Preparation method of 1-[2-(aminooxy) ethyoxyl] ethylene

Abstract

The invention discloses a preparation method of 1-[2-(aminooxy) ethyoxyl] ethylene, which comprises the following steps: taking N-hydroxyphthalimide and 2-chloroethyl vinyl ether as raw materials, and reacting in a reaction solvent under the action of alkali to obtain 2-[2-(ethyleneoxy) ethyoxyl] isoindoline-1, 3-diketone; then, the 2-[2-(ethyleneoxy) ethyoxyl] isoindoline-1, 3-diketone and hydrazine hydrate are subjected to a reaction in a reaction solvent, and 1-[2-(aminooxy) ethyoxyl] ethylene is obtained. According to the preparation method, the reaction controllability is better, low-temperature feeding and room-temperature feeding are not needed, the exothermic effect is not obvious, and the risk of a substrate is lower; according to the preparation method, a highly toxic product methylhydrazine does not need to be used, and hydrazine hydrate is used for replacing conditions, so that the safety is higher; the preparation method is low in raw material cost, simple in process, mild in condition, low in energy consumption, simple in product separation, better in atom economy, convenient to purify and capable of realizing amplified continuous production.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical intermediate synthesis, and in particular to a method for preparing 1-[2-(aminooxy)ethoxy]ethylene. Background Art

[0002] 1-[2-(Aminooxy)ethoxy]ethylene is an important intermediate in drug synthesis.

[0003]

[0004] The prior art discloses the following methods for preparing 1-[2-(aminooxy)ethoxy]ethylene:

[0005] Method 1: Using N-hydroxyphthalimide, 2-vinyloxyethanol, diethyl azodicarboxylate (DEAD) and triphenylphosphine as raw materials and tetrahydrofuran as reaction solvent, 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione is obtained by Mitsunonu reaction. Then, 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione and methylhydrazine are used as substrates and dichloromethane is used as reaction solvent to obtain 1-[2-(aminooxy)ethoxy]ethylene with a yield of 72%.

[0006] Reference: ASAN FOUNDATION-US2012 / 238599,2012,A1

[0007]

[0008] This approach has many disadvantages:

[0009] (1) First, this method has poor atom economy and is not environmentally friendly;

[0010] (2) The first step reaction raw material diethyl azodicarboxylate has poor safety, and methylhydrazine is a highly toxic and explosive substance, which is not suitable for industrial production;

[0011] (3) This method requires the use of triphenylphosphine and methylhydrazine for reaction, and the three wastes produced are serious (see Figure 1 ), which increases the difficulty of subsequent product post-processing and product separation and purification;

[0012] (4) Moreover, the reaction process of this method is highly exothermic and difficult to control. Summary of the invention

[0013] In view of the above-mentioned shortcomings, the object of the present invention is to provide a new method for preparing 1-[2-(aminooxy)ethoxy]ethylene to improve the production safety and atom economy of the synthesis of 1-[2-(aminooxy)ethoxy]ethylene.

[0014] To achieve this object, the present invention adopts the following technical solutions:

[0015] A method for preparing 1-[2-(aminooxy)ethoxy]ethylene comprises: firstly, using N-hydroxyphthalimide (M1) and 2-chloroethyl vinyl ether as raw materials, reacting in a reaction solvent under the action of a base to obtain 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione (M3); then, reacting 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione and hydrazine hydrate in a reaction solvent to obtain 1-[2-(aminooxy)ethoxy]ethylene (M4).

[0016] The reaction process is as follows:

[0017]

[0018] Furthermore, when preparing 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione, the reaction solvent is tetrahydrofuran; when reacting 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione with hydrazine hydrate, the reaction solvent is dichloromethane.

[0019] Further, a method for preparing 1-[2-(aminooxy)ethoxy]ethylene comprises the following steps:

[0020] (1) N-hydroxyphthalimide and a reaction solvent are added to a reaction container, and then a base and 2-chloroethyl vinyl ether are added in sequence with stirring. After the reaction is completed, the mixture is filtered and concentrated to obtain 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione.

[0021] (2) 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione (M3) and dichloromethane are added to a reaction vessel, and then an aqueous solution of hydrazine hydrate is added and stirred. After the reaction is completed, the mixture is filtered, concentrated, and distilled to obtain 1-[2-(aminooxy)ethoxy]ethylene.

