Methods of making glufosinate or analogs thereof

Abstract

Methods relating to the preparation of glufosinate or its analogs and intermediates thereof. The methods include, a) reacting a compound of formula (II), an alcohol of formula (III), and a compound of formula (V), b) hydrolyzing the product of the above reaction to obtain glufosinate or its analog of formula (IV).

Description

Technical Field

[0001] This invention relates to a method for preparing glufosinate or its analogues and intermediates. Background Technology

[0002] Glufosinate is a highly effective, broad-spectrum, low-toxicity, non-selective (non-selective) organophosphorus herbicide developed by Hearst Corporation in the 1980s. It has partial systemic action and can be used to control annual and perennial dicotyledonous and grassy weeds.

[0003] Existing preparation methods are complex and limited by raw materials, so it is necessary to develop a new method for preparing glufosinate or its analogues. Summary of the Invention

[0004] This invention provides a method for preparing glufosinate of formula (IV) or its analogues.

[0005]

[0006] The method includes:

[0007] a) React the compound of formula (II), the alcohol of formula (III), and the compound of formula (V)

[0008]

[0009] b) Hydrolyze the product of the above reaction to obtain glufosinate or its analogues of formula (IV).

[0010] R1 and R2 are each independently selected from C1-C 16 Alkyl, C6-C 12 Aryl, C3-C 10 cycloalkyl, C7-C 12 Alkyl and C7-C 12 Aryl group, each group being unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, dialkyl or dialkylamino; for example, R1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, phenyl, benzyl, phenethyl, phenylpropyl, methylphenyl, ethylphenyl and propylphenyl, and R2 is C1-C8 alkyl;

[0011] Hal1 is a halogen.

[0012] Hal 2 Halogen,

[0013] PG is a hydrogen or amino protecting group. When PG is an amino protecting group, the method further includes removing the amino protecting group.

[0014] X is either -OR3 or -NR3R4, where R3 is C1-C 16 Alkyl, C6-C 16 Aryl, C3-C 16 cycloalkyl, C7-C 16 Aryl or C7-C 16 Alkyl aryl, wherein each of the groups is unsubstituted or substituted with a C1-C6 alkyl group; R4 is hydrogen or as defined by R3. Attached Figure Description

[0015] Figure 1 The reaction flow charts for Examples A1 to A3 are shown.

[0016] Figure 2 The reaction flow diagrams are for Examples B1 to B3.

[0017] Figure 3 The reaction flow diagrams for Examples C1 to C2 are shown below.

[0018] Figure 4 The reaction flow diagrams for Examples D1 to D14 are shown. Detailed Implementation

[0019] The invention will be described in more detail in the following paragraphs. Unless expressly stated to the contrary, each aspect thus described may be combined with any one or more other aspects. In particular, any preferred or advantageous feature may be combined with any one or more preferred or advantageous features.

[0020] In the context of this invention, unless the context otherwise indicates, the terms used will be interpreted according to the following definitions.

[0021] As used herein, the singular forms “a,” “an,” “the,” and “the” include both singular and plural references to the object, unless the context clearly indicates otherwise.

[0022] As used herein, the terms “comprising” and “consisting of” are synonymous with “including,” “containing,” or “containing”, and are inclusive or open-ended, and do not exclude other non-enumerated members, elements, or method steps.

[0023] The list of numerical endpoints includes all numbers and fractions that fall within the corresponding range, as well as the listed endpoints.

[0024] Unless otherwise defined, all terms (including technical and scientific terms) used in the disclosure of this invention shall have the meanings commonly understood by one of ordinary skill in the art to which this invention pertains.

[0025] definition

[0026] The term "microchannel reactor" as used in this article refers to a continuous flow reactor with an effective diameter of less than 5 mm for the reaction channel.

[0027] The term "tubular reactor" as used in this article refers to a continuous flow reactor in which the reaction channel is not filled with packing material and the effective diameter of the reaction channel is larger than that of the "microchannel reactor" mentioned above.

[0028] The term "tubular packed reactor" as used in this article refers to a continuous flow reactor in which the reaction channel is filled with packing material and the effective diameter of the reaction channel is larger than the effective diameter of the reaction channel of the aforementioned "microchannel reactor".

[0029] The term "residence time" as used in this article refers to the time from the start of the reaction when various reactants are simultaneously mixed in the reactor until they leave the reactor after the reaction. Residence time can be calculated using the following methods:

[0030] Duration T s The calculation method is as follows:

[0031]

[0032]

[0033] Wherein: T s - Dwell time, seconds (s);

[0034] V - Total reactor volume, mL;

[0035] Q - Total volumetric flow rate of reactants, mL / min;

[0036] G i - Mass flow rate of each reactant, g / min;

[0037] ρ i - Density of each reactant, g / mL.

[0038] In this disclosure, when ammonia is involved as a reactant, ammonia is not included as a reactant in the calculations described above.

[0039] As used herein, the term "amino protecting group" refers to a group that can be attached to a nitrogen atom of an amino group, thereby protecting the amino group from reaction and allowing it to be readily removed in subsequent reactions. Suitable amino protecting groups include, but are not limited to, the following protecting groups: urethane groups of the formula -C(O)OR, wherein R is, for example, methyl, ethyl, tert-butyl, benzyl, phenethyl, CH2=CH-CH2-, etc.; amide groups of the formula -C(O)-R′, wherein R′ is, for example, methyl, ethyl, phenyl, trifluoromethyl, etc.; N-sulfonyl derivatives of the formula -SO2-R″, wherein R″ is, for example, tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, etc.

[0040] Methods for preparing compounds of formula (I)

[0041] This invention provides a method for preparing compound (I).

[0042]

[0043] The method comprises reacting a compound of formula (II) with an alcohol of formula (III) in a molar ratio greater than 1:2.

[0044]

[0045] R1 and R2 are each independently selected from C1-C 16 Alkyl, C6-C 12 Aryl, C3-C 10 cycloalkyl, C7-C 12 Alkyl and C7-C 12 Aryl group, each group being unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy, dialkyl or dialkylamino; for example, R1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, phenyl, benzyl, phenethyl, phenylpropyl, methylphenyl, ethylphenyl and propylphenyl, and R2 is C1-C8 alkyl;

[0046] Hal1 is a halogen.

[0047] In a preferred embodiment, R1 is C1-C 16 The alkyl, cyclohexyl, cyclopentyl, or phenyl groups are used, wherein each group is unsubstituted or substituted by a C1-C6 alkyl, C1-C6 alkoxy, or dialkylamino group; preferably phenyl or C1-C6 alkyl, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl; more preferably C1-C4 alkyl, such as methyl, ethyl, propyl, or butyl; most preferably methyl.

[0048] In another preferred embodiment, R2 is a C1-C6 alkyl group, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl; preferably a C1-C4 alkyl group, such as methyl, ethyl, propyl, or butyl; more preferably ethyl.

[0049] In another preferred embodiment, Hal1 is fluorine, chlorine, bromine or iodine, preferably chlorine.

[0050] In a preferred embodiment, the compound of formula (II) is dichloromethylphosphine, dichloroethylphosphine, dichloropropylphosphine, dichlorobutylphosphine, dichlorocyclohexylphosphine, dichlorophenylphosphine, dichloro-4-methoxyphenylphosphine, or dichloro-4-dimethylaminophenylphosphine.

[0051] In another preferred embodiment, the alcohol in formula (III) is methanol, ethanol, n-propanol, isopropanol or n-butanol, preferably ethanol, n-propanol, isopropanol or n-butanol, more preferably n-butanol or ethanol, and most preferably ethanol.

[0052] In one preferred embodiment, the molar ratio of the compound of formula (II) to the alcohol of formula (III) is 1:(0.1-1.9), preferably 1:(0.5-1.5), and more preferably 1:(0.9-1.1). For example, the molar ratio of the compound of formula (II) to the alcohol of formula (III) is 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, or 1:1.9, with 1:1 being the most preferred.

