Preparation method of medical intermediate

Abstract

The invention discloses a preparation method of a medical intermediate, which comprises the following steps: S1, putting raw materials p-chlorophenylhydrazone and dimethyl sulfoxide into a reactor, reacting, and stirring for a period of time to obtain N-methyl-p-chlorophenylhydrazone and dimethyl sulfoxide methanol; s2, concentrated nitric acid is added into the reactor, cooling is conducted, after dimethyl sulfoxide methanol is crystallized and precipitated, filtering is conducted, and concentrated nitric acid and N-methyl-p-chloromethylhydrazone are obtained; s3, 4-methyl phenylacetyl chloride is added into the reactor, N-methyl-p-chlorophenylhydrazone and 4-methyl phenylacetyl chloride are subjected to an acylation reaction, the reaction temperature and the reaction time are controlled, and arunine and hydrochloric acid are obtained; and S4, adding an alkaline substance into the reactor, adjusting the pH value, filtering and collecting arunine, cleaning and airing, and removing dimethyl sulfoxide methanol, thereby ensuring the effect of the reaction of N-methyl-p-chlorophenylhydrazone and 4-methyl phenylacetyl chloride, avoiding the influence on the production of products in the reaction process, and ensuring the yield.

Description

Technical Field

[0001] The present invention relates to the technical field of preparation of pharmaceutical intermediates, and in particular to a method for preparing a pharmaceutical intermediate. Background Art

[0002] Phragmites australis has extremely high biological activity. It is widely distributed in nature and is an alkaloid with allelopathic effects produced by gramineous plants such as wheat, barley and Phragmites australis during the evolution process (Phytochemistry, 1984, 23 (3), 539-541; Phytochemistry, 1985, 24 (5), 945-947; Exp.Appl., 1986, 40 (3), 259-262.), and has growth inhibitory effects on environmental plants, insects, microorganisms, etc. (Journal of Shaoyang University, 2003, 2 (2), 131-135.). People use the different biological activities of phyragmites australis to develop biological pesticides for different purposes. For example, gramine secreted by barley has a strong inhibitory effect on the weeds of the genus Celastrus (World Agriculture, 2002, 279 (7), 41-44.), and a concentration of 10 mg / kg has a 77% inhibitory effect on its growth. It can be developed as a biological herbicide (J. Org. Chem., 1959, 24, 1285-1287.). Gramine is resistant to insect feeding (Insect Knowledge, 2003, 40 (1), 24-27; Journal of Shenyang Agricultural University, 2002, 33 (4), 309-314.), and related pesticides can be developed for crop insecticides. Gramine and its derivatives have the characteristics of high efficiency, low toxicity, resistance and low residue, making them a biological pesticide with broad development prospects (Pesticides, 2004, 43 (2), 76-77).

[0003] The existing preparation method of pharmaceutical intermediates does not remove the intermediate by-products during the preparation of gramine, which results in low reaction efficiency when some by-products are used to generate gramine during the production process, requiring the use of catalysts and affecting its yield. Summary of the invention

[0004] The purpose of the present invention is to solve at least one of the technical problems existing in the prior art and provide a method for preparing a pharmaceutical intermediate, by removing dimethyl sulfoxide methanol, thereby ensuring the effect of the reaction between N-methyl-p-chlorobenzylhydrazone and 4-methylphenylacetyl chloride, avoiding affecting the product generation during the reaction process, and ensuring the yield.

[0005] The present invention also provides a method for preparing the above-mentioned pharmaceutical intermediate, comprising the following steps:

[0006] S1, taking the raw materials p-chlorobenzylhydrazone and dimethyl sulfoxide and putting them into a reactor, after the reaction, stirring for a period of time, and obtaining N-methyl-p-chlorobenzylhydrazone and dimethyl sulfoxide methanol;

[0007] S2, adding concentrated nitric acid to the reactor and cooling it to allow dimethyl sulfoxide methanol to crystallize. After precipitation, filtering is performed to obtain concentrated nitric acid and N-methyl-p-chlorophenylmethylhydrazone;

[0008] S3, adding 4-methylphenylacetyl chloride to the reactor, causing N-methyl-p-chlorobenzoylhydrazone to undergo an acylation reaction with 4-methylphenylacetyl chloride, and controlling the reaction temperature and reaction time to obtain gramine and hydrochloric acid;

[0009] S4, adding alkaline substances into the reactor, adjusting the pH value, filtering and collecting the gramine, and washing and drying.

[0010] According to a method for preparing a pharmaceutical intermediate provided by the present invention, the stirring for a period of time in S1 is specifically stirring for 10-15 minutes.

[0011] According to a method for preparing a pharmaceutical intermediate provided by the present invention, the cooling in S2 specifically involves lowering the temperature of the reactor to 5-15°C.

[0012] According to a method for preparing a pharmaceutical intermediate provided by the present invention, the filtration in S2 is specifically performed using a filter with a pore size of 0.075 mm.

[0013] According to a method for preparing a pharmaceutical intermediate provided by the present invention, the control of the reaction temperature and reaction time in S3 is specifically to control the reaction temperature at 45-55° C. and the reaction time is 2 h.

[0014] According to a method for preparing a pharmaceutical intermediate provided by the present invention, the added alkaline substance in S4 is specifically one of sodium hydroxide and calcium hydroxide.