[0022] Preferably, when preparing 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione, the molar ratio of N-hydroxyphthalimide to 2-chloroethyl vinyl ether is 1:1.2-1.5.

[0023] Preferably, when preparing 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione, the reaction temperature is 35-45° C. and the reaction time is 1-24 h.

[0024] Preferably, when preparing 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione, the base used is one or more of potassium carbonate, potassium tert-butoxide, and sodium hydrogen hydride, and the feed equivalent ratio of N-hydroxyphthalimide and the base is 1:1.2-2.

[0025] Preferably, the process for preparing 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione is carried out in a nitrogen atmosphere.

[0026] Preferably, in the step of preparing 1-[2-(aminooxy)ethoxy]ethylene, the molar ratio of 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione (M3) and hydrazine hydrate is 1:1.3-2; and the effective hydrazine hydrate content of the hydrazine hydrate aqueous solution is 80wt%.

[0027] Preferably, in the step of preparing 1-[2-(aminooxy)ethoxy]ethylene, the reaction temperature is 20-45°C, more preferably 20-35°C, and more preferably 30-35°C, at which the yield is higher. The reaction time is 1-24h.

[0028] Preferably, in the step of preparing 1-[2-(aminooxy)ethoxy]ethylene, the hydrazine hydrate aqueous solution is added dropwise within 30 minutes.

[0029] A method for preparing 1-[2-(aminooxy)ethoxy]ethylene comprises the following steps:

[0030] S1) adding a tetrahydrofuran solution of N-hydroxyphthalimide into a reaction vessel, and then sequentially adding a base and 2-chloroethyl vinyl ether with stirring, after the reaction is completed, filtering and concentrating to obtain 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione;

[0031] S2) Add 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione and dichloromethane to a reaction vessel, then add hydrazine hydrate aqueous solution and stir. After the reaction is completed, filter and concentrate, and distill to obtain 1-[2-(aminooxy)ethoxy]ethylene.

[0032] In some embodiments, in step S1), the reaction temperature is 35° C.-45° C., the reaction time is 1-24 h, and the molar ratio of N-hydroxyphthalimide to 2-chloroethyl vinyl ether is 1:1.2-1.5.

[0033] In other embodiments, in step S1), the reaction temperature is 35-38° C., the reaction time is 1-24 h, and the molar ratio of N-hydroxyphthalimide to potassium carbonate is 1:1.2-2.

[0034] In some embodiments, in step S2), the reaction temperature is 20-45° C., the reaction time is 1-24 h, and the molar ratio of M3 to hydrazine hydrate is 1:1.3-2.

[0035] In some embodiments, in step S2), the reaction temperature is 20°C-35°C, the reaction time is 1-24h, and the molar ratio of M3 to hydrazine hydrate aqueous solution is 1:1.4-2.

[0036] The beneficial effects of the technical solution of the present invention are:

[0037] (1) The preparation method has better reaction controllability, no need to add materials at low temperature, materials can be added at room temperature, the exothermic effect is not obvious, and the substrate hazard is lower;

[0038] (2) The preparation method does not require the use of highly toxic methylhydrazine, and using hydrazine hydrate instead makes the conditions milder and safer;

[0039] (3) The preparation method has low-cost raw materials, simple process, mild conditions, low energy consumption, simple product separation, better atom economy, easy purification, and can achieve scale-up and continuous production. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 The figure is a comparison result of the three wastes between the method of the present invention and the method of the prior art. DETAILED DESCRIPTION

[0041] The compound 1-[2-(aminooxy)ethoxy]ethylene (M4) was synthesized according to the following steps:

[0042]

[0043] Embodiment 1:

[0044] S1) Synthesis of Compound M3: In a 1L round-bottom flask containing a tetrahydrofuran (600ml) solution of N-hydroxyphthalimide (100g, 0.613mol), potassium carbonate (101.7g, 0.735mol) was added at once at a temperature range of 35°C-38°C and under a nitrogen atmosphere, the mixed solution was cooled to 0-10°C, and 2-chloroethyl vinyl ether (78.3g, 0.735mol) was slowly added dropwise to the reaction solution within 30 minutes (there was an exothermic phenomenon during the addition, which was controlled at 0-10°C). After the addition was completed, the temperature was raised to 35°C-38°C, and stirred for one hour under nitrogen protection within this temperature range until the reaction was complete. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly decompressed and dried under a water pump vacuum until there was no liquid to obtain a crude compound M3 (150g, 0.643mol, 80% purity, 100% yield).

