A synthesis process of trimethylhydrazine and product thereof

Abstract

The application discloses a synthesis process of trimethylhydrazine and a product, and relates to the technical field of chemical synthesis. The synthesis process takes methanol and hydrazine hydrochloride as raw materials in a molar ratio of 3-5:1, and obtains trimethylhydrazine hydrochloride through alkylation, and then obtains trimethylhydrazine by freeing the trimethylhydrazine hydrochloride with sodium hydroxide, and through distillation and rectification. The reaction process is simple, the reaction route is short, and the large-scale industrial production is facilitated. In the whole reaction process, the conversion rate during the reaction is greatly improved by making the methanol excessive relative to the hydrazine hydrochloride and strictly controlling the excessive ratio of the methanol, the generation of by-products such as methylhydrazine and dimethylhydrazine is inhibited, the reaction selectivity during the preparation of trimethylhydrazine is improved, the yield of the trimethylhydrazine is greatly improved, and the realization of the industrialized large-scale preparation of the trimethylhydrazine is further facilitated.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of chemical synthesis, in particular to a synthesis process and product of trimethylhydrazine. BACKGROUND

[0002] Trimethylhydrazine, also known as 1,1,2-trimethylhydrazine hydrochloride in Chinese, CAS number: 1741-01-1, chemical formula C3H 10 N2, is an important intermediate for synthesizing an important finished product drug Anamorelin in the medical field, wherein Anamorelin is a growth hormone releasing peptide receptor agonist developed by Helsinn, and is usually developed for the treatment of anorexia, cachexia or unexpected weight loss in non-small cell lung cancer patients, and is expected to become the first drug to effectively improve cancer cachexia.

[0003] Traditional synthesis processes of trimethylhydrazine, such as using 1,1-dimethylhydrazine as a raw material, formylating to obtain 2,2-dimethylhydrazine, and then reducing with lithium aluminum hydride to obtain trimethylhydrazine, often have the problems of high cost of raw materials, high overall investment cost, many generated impurities, low yield, and lower yield after purification.

[0004] And the related synthesis processes of trimethylhydrazine and its related derivatives in the prior art, such as the article “New synthesis process of (R)-3-benzylpiperidine-3-formyl (1,2,2-trimethyl) hydrazine hydrochloride” published in Chinese Journal of Pharmaceuticals, No. 6, 2017, can reduce the cost of raw materials to some extent by using cheap and readily available methylhydrazine sulfate as a raw material, but the reaction selectivity of the preparation of trimethylhydrazine in the prior art is generally low, so the yield of trimethylhydrazine is also generally low, and the reaction route of the prior art is complicated and is not conducive to large-scale industrial production.

[0005] Therefore, a new technical solution is needed to solve the above technical problems. SUMMARY

[0006] The present application aims to provide a synthesis process and product of trimethylhydrazine to solve the technical problems that the reaction selectivity of the preparation of trimethylhydrazine in the prior art is generally low, so the yield of trimethylhydrazine is also generally low, and the reaction route of the prior art is complicated and is not conducive to large-scale industrial production.

[0007] To achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0008] A synthesis process of trimethylhydrazine, wherein methanol and hydrazine hydrochloride are used as raw materials in a molar ratio of 3-5:1, trimethylhydrazine hydrochloride is obtained through alkylation, and trimethylhydrazine is obtained by freeing the trimethylhydrazine hydrochloride with sodium hydroxide, through distillation and rectification, wherein the reaction equation of alkylation is as follows: , The reaction equation of freeing with sodium hydroxide is as follows:

[0009] .

[0010] Further, the specific operation process of the alkylation is as follows:

[0011] S1, hydrazine hydrochloride and water are used to prepare hydrazine hydrochloride aqueous solution, and methanol and hydrochloric acid aqueous solution are used to prepare methanol hydrochloride solution;

[0012] S2, the reaction kettle is cleaned and replaced to complete the feeding;

[0013] S3, the steam is turned on to heat, the stirring is started, and after the temperature reaches a certain value, the temperature is kept constant, and the pressure in the kettle is controlled at the same time, wherein the heating temperature is 150 DEG C, the holding time is 8h, and the pressure in the kettle is 1.0-1.2MPa.

