Preparation method of N-Boc-3-amino azetidine

Abstract

The invention discloses a preparation method of N-Boc-3-amino azetidine. The preparation method comprises the following steps: enabling N-Boc-3-hydroxyl azetidine to react with paratoluensulfonyl chloride under the action of alkali to obtain an intermediate A1; preparing a mixed solution A of A1 and a solvent in a batching kettle; the preheating temperature range of the micro-channel reactor is controlled to be 70-80 DEG C, the flow speed of the mixed solution A and the flow speed of the ammonia water are adjusted, the mixed solution A and the ammonia water are pumped into the micro-channel reactor to form reaction solutions, the reaction temperature is 130-160 DEG C, and the reaction pressure is 1-3 MPa; and distilling the reaction material out of the micro-channel reactor, and carrying out post-treatment to obtain N-Boc-3-amino azetidine. According to the preparation method, the reaction time is remarkably shortened, few reaction byproducts are produced, the yield is high, and industrial large-scale production is facilitated.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a method for preparing N-Boc-3-aminoazetidine. Background Art

[0002] In recent years, a large number of compounds and pharmaceutical intermediates have been successfully prepared by modifying azetidine compounds with various functional groups, many of which have good pharmaceutical activity. For example, 1-diphenylmethyl-3-aminoazetidine and 1-diphenylmethyl-3-hydroxy-3-aminomethylazetidine have been used in the synthesis of some antibacterial and antidepressant drugs in recent years. 1-tert-Butyloxycarbonyl-3-aminocyclobutane is also an important pharmaceutical intermediate used in the synthesis of IRAK-4 inhibitors.

[0003] Patent CN 109503450 A discloses a method for synthesizing 3-aminoazetidine as follows:

[0004]

[0005] Reagents and conditions: (a) MsCl, TEA, acetonitrile; (b) methanol, ammonia, 2.5 h; (c) Pd / C, methanol, water, 1.0 MPa.

[0006] The method discloses a sulfonation reaction of 1-benzyl-3-acridinebutanol hydrochloride and methanesulfonyl chloride in acetonitrile to replace the hydroxyl group to obtain an intermediate I, followed by aminolysis, and then replacing the sulfonyl group with the amino group to obtain an intermediate II; in step (b), the reaction time is long, and tert-butyloxycarbonyl substitution is more likely to produce by-products in the reaction over a long period of time than benzyl substitution, resulting in a lower yield and a lower product purity.

[0007] At present, the synthesis method of N-Boc-3-aminoazetidine is by the azide method and the Mitsunobu reaction. The azide method uses N-Boc-3-hydroxyazetidine and methylsulfonyl chloride to synthesize sulfonate, sodium azide replaces the sulfonate group, and hydrogenation reduction obtains N-Boc-3-aminoazetidine, which has low purity and low yield. Methylsulfonyl chloride and sodium azide are both highly toxic, dangerous, and difficult to industrialize; the Mitsunobu reaction uses N-Boc-3-hydroxyazetidine to react with triphenylphosphine, diethyl azodicarboxylate, and phthalimide, and then hydrolyzes to obtain N-Boc-3-hydroxyazetidine. The raw materials are expensive, and the byproducts triphenylphosphine and phthalic acid hydrazide produced are difficult to separate industrially, and the economic efficiency is poor. In view of the shortcomings of the existing technology, the market needs a safe, efficient, and inexpensive preparation method for producing N-Boc-3-aminoazetidine. Summary of the invention

[0008] Purpose of the invention: The purpose of the present invention is to overcome the deficiencies of the above-mentioned prior art and provide a method for preparing N-Boc-3-aminoazetidine. To achieve the above-mentioned purpose, the technical solution provided by the present invention is as follows:

[0009] A method for preparing N-Boc-3-aminoazetidine comprises the following steps:

[0010] Step 1: N-Boc-3-hydroxyazetidine reacts with p-toluenesulfonyl chloride in the presence of a base to obtain intermediate A1;

[0011] Step 2: preparing a mixed solution A of A1 and solvent in a batching kettle;

[0012] Step 3: controlling the preheating temperature range of the microchannel reactor to be 70-80° C., adjusting the flow rates of the mixed solution A and the ammonia water, and pumping them into the microchannel reactor with metering pumps to form a reaction solution, the reaction temperature is 130-160° C., preferably 140-150° C., and the reaction pressure is 1-3 MPa, preferably 2-3 MPa;

[0013] Step 4: After the reaction materials are distilled out of the microchannel reactor, post-treatment is performed to obtain N-Boc-3-aminoazetidine.