[0053] In another preferred embodiment, the reaction is carried out at a temperature of -35°C to 50°C, preferably -30°C to 30°C, more preferably -20°C to 0°C, and most preferably -10°C to 0°C. For example, the reaction temperature can be -35°C, -34°C, -33°C, -32°C, -31°C, -30°C, -29°C, -28°C, -27°C, -26°C, -25°C, -24°C, -23°C, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C, -14°C, -13°C, -12°C, -11°C, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C. 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃ or 50℃.

[0054] In another preferred embodiment, the reaction is carried out in a continuous flow reactor selected from microchannel reactors, tubular reactors, tubular packed reactors, stirred tank reactors, or any combination thereof. For example, the reactor consists of one or more microchannel continuous flow reactors, or the reactor consists of one or more microchannel continuous flow reactors and one or more tubular reactors.

[0055] In another preferred embodiment, the temperature within the continuous flow reactor group is -35°C to 50°C, preferably -30°C to 30°C, more preferably -20°C to 30°C, and most preferably -10°C to 30°C. For example, the temperature can be -35°C, -34°C, -33°C, -32°C, -31°C, -30°C, -29°C, -28°C, -27°C, -26°C, -25°C, -24°C, -23°C, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C, -14°C, -13°C, -12°C, -11°C, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, etc. 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃ or 50℃.

[0056] The flow rates of compounds of formula (II) and alcohols of formula (III) are not limited and can vary with the size of the equipment.

[0057] In another preferred embodiment, when the continuous flow reactor is composed of a microchannel reactor, the residence time of the compound of formula (II) and the alcohol of formula (III) in the continuous flow reactor is from 0.1 seconds to 300 seconds, preferably from 1 second to 30 seconds, and more preferably from 15 seconds to 28 seconds. For example, the dwell time can be 0.1 seconds, 0.2 seconds, 0.5 seconds, 0.8 seconds, 1 second, 1.2 seconds, 1.4 seconds, 1.6 seconds, 1.8 seconds, 2 seconds, 2.5 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 11 seconds, 12 seconds, 13 seconds, 14 seconds, 15 seconds, 16 seconds, 17 seconds, 18 seconds, 19 seconds, 20 seconds, 21 seconds, 22 seconds, 23 seconds, 24 seconds, 25 seconds, 26 seconds, 27 seconds, 28 seconds, 29 seconds, 30 seconds, 31 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds, 60 seconds, 65 seconds, 70 seconds, 75 seconds, 80 seconds, or 85 seconds. 100 seconds, 90 seconds, 95 seconds, 100 seconds, 105 seconds, 110 seconds, 115 seconds, 120 seconds, 125 seconds, 130 seconds, 135 seconds, 140 seconds, 145 seconds, 150 seconds, 155 seconds, 160 seconds, 165 seconds, 170 seconds, 175 seconds, 180 seconds, 185 seconds, 190 seconds, 195 seconds, 200 seconds, 205 seconds, 210 seconds, 215 seconds, 220 seconds, 225 seconds, 230 seconds, 235 seconds, 240 seconds, 245 seconds, 250 seconds, 255 seconds, 260 seconds, 265 seconds, 270 seconds, 275 seconds, 280 seconds, 285 seconds, 290 seconds, 295 seconds, or 300 seconds.

[0058] In another preferred embodiment, the reaction is carried out in a reaction vessel.

[0059] In another preferred embodiment, the reaction vessel is a continuous batch reactor.

[0060] In one preferred embodiment, the temperature inside the reactor is -35°C to 50°C, preferably -30°C to 30°C, more preferably -20°C to 30°C, and most preferably -18°C to 30°C. For example, the temperature can be -35°C, -34°C, -33°C, -32°C, -31°C, -30°C, -29°C, -28°C, -27°C, -26°C, -25°C, -24°C, -23°C, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C, -14°C, -13°C, -12°C, -11°C, -10°C, -9°C, -8°C, -7°C, -6°C, -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C. 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃ or 50℃.

[0061] Method for preparing glufosinate or its analogues of formula (IV)

[0062] The present invention also provides a method for preparing glufosinate of formula (IV) or its analogues.

[0063]

[0064] The method includes:

[0065] a) React the compound of formula (II), the alcohol of formula (III), and the compound of formula (V)

[0066]

[0067] b) Hydrolyze the product of the above reaction to obtain glufosinate or its analogues of formula (IV).

[0068] R1, R2 and Hal1 are each as defined above in the method for preparing compound (I);

[0069] Hal 2 Halogen,

[0070] PG is a hydrogen or amino protecting group. When PG is an amino protecting group, the method further includes removing the amino protecting group.

[0071] X is either -OR3 or -NR3R4, where R3 is C1-C 16 Alkyl, C6-C16 Aryl, C3-C 16 cycloalkyl, C7-C 16 Aryl or C7-C 16 Alkyl aryl, wherein each of the groups is unsubstituted or substituted with a C1-C6 alkyl group; R4 is hydrogen or as defined by R3.

[0072] For R1, R2, and Hal1, the groups, preferred groups, more preferred groups, and most preferred groups defined in the aforementioned methods for preparing glufosinate of formula (IV) or similar compounds are all applicable to the methods of the present invention.

[0073] In this invention, the order in which the three substances are added during the reaction of compound (II), alcohol of formula (III), and compound (V) does not affect the effect achieved by the embodiment of the invention. In a preferred embodiment, step a) can be achieved by mixing compound (II), alcohol of formula (III), and compound (V) together with a solvent; or by mixing compound (II) with alcohol of formula (III) and then mixing the resulting product with compound (V), preferably without the need for other solvents; or by mixing compound (II) with compound (V) and then mixing the resulting product with alcohol of formula (III).

[0074] In another preferred embodiment, when the reaction in step a) occurs in a microchannel reactor, the reaction in step a) is carried out at a reaction temperature of -30°C to 50°C, preferably -10°C to 30°C, more preferably -5°C to 30°C; or when the reaction in step a) occurs in a reactor consisting of a microchannel reactor and a tubular reactor or in a reaction vessel, the reaction in step a) is carried out at a reaction temperature of -30°C to 50°C, preferably -20°C to 10°C, more preferably -15°C to 5°C. For example, the reaction temperature can be -30℃, -29℃, -28℃, -27℃, -26℃, -25℃, -24℃, -23℃, -22℃, -21℃, -20℃, -19℃, -18℃, -17℃, -16℃, -15℃, -14℃, -13℃, -12℃, -11℃, -10℃, -9℃, -8℃, -7℃, -6℃, -5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃ or 50℃.

