CN-122011010-A - Preparation method of 1-aminomethyl hetero-silatrane and preparation method of N-acyl derivative

CN122011010ACN 122011010 ACN122011010 ACN 122011010ACN-122011010-A

Abstract

The invention provides a preparation method of 1-aminomethyl silatrane and a preparation method of N-acyl derivatives, wherein the preparation method comprises the steps of 1) reacting 1-chloromethyl silatrane with saturated aminoethanol solution in a first organic solvent under the condition of sealing-5~0 ℃ to obtain a first mixture containing 1-aminomethyl silatrane hydrochloride and ammonium chloride, 2) removing the organic solvent and ammonia in the first mixture, extracting and removing ammonium chloride by using cold acetonitrile at 0-5 ℃, concentrating the extracted filtrate, and crystallizing to obtain the 1-aminomethyl silatrane. The high-purity 1-aminomethyl silatrane is obtained by adopting saturated aminoethanol solution to replace high-pressure ammonia gas or strong ammonia water, carrying out ammonolysis reaction under a low-pressure sealing strip, eliminating high-pressure operation risk, reducing the generation of ammonia-containing wastewater and combining a cold acetonitrile extraction/crystallization combination process.

Inventors

CHENG WEI
ZHANG HONG
LIU JIHONG
DONG JINGLONG
LU JIAHAO
ZHOU PENG
ZHANG TIEJUN
LIANG HAITAO
CAI MENGYUN
You tianyu

Assignees

山东省科学院菏泽分院

Dates

Publication Date: 20260512
Application Date: 20260202

Claims (10)

1. The preparation method of the 1-aminomethyl hetero-silicon tricyclic is characterized by comprising the following steps: (1) Reacting the 1-chloromethyl silatrane with saturated aminoethanol solution in a first organic solvent at a temperature of-5~0 ℃ to obtain a first mixture containing the 1-aminomethyl silatrane hydrochloride and ammonium chloride; (2) Removing the organic solvent and ammonia in the first mixture, extracting with cold acetonitrile at 0-5 ℃ to remove ammonium chloride, concentrating the extracted filtrate, and crystallizing to obtain the 1-aminomethyl hetero-silatrane.
2. The preparation method of the 1-aminomethyl silatrane according to claim 1, wherein the mass-volume ratio of the 1-chloromethyl silatrane to saturated aminoethanol solution is 1 g/5-8 ml; and/or the reaction time of the step (1) is 12-48 h; and/or the concentration of the saturated aminoethanol solution is 8-12 mol/L, preferably 9-11 mol/L; and/or the first organic solvent is at least one selected from ethanol, methanol and isopropanol.
3. The method for preparing the 1-aminomethyl silatrane according to claim 1, wherein the organic solvent and ammonia in the first mixture are removed by reduced pressure distillation at an operating temperature of 30-50 ℃ and an operating pressure of-0.05 to-0.1 MPa.
4. The method for preparing the 1-aminomethyl silazane tricyclic according to claim 1, wherein said crystallization operation comprises concentrating said filtrate to 40% -60% of original volume, standing at-10 to-20 ℃ for crystallization; And/or the mass ratio of the cold acetonitrile to the 1-chloromethyl hetero-silatrane is (2-7): 1, preferably (4-6): 1.
5. A method for preparing an N-acyl-1-aminomethyl hetero-silicon tricyclic compound, which is characterized by comprising the following steps: s1, in the presence of organic alkali, carrying out acylation reaction on the 1-aminomethyl hetero-silatrane prepared by the preparation method according to any one of claims 1-4 and C 8 ~C 22 linear or branched alkyl acyl chloride to obtain a second mixture; s2, carrying out post-treatment and recrystallization on the second mixture to obtain the N-acyl-1-aminomethyl hetero-silatrane.
6. The method for preparing an N-acyl-1-aminomethyl silatrane according to claim 5, wherein the organic base is at least one of triethylamine, N-diisopropylethylamine, 4-dimethylaminopyridine and pyridine, and the amount of the organic base is 1.25-1.5 times of the molar amount of the 1-aminomethyl silatrane; And/or the dosage of the linear or branched chain alkyl acyl chloride of the C 8 ~C 22 is 1 to 1.05 times of the molar quantity of the 1-aminomethyl hetero-silicon tricyclic.
7. The method for preparing an N-acyl-1-aminomethyl silatrane according to claim 5, wherein said step S1 comprises: S11, respectively preparing a first reaction solution containing the inorganic base, the 1-aminomethyl silatrane and a second organic solvent, and a second reaction solution containing the C 8 ~C 22 linear or branched alkyl chloride and a third organic solvent; And S12, dropwise adding the second reaction solution into the first reaction solution, and stirring for reaction after the dropwise adding is finished to obtain the second mixture.
8. The preparation method of the N-acyl-1-aminomethyl hetero-silicon tricyclic compound according to claim 7, wherein the rate of the dropping operation is 2-10 mL/min, and the control temperature of the dropping operation is 0-10 ℃; And/or stirring the mixture to react for 8-24 hours at room temperature; And/or, the second organic solvent and the third organic solvent are respectively and independently selected from at least one of tetrahydrofuran, ethyl acetate and toluene; and/or, the step S12 is carried out under an inert atmosphere.
9. The method for preparing an N-acyl-1-aminomethyl silatrane according to claim 5, wherein said post-treatment comprises diluting said second mixture, washing, drying, concentrating in sequence to obtain a crude product; Preferably, the dilution operation comprises adding a fourth organic solvent to the second mixture, wherein the fourth organic solvent is at least one selected from dichloromethane, ethyl acetate and methyl tertiary butyl ether, and the dosage of the fourth organic solvent is 0.4-1 of the mass of the second mixture; Preferably, the washing operation comprises water washing, alkali liquor washing and brine washing, wherein the alkali liquor is sodium bicarbonate solution, potassium bicarbonate solution, sodium carbonate solution or potassium carbonate solution, and the brine is sodium chloride solution.
10. The method for producing an N-acyl-1-aminomethyl silatrane according to claim 5, wherein said solvent for recrystallization is at least one selected from the group consisting of acetone, ethyl acetate, N-hexane, isopropyl alcohol, and petroleum ether; preferably, the mass ratio of the recrystallization solvent to the 1-aminomethyl silatrane is (2-5): 1.