[0014] In step 1, the base is triethylamine or sodium hydroxide; in step 2, the solvent is isopropanol, ethanol, acetonitrile, N,N-dimethylformamide or N,N-dimethylacetamide, preferably isopropanol.

[0015] In step 2, the mass ratio of A1 to the solvent is 1:3-10, preferably 1:3-8.

[0016] In step 3, the molar ratio of Al to aqueous ammonia in the reaction solution is 1:2-5, preferably 1:3-4.

[0017] In step 3, the flow rate of the mixed solution A is 20-30 ml / min, and the flow rate of the ammonia water is 2-6 ml / min.

[0018] In step 3, the reaction time is 60 to 300 s, preferably 150 to 300 s.

[0019] In step 4, the post-treatment method is: concentrating the reaction solution, adding ethyl acetate and water, extracting and separating the liquids, adding anhydrous sodium sulfate to the organic phase to dry, concentrating, and distilling to collect 70-90° C., 0.1-1 mmHg fractions to obtain N-Boc-3-aminoazetidine.

[0020] In step 3, the metering pump is a peristaltic pump, a diaphragm pump or a plunger pump.

[0021] The material of the microchannel reactor is silicon carbide, PTFE, Hastelloy, Monel or titanium.

[0022] The characteristic is that the inner diameter of the microchannel reactor is 0.5-5 mm.

[0023] Beneficial effects: The present invention reacts N-Boc-3-hydroxyazetidine with p-toluenesulfonyl chloride under the action of a base to obtain an intermediate A1, which is mixed with a solvent to obtain a mixed solution A, and the flow rates of the mixed solution A and ammonia water are adjusted, and the mixed solution A and ammonia water are respectively pumped into a microchannel reactor for post-treatment to obtain N-Boc-3-aminoazetidine. The reaction requires a relatively high temperature, and ammonia water evaporates in large quantities at high temperatures, resulting in the inability to achieve the reaction at normal pressure and high temperature. The long-term high temperature in the autoclave makes the raw materials and products easily deteriorate, resulting in low yield and purity. Due to the back pressure function of the microchannel reactor and the inner diameter of the channel reaching the millimeter level, the specific surface area of ​​contact between materials is increased, and at the same time, it has a good heat transfer effect, shortens the reaction time, avoids the formation of by-products caused by the long reaction time in the kettle, and realizes the efficient preparation of N-Boc-3-aminoazetidine; the various influencing factors of the synthesis of N-Boc-3-aminoazetidine are studied through the microchannel reactor, the optimal parameter range is found, the yield of N-Boc-3-aminoazetidine is improved, and at the same time, the temperature is efficiently controlled, and the product purity is as high as 98%.

[0024] The abbreviations of the reaction reagents involved in the instructions are as follows:

[0025] DMF: N,N-dimethylformamide;

[0026] DMAC: N,N-dimethylacetamide;

[0027] TsCl: p-toluenesulfonyl chloride;

[0028] TEA: triethylamine. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] Figure 1 The process flow chart of the embodiment is shown in FIG. DETAILED DESCRIPTION

[0030] The present invention is further illustrated below in conjunction with specific embodiments. The embodiments are implemented based on the technical solutions of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0031] Example 1: Preparation of A1

[0032]

[0033] Add 500 ml of dichloromethane, 150 g of triethylamine and 173 g of N-Boc-3-hydroxyazetidine to a 2L reaction bottle, control the internal temperature at 10-20°C, and add 220 g of p-toluenesulfonyl chloride in batches. Keep at 20°C for 2 hours, add 500 ml of water after the reaction, stir for 2 hours, separate the liquids, and spin dry to obtain 300 g of brown-yellow solid, with a yield of 92% and a HPLC purity of 95%.

