A method for synthesizing n-(trimethylsilyl)morpholine

Abstract

The application discloses a synthesis method of N-(trimethylsilyl) morpholine, relates to the field of organic synthesis of medical intermediate compounds, and discloses a new source of trimethylsilyl, i.e. hexamethyldisilane. Under the catalysis of Lewis acid, hexamethyldisilane can generate trimethylsilyl, and in-situ reaction with morpholine to synthesize N-(trimethylsilyl) morpholine. The boiling point of hexamethyldisilane is 113 DEG C, and hexamethyldisilane is convenient to use and cannot generate corrosive gases such as hydrogen chloride. Hexamethyldisilane is a large chemical product, and is relatively cheap, so that hexamethyldisilane is suitable for large-scale use.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis of pharmaceutical intermediates, in particular to a synthesis method of N-(trimethylsilyl) morpholine. BACKGROUND

[0002] The synthesis of N-(trimethylsilyl) morpholine generally uses morpholine as raw material. Two synthesis methods have been reported:

[0003] The first method uses morpholine and trimethylsilyl chloride to obtain N-(trimethylsilyl) morpholine. However, trimethylsilyl chloride has high reactivity, is not easy to store, and produces hydrogen chloride gas during reaction, which can corrode equipment.

[0004] The second method uses morpholine and trimethylsilyl triflate to obtain the final product. However, trimethylsilyl triflate is relatively expensive and is not suitable for large-scale industrial production. SUMMARY

[0005] The present application provides a synthesis method of N-(trimethylsilyl) morpholine, which solves the problems of high reactivity of the source material of trimethylsilyl, the production of corrosive gas, and high price of the raw material in the existing preparation technology.

[0006] A synthesis method of N-(trimethylsilyl) morpholine, comprising:

[0007]

[0008] Preferably, the molar ratio of morpholine to hexamethyldisilane is 3-10:1-5.

[0009] Preferably, the solvent is methyl tert-butyl ether.

[0010] Preferably, the catalyst is sulfuric acid.

[0011] Preferably, the sulfuric acid is 1N sulfuric acid aqueous solution.

[0012] Preferably, the reaction conditions are that the sulfuric acid aqueous solution is added dropwise into morpholine and hexamethyldisilane, the internal temperature of the reaction solution is controlled not to exceed 30℃, and after the addition of the sulfuric acid aqueous solution is completed, the stirring reaction is continued for 6h.

[0013] Preferably, the synthesis reaction further comprises a post-treatment step, specifically, the reaction solution is added dropwise into saturated sodium carbonate solution, after stirring, the liquid is separated, the organic phase is washed and dried, the solvent is rotary evaporated, hexamethyldisilane is removed by reduced pressure distillation, and the compound A2 pure product is obtained by pressure distillation at a top temperature of 70℃.

[0014] The present application has the following beneficial effects:

[0015] The present application discloses a new source of trimethylsilyl group, i.e. hexamethyldisilane. Hexamethyldisilane can generate trimethylsilyl group under the catalysis of Lewis acid, and in-situ react with morpholine to synthesize N-(trimethylsilyl)morpholine. The boiling point of hexamethyldisilane is 113℃, which is convenient to use and does not produce corrosive gas such as hydrogen chloride. Hexamethyldisilane is a large chemical product, and its price is relatively low, so it is suitable for large-scale use. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 The gas chromatography detection results of the final product prepared in Example 1. DETAILED DESCRIPTION

[0017] The specific embodiments of the present application are described in detail below. Obviously, the described embodiments are only a part of the embodiments of the present application, not all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0018] Example 1: N-(trimethylsilyl)morpholine is synthesized as follows:

[0019]