[0075] In one preferred embodiment, the molar ratio of the compound of formula (II), the alcohol of formula (III) and the compound of formula (V) is 1:(0.1-1.9):(0.1-2), preferably 1:(0.5-1.5):(0.5-1), more preferably 1:(0.9-1.1):(0.7-1), and most preferably 1:1:(0.7-0.9). For example, the molar ratios of compound (II), alcohol of formula (III), and compound (V) are 1:0.1:0.1, 1:0.1:0.2, 1:0.1:0.3, 1:0.1:0.4, 1:0.1:0.5, 1:0.1:0.6, 1:0.1:0.7, 1:0.1:0.8, 1:0.1:0.9, 1:0.1:1, 1:0.1:1.1, 1:0.1:1.2, 1:0.1:1.3, 1:0.1:1.4, 1:0.1:1.5, 1:0.1:1.6, 1:0.1:1.7, 1:0.1:1.8, and 1:0.1:1. 9, 1:0.1:2, 1:0.2:0.1, 1:0.2:0.2, 1:0.2:0.3, 1:0.2:0.4, 1:0.2:0.5, 1:0.2:0.6, 1:0.2:0.7, 1:0.2:0.8, 1:0.2:0.9, 1:0.2:1, 1:0.2:1.1, 1:0.2:1.2, 1:0.2:1.3, 1:0.2:1.4, 1:0.2:1.5, 1:0.2:1.6, 1:0.2:1.7, 1:0.2:1.8, 1:0.2:1.9, 1:0.2:2, 1:0.3:0.1, 1: 0.3:0.2, 1:0.3:0.3, 1:0.3:0.4, 1:0.3:0.5, 1:0.3:0.6, 1:0.3:0.7, 1:0.3:0.8, 1:0.3:0.9, 1:0.3:1, 1:0.3:1.1, 1:0.3:1.2, 1:0.3:1.3, 1:0.3:1.4, 1:0.3:1.5, 1:0.3:1.6, 1:0.3:1.7, 1:0.3:1.8, 1:0.3:1.9, 1:0.3:2, 1:0.4:0.1, 1:0.4:0.2, 1:0.4:0.3, 1:0.4 :0.4, 1:0.4:0.5, 1:0.4:0.6, 1:0.4:0.7, 1:0.4:0.8, 1:0.4:0.9, 1:0.4:1, 1:0.4:1.1, 1:0.4:1.2, 1:0.4:1.3, 1:0.4:1.4, 1:0.4:1.5, 1:0.4:1.6, 1:0.4:1.7, 1:0.4:1.8, 1:0.4:1.9, 1:0.4:2, 1:0.5:0.1, 1:0.5:0.2, 1:0.5:0.3, 1:0.5:0.4, 1:0.5:0.5, 1:0.5:0.6、1：0.5：0.7、1：0.5：0.8、1：0.5：0.9、1：0.5：1、1：0.5：1.1、1：0.5：1.2、1：0.5：1.3、1：0.5：1.4、1：0.5：1.5、1：0.5：1.6、1：0.5：1.7、1：0.5:1.8、1：0.5：1.9、1：0.5：2、1：0.6：0.1、1：0.6：0.2、1：0.6：0.3、1：0.6：0.4、1：0.6：0.5、1：0.6：0.6、1：0.6：0.7、1：0.6：0.8、1：0.6：0.9、1：0.6：1、1：0.6：1.1、1：0.6：1.2、1：0.6：1.3、1：0.6：1.4、1：0.6：1.5、1：0.6：1.6、1：0.6：1.7、1：0.6:1.8、1：0.6：1.9、1：0.6：2、1：0.7：0.1、1：0.7：0.2、1：0.7：0.3、1：0.7：0.4、1：0.7：0.5、1：0.7：0.6、1：0.7：0.7、1：0.7：0.8、1：0.7：0.9、1：0.7：1、1：0.7：1.1、1：0.7：1.2、1：0.7：1.3、1：0.7：1.4、1：0.7：1.5、1：0.7：1.6、1：0.7：1.7、1：0.7:1.8、1：0.7：1.9、1：0.7：2、1：0.8：0.1、1：0.8：0.2、1：0.8：0.3、1：0.8：0.4、1：0.8：0.5、1：0.8：0.6、1：0.8：0.7、1：0.8：0.8、1：0.8：0.9、1：0.8：1、1：0.8：1.1、1：0.8：1.2、1：0.8：1.3、1：0.8：1.4、1：0.8：1.5、1：0.8：1.6、1：0.8：1.7、1：0.8:1.8、1：0.8：1.9、1：0.8：2、1：0.9：0.1、1：0.9：0.2、1：0.9：0.3、1：0.9：0.4、1：0.9：0.5、1：0.9：0.6、1：0.9：0.7、1：0.9：0.8、1：0.9：0.9、1：0.9：1、1：0.9：1.1、1：0.9：1.2、1：0.9：1.3、1：0.9：1.4、1：0.9：1.5、1：0.9：1.6、1：0.9：1.7、1：0.9:1.8、1：0.9：1.9、1：0.9：2、1：1：0.1、1：1：0.2、1：1：0.3、1：1：0.4、1：1：0.5、1：1：0.6、1：1：0.7、1：1：0.8、1：1：0.9、1：1：1、1：1：1.1、1：1：1.2、1：1：1.3、1：1：1.4、1：1：1.5、1：1：1.6、1：1：1.7、1：1:1.8、1：1：1.9、1：1：2、1：1.1：0.1、1：1.1：0.2、1：1.1：0.3、1：1.1：0.4、1：1.1：0.5、1：1.1：0.6、1：1.1：0.7、1：1.1：0.8、1：1.1：0.9、1：1.1：1、1：1.1：1.1、1：1.1：1.2、1：1.1：1.3、1：1.1：1.4、1：1.1：1.5、1：1.1：1.6、1：1.1：1.7、1：1.1：1.8、1：1.1：1.9、1：1.1：2、1：1.2：0.1、1：1.2：0.2、1：1.2：0.3、1：1.2：0.4、1：1.2：0.5、1：1.2：0.6、1：1.2：0.7、1：1.2：0.8、1：1.2：0.9、1：1.2：1、1：1.2：1.1、1：1.2：1.2、1：1.2：1.3、1：1.2：1.4、1：1.2：1.5、1：1.2：1.6、1：1.2：1.7、1：1.2:1.8、1：1.2：1.9、1：1.2：2、1：1.3：0.1、1：1.3：0.2、1：1.3：0.3、1：1.3：0.4、1：1.3：0.5、1：1.3：0.6、1：1.3：0.7、1：1.3：0.8、1：1.3：0.9、1：1.3：1、1：1.3：1.1、1：1.3：1.2、1：1.3：1.3、1：1.3：1.4、1：1.3：1.5、1：1.3：1.6、1：1.3：1.7、1：1.3:1.8、1：1.3：1.9、1：1.3：2、1：1.4：0.1、1：1.4：0.2、1：1.4：0.3、1：1.4：0.4、1：1.4：0.5、1：1.4：0.6、1：1.4：0.7、1：1.4：0.8、1：1.4：0.9、1：1.4：1、1：1.4：1.1、1：1.4：1.2、1：1.4：1.3、1：1.4：1.4、1：1.4：1.5、1：1.4：1.6、1：1.4：1.7、1：1.4:1.8、1：1.4：1.9、1：1.4：2、1：1.5：0.1、1：1.5：0.2、1：1.5：0.3、1：1.5：0.4、1：1.5：0.5、1：1.5：0.6、1：1.5：0.7、1：1.5：0.8、1：1.5：0.9、1：1.5：1、1：1.5：1.1、1：1.5：1.2、1：1.5：1.3, 1:1.5:1.4, 1:1.5:1.5, 1:1.5:1.6, 1:1.5:1.7, 1:1.5:1.8, 1:1.5:1.9, 1:1.5:2, 1:1.6:0.1, 1:1.6:0.2, 1:1.6:0.3, 1:1.6:0.4, 1:1.6:0.5, 1:1.6:0.6, 1:1.6:0.7, 1:1.6:0.8, 1:1.6:0.9, 1:1.6:1, 1:1.6:1.1, 1:1.6:1.2, 1:1.6:1.3, 1:1.6:1.4, 1:1.6:1.5, 1:1 .6:1.6, 1:1.6:1.7, 1:1.6:1.8, 1:1.6:1.9, 1:1.6:2, 1:1.7:0.1, 1:1.7:0.2, 1:1.7:0.3, 1:1.7:0.4, 1:1.7:0.5, 1:1.7:0.6, 1:1.7:0.7, 1:1.7:0.8, 1:1.7:0.9, 1:1.7:1, 1:1.7:1.1, 1:1.7:1.2, 1:1.7:1.3, 1:1.7:1.4, 1:1.7:1.5, 1:1.7:1.6, 1:1.7:1.7, 1:1.7:1. 8, 1:1.7:1.9, 1:1.7:2, 1:1.8:0.1, 1:1.8:0.2, 1:1.8:0.3, 1:1.8:0.4, 1:1.8:0.5, 1:1.8:0.6, 1:1.8:0.7, 1:1.8:0.8, 1:1.8:0.9, 1:1.8:1, 1:1.8:1.1, 1:1.8:1.2, 1:1.8:1.3, 1:1.8:1.4, 1:1.8:1.5, 1:1.8:1.6, 1:1.8:1.7, 1:1.8:1.8, 1:1.8:1.9, 1:1.8:2, 1:1.9 :0.1, 1:1.9:0.2, 1:1.9:0.3, 1:1.9:0.4, 1:1.9:0.5, 1:1.9:0.6, 1:1.9:0.7, 1:1.9:0.8, 1:1.9:0.9, 1:1.9:1, 1:1.9:1.1, 1:1.9:1.2, 1:1.9:1.3, 1:1.9:1.4, 1:1.9:1.5, 1:1.9:1.6, 1:1.9:1.7, 1:1.9:1.8, 1:1.9:1.9, 1:1.9:2, 1.1:1.1:1, 1.2:1.2:1 or 1.3:1.3:1.