[0014] In addition to the above technical solutions, the application also provides a trimethylhydrazine prepared by the above synthesis process of trimethylhydrazine.

[0015] Compared with the prior art, the application has the following beneficial effects:

[0016] 1. In the application, methanol and hydrazine hydrochloride are used as raw materials, trimethylhydrazine hydrochloride is obtained through alkylation, and trimethylhydrazine is obtained by freeing the trimethylhydrazine hydrochloride with sodium hydroxide, through distillation and rectification, which realizes one-step synthesis of trimethylhydrazine, the reaction process is simple, the reaction route is short, and it is fully conducive to large-scale industrial production, and in the whole reaction process, by making methanol excessive relative to hydrazine hydrochloride and strictly controlling the excessive ratio of methanol, the conversion rate during the reaction is greatly improved, the generation of by-products such as methylhydrazine and dimethylhydrazine is inhibited, the reaction selectivity during the preparation of trimethylhydrazine is improved, thereby the yield of trimethylhydrazine is greatly improved, and the realization of industrialized large-scale preparation of trimethylhydrazine is further facilitated;

[0017] 2. The present application is based on the use of inexpensive methanol as a methylating agent, thereby further reducing the cost of investment, and through the use of hydrochloric acid and the catalytic conditions, the number of reactants and reaction steps is further reduced, effectively ensuring the realization of one-step synthesis of trimethylhydrazine, thereby fully improving the preparation efficiency and yield of trimethylhydrazine, and ultimately ensuring the realization of industrialized large-scale preparation of trimethylhydrazine; at the same time, strict control of the reaction time and reaction temperature in the present application further ensures the improvement of the yield of trimethylhydrazine. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 The process flow chart of the present application. DETAILED DESCRIPTION

[0019] The present application will be further described below in conjunction with examples, but in no way limits the present application. Example 1

[0020] Synthesis of trimethylhydrazine:

[0021] S1, hydrochloric acid hydrazine and water are used to prepare a hydrochloric acid hydrazine aqueous solution, and methanol and hydrochloric acid aqueous solution are used to prepare a hydrochloric acid methanol solution, wherein the molar ratio of methanol to hydrochloric acid hydrazine is 4:1;

[0022] S2, the reaction kettle is cleaned and replaced, and then the feeding is completed;

[0023] S3, the steam is turned on to warm up, the stirring is turned on, and after the temperature is warmed up to 150℃, the temperature is kept for 8h, and the pressure in the kettle is controlled to be 1.0-1.2MPa during the period;

[0024] S4, after the reaction is completed, the material is transferred to a four-necked distillation flask, and after the methanol and excess water are distilled off, sodium hydroxide is added;

[0025] S5, the crude product (containing trimethylhydrazine, methylhydrazine and dimethylhydrazine) is obtained by vacuum distillation;

[0026] S6, the finished product trimethylhydrazine is obtained by separation with a rectifying column.

[0027] The reaction equation of the above synthesis process is as follows:

[0028] , .

[0029] In addition, the equipment used in the above synthesis process includes one high-pressure reaction kettle (1000ml), one distillation flask (2000ml), one water ring vacuum pump, two rectifying columns (glass, 2m), one oil bath, and several baking cakes. Example 2:

[0030] The synthetic process of this example is the same as that of Example 1, except that the molar ratio of methanol to hydrazine hydrochloride is 3:1. Example 3:

[0031] The synthetic process of this example is the same as that of Example 1, except that the molar ratio of methanol to hydrazine hydrochloride is 3.5:1. Example 4:

[0032] The synthetic process of this example is the same as that of Example 1, except that the molar ratio of methanol to hydrazine hydrochloride is 4.5:1. Example 5:

[0033] The synthetic process of this example is the same as that of Example 1, except that the molar ratio of methanol to hydrazine hydrochloride is 5:1.

