Microchannel continuous flow preparation method for (S)-4-chloro-2-aminobutyric acid hydrochloride

Abstract

The present invention provides a continuous flow preparation method for preparing (S)-4-chloro-2-aminobutyric acid hydrochloride shown in formula (I), characterized in that: the method comprises allowing a hydrochloric acid solution of L-homoserine of formula (II) to flow through a continuous flow reactor for reaction, and the reaction obtains a reaction solution of (S)-4-chloro-2-aminobutyric acid hydrochloride shown in formula (I), and the reaction temperature is 120° C. to 180° C. The present invention achieves the goals of environmental protection, cost saving and high yield.

Description

Technical Field

[0001] The invention relates to a microchannel continuous flow preparation method of (S)-4-chloro-2-aminobutyric acid hydrochloride. Background Art

[0002] As a highly effective, low-toxic, broad-spectrum contact-type organophosphorus herbicide, glufosinate is used in increasing quantities year by year, and has huge market potential. The glufosinate commonly produced is a racemate of L-glufosinate and D-glufosinate (i.e., a mixture of L-glufosinate and D-glufosinate, each accounting for half), wherein D-glufosinate has no biological activity, and the biological activity of L-glufosinate is twice that of the racemate.

[0003] As an intermediate for synthesizing L-phosphinothricin, the preparation of (S)-4-chloro-2-aminobutyrate has attracted extensive attention. U.S. Patent Application US20060135602A1 discloses that (S)-4-chloro-2-aminobutyrate is prepared by reacting L-homoserine (i.e., L-2-amino-4-hydroxybutyric acid) with thionyl chloride and ethanol. However, in this method, the thionyl chloride consumption is too large, the cost is too high, and a large amount of waste acid and waste water are produced.

[0004] Chinese patent application CN109369432A discloses that (S)-2-aminobutyrolactone hydrochloride (ie, L-homoserine lactone hydrochloride) is first subjected to ring-opening alcoholysis to obtain (S)-homoserine ester, and then subjected to chlorination to prepare (S)-4-chloro-2-aminobutyrate.

[0005] However, there is still a need to develop alternative methods for preparing (S)-4-chloro-2-aminobutyrate in order to simultaneously achieve the goals of environmental protection, cost savings, and high yield. Summary of the invention

[0006] To this end, after in-depth research, the inventors of the present invention provide a continuous flow preparation method for preparing (S)-4-chloro-2-aminobutyric acid hydrochloride, which comprises the following steps:

[0007]

[0008] A hydrochloric acid solution of L-homoserine of formula (II) is passed through a continuous flow reactor for reaction to obtain a reaction solution of (S)-4-chloro-2-aminobutyric acid hydrochloride of formula (I), wherein the reaction temperature is 120° C. to 180° C.

[0009] The temperature of the aforementioned reaction is 120° C. to 180° C. In certain embodiments, the reaction temperature can be 125° C., 130° C., 135° C., 140° C., 145° C., 150° C., 155° C., 160° C., 165° C., 170° C., 175° C., or 180° C.

[0010] Furthermore, the temperature of the above reaction is 150°C to 170°C.

[0011] Furthermore, the temperature of the aforementioned reaction is 160°C to 170°C.

[0012] Furthermore, the temperature of the aforementioned reaction is 165°C to 170°C.

[0013] Furthermore, the temperature of the above reaction is 165°C.

[0014] The continuous flow reactor is one or a combination of a microchannel reactor or a tubular reactor.

[0015] Furthermore, the aforementioned continuous flow reactor is a microchannel continuous flow reactor.

[0016] The aforementioned microchannel continuous flow reactor comprises one or more separate fluid modules connected in sequence; preferably, the microchannel continuous flow reactor comprises 1 to 15 separate fluid modules connected in sequence. In a specific embodiment of the present invention, the microchannel continuous flow reactor is a Corning microchannel reactor, comprising 5 separate fluid modules connected in sequence, of which there are 4 reaction modules, with a total volume of 34 mL (excluding the reactor module used for cooling the reaction solution).

[0017] The residence time of the aforementioned reaction is 2 min to 60 min. In certain embodiments, the residence time can be 2.2 min, 2.4 min, 2.6 min, 2.8 min, 3 min, 3.2 min, 3.4 min, 3.6 min, 3.8 min, 4 min, 4.5 min, 5 min, 5.5 min, 6 min, 6.5 min, 6.8 min, 7 min, 7.5 min, 8 min, 8.5 min, 9 min, 9.5 min, 10 min, 11 min, 12 min, 13 min, 14 min, 15 min, 16 min, 18 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min, 55 min or 60 min.

[0018] Furthermore, the residence time of the above reaction is 3 min to 15 min.

