Preparation method and application of L-methionine lactone as raw material of refined glufosinate ammonium

Abstract

The present invention relates to a method for synthesizing L-methionine lactone, wherein L-methionine, halogenated hydrocarbon and phase transfer catalyst are dissolved in water, stirred to dissolve, then acid is added and stirred until the reaction is complete; without separating the intermediate, a base is added to the system, and an amino protecting agent is added dropwise, then stirred at room temperature to dissolve, and the solid precipitated after the reaction is completed is washed with anhydrous ethanol, filtered and dried to obtain the product L-methionine lactone hydrochloride. The reaction avoids separating the intermediate L-methionine lactone hydrochloride, and uses greener water as a reaction solvent, and synthesizes the target compound with a green and energy-saving method at a high yield. It has the advantages of short reaction time, simple operating steps, simple post-processing, less pollution, and is easy to industrialize.

Description

Technical Field

[0001] The invention relates to a method for preparing L-methionine lactone, and in particular to a method for preparing L-methionine lactone by a one-pot method in a green and environmentally friendly manner. Background Art

[0002] L-methionine lactone is an important biochemical reagent and pesticide intermediate, and an important raw material for producing refined glufosinate ammonium. It is in the form of white crystalline powder. It is generally produced by reacting L-methionine with methyl chloroacetate under the condition of phase transfer catalyst, and then separated and purified to obtain hydrochloride, which is further reacted with amino protecting reagent to produce L-methionine lactone.

[0003] At present, the existing technology synthesizes L-methionine lactone by a step-by-step method, which has complicated steps, low overall yield, and produces a large amount of wastewater, increasing the cost of three waste treatment. The operation process is very complicated and dangerous.

[0004] In view of the above reasons, a one-pot reaction is adopted without separating the intermediate to obtain the product L-methionine lactone. This process adopts a one-pot method to synthesize L-methionine lactone with high yield. This reaction avoids the separation of the intermediate L-methionine lactone hydrochloride, and uses greener water as the reaction solvent, synthesizing the target compound with high yield in a green and energy-saving method. Summary of the invention

[0005] The main problem to be solved by the invention is the defect that the intermediate needs to be separated in the process of preparing L-methionine lactone, and a one-pot method for preparing L-methionine lactone is provided, which is green, simple, efficient, low in cost and simple in post-processing.

[0006] The technical solution of the present invention is as follows:

[0007] An L-methionine lactone, the compound chemical structural formula is:

[0008]

[0009] A method for preparing L-methionine lactone by a one-pot process, the method comprising the following steps:

[0010] (1) Preparation of intermediates: Dissolve L-methionine, halogenated hydrocarbon, and phase transfer catalyst in water, stir to dissolve, then add acid and stir until the reaction is complete;

[0011] (2) Preparation of target compound: Without isolating the intermediate, add a base to the system and dropwise add an amino protecting agent, then stir at room temperature to dissolve it. After the reaction is completed, wash the precipitated solid with anhydrous ethanol, filter, and dry to obtain the product L-methionine lactone hydrochloride.

[0012]

[0013] In the steps: R includes -CH3, -CH2CH3, -CH2CH2CH3, - CH2CH2CH2CH 3、 - CH2CH2CH2CH2CH3, -CH2CH2CH2CH2CH2CH3, CH2CH2CH2CH2CH2CH2CH3, - C8H 17 , -CH(CH3)2, -C(CH3)3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2Ph, -CH2-CH=CH2, -CH2-CCH, - CH2COOH, - CH2COOCH3, - CH2COO CH2CH3, -CH2CN, -C7H 15 、2-X-C9H 19 、3-X-C8H 17 Any one of, X is Cl, Br or I.

