-2-nitroethyleneamine is 2 to 3:1.

[0010] In a preferred embodiment of the present invention, the reaction conditions are: temperature 45-50° C., time 4-8 h.

[0011] In a preferred embodiment of the present invention, the purification method is:

[0012] The reaction solution was allowed to stand for stratification, the lower layer of oil was taken out, washed, and its pH value was adjusted to acidic;

[0013] Washing the lower layer of oil with an organic solvent;

[0014] The mixture was allowed to stand for separation, and the pH value of the water layer was adjusted to be alkaline. The lower layer of oil was taken and dissolved with an organic solvent, washed, and the organic layer was collected, dried to remove water, filtered to remove salt, and distilled under reduced pressure to obtain the ranitidine hydrochloride impurity A.

[0015] In a preferred embodiment of the present invention, the acidic pH value is 2-4.

[0016] In a preferred embodiment of the present invention, the alkaline pH value is 10-11.

[0017] In a preferred embodiment of the present invention, the drying and dehydration method is drying with anhydrous sodium sulfate for 2 to 3 hours.

[0018] The invention has the beneficial effects of: a method for synthesizing impurity A of ranitidine hydrochloride, which is synthesized by taking 2-[(5-dimethylaminomethylfurfuryl]thioethylamine and 1,1-dimethylthio-2-nitroethyleneamine as raw materials, and the synthesis conditions are mild and controllable, the operation is simple, and the impurity A is suitable for industrial production; the synthesized impurity A of ranitidine hydrochloride has a high yield and excellent purity, can meet the needs of being used as an impurity control, and fills the gap of the industry in lacking impurity standard products for finished product detection. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is a liquid chromatogram of the ranitidine hydrochloride impurity A prepared in a preferred embodiment 1 of a method for synthesizing the ranitidine hydrochloride impurity A of the present invention;

[0020] Figure 2 This is the liquid chromatogram of ranitidine hydrochloride. DETAILED DESCRIPTION

[0021] The preferred embodiments of the present invention are described in detail below in conjunction with the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0022] The invention discloses a method for synthesizing a ranitidine hydrochloride impurity A. The method comprises taking 2-[(5-dimethylaminomethylfurfuryl]thioethylamine (aminoethyl sulfide) and 1,1-dimethylthio-2-nitroethyleneamine (intermediate side two) as raw materials, reacting them in a mass ratio of 2-3:1 in solvent purified water at 45-50° C. for 4-8 hours until no bubbles emerge, and purifying the mixture after the reaction to obtain the ranitidine hydrochloride impurity A.

[0023] Specifically, the purification method is:

[0024] The reaction solution was allowed to stand for stratification, the lower layer of oil was taken out, washed, and its pH value was adjusted to an acidic 2 to 4;

[0025] Washing the lower layer of oil with an organic solvent;

[0026] The mixture was allowed to stand for stratification, and the pH value of the aqueous layer was adjusted to alkaline 10-11. The lower layer of oil was taken and dissolved with an organic solvent of dichloromethane, and washed with purified water. The organic layer was collected and dried with anhydrous sodium sulfate for 2-3 hours to remove water, and the sodium sulfate was filtered out. The obtained solution was rotary evaporated with hot water at 45-50° C., and dichloromethane was removed under reduced pressure until no liquid was distilled out. The obtained oil was the ranitidine hydrochloride impurity A.

[0027] Example 1

[0028] Take 58g of aminoethyl sulfide, 10g of intermediate side II and 60g of purified water, put them into a three-necked reaction bottle, control the temperature of the reaction liquid to 50°C under stirring, and keep this temperature for 6 hours until no bubbles are generated in the tail gas, and the reaction is completed. The generated methyl mercaptan tail gas is sucked out by negative pressure, and is discharged after being absorbed by a two-stage liquid sodium hydroxide solution with a mass concentration of 20%.

[0029] After the reaction is completed, the reaction solution is cooled to about 25°C, separated into layers through a separatory funnel, and the lower layer of oil is separated. The separated lower layer of oil is washed with 2×60g of purified water, and the washed lower layer of oil is collected, 60g of purified water is added thereto, and then hydrochloric acid with a mass concentration of 10% is added, stirred, and the pH value is adjusted to 2-4, preferably 3.

