阅读说明：本技术 一种樟脑化合物及其制备方法 (Camphor compound and preparation method thereof ) 是由 胡成忠 乐惠军 干志华 于 2020-11-27 设计创作，主要内容包括：本发明涉及一种樟脑化合物及其制备方法。所述的樟脑化合物为晶体,采用X-射线粉末衍射测定,其图谱中特征峰在2θ±0.2°为6.9°、8.1°、9.2°、10.2°、11.6°、13.8°、14.3°、15.4°、18.0°、18.8°、21.2°、23.2°、24.3°、25.0°、34.6°显示。本发明制备的樟脑化合物纯度高、引湿性低、溶解性好、稳定性好。(The invention relates to a camphor compound and a preparation method thereof. The camphor compound is a crystal, and characteristic peaks in a map of the camphor compound are shown at 6.9 degrees, 8.1 degrees, 9.2 degrees, 10.2 degrees, 11.6 degrees, 13.8 degrees, 14.3 degrees, 15.4 degrees, 18.0 degrees, 18.8 degrees, 21.2 degrees, 23.2 degrees, 24.3 degrees, 25.0 degrees and 34.6 degrees at 2 theta +/-0.2 degrees by adopting X-ray powder diffraction measurement. The camphor compound prepared by the invention has high purity, low hygroscopicity, good solubility and good stability.)

1. A camphor compound characterized by: the camphor compound is a crystal, and characteristic peaks in a map of the camphor compound are shown at 6.9 degrees, 8.1 degrees, 9.2 degrees, 10.2 degrees, 11.6 degrees, 13.8 degrees, 14.3 degrees, 15.4 degrees, 18.0 degrees, 18.8 degrees, 21.2 degrees, 23.2 degrees, 24.3 degrees, 25.0 degrees and 34.6 degrees at 2 theta +/-0.2 degrees by adopting X-ray powder diffraction measurement.

2. The camphor compound of claim 1 wherein: the melting point of the camphor compound is 182-185 ℃.

3. A process for preparing the camphor compound as claimed in claim 1 or 2, comprising the steps of:

(1) dissolving camphor raw material in a mixed solution of trichloromethane and ethanol with a volume ratio of 1: 9; the dosage ratio of the camphor raw material to the mixed solution of the trichloromethane and the ethanol is 1g:5 ml;

(2) keeping the temperature of the solution in the step (1) at 20-25 ℃, adding purified water with the volume 8 times that of the mixed solution of the trichloromethane and the ethanol in the step (1) into the solution in the step (1) at the speed of 120-140 ml/min while stirring at the stirring speed of 110-130 r/min, stopping stirring after the purified water is added, cooling to-2-4 ℃ at the speed of 1.0-1.2 ℃/min, standing for crystal growth for 3 hours, and filtering to obtain a filter cake;

(3) and (3) washing the filter cake obtained by filtering in the step (2) with 2 times of purified water for 1 time, and drying for 10 hours at the temperature of 22-24 ℃ under reduced pressure to obtain the camphor compound.

Technical Field

The invention belongs to the technical field of medicines, and relates to a camphor compound and a preparation method thereof.

Background

Camphor: chemical name: (1 RS, 4 RS) -1, 7, 7-trimethylbicyclo [2.2.1] heptan-2-one, a potent histamine H2 receptor antagonist. Has camphorwood smell and wide application. The camphor is used as a nerve stimulant and a local stimulant in medicine, and can be used in medicaments for cooling and cooling, such as ten drops of water, minium and the like; it can also be used for preparing food essence such as herba Menthae, fructus Citri Limoniae, and nut, and daily essence such as floral water and daily cosmetics. In addition, camphor is widely used in celluloid and photographic films, as a stabilizer for manufacturing smokeless powder, as a raw material for manufacturing sodium camphorsulfonate, and the like, and pharmaceutical preparations using camphor as a raw material are widely used in the technical field of medicine.