[0045] S2) Synthesis of compound M4: M3 (150 g, 0.643 mol) and 200 mL of dichloromethane were added into a 500 ml round-bottom flask, and after stirring to dissolve, hydrazine hydrate aqueous solution (44.8 g, 0.9 mol, 80 wt%) was added dropwise, and the temperature was controlled at 20°C-25°C. The addition was completed within 30 minutes, and the temperature was kept at 20°C-25°C for overnight reaction. After the reaction was completed, the mixture was filtered, and the dichloromethane in the filtrate was dried by rotary evaporation, and then distilled to obtain compound M4 (45 g, 0.436 mol, 98% purity, 71.2%)

[0046] Embodiment 2:

[0047] S1) Synthesis of compound M3: Potassium carbonate (101.67 g, 0.735 mol) was added at once to a 1L round-bottom flask containing 600 mL of tetrahydrofuran solution of N-hydroxyphthalimide (100 g, 0.613 mol) at a temperature range of 35°C-38°C and under a nitrogen atmosphere, and the mixed solution was cooled to 0-10°C, and 2-chloroethyl vinyl ether (97.9 g, 0.919 mol) was slowly added dropwise to the reaction solution within 30 minutes (there was an exothermic phenomenon during the addition, which was controlled at 0-10°C). After the addition was completed, the temperature was raised to 35°C-38°C, and stirred for one hour under nitrogen protection within this temperature range until the reaction was complete. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly dried with a water pump until no liquid was discharged to obtain a crude compound M3 (145 g, 0.622 mol, 82% purity, 100% yield).

[0048] S2) Synthesis of compound M4: Into a 500 ml round-bottom flask, put M3 (145 g, 0.622 mol) and dichloromethane (200 mL). After stirring to dissolve, add dropwise hydrazine hydrate aqueous solution (60.1 g, 1.2 mol, 80 wt%). Control the temperature at 20-25°C and complete the addition within 30 minutes. Keep the temperature at 20-25°C to react overnight. After the reaction is completed, filter and dry the dichloromethane in the filtrate. Then distill to obtain compound M4 (50 g, 0.485 mol, 98% purity, 79.1% yield).

[0049] Embodiment 3:

[0050] S1) Synthesis of compound M3: Potassium carbonate (169.4 g, 1.2 mol) was added at once to a 1L round-bottom flask containing a tetrahydrofuran (600 mL) solution of N-hydroxyphthalimide (100 g, 0.613 mol) at a temperature range of 35°C-38°C and under a nitrogen atmosphere. After the addition, the mixture was cooled to 0-10°C, and 2-chloroethyl vinyl ether (98.0 g, 0.919 mol) was slowly added dropwise to the reaction solution within 30 minutes (there was heat release during the addition). After the addition was completed, the temperature was raised to 35°C-38°C, and stirred for one hour under nitrogen protection within this temperature range until the reaction was complete. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly dried with a water pump until there was no liquid to obtain a crude compound M3 (140 g, 0.6 mol, 85% purity, 98% yield).

[0051] S2) Synthesis of compound M4: Into a 500 ml round-bottom flask, put M3 (140 g, 0.6 mol) and dichloromethane (200 mL). After stirring to dissolve, add dropwise hydrazine hydrate aqueous solution (45 g, 0.9 mol, 80 wt%). Control the temperature at 30-35 °C and complete the addition within 30 minutes. Keep the temperature at 30-35 °C and react overnight. After the reaction is completed, filter and dry the dichloromethane in the filtrate. Then distill to obtain compound M4 (55.8 g, 0.541 mol, 99% purity, 90.1% yield).

[0052] For the above-mentioned compound, the present invention uses nuclear magnetic resonance spectrum 1H NMR nuclear magnetic spectrum to determine its structure; 1HNMR (CDCl3, Varian 400MHz) δ3.85-3.93 (4H, m), 4.03 (1H, dd, J = 6.8, 2.0Hz), 4.22 (1H, dd, J = 14.2, 2.0Hz), 5.51 (2H, brs), 6.50 (1H, dd, J = 14.2, 6.8Hz).