[0076] In another preferred embodiment, Hal 2 It can be fluorine, chlorine, bromine or iodine, preferably chlorine.

[0077] In another preferred embodiment, PG is H, -C(O)-R5, -SO2-R6, -CHC(O)O-R7, or -C(O)OR8, wherein R5 is C6-C 16 Aryl, C7-C 16 Aryl or C7-C 16 Alkyl aryl, preferably C6-C 12 Aryl, C7-C 13 Aryl or C7-C 13 Alkyl, more preferably phenyl, tolyl, benzyl or phenethyl, most preferably phenyl; R6 is C6-C 16 Aryl, C7-C 16 Aryl or C7-C 16 Alkyl aryl, preferably C6-C 12 Aryl, C7-C 13 Aryl or C7-C 13 Alkyl, more preferably phenyl, tolyl, benzyl or phenethyl, most preferably tolyl; R7 and R8 are each independently C1-C. 16 Alkyl, C6-C 16 Aryl, C3-C 16 cycloalkyl, C7-C 16 Aryl or C7-C 16 Alkyl aryl, preferably C1-C8 alkyl, C6-C 12 Aryl, C3-C 10 cycloalkyl, C7-C 12 Aryl or C7-C 12 Alkyl, more preferably methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, tolyl, ethylphenyl, cyclopropyl, cyclobutyl or cyclopentyl, most preferably various isomers of methyl, ethyl, propyl or butyl.

[0078] In another preferred embodiment, X is -OR3, where R3 is a C1-C8 alkyl or C7-C 10 Aryl alkyl group, preferably C1-C6 alkyl or C7-C9 aryl alkyl group, more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or benzyl.

[0079] In another preferred embodiment, X is -NR3R4, where R3 is a C1-C8 alkyl or C7-C6 alkyl group. 10 Aryl group, preferably C1-C6 alkyl or C7-C9 aryl group, more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or benzyl, particularly preferably methyl, propyl, isopropyl or butyl; R4 is H or as defined by R3, preferably H or methyl.

[0080] In a preferred embodiment, the hydrolysis is either acid hydrolysis or alkaline hydrolysis, wherein the acid hydrolysis is preferably carried out using an inorganic acid or an organic acid, and the alkaline hydrolysis is preferably carried out using an inorganic base or an organic base, wherein the inorganic acid is preferably hydrochloric acid or sulfuric acid.

[0081] In another preferred embodiment, step a) is carried out in the absence of a solvent or in an inert solvent, wherein the inert solvent is preferably any one or more of benzene solvents, amide solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, sulfone or sulfoxide solvents, ether solvents or ester solvents; preferably, the inert solvent is selected from any one or more of chlorobenzene, thallium, 1,4-dioxane, 1,2-dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate.

[0082] In a preferred embodiment, a base is added at the start of the reaction in step a), during the reaction, or after the reaction, preferably after the reaction in step a), wherein the base is preferably an organic base or ammonia, more preferably ammonia.

[0083] In another preferred embodiment, the organic base is an organic amine, such as triethylamine, pyridine, or a pyridine derivative having 1 to 3 substituents attached to one or more carbon atoms of the heterocycle, piperidine, or a piperidine derivative having 1 to 3 substituents attached to one or more carbon atoms of the heterocycle.

[0084] In another preferred embodiment, step a) is carried out by: (i) simultaneously introducing the compound of formula (II) with the alcohol of formula (III) and the compound of formula (V) into a first reactor to react in the presence of a solvent, and then introducing the resulting product with a base, preferably ammonia, into a second reactor; or (ii) simultaneously introducing the compound of formula (II) with the alcohol of formula (III) into a first reactor to react in the presence or absence of a solvent, then introducing the resulting product with the compound of formula (V) into a second reactor, and finally introducing the resulting product with a base, preferably ammonia, into a third reactor. The reaction occurs; or (iii) the compound of formula (II) and the compound of formula (V) are simultaneously introduced into the first reactor to react in the presence or absence of a solvent, and the resulting product is then introduced into the second reactor with the alcohol of formula (III), and finally the resulting product is introduced into the third reactor with a base, preferably ammonia, to react; or (iv) the compound of formula (II) and the alcohol of formula (III) are simultaneously introduced into the first reactor to react in the presence or absence of a solvent, and the resulting product is then introduced into the second reactor with the compound of formula (V) and a base, preferably ammonia, to react.

[0085] In a preferred embodiment, the first reactor, the second reactor, and / or the third reactor are each independently one or more reactors.

[0086] In another preferred embodiment, the first reactor, the second reactor, and / or the third reactor are each independently selected from a microchannel reactor, a tubular reactor, a tubular packed reactor, a stirred tank reactor, or any combination thereof. For example, the first reactor, the second reactor, and / or the third reactor are each independently composed of one or more microchannel continuous flow reactors, or each are each independently composed of one or more microchannel continuous flow reactors and one or more tubular reactors.

[0087] In another preferred embodiment, step a) is carried out by: (i) simultaneously introducing the compound of formula (II) with the alcohol of formula (III) and the compound of formula (V) into a first microchannel reactor to react in the presence of a solvent, and then introducing the resulting product with a base, preferably ammonia, into a second microchannel reactor; or (ii) simultaneously introducing the compound of formula (II) with the alcohol of formula (III) into a first microchannel reactor to react in the presence or absence of a solvent, then introducing the resulting product with the compound of formula (V) into a second microchannel reactor, and finally introducing the resulting product with a base, preferably ammonia, into a third microchannel. The reaction occurs in a reactor; or (iii) the compound of formula (II) and the compound of formula (V) are simultaneously introduced into a first microchannel reactor to react in the presence or absence of a solvent, and the resulting product is then introduced into a second microchannel reactor with an alcohol of formula (III), and finally the resulting product is introduced into a third microchannel reactor with a base, preferably ammonia, to react; or (iv) the compound of formula (II) and the alcohol of formula (III) are simultaneously introduced into a first microchannel reactor to react in the presence or absence of a solvent, and the resulting product, the compound of formula (V), and a base, preferably ammonia, are then introduced into a tubular reactor to react.

[0088] In a preferred embodiment, in scheme (i), the temperatures within the first microchannel reactor and / or the second microchannel reactor are each independently -30°C to 50°C, preferably -10°C to 30°C, more preferably -5°C to 30°C, wherein the aforementioned temperatures may be the same or different. For example, the reaction temperature may be -30°C, -29°C, -28°C, -27°C, -26°C, -25°C, -24°C, -23°C, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C, -14°C, -13°C, -12°C, -11°C, -10°C, -9°C, -8°C, -7°C, -6°C, - 5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃ or 30℃.

[0089] In scheme (ii), the temperatures within the first microchannel reactor, the second microchannel reactor, and / or the third microchannel reactor are each independently -30°C to 50°C, preferably -10°C to 30°C, more preferably -5°C to 30°C, wherein the aforementioned temperatures may be the same or different. For example, the reaction temperatures may be -30°C, -29°C, -28°C, -27°C, -26°C, -25°C, -24°C, -23°C, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C, -14°C, -13°C, -12°C, -11°C, -10°C, -9°C, -8°C, -7°C, -6°C, - 5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃ or 30℃.

[0090] In scheme (iii), the temperature in the first microchannel reactor, the second microchannel reactor and / or the third microchannel reactor is independently -30°C to 50°C, preferably -10°C to 30°C, more preferably -5°C to 30°C, wherein the above temperatures may be the same or different.

[0091] In scheme (iv), the temperature of the first microchannel reactor is -30°C to 50°C, preferably -25°C to 5°C, more preferably -20°C to -10°C, and / or the temperature of the tubular reactor is -30°C to 50°C, preferably -25°C to 10°C, more preferably -20°C to 5°C.