[0019] Furthermore, the residence time of the above reaction is 4 min to 10 min.

[0020] Furthermore, the residence time of the above reaction is 4.5 min to 7 min.

[0021] Furthermore, the residence time of the aforementioned reaction is 6.8 min.

[0022] The aforementioned individual fluid modules are made of glass, ceramics, silicon carbide or glass-ceramics.

[0023] In the aforementioned L-homoserine hydrochloric acid solution, the molar ratio of L-homoserine to HCl is 1 to 4 to 20. In certain embodiments, the molar ratio of L-homoserine to HCl may be 1 to 4.5, 1 to 5, 1 to 5.5, 1 to 6, 1 to 6.5, 1 to 6.75, 1 to 7, 1 to 7.5, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19 or 1 to 20.

[0024] Furthermore, in the aforementioned L-homoserine hydrochloric acid solution, the molar ratio of L-homoserine to HCl is 1:6.5-15.

[0025] Furthermore, in the aforementioned L-homoserine hydrochloric acid solution, the molar ratio of L-homoserine to HCl is 1:7.5-15.

[0026] Furthermore, in the aforementioned L-homoserine hydrochloric acid solution, the molar ratio of L-homoserine to HCl is 1:7.5-13.

[0027] The aforementioned reaction may include the step of adding concentrated sulfuric acid, that is, adding a certain amount of concentrated sulfuric acid to the aforementioned L-homoserine hydrochloric acid solution.

[0028] In the L-homoserine hydrochloric acid solution after adding concentrated sulfuric acid, the molar ratio of concentrated sulfuric acid (calculated as H2SO4) to L-homoserine is 0.1 to 0.4 to 1. In certain embodiments, the molar ratio of concentrated sulfuric acid (calculated as H2SO4) to L-homoserine may be 0.12 to 1, 0.15 to 1, 0.17 to 1, 0.2 to 1, 0.22 to 1, 0.25 to 1, 0.27 to 1, 0.3 to 1, 0.32 to 1, 0.35 to 1, 0.37 to 1, or 0.4 to 1.

[0029] Furthermore, in the L-homoserine hydrochloric acid solution after adding concentrated sulfuric acid, the molar ratio of concentrated sulfuric acid (calculated as H2SO4) to L-homoserine is 0.2 to 0.3:1, preferably 0.25:1.

[0030] As a preferred embodiment, the reaction liquid enters the cooling module after flowing out of the reaction module, but the residence time of the reactor module for temperature control and cooling of the reaction liquid is not included in the calculation of the aforementioned reaction residence time. In a specific embodiment, in order to simplify the temperature control and cooling operation, a module of a microchannel continuous flow reactor is also used, but those skilled in the art are aware that a variety of alternatives can be adopted to achieve the same effect, such as a temperature-controlled container. The reaction also includes the step of cooling the aforementioned reaction liquid through a microchannel continuous flow reactor, and the cooling temperature is 45°C to 70°C, preferably 60°C.

[0031] The hydrochloric acid solution of L-homoserine of the formula (II) is obtained by dissolving L-homoserine (II) in a hydrochloric acid solution.

[0032] The mass concentration of the hydrochloric acid is 18% to 36%.

[0033] Furthermore, the mass concentration of the hydrochloric acid is 30% to 36%.

[0034] Furthermore, the mass concentration of the hydrochloric acid is 30%.

[0035] The above reaction also includes the step of introducing hydrogen chloride into the microchannel continuous flow reactor, specifically, introducing hydrogen chloride into any one or more separate fluid modules of the microchannel continuous flow reactor. In a specific embodiment of the present invention, there are a total of 5 separate fluid modules (the first to fourth blocks are reaction modules, and the fifth block is a cooling module), and hydrogen chloride gas is introduced into the third module.

[0036] In the aforementioned step of introducing hydrogen chloride, the molar ratio of the introduced hydrogen chloride to L-homoserine is 0.5 to 5 to 1. In certain embodiments, the molar ratio of the introduced hydrogen chloride to L-homoserine is 0.6 to 1, 0.7 to 1, 0.8 to 1, 0.9 to 1, 1.0 to 1, 1.1 to 1, 1.2 to 1, 1.5 to 1, 2 to 1, 2.5 to 1, 3 to 1, 4 to 1 or 5 to 1.

[0037] The above reaction is carried out under normal pressure, natural pressure or pressurized state.

[0038] The beneficial effects of the invention include safe and efficient production, simple and environmentally friendly operation, cost saving and higher yield.

[0039] Obviously, according to the above contents of the present invention, in accordance with common technical knowledge and customary means in the art, without departing from the above basic technical ideas of the present invention, other various forms of modification, replacement or change may be made.