The camphor is extremely unstable when being heated and wetted, the quality of a preparation product is seriously influenced due to the reasons of agglomeration, poor stability and the like caused by the fact that raw material medicines easily absorb moisture, meanwhile, the dissolubility is poor, the difficulty is increased for the production of the preparation, meanwhile, certain risks are caused for the medication safety, and the research on the application of a more stable camphor compound to the camphor has a positive effect because the camphor is unstable and the camphor has a positive curative effect in clinical use. The inventor unexpectedly obtains a camphor compound in a crystal form in the process of a large amount of researches on camphor for a long time, and the compound has the advantages of extremely high quality stability, high purity, low hygroscopicity, good solubility, increased medication safety and preparation convenience, and is obviously superior to the prior art.

Disclosure of Invention

The present invention provides a stable camphor compound.

The camphor compound provided by the invention is a crystal, and the characteristic peaks in the map are shown at 6.9 degrees, 8.1 degrees, 9.2 degrees, 10.2 degrees, 11.6 degrees, 13.8 degrees, 14.3 degrees, 15.4 degrees, 18.0 degrees, 18.8 degrees, 21.2 degrees, 23.2 degrees, 24.3 degrees, 25.0 degrees and 34.6 degrees at 2 theta +/-0.2 degrees by adopting X-ray powder diffraction measurement.

The X-ray powder diffraction pattern of the camphor compound is shown in fig. 1.

The melting point of the camphor compound is 182-185 ℃.

The preparation method of the camphor compound comprises the following steps:

1. dissolving camphor raw material in mixed solution of trichloromethane and ethanol; wherein the volume ratio of the trichloromethane to the ethanol is 1: 9; the dosage ratio of the camphor raw material to the mixed solution of the trichloromethane and the ethanol is 1g to 5 ml.

2. Keeping the temperature of the solution at 20-25 ℃, adding purified water with the volume 8 times that of the mixed solution of the trichloromethane and the ethanol in the step 1 into the solution in the step 1 at the speed of 120-140 ml/min while stirring at the stirring speed of 110-130 r/min, stopping stirring after the purified water is added, cooling to-2-4 ℃ at the speed of 1.0-1.2 ℃/min, standing for crystal growth for 3 hours, and filtering to obtain a filter cake.

3. And (3) washing the filter cake obtained by filtering in the step (2) with 2 times of purified water for 1 time, and drying for 10 hours at the temperature of 22-24 ℃ under reduced pressure to obtain the camphor compound.

The camphor raw material in the preparation process of the camphor compound is a commercially available synthesized camphor bulk drug.

The camphor compound prepared by the invention has high purity, good stability, low hygroscopicity, difficult agglomeration and better dissolubility according to the common knowledge in the field, and the camphor compound prepared by the invention has better dissolubility compared with the prior art under the condition of low hygroscopicity.

It should be noted that, the formation of a crystal form is influenced by many factors, and any one of the factors such as reaction temperature, time, stirring speed, reactant concentration, crystallization condition control and the like may produce unexpected changes even if small changes occur, and the inventors have experienced many failures in the research process, but finally spend much effort in researching control details, and finally obtain the camphor compound of the invention, and each control point in the preparation process of the compound of the invention is crucial to the result.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of a camphor compound prepared in example 1 of the present invention.

Detailed Description

EXAMPLE 1 preparation of Camphor Compound

1. Dissolving camphor raw material in a mixed solution of trichloromethane and ethanol according to a weight-volume ratio (g/ml) of 1:5, wherein the volume ratio of the trichloromethane to the ethanol is 1: 9.

2. Keeping the temperature of the solution at 20 ℃, adding purified water with the volume 8 times that of the mixed solution of the trichloromethane and the ethanol in the step 1 into the solution in the step 1 at the speed of 120ml/min while stirring at the stirring speed of 110 revolutions per minute, stopping stirring after the purified water is added, cooling to-2 ℃ at the speed of 1.0 ℃/min, standing for crystal growth for 3 hours, and filtering to obtain a filter cake.

3. And (3) washing the filter cake obtained by filtering in the step (2) with 2 times of purified water for 1 time, and drying for 10 hours at 22 ℃ under reduced pressure to obtain the camphor compound.

The X-ray powder diffraction pattern is shown in figure 1, and the characteristic peaks in the pattern are shown at 2 theta of 6.9 degrees, 8.1 degrees, 9.2 degrees, 10.2 degrees, 11.6 degrees, 13.8 degrees, 14.3 degrees, 15.4 degrees, 18.0 degrees, 18.8 degrees, 21.2 degrees, 23.2 degrees, 24.3 degrees, 25.0 degrees and 34.6 degrees.