[0053] Taking the preparation of 100g of compound M3 as an example, the feed amount and the three waste discharge of the existing method Example 2 (US2012238599A1) and the method of the present invention (comparative example) are compared. The results are shown in Figure 1 .Depend on Figure 1 It can be seen that the method of the present invention can greatly reduce the amount of three wastes in step 1.

[0054] In summary, the method for preparing 1-[2-(aminooxy)ethoxy]ethylene of the present invention is a green, safe and low-cost synthesis method.

[0055] In the description of this specification, the description with reference to the terms "embodiment", "example", etc. means that the specific features, structures, materials or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present invention. In this specification, the schematic representation of the above terms does not necessarily refer to the same embodiment or example. Moreover, the specific features, structures, materials or characteristics described can be combined in any one or more embodiments or examples in a suitable manner.

[0056] Although the embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the claims and their equivalents.

[0057] The above content is a further detailed description of the present invention in combination with specific optimized implementation methods, and it cannot be determined that the specific implementation of the present invention is limited to these descriptions. For ordinary technicians in the technical field to which the present invention belongs, under the premise of the core concept of the present invention, several simple deductions and substitutions can also be made, which should all be deemed to belong to the protection scope of the present invention. As ordinary technicians in the technical field to which the present invention belongs, based on the present invention, several simple inferences can also be made to obtain other field applications of the compounds of the present invention, which should all be deemed to belong to the protection scope of the present invention.

Claims

1. A method for preparing 1-[2-(aminooxy)ethoxy]ethylene, comprising: Firstly, N-hydroxyphthalimide and 2-chloroethyl vinyl ether are used as raw materials, and react in a reaction solvent under the action of a base to obtain 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione; then 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione and hydrazine hydrate are reacted in a reaction solvent to obtain 1-[2-(aminooxy)ethoxy]ethylene.

2. The method for preparing 1-[2-(aminooxy)ethoxy]ethylene according to claim 1, characterized in that: The steps include: (1) adding N-hydroxyphthalimide and a reaction solvent into a reaction container, and then sequentially adding a base and 2-chloroethyl vinyl ether with stirring, after the reaction is completed, filtering and concentrating to obtain 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione; (2) 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione and a reaction solvent are added to a reaction container, and then a hydrazine hydrate aqueous solution is added. After the reaction is completed, the reaction system is filtered and concentrated, and then distilled to obtain 1-[2-(aminooxy)ethoxy]ethylene.

3. The method for preparing 1-[2-(aminooxy)ethoxy]ethylene according to claim 1 or 2, characterized in that: When preparing 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione, the reaction solvent is tetrahydrofuran, and when preparing 1-[2-(aminooxy)ethoxy]ethylene, the reaction solvent is dichloromethane.

4. The method for preparing 1-[2-(aminooxy)ethoxy]ethylene according to claim 1 or 2, characterized in that: When preparing 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione, the reaction temperature is 35-45°C, and when preparing 1-[2-(aminooxy)ethoxy]ethylene, the reaction temperature is 20-45°C.

5. The method for preparing 1-[2-(aminooxy)ethoxy]ethylene according to claim 1 or 2, characterized in that: The molar ratio of N-hydroxyphthalimide to 2-chloroethyl vinyl ether is 1:1.2-1.5; the molar ratio of N-hydroxyphthalimide to alkali is 1:1.2-2.

6. The method for preparing 1-[2-(aminooxy)ethoxy]ethylene according to claim 1 or 2, characterized in that: The feeding molar ratio of 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione and hydrazine hydrate is 1:1.3-2.

7. The method for preparing 1-[2-(aminooxy)ethoxy]ethylene according to claim 1 or 2, characterized in that: The base is selected from potassium carbonate, potassium tert-butoxide, and sodium hydrogen sulfide.

8. The method for preparing 1-[2-(aminooxy)ethoxy]ethylene according to claim 1 or 2, characterized in that: The process for preparing 2-[2-(vinyloxy)ethoxy]isoindoline-1,3-dione was carried out under a nitrogen atmosphere.

9. The method for preparing 1-[2-(aminooxy)ethoxy]ethylene according to claim 1 or 2, characterized in that: The 2-chloroethyl vinyl ether is added dropwise, and the dropping temperature is controlled at 0-10°C.

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