[0020] 6L methyl tert-butyl ether is added to a 10L four-necked flask, then raw material morpholine 522.6g (6mol, 1eq) is added, followed by the addition of hexamethyldisilane 527.8g (3.6mol, 0.6eq), after stirring uniformly, 1N sulfuric acid aqueous solution 600mL is added dropwise, there will be heat release during the dropwise addition process, the dropwise addition speed is controlled to make the internal temperature of the reaction liquid not exceed 30℃, about 2h for dropwise addition, after dropwise addition, the stirring reaction is continued for 6h. GC shows that the raw material is completely reacted, and there is a product peak. Then the reaction liquid is slowly added to 10L saturated sodium carbonate solution, stirred for 10min, then separated, the upper organic phase is washed with water twice, each time using 2L. The organic phase is dried with anhydrous sodium sulfate. Then methyl tert-butyl ether is spun dry to obtain a crude product. The remaining hexamethyldisilane is distilled out by using a water pump for reduced pressure distillation. Then the oil pump is used for pressure distillation, and the top temperature is 70℃ to collect A2 pure product 917.6g. Gas chromatography shows that the purity is 99% (as shown in Figure 1

[0021] Example 2: the rest are the same as Example 1, except that:

[0022] The molar ratio of morpholine to hexamethyldisilane is 5:5.

[0023] Example 3: the rest are the same as Example 1, except that:

[0024] The molar ratio of morpholine to hexamethyldisilane is 10:1.​

[0025] Example 4: The same as Example 1 except that:

[0026] the molar ratio of morpholine to hexamethyldisilane was 3:1 ;

[0027] Example 5: The same as Example 1 except that:

[0028] the molar ratio of morpholine to hexamethyldisilane was 7:4;

[0029] Example 6: The same as Example 1 except that:

[0030] the molar ratio of morpholine to hexamethyldisilane was 4:2;

[0031] The application has been described in detail with specific reference to particular embodiments and exemplifying examples, but it will be understood that these are presented for purposes of illustration and example, and not limitation. The application will now be described in detail with reference to the specific embodiments and exemplifying examples, but it will be understood that these are presented for purposes of illustration and example, and not limitation. The application will now be described in detail with reference to the specific embodiments and exemplifying examples, but it will be understood that these are presented for purposes of illustration and example, and not limitation. The application will now be described in detail with reference to the specific embodiments and exemplifying examples, but it will be understood that these are presented for purposes of illustration and example, and not limitation. The application will now be described in detail with reference to the specific embodiments and exemplifying examples, but it will be understood that these are presented for purposes of illustration and example, and not limitation. The application will now be described in detail with reference to the specific embodiments and exemplifying examples, but it will be understood that these are presented for purposes of illustration and example, and not limitation. The application will now be described in detail with reference to the specific embodiments and exemplifying examples, but it will be understood that these are presented for purposes of illustration and example, and not limitation. The application will now be described in detail with reference to the specific embodiments and exemplifying examples, but it will be understood that these are presented for purposes of illustration and example, and not limitation. The application will now be described in detail with reference to the specific embodiments and exemplifying examples, but it will be understood that these are presented for purposes of illustration and example, and not limitation. The application will now be described in detail with reference to the specific embodiments and exemplifying examples, but it will be understood that these are presented for purposes of illustration and example, and not

Claims

1. A method for synthesizing N-(trimethylsilyl)morpholine, characterized in that: include: The molar ratio of the morpholine to hexamethyldisilane is 3-10:1-5, the solvent is methyl tert-ether, and the catalyst is sulfuric acid.

2. A method for synthesizing N-(trimethylsilyl)morpholine according to claim 1, characterized in that: The sulfuric acid is a 1N sulfuric acid aqueous solution.

3. A method for synthesizing N-(trimethylsilyl)morpholine according to claim 2, characterized in that: The reaction conditions are as follows: adding the sulfuric acid aqueous solution dropwise into morpholine and hexamethyldisilane, controlling the internal temperature of the reaction solution to not exceed 30° C., and continuing to stir the reaction for 6 hours after the sulfuric acid aqueous solution is added dropwise.

4. A method for synthesizing N-(trimethylsilyl)morpholine according to claim 3, characterized in that: The synthesis reaction also includes a post-processing step, specifically, dropping the reaction solution into a saturated sodium carbonate solution, stirring and then separating the liquids, taking the organic phase, washing and drying, spin-drying the solvent, and then distilling under reduced pressure to remove hexamethyldisilane, and then distilling under reduced pressure to collect the fraction with a top temperature of 70°C to obtain pure compound A2.

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