[0092] In a preferred embodiment, in step a), when the reactor consists only of microchannel reactors, the total residence time in all reactors is 0.1 seconds to 300 seconds, preferably 1 second to 50 seconds, more preferably 10 seconds to 40 seconds; or when the reactor consists of microchannel reactors and tubular reactors, the total residence time in all reactors is 1 minute to 20 minutes, preferably 5 minutes to 18 minutes, more preferably 9 minutes to 14 minutes. For example, the dwell time can be 0.1 seconds, 0.2 seconds, 0.5 seconds, 0.8 seconds, 1 second, 1.2 seconds, 1.4 seconds, 1.6 seconds, 1.8 seconds, 2 seconds, 2.5 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 11 seconds, 12 seconds, 13 seconds, 14 seconds, 15 seconds, 16 seconds, 17 seconds, 18 seconds, 19 seconds, 20 seconds, 21 seconds, 22 seconds, 23 seconds, 24 seconds, 25 seconds, 26 seconds, 27 seconds, 28 seconds, 29 seconds, 30 seconds, 31 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds, 60 seconds, 65 seconds, 70 seconds, 75 seconds, 80 seconds, or 85 seconds. 100 seconds, 90 seconds, 95 seconds, 100 seconds, 105 seconds, 110 seconds, 115 seconds, 120 seconds, 125 seconds, 130 seconds, 135 seconds, 140 seconds, 145 seconds, 150 seconds, 155 seconds, 160 seconds, 165 seconds, 170 seconds, 175 seconds, 180 seconds, 185 seconds, 190 seconds, 195 seconds, 200 seconds, 205 seconds, 210 seconds, 215 seconds, 220 seconds, 225 seconds, 230 seconds, 235 seconds, 240 seconds, 245 seconds, 250 seconds, 255 seconds, 260 seconds, 265 seconds, 270 seconds, 275 seconds, 280 seconds, 285 seconds, 290 seconds, 295 seconds, or 300 seconds.

[0093] In another preferred embodiment, step b) is carried out by heating the reaction product of step a) to 30°C to 130°C, preferably 60°C to 120°C, more preferably 90°C to 100°C, and holding it at that temperature for 1 to 24 hours, preferably 2 to 10 hours, more preferably 5 to 8 hours, and then hydrolyzing it with an acid, preferably hydrochloric acid, at a temperature of 50°C to 120°C, preferably 80°C to 120°C, more preferably 100°C to 110°C. For example, the temperature at which the reaction product of step a) is held can be 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, or 130°C. For example, the reaction product of step a) can be maintained for 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, 15 hours, 15.5 hours, 16 hours, 16.5 hours, 17 hours, 17.5 hours, 18 hours, 18.5 hours, 19 hours, 19.5 hours, 20 hours, 20.5 hours, 21 hours, 21.5 hours, 22 hours, 22.5 hours, 23 hours, 23.5 hours, or 24 hours. For example, the hydrolysis temperature can be 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃ or 120℃.

[0094] Method for preparing glufosinate or its analogues of formula (IV)

[0095] The present invention also provides a method for preparing glufosinate of formula (IV) or its analogues.

[0096]

[0097] The method includes:

[0098] a) Feeding the compound of formula (II), the alcohol of formula (III), and the compound of formula (V) into the reactor to obtain a mixed stream.

[0099]

[0100] b) The mixture stream is reacted at a temperature of -30°C to 50°C, preferably -10°C to 30°C, more preferably -5°C to 5°C.

[0101] c) Hydrolyze the product stream from step b) to obtain glufosinate or its analogues of formula (IV).

[0102] R1, R2 and Hal1 are each as defined above in the method for preparing compound (I);

[0103] Hal 2 Halogen,

[0104] PG is a hydrogen or amino protecting group. When PG is an amino protecting group, the method further includes removing the amino protecting group.

[0105] X is either -OR3 or -NR3R4, where R3 is C1-C 16 Alkyl, C6-C 16 Aryl, C3-C 16 cycloalkyl, C7-C 16 Aryl or C7-C 16 Alkyl aryl, wherein each of the groups is unsubstituted or substituted with a C1-C6 alkyl group; R4 is hydrogen or as defined by R3.

[0106] For R1, R2, and Hal1, the groups, preferred groups, more preferred groups, and most preferred groups defined in the aforementioned methods for preparing glufosinate of formula (IV) or similar compounds are all applicable to the methods of the present invention.

[0107] In this invention, "feeding the compound of formula (II), the alcohol of formula (III), and the compound of formula (V) into the reactor" encompasses feeding these three substances in any order, and the feeding of any two substances can be carried out simultaneously or at intervals without affecting the effect of the embodiment of this invention. In a preferred embodiment, step a) can be achieved by mixing the compound of formula (II), the alcohol of formula (III), and the compound of formula (V) with a solvent; or mixing the compound of formula (II) with the alcohol of formula (III), and then mixing the resulting product with the compound of formula (V), preferably without the need for other solvents; or mixing the compound of formula (II) with the compound of formula (V), and then mixing the resulting product with the alcohol of formula (III).

[0108] In another preferred embodiment, when the reaction in step a) occurs in a microchannel reactor, the reaction in step a) is carried out at a reaction temperature of -30°C to 50°C, preferably -10°C to 30°C, more preferably -5°C to 30°C; or when the reaction in step a) occurs in a reactor consisting of a microchannel reactor and a tubular reactor or in a reaction vessel, the reaction in step a) is carried out at a reaction temperature of -30°C to 50°C, preferably -20°C to 10°C, more preferably -15°C to 5°C. For example, the reaction temperature can be -30℃, -29℃, -28℃, -27℃, -26℃, -25℃, -24℃, -23℃, -22℃, -21℃, -20℃, -19℃, -18℃, -17℃, -16℃, -15℃, -14℃, -13℃, -12℃, -11℃, -10℃, -9℃, -8℃, -7℃, -6℃, -5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, 30℃, 31℃, 32℃, 33℃, 34℃, 35℃, 36℃, 37℃, 38℃, 39℃, 40℃, 41℃, 42℃, 43℃, 44℃, 45℃, 46℃, 47℃, 48℃, 49℃ or 50℃.