[0034] Comparative Example 1:

[0035] The synthetic process of this example is the same as that of Example 1, except that the holding time is 6h.

[0036] Comparative Example 2:

[0037] The synthetic process of this example is the same as that of Example 1, except that the holding time is 7h.

[0038] Comparative Example 3:

[0039] The synthetic process of this example is the same as that of Example 1, except that the holding time is 9h.

[0040] Comparative Example 4:

[0041] The synthetic process of this example is the same as that of Example 1, except that the holding time is 10h.

[0042] Comparative Example 5:

[0043] The synthetic process of this example is the same as that of Example 1, except that the reaction temperature is 130℃.

[0044] Comparative Example 6:

[0045] The synthetic process of this example is the same as that of Example 1, except that the reaction temperature is 140℃.

[0046] Comparative Example 7:

[0047] The synthetic process of this example is the same as that of Example 1, except that the reaction temperature is 160℃.

[0048] Comparative Example 8:

[0049] The synthetic process of the present comparative example is the same as that of Example 1, except that the reaction temperature is 170°C.

[0050] In combination with Examples 1-5, the effect of different molar ratios of methanol to hydrazine hydrochloride on the yield of trimethylhydrazine was investigated when the holding time (reaction time) was 8 h and the reaction temperature was 150°C, and the results are shown in the following table:

[0051] ,

[0052] As can be seen from the above table, as the excess ratio of methanol increases, the yield of trimethylhydrazine also increases, but the effect is not obvious after reaching 4:1, and the input of methanol material is increased, which reduces the yield, so the molar ratio of methanol to hydrazine hydrochloride of 4:1 is more appropriate.

[0053] In combination with Examples 1 and Comparative Examples 1-4, the effect of different holding times (reaction times) on the yield of trimethylhydrazine was investigated when the molar ratio of methanol to hydrazine hydrochloride was 4:1 and the reaction temperature was 150°C, and the results are shown in the following table:

[0054] ,

[0055] As can be seen from the above table, as the reaction time increases, the conversion rate is highest after 8 h, and then the yield decreases slightly as the time increases, so the holding time of 8 h is more appropriate.

[0056] In combination with Examples 1 and Comparative Examples 5-8, the effect of different reaction temperatures on the yield of trimethylhydrazine was investigated when the molar ratio of methanol to hydrazine hydrochloride was 4:1 and the holding time (reaction time) was 8 h, and the results are shown in the following table:

[0057] ,

[0058] As can be seen from the above table, as the reaction temperature increases, the conversion rate first increases and then decreases, and the yield is highest at 150°C, so the reaction temperature of 150°C is appropriate.

[0059] In summary, at a temperature of 150°C, a holding time of 8 hours, and a molar ratio of methanol to hydrazine hydrochloride of 4:1, the yield of trimethylhydrazine synthesized is fully improved; at the same time, the entire synthesis process is simple and the input cost is low.

Claims

1. A process for the synthesis of trimethylhydrazine, characterized in that, The raw material is methanol and hydrazine hydrochloride with a molar ratio of 3-5:1, and trimethylhydrazine hydrochloride is obtained by alkylation, and trimethylhydrazine is obtained by distillation and rectification of the trimethylhydrazine hydrochloride released by sodium hydroxide; The specific operation process of the alkylation is as follows: S1, hydrazine hydrochloride and water are used to prepare hydrazine hydrochloride aqueous solution, and methanol and hydrochloric acid aqueous solution are used to prepare methanol hydrochloride solution; S2, the reaction kettle is cleaned and replaced to complete the feeding; S3, open the steam to warm up, start stirring, and then warm up to 150 DEG C, start to keep warm, and control the pressure in the kettle to be 1.0-1.2 MPa while keeping warm for 8 hours.

2. A process for the synthesis of trimethylhydrazine as claimed in claim 1, wherein, The reaction equation of the alkylation is as follows: 。 3. The process for synthesis of trimethylhydrazine as claimed in claim 1 wherein, The reaction equation of the sodium hydroxide release is as follows: 。

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