[0034] Example 2

[0035] Synthesis of Compound I (N-Boc-3-aminoazetidine):

[0036]

[0037] A mixed solution A of compound A1 and isopropanol is prepared in a batching kettle, and the mass ratio of A1 to isopropanol in the mixed solution A is 1:5. The preheating temperature range of the microchannel reactor is controlled to 70°C, the flow rate of the mixed solution A is adjusted to 20ml / min, and the flow rate of the ammonia water is adjusted to 2ml / min. The molar ratio of A1 and ammonia water is 1:3, and they are pumped into the microchannel reactor for mixing and reaction. The reaction temperature range is 150°C, the reaction pressure is 2MPa, and the retention time is 200s. After the reaction materials are distilled out of the microchannel reactor, the solvent is concentrated, ethyl acetate and water are added, and the volume ratio of ethyl acetate to water is 3:2. The liquid is extracted and separated, the organic phase is dried over anhydrous sodium sulfate, and then concentrated. The fractions of 70-90°C and 0.1-1mmHg are collected by distillation to obtain N-Boc-3-aminoazetidine. The process flow is as follows: Figure 1 As shown, the material of the microchannel reactor is silicon carbide, PTFE, Hastelloy, monel or titanium, and the inner diameter of the microchannel reactor is 0.5 to 5 mm. The results are shown in Table 1 below:

[0038] Table 1 Examples of preparing compound I under different temperature conditions

[0039]

[0040]

[0041] From the results in Table 1, it can be seen that when the reaction temperature is between 140 and 150 MPa, the conversion rate of A1 and the yield of compound I are higher.

[0042] Example 3

[0043] Synthesis of Compound I (N-Boc-3-aminoazetidine):

[0044]

[0045] A mixed solution A of compound A1 and isopropanol is prepared in a batching kettle, and the mass ratio of A1 to isopropanol in the mixed solution A is 1:5. The preheating temperature range of the microchannel reactor is controlled to 70°C, the flow rate of the mixed solution A is adjusted to 20ml / min, and the flow rate of the ammonia water is adjusted to 2ml / min. The molar ratio of A1 and ammonia water is 1:3, and they are pumped into the microchannel reactor for mixing and reaction. The reaction temperature range is 150°C, the reaction pressure is 2MPa, and the retention time is 200s. After the reaction materials are distilled out of the microchannel reactor, the solvent is concentrated, ethyl acetate and water are added, and the volume ratio of ethyl acetate to water is 3:2. The liquid is extracted and separated, the organic phase is dried over anhydrous sodium sulfate, and then concentrated. The fractions of 70-90°C and 0.1-1mmHg are collected by distillation to obtain N-Boc-3-aminoazetidine. The process flow is as follows: Figure 1 As shown, the material of the microchannel reactor is silicon carbide, PTFE, Hastelloy, monel or titanium, and the inner diameter of the microchannel reactor is 0.5 to 5 mm. The results are shown in Table 2 below:

[0046] Table 2 Examples of preparing compound I under different solvents and different solvent dosage conditions

[0047]

[0048] From the results in Table 2, it can be seen that when the mass ratio of A1:solvent is 1:3-8, the yield of compound I is high, and when the mass ratio of A1:solvent is 1:5, the yield is the highest. Among the different solvents, when the solvent is isopropanol, the yield and purity are the best.