[0109] In one preferred embodiment, the molar ratio of the compound of formula (II), the alcohol of formula (III) and the compound of formula (V) is 1:(0.1-1.9):(0.1-2), preferably 1:(0.5-1.5):(0.5-1), more preferably 1:(0.9-1.1):(0.7-1), and most preferably 1:1:(0.7-0.9). For example, the molar ratios of compound (II), alcohol of formula (III), and compound (V) are 1:0.1:0.1, 1:0.1:0.2, 1:0.1:0.3, 1:0.1:0.4, 1:0.1:0.5, 1:0.1:0.6, 1:0.1:0.7, 1:0.1:0.8, 1:0.1:0.9, 1:0.1:1, 1:0.1:1.1, 1:0.1:1.2, 1:0.1:1.3, 1:0.1:1.4, 1:0.1:1.5, 1:0.1:1.6, 1:0.1:1.7, 1:0.1:1.8, and 1:0.1:1. 9, 1:0.1:2, 1:0.2:0.1, 1:0.2:0.2, 1:0.2:0.3, 1:0.2:0.4, 1:0.2:0.5, 1:0.2:0.6, 1:0.2:0.7, 1:0.2:0.8, 1:0.2:0.9, 1:0.2:1, 1:0.2:1.1, 1:0.2:1.2, 1:0.2:1.3, 1:0.2:1.4, 1:0.2:1.5, 1:0.2:1.6, 1:0.2:1.7, 1:0.2:1.8, 1:0.2:1.9, 1:0.2:2, 1:0.3:0.1, 1: 0.3:0.2, 1:0.3:0.3, 1:0.3:0.4, 1:0.3:0.5, 1:0.3:0.6, 1:0.3:0.7, 1:0.3:0.8, 1:0.3:0.9, 1:0.3:1, 1:0.3:1.1, 1:0.3:1.2, 1:0.3:1.3, 1:0.3:1.4, 1:0.3:1.5, 1:0.3:1.6, 1:0.3:1.7, 1:0.3:1.8, 1:0.3:1.9, 1:0.3:2, 1:0.4:0.1, 1:0.4:0.2, 1:0.4:0.3, 1:0.4 :0.4, 1:0.4:0.5, 1:0.4:0.6, 1:0.4:0.7, 1:0.4:0.8, 1:0.4:0.9, 1:0.4:1, 1:0.4:1.1, 1:0.4:1.2, 1:0.4:1.3, 1:0.4:1.4, 1:0.4:1.5, 1:0.4:1.6, 1:0.4:1.7, 1:0.4:1.8, 1:0.4:1.9, 1:0.4:2, 1:0.5:0.1, 1:0.5:0.2, 1:0.5:0.3, 1:0.5:0.4, 1:0.5:0.5, 1:0.5:0.6、1：0.5：0.7、1：0.5：0.8、1：0.5：0.9、1：0.5：1、1：0.5：1.1、1：0.5：1.2、1：0.5：1.3、1：0.5：1.4、1：0.5：1.5、1：0.5：1.6、1：0.5：1.7、1：0.5:1.8、1：0.5：1.9、1：0.5：2、1：0.6：0.1、1：0.6：0.2、1：0.6：0.3、1：0.6：0.4、1：0.6：0.5、1：0.6：0.6、1：0.6：0.7、1：0.6：0.8、1：0.6：0.9、1：0.6：1、1：0.6：1.1、1：0.6：1.2、1：0.6：1.3、1：0.6：1.4、1：0.6：1.5、1：0.6：1.6、1：0.6：1.7、1：0.6:1.8、1：0.6：1.9、1：0.6：2、1：0.7：0.1、1：0.7：0.2、1：0.7：0.3、1：0.7：0.4、1：0.7：0.5、1：0.7：0.6、1：0.7：0.7、1：0.7：0.8、1：0.7：0.9、1：0.7：1、1：0.7：1.1、1：0.7：1.2、1：0.7：1.3、1：0.7：1.4、1：0.7：1.5、1：0.7：1.6、1：0.7：1.7、1：0.7:1.8、1：0.7：1.9、1：0.7：2、1：0.8：0.1、1：0.8：0.2、1：0.8：0.3、1：0.8：0.4、1：0.8：0.5、1：0.8：0.6、1：0.8：0.7、1：0.8：0.8、1：0.8：0.9、1：0.8：1、1：0.8：1.1、1：0.8：1.2、1：0.8：1.3、1：0.8：1.4、1：0.8：1.5、1：0.8：1.6、1：0.8：1.7、1：0.8:1.8、1：0.8：1.9、1：0.8：2、1：0.9：0.1、1：0.9：0.2、1：0.9：0.3、1：0.9：0.4、1：0.9：0.5、1：0.9：0.6、1：0.9：0.7、1：0.9：0.8、1：0.9：0.9、1：0.9：1、1：0.9：1.1、1：0.9：1.2、1：0.9：1.3、1：0.9：1.4、1：0.9：1.5、1：0.9：1.6、1：0.9：1.7、1：0.9:1.8、1：0.9：1.9、1：0.9：2、1：1：0.1、1：1：0.2、1：1：0.3、1：1：0.4、1：1：0.5、1：1：0.6、1：1：0.7、1：1：0.8、1：1：0.9、1：1：1、1：1：1.1、1：1：1.2、1：1：1.3、1：1：1.4、1：1：1.5、1：1：1.6、1：1：1.7、1：1:1.8、1：1：1.9、1：1：2、1：1.1：0.1、1：1.1：0.2、1：1.1：0.3、1：1.1：0.4、1：1.1：0.5、1：1.1：0.6、1：1.1：0.7、1：1.1：0.8、1：1.1：0.9、1：1.1：1、1：1.1：1.1、1：1.1：1.2、1：1.1：1.3、1：1.1：1.4、1：1.1：1.5、1：1.1：1.6、1：1.1：1.7、1：1.1：1.8、1：1.1：1.9、1：1.1：2、1：1.2：0.1、1：1.2：0.2、1：1.2：0.3、1：1.2：0.4、1：1.2：0.5、1：1.2：0.6、1：1.2：0.7、1：1.2：0.8、1：1.2：0.9、1：1.2：1、1：1.2：1.1、1：1.2：1.2、1：1.2：1.3、1：1.2：1.4、1：1.2：1.5、1：1.2：1.6、1：1.2：1.7、1：1.2:1.8、1：1.2：1.9、1：1.2：2、1：1.3：0.1、1：1.3：0.2、1：1.3：0.3、1：1.3：0.4、1：1.3：0.5、1：1.3：0.6、1：1.3：0.7、1：1.3：0.8、1：1.3：0.9、1：1.3：1、1：1.3：1.1、1：1.3：1.2、1：1.3：1.3、1：1.3：1.4、1：1.3：1.5、1：1.3：1.6、1：1.3：1.7、1：1.3:1.8、1：1.3：1.9、1：1.3：2、1：1.4：0.1、1：1.4：0.2、1：1.4：0.3、1：1.4：0.4、1：1.4：0.5、1：1.4：0.6、1：1.4：0.7、1：1.4：0.8、1：1.4：0.9、1：1.4：1、1：1.4：1.1、1：1.4：1.2、1：1.4：1.3、1：1.4：1.4、1：1.4：1.5、1：1.4：1.6、1：1.4：1.7、1：1.4:1.8、1：1.4：1.9、1：1.4：2、1：1.5：0.1、1：1.5：0.2、1：1.5：0.3、1：1.5：0.4、1：1.5：0.5、1：1.5：0.6、1：1.5：0.7、1：1.5：0.8、1：1.5：0.9、1：1.5：1、1：1.5：1.1、1：1.5：1.2、1：1.5：1.3, 1:1.5:1.4, 1:1.5:1.5, 1:1.5:1.6, 1:1.5:1.7, 1:1.5:1.8, 1:1.5:1.9, 1:1.5:2, 1:1.6:0.1, 1:1.6:0.2, 1:1.6:0.3, 1:1.6:0.4, 1:1.6:0.5, 1:1.6:0.6, 1:1.6:0.7, 1:1.6:0.8, 1:1.6:0.9, 1:1.6:1, 1:1.6:1.1, 1:1.6:1.2, 1:1.6:1.3, 1:1.6:1.4, 1:1.6:1.5, 1:1 .6:1.6, 1:1.6:1.7, 1:1.6:1.8, 1:1.6:1.9, 1:1.6:2, 1:1.7:0.1, 1:1.7:0.2, 1:1.7:0.3, 1:1.7:0.4, 1:1.7:0.5, 1:1.7:0.6, 1:1.7:0.7, 1:1.7:0.8, 1:1.7:0.9, 1:1.7:1, 1:1.7:1.1, 1:1.7:1.2, 1:1.7:1.3, 1:1.7:1.4, 1:1.7:1.5, 1:1.7:1.6, 1:1.7:1.7, 1:1.7:1. 8, 1:1.7:1.9, 1:1.7:2, 1:1.8:0.1, 1:1.8:0.2, 1:1.8:0.3, 1:1.8:0.4, 1:1.8:0.5, 1:1.8:0.6, 1:1.8:0.7, 1:1.8:0.8, 1:1.8:0.9, 1:1.8:1, 1:1.8:1.1, 1:1.8:1.2, 1:1.8:1.3, 1:1.8:1.4, 1:1.8:1.5, 1:1.8:1.6, 1:1.8:1.7, 1:1.8:1.8, 1:1.8:1.9, 1:1.8:2, 1:1.9 :0.1, 1:1.9:0.2, 1:1.9:0.3, 1:1.9:0.4, 1:1.9:0.5, 1:1.9:0.6, 1:1.9:0.7, 1:1.9:0.8, 1:1.9:0.9, 1:1.9:1, 1:1.9:1.1, 1:1.9:1.2, 1:1.9:1.3, 1:1.9:1.4, 1:1.9:1.5, 1:1.9:1.6, 1:1.9:1.7, 1:1.9:1.8, 1:1.9:1.9, 1:1.9:2, 1.1:1.1:1, 1.2:1.2:1 or 1.3:1.3:1.

[0110] In another preferred embodiment, Hal 2 It can be fluorine, chlorine, bromine or iodine, preferably chlorine.