[0014] In the step, the molar ratio of L-methionine, methyl chloroacetate, tetrabutylammonium bromide, sodium carbonate and amino protection agent is 1:1-1.5:0.05-0.1:1-1.5:1.2-1.5;

[0015] In the step, the amino protecting agent includes any one of 2,2,2-trichloroethyl chloroformate, Boc anhydride, methyl chloroacetate, p-toluenesulfonyl, trifluoroacetyl, phthalimide, 4,4'-bismethoxytrityl chloride, N-benzyloxycarbonylamino acid, methoxycarbonyl, p-methoxybenzyl, benzyl, trityl, and allyloxycarbonyl;

[0016] The alkali in the step includes any one of sodium hydroxide, sodium carbonate, potassium hydroxide, calcium hydroxide and cesium hydroxide.

[0017] The acid used in the step includes any one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid and acetic acid.

[0018] The solvent used in the step includes any one of methanol, ethanol, dichloromethane, toluene, ethyl acetate, tetrahydrofuran and water, wherein water is preferred.

[0019] The temperature in step (1) is 40-90 o C, reaction time is 1-5h.

[0020] The steps are a "one-pot" preparation method, and the intermediates do not require separation and purification steps.

[0021] The preferred solvent in the step is water, which is a green solvent.

[0022] The beneficial effects of the present invention are as follows:

[0023] 1. The present invention discloses a method for obtaining the product L-methionine lactone by a one-pot reaction without separating the intermediates.

[0024] 2. The present invention avoids the need to separate intermediates in the traditional process, which is very cumbersome and dangerous, and requires additional manpower, material and financial resources, and the yield is not very high. At the same time, a large amount of wastewater is generated, which increases the cost of three waste treatment. A new method with low preparation cost, simple operation and high reaction efficiency is provided.

[0025] 3. The present invention prepares L-methionine lactone, which is a common and important structural unit with relatively stable properties and can be used as a raw material for synthesizing refined glufosinate-ammonium intermediates to further generate refined glufosinate-ammonium.

[0026] 4. The process of preparing L-methionine lactone in the present invention is a "one-pot" preparation, and the intermediate does not need to be separated and purified. The reaction solvent is water. It is a green reaction process. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 : H NMR spectrum of compound 2a ( 1 H NMR) spectrum.

[0028] Figure 2 :C NMR spectrum of compound 2a ( 13 C NMR) graph. DETAILED DESCRIPTION

[0029] The present invention is further described below with reference to embodiments, but the scope of protection claimed by the present invention is not limited to the scope described in the embodiments.

[0030] Instruments and reagents:

[0031] Nuclear magnetic resonance spectroscopy (NMR) was tested using a Bruker AVANCE III 400 MHz Plus NMR spectrometer.

[0032] TMS was used as the internal standard and CDCl3 was used as the solvent. The solvent was evaporated under reduced pressure using an EYELA SB-1100 rotary evaporator at 65°C. Other instruments were conventional experimental instruments: ACO series electromagnetic air pump, SHZ-E circulating water vacuum pump, DZE-6120 vacuum drying oven, EB2005A electronic balance, DFX-5L / 30 low temperature constant temperature reaction bath and 2YZ-4A rotary vane vacuum oil pump. All reagents used were analytical grade.

[0033] Example 1

[0034] A method for preparing L-methionine lactone 2a comprises the following experimental steps:

[0035] 0.29 g (2 mmol) of L-methionine was weighed into a 50 ml round-bottom double-necked flask, and 1.5 ml of H2O was added, followed by 0.032 g (0.1 mmol) of tetrabutylammonium bromide. 0.30 g (2.4 mmol) of benzyl chloride was added into the round-bottom flask, and the mixture was placed in an oil bath and heated at 90 °C with stirring to dissolve the mixture. The mixture was reacted for 5 h. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature without isolating the intermediate, and then 0.297 g (2.8 mmol) of sodium carbonate was added. Then 0.699 g (3.3 mmol) of 2,2,2-trichloroethyl chloroformate was slowly added dropwise, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the solvent was evaporated, acetone was added and stirred for 30 min, the by-product sodium chloride was removed by filtration, the solvent was removed under reduced pressure, and the product 2a (478 mg) was obtained by recrystallization from anhydrous ethanol with a yield of 87%.