[0030] The acidic aqueous solution was washed twice with 2×50g of dichloromethane. The water layer was then stirred and neutralized with a sodium hydroxide solution having a mass concentration of 10%, and the pH value was adjusted to 10-11. The lower layer of oil was separated, and the oil was dissolved with 100g of dichloromethane. The dichloromethane layer was washed twice with 2×50g of purified water, and the dichloromethane layer was collected. The dichloromethane layer was dried with 10g of anhydrous sodium sulfate for 2 hours, and the salt was filtered to remove the salt. The liquid dichloromethane was removed by rotary evaporation under reduced pressure with 50°C hot water until no liquid was distilled out. The oil collected in the rotary flask was ranitidine impurity A, and 58g was obtained, with a yield of 85%.

[0031] Liquid chromatography analysis:

[0032] Chromatographic conditions: octadecylsilane bonded silica gel is used as filler (Kromasil C18, 4.6mm×150mm, 5μm or chromatographic column with equivalent performance); phosphate buffer (take 6.8ml of phosphoric acid and put it in 1900ml of water, add 8.6ml of 50% sodium hydroxide solution, add water to 2000ml, and adjust the pH value to 7.1±0.05 with phosphoric acid or 50% sodium hydroxide solution)-acetonitrile (98:2) is used as mobile phase A, and phosphate buffer-acetonitrile (78:22) is used as mobile phase B; gradient elution is performed according to Table 1 below; the flow rate is 1.5ml per minute; the column temperature is 35℃; the detection wavelength is 230nm; the injection volume is 10μl.

[0033] Table 1

[0034] Time (minutes) Mobile phase A (%) Mobile phase B (%) 0 100 0 15 0 100 23 0 100 24 100 0 30 100 0

[0035] Take appropriate amounts of ranitidine hydrochloride and ranitidine hydrochloride impurity A, dilute with water to prepare 1 mg / ml solutions respectively, inject according to the above chromatographic conditions and record the chromatograms.

[0036] The chromatogram of impurity A of ranitidine hydrochloride is shown in the attached figure. Figure 1 As shown, the main peak is Ranitidine hydrochloride impurity A, and the purity according to the area normalization method is about 91%, which can meet the needs of being used as an impurity control. Its peak area value is shown in Table 2 below.

[0037] Table 2

[0038]

[0039] The liquid chromatogram of ranitidine hydrochloride is shown in the attached figure. Figure 2 As shown, the main peak is ranitidine hydrochloride, and the impurity around 17 minutes should be ranitidine hydrochloride impurity A. The peak area data are as follows

[0040] As shown in Table 3.

[0041]

[0042] The above descriptions are merely embodiments of the present invention and are not intended to limit the patent scope of the present invention. Any equivalent structure or equivalent process transformation made using the contents of the present invention specification and drawings, or directly or indirectly applied in other related technical fields, are also included in the patent protection scope of the present invention.

Claims

1. A method for synthesizing impurity A of ranitidine hydrochloride, characterized in that: The reaction process is as follows:

2. A method for synthesizing ranitidine hydrochloride impurity A according to claim 1, characterized in that: Using 2-[(5-dimethylaminomethylfurfuryl]thioethylamine and 1,1-dimethylthio-2-nitroethyleneamine as raw materials, reacting in a solvent until no bubbles emerge, and purifying after the reaction to obtain the ranitidine hydrochloride impurity A.

3. A method for synthesizing ranitidine hydrochloride impurity A according to claim 2, characterized in that: The mass ratio of the 2-[(5-dimethylaminomethylfurfuryl]thioethylamine to 1,1-dimethylthio-2-nitroethyleneamine is 2 to 3:

1.

4. A method for synthesizing ranitidine hydrochloride impurity A according to claim 2, characterized in that: The reaction conditions are: temperature 45-50°C, time 4-8h.

5. A method for synthesizing ranitidine hydrochloride impurity A according to claim 2, characterized in that: The purification method is: The reaction solution was allowed to stand for stratification, the lower layer of oil was taken out, washed, and its pH value was adjusted to acidic; Washing the lower layer of oil with an organic solvent; The mixture was allowed to stand for separation, and the pH value of the water layer was adjusted to be alkaline. The lower layer of oil was taken and dissolved with an organic solvent, washed, and the organic layer was collected, dried to remove water, filtered to remove salt, and distilled under reduced pressure to obtain the ranitidine hydrochloride impurity A.

6. The method for synthesizing the impurity A of ranitidine hydrochloride according to claim 5, characterized in that: The acidic pH value is 2-4.

7. The method for synthesizing the impurity A of ranitidine hydrochloride according to claim 5, characterized in that: The alkaline pH value is 10-11.

8. The method for synthesizing the impurity A of ranitidine hydrochloride according to claim 5, characterized in that: The drying and dehydration method is to dry with anhydrous sodium sulfate for 2 to 3 hours.

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