[0111] In another preferred embodiment, PG is H, -C(O)-R5, -SO2-R6, -CHC(O)O-R7, or -C(O)OR8, wherein R5 is C6-C 16 Aryl, C7-C 16 Aryl or C7-C 16 Alkyl aryl, preferably C6-C 12 Aryl, C7-C 13 Aryl or C7-C 13 Alkyl, more preferably phenyl, tolyl, benzyl or phenethyl, most preferably phenyl; R6 is C6-C 16 Aryl, C7-C 16 Aryl or C7-C 16 Alkyl aryl, preferably C6-C 12 Aryl, C7-C 13 Aryl or C7-C 13 Alkyl, more preferably phenyl, tolyl, benzyl or phenethyl, most preferably tolyl; R7 and R8 are each independently C1-C. 16 Alkyl, C6-C 16 Aryl, C3-C 16 cycloalkyl, C7-C 16 Aryl or C7-C 16 Alkyl aryl, preferably C1-C8 alkyl, C6-C 12 Aryl, C3-C 10 cycloalkyl, C7-C 12 Aryl or C7-C 12 Alkyl, more preferably methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, tolyl, ethylphenyl, cyclopropyl, cyclobutyl or cyclopentyl, most preferably various isomers of methyl, ethyl, propyl or butyl.

[0112] In another preferred embodiment, X is -OR3, where R3 is a C1-C8 alkyl or C7-C 10 Aryl alkyl group, preferably C1-C6 alkyl or C7-C9 aryl alkyl group, more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or benzyl.

[0113] In another preferred embodiment, X is -NR3R4, where R3 is a C1-C8 alkyl or C7-C6 alkyl group. 10 Aryl group, preferably C1-C6 alkyl or C7-C9 aryl group, more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl or benzyl, particularly preferably methyl, propyl, isopropyl or butyl; R4 is H or as defined by R3, preferably H or methyl.

[0114] In a preferred embodiment, the hydrolysis is either acid hydrolysis or alkaline hydrolysis, wherein the acid hydrolysis is preferably carried out using an inorganic acid or an organic acid, and the alkaline hydrolysis is preferably carried out using an inorganic base or an organic base, wherein the inorganic acid is preferably hydrochloric acid or sulfuric acid.

[0115] In another preferred embodiment, step a) is carried out in the absence of a solvent or in an inert solvent, wherein the inert solvent is preferably any one or more of benzene solvents, amide solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, sulfone or sulfoxide solvents, ether solvents or ester solvents; preferably, the inert solvent is selected from any one or more of chlorobenzene, thallium, 1,4-dioxane, 1,2-dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate.

[0116] In a preferred embodiment, a base is added at the start of the reaction in step a), during the reaction, or after the reaction, preferably after the reaction in step a), wherein the base is preferably an organic base or ammonia, more preferably ammonia.

[0117] In another preferred embodiment, the organic base is an organic amine, such as triethylamine, pyridine, or a pyridine derivative having 1 to 3 substituents attached to one or more carbon atoms of the heterocycle, piperidine, or a piperidine derivative having 1 to 3 substituents attached to one or more carbon atoms of the heterocycle.

[0118] In another preferred embodiment, step a) is carried out by: (i) simultaneously introducing the compound of formula (II) with the alcohol of formula (III) and the compound of formula (V) into a first reactor to react in the presence of a solvent, and then introducing the resulting product with a base, preferably ammonia, into a second reactor; or (ii) simultaneously introducing the compound of formula (II) with the alcohol of formula (III) into a first reactor to react in the presence or absence of a solvent, then introducing the resulting product with the compound of formula (V) into a second reactor, and finally introducing the resulting product with a base, preferably ammonia, into a third reactor. The reaction occurs; or (iii) the compound of formula (II) and the compound of formula (V) are simultaneously introduced into the first reactor to react in the presence or absence of a solvent, and the resulting product is then introduced into the second reactor with the alcohol of formula (III), and finally the resulting product is introduced into the third reactor with a base, preferably ammonia, to react; or (iv) the compound of formula (II) and the alcohol of formula (III) are simultaneously introduced into the first reactor to react in the presence or absence of a solvent, and the resulting product is then introduced into the second reactor with the compound of formula (V) and a base, preferably ammonia, to react.

[0119] In a preferred embodiment, the first reactor, the second reactor, and / or the third reactor are each independently one or more reactors.

[0120] In another preferred embodiment, the first reactor, the second reactor, and / or the third reactor are each independently selected from a microchannel reactor, a tubular reactor, a tubular packed reactor, a stirred tank reactor, or any combination thereof. For example, the first reactor, the second reactor, and / or the third reactor are each independently composed of one or more microchannel continuous flow reactors, or each are each independently composed of one or more microchannel continuous flow reactors and one or more tubular reactors.

[0121] In another preferred embodiment, step a) is carried out by: (i) simultaneously introducing the compound of formula (II) with the alcohol of formula (III) and the compound of formula (V) into a first microchannel reactor to react in the presence of a solvent, and then introducing the resulting product with a base, preferably ammonia, into a second microchannel reactor; or (ii) simultaneously introducing the compound of formula (II) with the alcohol of formula (III) into a first microchannel reactor to react in the presence or absence of a solvent, then introducing the resulting product with the compound of formula (V) into a second microchannel reactor, and finally introducing the resulting product with a base, preferably ammonia, into a third microchannel. The reaction occurs in a reactor; or (iii) the compound of formula (II) and the compound of formula (V) are simultaneously introduced into a first microchannel reactor to react in the presence or absence of a solvent, and the resulting product is then introduced into a second microchannel reactor with an alcohol of formula (III), and finally the resulting product is introduced into a third microchannel reactor with a base, preferably ammonia, to react; or (iv) the compound of formula (II) and the alcohol of formula (III) are simultaneously introduced into a first microchannel reactor to react in the presence or absence of a solvent, and the resulting product, the compound of formula (V), and a base, preferably ammonia, are then introduced into a tubular reactor to react.

[0122] In a preferred embodiment, in scheme (i), the temperatures within the first microchannel reactor and / or the second microchannel reactor are each independently -30°C to 50°C, preferably -10°C to 30°C, more preferably -5°C to 30°C, wherein the aforementioned temperatures may be the same or different. For example, the reaction temperature may be -30°C, -29°C, -28°C, -27°C, -26°C, -25°C, -24°C, -23°C, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C, -14°C, -13°C, -12°C, -11°C, -10°C, -9°C, -8°C, -7°C, -6°C, - 5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃ or 30℃.

[0123] In scheme (ii), the temperatures within the first microchannel reactor, the second microchannel reactor, and / or the third microchannel reactor are each independently -30°C to 50°C, preferably -10°C to 30°C, more preferably -5°C to 30°C, wherein the aforementioned temperatures may be the same or different. For example, the reaction temperatures may be -30°C, -29°C, -28°C, -27°C, -26°C, -25°C, -24°C, -23°C, -22°C, -21°C, -20°C, -19°C, -18°C, -17°C, -16°C, -15°C, -14°C, -13°C, -12°C, -11°C, -10°C, -9°C, -8°C, -7°C, -6°C, - 5℃, -4℃, -3℃, -2℃, -1℃, 0℃, 1℃, 2℃, 3℃, 4℃, 5℃, 6℃, 7℃, 8℃, 9℃, 10℃, 11℃, 12℃, 13℃, 14℃, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃ or 30℃.

[0124] In scheme (iii), the temperature in the first microchannel reactor, the second microchannel reactor and / or the third microchannel reactor is independently -30°C to 50°C, preferably -10°C to 30°C, more preferably -5°C to 30°C, wherein the above temperatures may be the same or different.

[0125] In scheme (iv), the temperature of the first microchannel reactor is -30°C to 50°C, preferably -25°C to 5°C, more preferably -20°C to -10°C, and / or the temperature of the tubular reactor is -30°C to 50°C, preferably -25°C to 10°C, more preferably -20°C to 5°C.