The content is as follows: 99.92 percent. Melting point: 182 to 185 ℃.

EXAMPLE 2 preparation of Camphor Compound

1. Dissolving camphor raw material in a mixed solution of trichloromethane and ethanol according to a weight-volume ratio (g/ml) of 1:5, wherein the volume ratio of the trichloromethane to the ethanol is 1: 9.

2. Keeping the temperature of the solution at 23 ℃, adding purified water with the volume 8 times that of the mixed solution of the trichloromethane and the ethanol in the step 1 into the solution in the step 1 at the speed of 130ml/min while stirring at the stirring speed of 120 r/min, stopping stirring after the purified water is added, cooling to-3 ℃ at the speed of 1.1 ℃/min, standing for crystal growth for 3 hours, and filtering to obtain a filter cake.

3. And (3) washing the filter cake obtained by filtering in the step (2) with 2 times of purified water for 1 time, and drying for 10 hours at 23 ℃ under reduced pressure to obtain the camphor compound.

The X-ray powder diffraction pattern is consistent with example 1. The content is as follows: 99.95 percent. Melting point: 182 to 185 ℃.

EXAMPLE 3 preparation of Camphor Compound

1. Dissolving camphor raw material in a mixed solution of trichloromethane and ethanol according to a weight-volume ratio (g/ml) of 1:5, wherein the volume ratio of the trichloromethane to the ethanol is 1: 9.

2. Keeping the temperature of the solution at 25 ℃, adding purified water with the volume 8 times that of the mixed solution of the trichloromethane and the ethanol in the step 1 into the solution in the step 1 at a stirring speed of 130 r/min while stirring, stopping stirring after the purified water is added, cooling to-4 ℃ at a speed of 1.2 ℃/min, standing for 3 hours for crystal growth, and filtering to obtain a filter cake.

3. And (3) washing the filter cake obtained by filtering in the step (2) with 2 times of purified water for 1 time, and drying for 10 hours at 24 ℃ under reduced pressure to obtain the camphor compound.

The X-ray powder diffraction pattern is consistent with example 1. The content is as follows: 99.95 percent. Melting point: 182 to 185 ℃.

The present invention provides the following test and comparative results: (test detection method is carried out according to the standard method of synthesizing camphor raw material in the second part of Chinese pharmacopoeia 2015 edition)

Sample 1: camphor Compound produced in example 1 of the present invention

Sample 2: commercially available synthetic camphor bulk drug

The sample 1 and the sample 2 are subjected to influence factor tests and are respectively placed in high humidity (humidity is 90 +/-5%) and strong light (4500 lx +/-500 lx) for 10 days, sampling and verification are respectively carried out on the 10 th day, the results are compared with the results of 0 day, and the stability results of the examined samples are shown in the following tables 1-2.

TABLE 1 high humidity Effect factor test results

TABLE 2 test results of strong light influence factors

As can be seen from the results of tables 1 to 2, the camphor compound prepared according to the present invention has good stability, low impurity content, low hygroscopicity, and significant advantages over the prior art. The same tests were carried out on camphor compounds prepared in other examples of the invention, with similar results.

Samples 1-2 were tested for solubility in water (25 ℃. + -. 2 ℃) and the results are shown in Table 3:

TABLE 3 results of solubility test

Sample (I)	Solubility (g/100 ml)
		1	0.1
2	0.02

As can be seen from the results of table 3, the camphor compound prepared according to the present invention has better solubility, and has a significant advantage over the prior art. The same tests were carried out on camphor compounds prepared in other examples of the invention, with similar results.

Long-term stability studies (25 ℃ C. + -. 2 ℃ C., RH 60%. + -. 10%) were performed on samples 1-2, and the results are shown in Table 4.

TABLE 4 Camphor Long-term test results

As can be seen from the results of table 4, the camphor compound prepared according to the present invention has good stability, low impurity content, low hygroscopicity, and significant advantages over the prior art. The same tests were carried out on camphor compounds prepared in other examples of the invention, with similar results.

Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.