[0049] Example 4

[0050] Synthesis of Compound I (N-Boc-3-aminoazetidine):

[0051]

[0052] A mixed solution A of compound A1 and isopropanol is prepared in a batching kettle, and the mass ratio of A1 to isopropanol in the mixed solution A is 1:5. The preheating temperature range of the microchannel reactor is controlled to 70°C, the flow rate of the mixed solution A is adjusted to 20ml / min, and the flow rate of the ammonia water is adjusted to 2ml / min. The molar ratio of A1 and ammonia water is 1:3, and they are pumped into the microchannel reactor for mixing and reaction. The reaction temperature range is 150°C, the reaction pressure is 2MPa, and the retention time is 200s. After the reaction materials are distilled out of the microchannel reactor, the solvent is concentrated, ethyl acetate and water are added, and the volume ratio of ethyl acetate to water is 3:2. The liquid is extracted and separated, the organic phase is dried over anhydrous sodium sulfate, and then concentrated. The fractions of 70-90°C and 0.1-1mmHg are collected by distillation to obtain N-Boc-3-aminoazetidine. The process flow is as follows: Figure 1As shown, the material of the microchannel reactor is silicon carbide, PTFE, Hastelloy, monel or titanium, and the inner diameter of the microchannel reactor is 0.5 to 5 mm. The results are shown in Table 3 below:

[0053] Table 3 Examples of preparing compound I under different reaction pressures

[0054]

[0055] From the results in Table 3, it can be seen that when the reaction pressure is between 2 and 3 MPa, the conversion rate of A1 and the yield of compound I are higher.

[0056] Example 5

[0057] Synthesis of Compound I (N-Boc-3-aminoazetidine):

[0058]

[0059] A mixed solution A of compound A1 and isopropanol is prepared in a batching kettle, and the mass ratio of A1 to isopropanol in the mixed solution A is 1:5. The preheating temperature range of the microchannel reactor is controlled to 70°C, the flow rate of the mixed solution A is adjusted to 20ml / min, and the flow rate of the ammonia water is adjusted to 2ml / min. The molar ratio of A1 and ammonia water is 1:3, and they are pumped into the microchannel reactor for mixing and reaction. The reaction temperature range is 150°C, the reaction pressure is 2MPa, and the retention time is 200s. After the reaction materials are distilled out of the microchannel reactor, the solvent is concentrated, ethyl acetate and water are added, and the volume ratio of ethyl acetate to water is 3:2. The liquid is extracted and separated, the organic phase is dried over anhydrous sodium sulfate, and then concentrated. The fractions of 70-90°C and 0.1-1mmHg are collected by distillation to obtain N-Boc-3-aminoazetidine. The process flow is as follows: Figure 1 As shown, the material of the microchannel reactor is silicon carbide, PTFE, Hastelloy, monel or titanium, and the inner diameter of the microchannel reactor is 0.5 to 5 mm. The results are shown in Table 4 below:

[0060] Table 4 Examples of preparing compound I under different reaction time conditions

[0061]

[0062] From the results in Table 4, it can be seen that when the reaction time is between 150 and 300 seconds, the conversion rate of compound A1 reaches 100%.

[0063] Example 5

[0064] Synthesis of Compound I (N-Boc-3-aminoazetidine):

[0065]

[0066] A mixed solution A of compound A1 and isopropanol is prepared in a batching kettle, and the mass ratio of A1 to isopropanol in the mixed solution A is 1:5. The preheating temperature range of the microchannel reactor is controlled to 70°C, the flow rate of the mixed solution A is adjusted to 20ml / min, and the flow rate of the ammonia water is adjusted to 2ml / min. The molar ratio of A1 and ammonia water is 1:3, and they are pumped into the microchannel reactor for mixing and reaction. The reaction temperature range is 150°C, the reaction pressure is 2MPa, and the retention time is 200s. After the reaction materials are distilled out of the microchannel reactor, the solvent is concentrated, ethyl acetate and water are added, and the volume ratio of ethyl acetate to water is 3:2. The liquid is extracted and separated, the organic phase is dried over anhydrous sodium sulfate, and then concentrated. The fractions of 70-90°C and 0.1-1mmHg are collected by distillation to obtain N-Boc-3-aminoazetidine. The process flow is as follows: Figure 1 As shown, the material of the microchannel reactor is silicon carbide, PTFE, Hastelloy, monel or titanium, and the inner diameter of the microchannel reactor is 0.5 to 5 mm. The results are shown in Table 5 below:

[0067] Table 5 Examples of preparing compound I under different ammonia equivalent conditions

[0068]

[0069] From the results in Table 5, it can be seen that when the molar ratio of A1: ammonia water is 1:3-4, the conversion rate of compound III reaches 99% or more, and the yield and purity of compound I are relatively high.