[0040] The above contents of the present invention are further described in detail below through specific implementation methods in the form of embodiments. However, this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above contents of the present invention belong to the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 This is a schematic diagram of the reaction device of Example 1 of the present invention.

[0042] Figure 2 The HPLC spectrum of the reaction product of Example 1 of the present invention.

[0043] Figure 3 This is the ee value spectrum of the reaction product of Example 1 of the present invention.

[0044] Figure 4 This is a schematic diagram of the reaction apparatus of Example 23 of the present invention. Specific embodiments

[0045] Examples of the present disclosure will be described in detail below.

[0046] Example 1

[0047] The microchannel continuous flow reactor used in this embodiment is a Corning microchannel reactor. The system has a total of 5 modules, and the reaction volume of each module is 8.5 mL. Among them, the first 4 modules are reaction modules, and the heating medium is set to 165°C, that is, the module reaction temperature is 165°C; the fifth module is a condensation module, and the condensation medium temperature is set to 60°C.

[0048] Experimental process: 43.23 g of L-homoserine (hereinafter referred to as 0#) (molecular weight 119.1 g / mol, ee value 99.4%, 1 eq) was dissolved in 574.1 g of 30 wt% hydrochloric acid (calculated as HCl, molecular weight 36.5 g / mol, 13 eq), and homogeneous material A was obtained by ultrasonic dissolution at room temperature. The density of material A was 1.16 g / mL. Material A was pumped into a microchannel continuous flow reactor at a flow rate of 5 mL / min, and a reaction solution was obtained after continuous reaction and continuous condensation. The reaction residence time was 6.8 min.

[0049] After the reaction reached equilibrium, the reaction solution was collected continuously for 1 h. After post-treatment, 34.4 g of product 1# (molecular weight 174.02 g / mol, ee value 99.5%) was obtained. The yield of product 1# based on raw material 0# (1 h feed amount) was 98.11%.

[0050] The schematic diagram of the reaction device is as follows Figure 1 The reaction results are shown in Figure 2 and Figure 3 shown.

[0051] Example 2-19

[0052] According to the method of Example 1, the hydrochloric acid concentration and HCl equivalent were adjusted, the reaction temperature in the reaction module was adjusted, and the flow rate of material A pumped into the reactor was adjusted. The specific reaction conditions and reaction results are shown in Table 1 below:

[0053] Table 1

[0054] Examples Hydrochloric acid concentration HCl equivalent Reaction temperature Material A flow rate Dwell time Yield wt% eq ℃ mL / min min 2 18.57％ 4.5 120 10 3.40 16.57％ 3 18.57％ 4.5 160 10 3.40 38.18％ 4 30％ 6.75 160 5 6.80 87.75％ 5 30％ 7.87 160 5 6.80 90.25％ 6 30％ 8.99 160 5 6.80 91.75％ 7 30％ 13.0 160 5 6.80 92.80％ 8 30％ 15.0 160 5 6.80 91.80％ 7 30％ 13.0 160 5 6.80 92.80％ 1 30％ 13.0 165 5 6.80 98.11％ 9 30％ 13.0 170 5 6.80 96.20％ 5 30％ 7.87 160 5 6.80 90.25％ 10 30％ 7.87 165 5 6.80 93.13％ 11 30％ 7.87 170 5 6.80 88.24％ 12 30％ 7.87 165 10 3.40 92.16％ 13 30％ 7.87 165 7.5 4.53 98.45％ 10 30％ 7.87 165 5 6.80 93.13％ 14 30％ 7.87 165 2.5 13.6 91.31％ 15 30％ 7.87 170 5 6.80 95.15％ 5 30％ 7.87 160 5 6.80 90.25％ 16 36％ 7.87 160 5 6.80 85.76％ 17 36％ 13 160 5 6.80 92.10％ 18 36％ 13 150 5 6.80 86.45％ 19 36％ 13 130 5 6.80 55.54％

[0055] Examples 20-22

[0056] The microchannel continuous flow reactor used in this embodiment is a Corning microchannel reactor. The system has a total of 5 modules, and the reaction volume of each module is 8.5 mL. Among them, the first 4 modules are reaction modules, and the heating medium is set to 130°C, 160°C, and 170°C, respectively, that is, the module reaction temperatures are 130°C, 160°C, and 170°C, respectively; the fifth module is a condensation module, and the condensation medium temperature is set to 60°C.