[0036]

[0037] 1 H NMR (400 MHz, Chloroform-d) δ 5.71 (s, 1H), 4.90 – 4.62 (m, 2H), 4.48 (q, J = 10.9, 10.0 Hz, 2H), 4.30 (td, J = 10.4, 9.4, 5.8 Hz, 1H), 2.96 –2.70 (m, 1H), 2.37 – 2.17 (m, 1H). 13 C NMR (101 MHz, CDCl3) δ 174.44, 155.50,77.32, 77.00, 76.68, 74.82, 63.99, 50.99, 28.76.

[0038] Example 2

[0039] A method for preparing L-methionine lactone 2a, a gram-scale experiment, comprises the following experimental steps:

[0040] 4.47 g (30 mmol) of L-methionine was weighed into a 100 ml round-bottom double-necked flask, and 23 ml of H2O was added, followed by 0.483 g (1.5 mmol) of tetrabutylammonium bromide. 4.536 g (36 mmol) of benzyl chloride was added into the round-bottom flask, and the mixture was placed in an oil bath and heated at 90 °C and stirred to dissolve. The mixture was reacted for 5 h. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature without separating the intermediate, and then 4.45 g (42 mmol) of sodium carbonate was added. Then 10.4 g (50 mmol) of 2,2,2-trichloroethyl chloroformate was slowly added dropwise, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the solvent was evaporated, acetone was added and stirred for 30 min, the by-product sodium chloride was removed by filtration, the solvent was removed under reduced pressure, and the product 2a (6.98 g) was obtained by recrystallization from anhydrous ethanol with a yield of 84%.

[0041]

[0042] Example 3

[0043] A method for preparing L-methionine lactone 2a, the reaction temperature is 0 o C includes the following experimental steps:

[0044] Weigh 0.29 g (2 mmol) of L-methionine into a 50 ml round-bottom double-necked flask, add 1.5 ml of H2O, then add 0.032 g (0.1 mmol) of tetrabutylammonium bromide, add 0.23 g (2.4 mmol) of ethyl chloride into the round-bottom flask, place it in an oil bath, heat it at 90 °C, stir it to dissolve it, react for 5 h, monitor the reaction by TLC, and after the reaction is completed, cool it to room temperature without separating the intermediate, then add 0.297 g (2.8 mmol) of sodium carbonate, then slowly add 0.699 g (3.3 mmol) of 2,2,2-trichloroethyl chloroformate dropwise, and add 0. o C and stirred for 1 h. After the reaction was completed, the solvent was evaporated, acetone was added and stirred for 30 min, the by-product sodium chloride was removed by filtration, the solvent was removed under reduced pressure, and the product 2a (440 mg) was obtained by recrystallization from anhydrous ethanol with a yield of 80%.

[0045] Example 4

[0046] A method for preparing L-methionine lactone, using ethyl chloroformate as an amino protecting agent, comprises the following experimental steps:

[0047] Weigh 0.29 g (2 mmol) of L-methionine into a 50 ml round-bottom double-necked flask, add 1.5 ml of H2O, then add 0.030 g (0.1 mmol) of tetrabutylammonium chloride, add 0.26 g (2.4 mmol) of methyl chloroacetate into the round-bottom flask, place it in an oil bath and heat it at 90 °C with stirring to dissolve it, react for 5 h, and after the reaction is completed by TLC monitoring, cool to room temperature without separating the intermediate, then add 0.297 g (2.8 mmol) of sodium carbonate, and then slowly add 0.358 g (3.3 mmol) of ethyl chloroformate dropwise, stir at room temperature for 1 h, after the reaction is completed, evaporate the solvent, add acetone and stir for 30 min, filter to remove the by-product sodium chloride, remove the solvent under reduced pressure, and recrystallize from anhydrous ethanol to obtain the product 2b (297 mg) with a yield of 86%.