[0070] Comparative Example 6 (tank reactor)

[0071] Synthesis of Compound I (N-Boc-3-aminoazetidine):

[0072]

[0073] A1, isopropanol and ammonia water were added to the reaction kettle, wherein the molar ratio of A1 to ammonia water was 1:4, and the mass ratio of A1 to isopropanol was 1:5, and the reaction kettle was heated to an internal temperature of 80°C, kept warm for 12 hours, and tested. The solvent was concentrated, ethyl acetate and water were added, the liquid was separated, the organic phase was dried over anhydrous sodium sulfate, and then concentrated, and the fractions at 70-90°C and 0.1-1 mmHg were collected by distillation to obtain N-Boc-3-aminoazetidine. The results are shown in Table 6 below:

[0074] Table 6 Comparative Examples of Compound I Prepared under Different Conditions in Tank Reactors

[0075]

[0076] In a kettle reaction, a large amount of ammonia volatilizes in the heating system under normal pressure. There is no reaction at low temperatures, and the solubility of ammonia water decreases at high temperatures, resulting in no reaction of the raw materials. Under pressure, there is a reaction after heating. Since the N-Boc group is not resistant to high temperatures, the thermal stability of the product and the raw material is poor. Under long-term high-temperature reactions, the yield and purity of the product are not high.

[0077] The above specific implementation methods further illustrate the purpose, technical solutions and beneficial effects of the present application in detail. It should be understood that the above are only specific implementation methods of the present application and are not used to limit the protection scope of the present application. Any modifications, equivalent substitutions, improvements, etc. made on the basis of the technical solutions of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing N-Boc-3-aminoazetidine, characterized in that: The following steps are involved: Step 1: N-Boc-3-hydroxyazetidine reacts with p-toluenesulfonyl chloride in the presence of a base to obtain intermediate A1; Step 2: preparing a mixed solution A of A1 and solvent in a batching kettle; Step 3: Control the preheating temperature range of the microchannel reactor to 70-80° C., adjust the flow rates of the mixed solution A and the ammonia water, and pump them into the microchannel reactor with metering pumps to form a reaction solution, the reaction temperature is 130-160° C., and the reaction pressure is 1-3 MPa; Step 4: After the reaction materials are distilled out of the microchannel reactor, post-treatment is performed to obtain N-Boc-3-aminoazetidine.

2. The preparation method according to claim 1, characterized in that: In step 1, the base is triethylamine or sodium hydroxide; in step 2, the solvent is isopropanol, ethanol, acetonitrile, N,N-dimethylformamide or N,N-dimethylacetamide.

3. The preparation method according to claim 1 or 2, characterized in that: In step 2, the mass ratio of A1 to the solvent is 1:3-10.

4. The preparation method according to claim 1, characterized in that: In step 3, the molar ratio of A1 to aqueous ammonia in the reaction solution is 1:2-5.

5. The preparation method according to claim 1, characterized in that: In step 3, the flow rate of the mixed solution A is 20-30 ml / min, and the flow rate of the ammonia water is 2-6 ml / min.

6. The preparation method according to claim 1, characterized in that: In step 3, the reaction time is 60 to 300 seconds.

7. The preparation method according to claim 1, characterized in that: In step 4, the post-treatment method is: concentrating the reaction solution, adding ethyl acetate and water, extracting and separating the liquids, adding anhydrous sodium sulfate to the organic phase to dry, concentrating, and distilling to collect 70-90° C., 0.1-1 mmHg fractions to obtain N-Boc-3-aminoazetidine.

8. The preparation method according to claim 1, characterized in that: In step 3, the metering pump is a peristaltic pump, a diaphragm pump or a plunger pump.

9. The preparation method according to claim 1, characterized in that: The material of the microchannel reactor is silicon carbide, PTFE, Hastelloy, Monel or titanium.

10. The preparation method according to claim 1, characterized in that: The inner diameter of the microchannel reactor is 0.5-5 mm.

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