[0015] According to a method for preparing a pharmaceutical intermediate provided by the present invention, adjusting the pH value in S4 specifically involves adjusting the pH value to between 7 and 9.

[0016] According to a method for preparing a pharmaceutical intermediate provided by the present invention, the lycopene is collected by filtration in S4, and washed and dried in the air. Specifically, the lycopene is washed with cold water at 10-20° C., and then collected after drying.

[0017] Compared with the prior art, the preparation method of the pharmaceutical intermediate removes dimethyl sulfoxide methanol, thereby ensuring the effect of the reaction between N-methyl-p-chlorobenzylhydrazone and 4-methylphenylacetyl chloride, avoiding affecting the product generation during the reaction process, and ensuring the yield. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The present invention is further described below in conjunction with the accompanying drawings and embodiments;

[0019] Figure 1 The present invention is a flow chart of the preparation method of the pharmaceutical intermediate. DETAILED DESCRIPTION

[0020] This section will describe in detail the specific embodiments of the present invention. The preferred embodiments of the present invention are shown in the accompanying drawings. The purpose of the accompanying drawings is to supplement the description of the text part of the specification with graphics, so that people can intuitively and vividly understand each technical feature and the overall technical solution of the present invention, but it cannot be understood as a limitation on the scope of protection of the present invention.

[0021] Reference Figure 1 The present invention provides a method for preparing a pharmaceutical intermediate, which comprises: Figure 1 As shown, the following steps are included:

[0022] S1, taking the raw materials p-chlorobenzylhydrazone and dimethyl sulfoxide and putting them into a reactor, after the reaction, stirring for 10-15 minutes, to obtain N-methyl-p-chlorobenzylhydrazone and dimethyl sulfoxide methanol;

[0023] S2, adding concentrated nitric acid to the reactor, and cooling, so that dimethyl sulfoxide methanol crystallizes, after precipitation, filtering, to obtain concentrated nitric acid and N-methyl-p-chlorophenylmethylhydrazone, cooling specifically lowering the temperature of the reactor to 5-15° C., filtering specifically using a filter with a pore size of 0.075 mm for filtering;

[0024] S3, adding 4-methylphenylacetyl chloride to the reactor, causing N-methyl-p-chlorobenzoylhydrazone to undergo an acylation reaction with 4-methylphenylacetyl chloride, controlling the reaction temperature and reaction time to obtain gramine and hydrochloric acid, and controlling the reaction temperature and reaction time specifically by controlling the reaction temperature at 45-55° C. and the reaction time for 2 h;

[0025] S4, adding alkaline substances to the reactor, adjusting the pH value, filtering and collecting the gramine, and washing and drying. The alkaline substance added is specifically one of sodium hydroxide and calcium hydroxide, and the pH value is adjusted to between 7 and 9, and the gramine is filtered and collected. The gramine is washed and dried by washing the gramine with cold water at 10-20° C., and then collected after drying.

[0026] The embodiments of the present invention are described in detail above with reference to the accompanying drawings. However, the present invention is not limited to the above embodiments. Various changes can be made within the knowledge scope of ordinary technicians in the technical field without departing from the purpose of the present invention.

Claims

1. A method for preparing a pharmaceutical intermediate, characterized in that: The following steps are involved: S1, taking the raw materials p-chlorobenzylhydrazone and dimethyl sulfoxide and putting them into a reactor, after the reaction, stirring for a period of time, and obtaining N-methyl-p-chlorobenzylhydrazone and dimethyl sulfoxide methanol; S2, adding concentrated nitric acid to the reactor and cooling it to allow dimethyl sulfoxide methanol to crystallize. After precipitation, filtering is performed to obtain concentrated nitric acid and N-methyl-p-chlorophenylmethylhydrazone; S3, adding 4-methylphenylacetyl chloride to the reactor, causing N-methyl-p-chlorobenzoylhydrazone to undergo an acylation reaction with 4-methylphenylacetyl chloride, and controlling the reaction temperature and reaction time to obtain gramine and hydrochloric acid; S4, adding alkaline substances into the reactor, adjusting the pH value, filtering and collecting the gramine, and washing and drying.

2. The method for preparing a pharmaceutical intermediate according to claim 1, characterized in that: The stirring period in S1 is specifically 10-15 minutes.

3. The method for preparing a pharmaceutical intermediate according to claim 1, characterized in that: The cooling in S2 specifically involves lowering the temperature of the reactor to 5-15°C.

4. The method for preparing a pharmaceutical intermediate according to claim 1, characterized in that: The filtration in S2 is specifically performed using a filter with a pore size of 0.075 mm.

5. The method for preparing a pharmaceutical intermediate according to claim 1, characterized in that: The control of the reaction temperature and reaction time in S3 is specifically to control the reaction temperature at 45-55° C. and the reaction time at 2 h.

6. The method for preparing a pharmaceutical intermediate according to claim 1, characterized in that: The added alkaline substance in S4 is specifically one of sodium hydroxide and calcium hydroxide.

7. The method for preparing a pharmaceutical intermediate according to claim 1, characterized in that: The step of adjusting the pH value in S4 specifically involves adjusting the pH value to between 7 and 9.

8. The method for preparing a pharmaceutical intermediate according to claim 1, characterized in that: In S4, the gramine is collected by filtration, and then washed and dried. Specifically, the gramine is washed with cold water at 10-20° C., and then collected after drying.

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