[0048]

[0049] Example 5

[0050] A method for preparing L-methionine lactone, using Boc anhydride as an amino protecting agent, comprises the following experimental steps:

[0051] 0.29 g (2 mmol) of L-methionine was weighed into a 50 ml round-bottom double-necked flask, 1.5 ml of H2O was added, and then 0.032 g (0.1 mmol) of tetrabutylammonium bromide was added. 0.26 g (2.4 mmol) of methyl chloroacetate was added into the round-bottom flask, and the mixture was placed in an oil bath and heated at 90 °C and stirred to dissolve. The mixture was reacted for 5 h. After the reaction was completed as monitored by TLC, the mixture was cooled to room temperature without separating the intermediate, and then 0.297 g (2.8 mmol) of sodium carbonate was added. Then 0.719 g (3.3 mmol) of Boc anhydride was slowly added dropwise, and the mixture was stirred at room temperature for 1 h. After the reaction was completed, the solvent was evaporated, acetone was added and stirred for 30 min, the by-product sodium chloride was removed by filtration, the solvent was removed under reduced pressure, and the product 2c (519 mg) was obtained by recrystallization from anhydrous ethanol with a yield of 78%.

[0052]

[0053] Example 6

[0054] The method for preparing a refined glufosinate-ammonium intermediate generated by ring-opening of L-methionine lactone comprises the following experimental steps:

[0055] Weigh 0.55 g (2 mmol) of compound 2a into a round-bottom flask, add 0.014 g (0.1 mmol) of BF3 ether, then add 4 ml of anhydrous ethanol, stir in a 50 °C oil bath to dissolve it, then slowly add 0.476 g (4 mmol) of dichlorothionyl chloride dropwise, mechanically for 5 h. After the reaction is completed as monitored by TLC, the solvent is removed under reduced pressure, and the mixture is extracted with dichloromethane (3×25 ml) and water. The organic layers are combined and the solvent is removed under reduced pressure to obtain the target compound glufosinate intermediate 3 (600 mg) as an organic oil with a yield of 88%.

[0056]

[0057] The invention provides a method for obtaining the product L-methionine lactone through a one-pot reaction without separating the intermediate. The process adopts a one-pot method to synthesize L-methionine lactone with high yield. The reaction avoids separating the intermediate L-methionine lactone hydrochloride, and adopts greener water as a reaction solvent to synthesize the target compound with high yield in a green and energy-saving method. It has the advantages of short reaction time, simple operation steps, simple post-treatment, less pollution, and is easy to industrialize.

[0058] The above-mentioned embodiments are only preferred technical solutions of the present invention and should not be regarded as limitations of the present invention. The embodiments and features in the embodiments of the present application can be arbitrarily combined with each other without conflict. The protection scope of the present invention shall be the technical solutions recorded in the claims, including the equivalent replacement solutions of the technical features in the technical solutions recorded in the claims. That is, equivalent replacement improvements within this scope are also within the protection scope of the present invention.

Claims

1. A method for preparing L-methionine lactone, a raw material of glufosinate ammonium, characterized in that: The steps include: (1) Preparation of intermediates: L-methionine, benzyl chloride and a phase transfer catalyst are dissolved in water and stirred to dissolve, then an acid is added and stirred until the reaction is complete. The phase transfer catalyst used is any one of benzyltriethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride and tetradecyltrimethylammonium chloride. The temperature is 40-90°C and the reaction time is 1-5h. (2) Preparation of target compound: Without isolating the intermediate, add a base to the system and dropwise add the amino protecting reagent 2,2,2-trichloroethyl chloroformate, then stir at room temperature to dissolve it. The reaction is carried out at a temperature of 0-25°C for 1-4 hours. After the reaction is completed, the precipitated solid is washed with anhydrous ethanol, filtered, and dried to obtain the product L-methionine lactone hydrochloride.

2. The method according to claim 1, characterized in that The alkali used includes any one of sodium hydroxide, sodium carbonate, potassium hydroxide, calcium hydroxide, and cesium hydroxide.

3. The method according to claim 1, characterized in that In the reaction step, the molar ratio of L-methionine, benzyl chloride, phase transfer catalyst, base and amino protection reagent is 1:1-1.5:0.05-0.1:1-1.5:1.2-1.

5.

4. The method according to claim 1, characterized in that: The acid used in the reaction step (1) includes any one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid and acetic acid.

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