[0057] Experimental process: 43.23 g of L-homoserine (hereinafter referred to as 0#) (molecular weight 119.1 g / mol, ee value 99.4%, 1 eq) was dissolved in 574.1 g of 30 wt% hydrochloric acid (calculated as HCl, molecular weight 36.5 g / mol, 13 eq), and 8.9 g of 98 wt% concentrated sulfuric acid (molecular weight 98 g / mol, 0.25 eq) was added, and homogeneous material A was obtained by ultrasonic dissolution at room temperature. Material A was pumped into the microchannel continuous flow reactor at a flow rate of 5 mL / min, and a reaction solution was obtained after continuous reaction and continuous condensation, and the reaction residence time was 6.8 min. .

[0058] After the reaction is balanced, the reaction solution is collected continuously for 1 hour, and product 1# is obtained after post-treatment, and the yield of product 1# based on raw material 0# (1 hour feed amount) is calculated. The schematic diagram of the reaction device is the same as that of Example 1, and the reaction results are shown in Table 2 below.

[0059] Table 2

[0060] Examples Hydrochloric acid concentration HCl equivalent Reaction temperature Material A flow rate Dwell time Yield wt% eq ℃ mL / min min <![CDATA[20 b ]]> 30％ 13 130 5 6.80 45.33％ <![CDATA[21 b ]]> 30％ 13 160 5 6.80 93.12％ <![CDATA[22 b ]]> 30％ 13 170 5 6.80 95.72％

[0061] b: The amount of concentrated sulfuric acid used is 0.25eq (calculated as H2SO4).

[0062] Embodiment 23

[0063] The microchannel continuous flow reactor used in this embodiment is a Corning microchannel reactor. The system has a total of 5 modules, and the reaction volume of each module is 8.5 mL. Among them, the first 4 modules are reaction modules, and the heating medium is set to 170°C, that is, the module reaction temperature is 170°C; the fifth module is a condensation module, and the condensation medium temperature is set to 60°C.

[0064] Experimental process: 43.23 g of L-homoserine (molecular weight 119.1 g / mol, purity 95%, ee value 99.4%, 1 eq) was dissolved in 574.1 g of 30 wt% hydrochloric acid (calculated as HCl, molecular weight 36.5 g / mol, 13 eq), and homogeneous material A was obtained by ultrasonic dissolution at room temperature. The density of material A was 1.16 g / mL. Material A was pumped into the microchannel continuous flow reactor at a flow rate of 5 mL / min, and hydrogen chloride gas was introduced into the third module of the reaction module at a gas flow rate of 0.220 g / min, and a reaction solution was obtained after continuous reaction and continuous condensation.

[0065] After the reaction reached equilibrium, the reaction solution was collected continuously for 1 h. After post-treatment, 34.1 g of product 1# (ee value 99.6%) was obtained. The yield of product 1# based on raw material 0# (1 h feed amount) was 97.3%.

[0066] The schematic diagram of the reaction device is as follows Figure 4 shown.

Claims

1. A continuous flow preparation method for (S)-4-chloro-2-aminobutyric acid hydrochloride represented by formula (I), characterized in that: The method comprises the following steps: A hydrochloric acid solution of L-homoserine of formula (II) is passed through a continuous flow reactor for reaction to obtain a reaction solution of (S)-4-chloro-2-aminobutyric acid hydrochloride of formula (I), wherein the reaction temperature is 120° C. to 180° C.

2. The method according to claim 1, characterized in that: The continuous flow reactor is a microchannel continuous flow reactor.

3. The method according to claim 1 or 2, characterized in that: The reaction temperature is 150°C to 170°C, preferably 160°C to 170°C, more preferably 165°C to 170°C.

4. The method according to any one of claims 1 to 3, characterized in that: The residence time of the reaction is 2 min to 60 min, preferably 3 min to 15 min, more preferably 4 min to 10 min, most preferably 4.5 min to 7 min.

5. The method according to any one of claims 1 to 4, characterized in that: In the L-homoserine hydrochloric acid solution, the molar ratio of L-homoserine to HCl is 1:4-20, preferably 1:6.5-15, more preferably 1:7.5-15, and most preferably 1:7.5-13.

6. The method according to any one of claims 1 to 5, characterized in that: The method further comprises cooling the reaction solution through a microchannel reactor, wherein the cooling temperature is 45° C. to 70° C., preferably 60° C.

7. The method according to any one of claims 1 to 6, characterized in that: The hydrochloric acid solution of L-homoserine of formula (II) is obtained by dissolving L-homoserine (II) in a hydrochloric acid solution.

8. The method according to claim 7, characterized in that: The mass concentration of the hydrochloric acid is 18% to 36%, preferably 30% to 36%, more preferably 30%.

9. The method according to any one of claims 1 to 8, characterized in that: The reaction further comprises the step of introducing hydrogen chloride into the microchannel continuous flow reactor.

10. The method according to any one of claims 1 to 9, characterized in that: The reaction is carried out under normal pressure, natural pressure or pressurized state.

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