Description

Preparation method of 1-aminomethyl hetero-silatrane and preparation method of N-acyl derivative Technical Field The invention relates to the technical field of chemical synthesis, in particular to a preparation method of 1-aminomethyl hetero-silicon tricyclic and a method for preparing N-acyl derivatives. Background The hetero-nitrogen silicon tricyclic (Aza-silatrane) is used as a tricyclic organosilicon compound with a cage coordination structure, and a five-coordination structure formed by silicon atoms, three bridge oxygen atoms and one nitrogen atom in the molecule of the tricyclic organosilicon compound endows the compound with unique chemical stability and biological activity. In recent years, with the deep research of the structure-activity relationship, the azasilicon tricyclic and the derivatives thereof have clear application potential in the fields of pharmaceutical chemistry such as anti-tumor, antibacterial, neuroprotection and the like, and in the design and synthesis of functional materials and catalyst ligands. Wherein, by carrying out structural modification on the 1-position substituent of the hetero-nitrogen silicon tricyclic, particularly introducing aminomethyl as a functional group conversion site and further carrying out acylation reaction, the method has become a key strategy for regulating the lipid water distribution coefficient, improving the cell membrane penetrating capacity and optimizing the bioavailability. The introduction of long chain fatty acyl groups (such as palmitoyl groups) has been shown to significantly enhance the lipophilic character of molecules, and has important research value for the construction of targeted delivery systems and the development of novel bioactive molecules. At present, the main technical route for preparing the N-acyl-1-aminomethyl hetero-silicon tricyclic compound generally comprises two continuous steps, namely (1) taking 1-chloromethyl hetero-silicon tricyclic as a starting material, carrying out nucleophilic substitution reaction with an ammonia source to prepare a 1-aminomethyl hetero-silicon tricyclic intermediate, and (2) carrying out N-acylation reaction on the intermediate and a corresponding acyl chloride compound in the presence of an acid binding agent (such as triethylamine) to prepare a target product. However, the above process still has the following technical problems to be solved in terms of industrial implementation, particularly in the first ammonolysis reaction: In the prior art, a concentrated ammonia water system or ammonia gas filled in a steel cylinder is generally adopted as an ammoniation reagent. The adoption of the concentrated ammonia water process has the inherent defects of low reaction efficiency and long reaction period, and a large amount of high-concentration nitrogen-containing wastewater is generated in the post-treatment process, so that the environmental load is high, and the clean production requirement is not met. And the steel cylinder ammonia gas is directly used as a reactant, so that high-pressure operation is involved, strict requirements are put on the air tightness, pressure resistance level and safety interlocking device of reaction equipment, the complexity of the production process and the safety risk are obviously increased, and the feasibility of industrial amplification is not realized. In addition, due to poor selectivity of ammonolysis reaction and technical limitation of ammonia source, separation and purification of intermediates are difficult, quality reproducibility among batches is poor, total yield of target products is low, and purity is difficult to meet quality standards of drug research and development. The problems comprehensively lead to high preparation cost and severely restrict the large-scale preparation and subsequent patent drug property evaluation process of the compounds. Disclosure of Invention Aiming at the defects in the prior art, the invention discloses a preparation method of 1-aminomethyl hetero-silicon tricyclic and a preparation method of N-acyl derivatives, which are used for solving the technical problems of complex operation, low safety coefficient, low product yield and low purity of the existing 1-aminomethyl hetero-silicon tricyclic preparation technology. In order to achieve the technical aim, in one aspect, the invention provides a preparation method of 1-aminomethyl silatrane, which comprises the following steps: (1) Reacting the 1-chloromethyl silatrane with saturated aminoethanol solution in a first organic solvent at a temperature of-5~0 ℃ to obtain a first mixture containing the 1-aminomethyl silatrane hydrochloride and ammonium chloride; (2) Removing the organic solvent and ammonia in the first mixture, extracting with cold acetonitrile at 0-5 ℃ to remove ammonium chloride, concentrating the extracted filtrate, and crystallizing to obtain the 1-aminomethyl hetero-silatrane. The method solves the technical problem of high safety risk of the exi