[0126] In a preferred embodiment, in step a), when the reactor consists of microchannel reactors, the total residence time in all reactors is from 0.1 seconds to 300 seconds, preferably from 1 second to 30 seconds, and more preferably from 2 seconds to 8 seconds. For example, the dwell time can be 0.1 seconds, 0.2 seconds, 0.5 seconds, 0.8 seconds, 1 second, 1.2 seconds, 1.4 seconds, 1.6 seconds, 1.8 seconds, 2 seconds, 2.5 seconds, 3 seconds, 4 seconds, 5 seconds, 6 seconds, 7 seconds, 8 seconds, 9 seconds, 10 seconds, 11 seconds, 12 seconds, 13 seconds, 14 seconds, 15 seconds, 16 seconds, 17 seconds, 18 seconds, 19 seconds, 20 seconds, 21 seconds, 22 seconds, 23 seconds, 24 seconds, 25 seconds, 26 seconds, 27 seconds, 28 seconds, 29 seconds, 30 seconds, 31 seconds, 35 seconds, 40 seconds, 45 seconds, 50 seconds, 55 seconds, 60 seconds, 65 seconds, 70 seconds, 75 seconds, 80 seconds, or 85 seconds. 100 seconds, 90 seconds, 95 seconds, 100 seconds, 105 seconds, 110 seconds, 115 seconds, 120 seconds, 125 seconds, 130 seconds, 135 seconds, 140 seconds, 145 seconds, 150 seconds, 155 seconds, 160 seconds, 165 seconds, 170 seconds, 175 seconds, 180 seconds, 185 seconds, 190 seconds, 195 seconds, 200 seconds, 205 seconds, 210 seconds, 215 seconds, 220 seconds, 225 seconds, 230 seconds, 235 seconds, 240 seconds, 245 seconds, 250 seconds, 255 seconds, 260 seconds, 265 seconds, 270 seconds, 275 seconds, 280 seconds, 285 seconds, 290 seconds, 295 seconds, or 300 seconds.

[0127] In another preferred embodiment, step b) is carried out by heating the reaction product of step a) to 30°C to 130°C, preferably 60°C to 120°C, more preferably 90°C to 100°C, and holding it at that temperature for 1 to 24 hours, preferably 2 to 10 hours, more preferably 5 to 8 hours, and then hydrolyzing it with an acid, preferably hydrochloric acid, at a temperature of 50°C to 120°C, preferably 80°C to 120°C, more preferably 100°C to 110°C. For example, the temperature at which the reaction product of step a) is held can be 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, or 130°C. For example, the reaction product of step a) can be maintained for 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, 12 hours, 12.5 hours, 13 hours, 13.5 hours, 14 hours, 14.5 hours, 15 hours, 15.5 hours, 16 hours, 16.5 hours, 17 hours, 17.5 hours, 18 hours, 18.5 hours, 19 hours, 19.5 hours, 20 hours, 20.5 hours, 21 hours, 21.5 hours, 22 hours, 22.5 hours, 23 hours, 23.5 hours, or 24 hours. For example, the hydrolysis temperature can be 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃ or 120℃.

[0128] In the method of the present invention, glufosinate of formula (IV) or its analogues may be L-configuration, D-configuration, or a mixture of L and D-configurations.

[0129] Example

[0130] The invention will be further described in detail and illustrated with reference to the following embodiments. These embodiments are intended to help those skilled in the art better understand and practice the invention; however, they are not intended to limit the scope of the invention.

[0131] In the following examples, the absolute yield of the reaction solution was calculated by liquid phase detection of the mass percentage of L-glufosinate in the reaction solution.

[0132] The following reactions all occurred in the following examples:

[0133]

[0134] L-Glufosinate-ammonium hydrochloride Examples A1 to A3: Preparation of L-Glufosinate Hydrochloride (Microchannel Feeding)

[0135] A solution of 10% by weight methylphosphine dichloride (hereinafter referred to as "MDP") in chlorobenzene and a solution of 10% by weight H3 in chlorobenzene / ethanol were prepared.

[0136] The reaction flow diagram is attached. Figure 1 As shown in Table 1, the MDP solution was cooled to temperature T1 in a microchannel reactor at the flow rate shown in Table 1. Then, the MDP solution and H3 solution were simultaneously introduced into another microchannel reactor to react at temperature T2 for a residence time of t. The feed stream from the previous microchannel reactor, along with ammonia gas, entered the next microchannel reactor (reaction temperature T3). Subsequently, the reaction liquid exiting the microchannel reactor was heated to 90°C and held for 8 hours, and then hydrolyzed with hydrochloric acid at 100°C to obtain L-glufosinate hydrochloride.

[0137] Table 1

[0138]

[0139] Note: The volume of each microchannel reactor is approximately 8.5 mL. The density of the MDP solution is approximately 1.16 g / mL, and the density of the H3 solution is approximately 1.1 g / mL.

[0140] Examples B1 to B3: Preparation of L-Glufosinate Hydrochloride (Microchannel Feeding)

[0141]

[0142] The reactions that occur in Examples B1 to B3 include the reactions described above.

[0143] Solutions of 10% by weight MDP in chlorobenzene, 10% by weight H3 in chlorobenzene, and 10% by weight ethanol in chlorobenzene were prepared respectively.

[0144] The reaction flow diagram is attached. Figure 2 As shown in Table 2, the MDP solution was cooled to temperature T1 in a microchannel reactor at the flow rates shown in Table 2. Then, the MDP solution and ethanol solution were simultaneously introduced into another microchannel reactor at temperature T1, under the reaction conditions shown in Table 2, with a residence time of t1, to generate MCP. The resulting MCP reaction solution, along with the H3 solution at the flow rates listed in Table 2, was introduced into the first microchannel reactor (reaction temperature T2) of a series of two microchannel reactors, with a residence time of t2. The feed stream from the first microchannel reactor, along with ammonia, entered the second microchannel reactor (reaction temperature T3), under the reaction conditions shown in Table 2. Subsequently, the reaction solution exiting the microchannel reactor was heated to 90°C and maintained for 8 hours, then hydrolyzed with hydrochloric acid at 100°C to obtain L-glufosinate hydrochloride.

[0145] Table 2

[0146]

[0147] Note: The volume of each microchannel reactor is approximately 8.5 mL. The density of the MDP solution is approximately 1.16 g / mL, the density of the ethanol solution is 1.059 g / mL, and the density of the H3 solution is approximately 1.136 g / mL.

[0148] Examples C1 to C2: Preparation of L-Glufosinate Hydrochloride (Microchannel Feeding)

[0149] Solutions of 10% by weight MDP in chlorobenzene, 10% by weight H3 in chlorobenzene, and 10% by weight ethanol in chlorobenzene were prepared respectively.

[0150] The reaction flow diagram is attached. Figure 3 As shown in Table 3, the above MDP solution and H3 solution were simultaneously introduced into another microchannel reactor at the flow rates shown in Table 3. The reaction took place at temperature T1, with a residence time of t1. The resulting reaction solution, along with the above ethanol solution at the flow rates listed in Table 3, was then introduced into the first microchannel reactor (reaction temperature T2) of a series of two microchannel reactors, with a residence time of t2. The feed stream from the first microchannel reactor, along with ammonia, entered the second microchannel reactor. Subsequently, the reaction solution exiting the microchannel reactor was heated to 90°C and maintained for 8 hours, and then hydrolyzed with hydrochloric acid at 100°C to obtain L-glufosinate hydrochloride.

[0151] Table 3

[0152]

[0153] Note: The volume of each microchannel reactor is approximately 8.5 mL. The density of the MDP solution is approximately 1.16 g / mL, the density of the ethanol solution is 1.059 g / mL, and the density of the H3 solution is approximately 1.136 g / mL.

[0154] Examples D1 to D14: Preparation of L-Glufosinate Hydrochloride (Microchannel + Tubular Feeding)

[0155] Solutions of MDP in chlorobenzene, H3 in chlorobenzene, and ethanol in chlorobenzene were prepared at the concentrations shown in Table 4.

[0156] The reaction flow diagram is attached. Figure 4As shown in Table 4, the MDP solution and ethanol solution were pre-cooled separately through a microchannel reactor at the flow rates shown in Table 4. They were then simultaneously introduced into a microchannel reactor (reaction temperature T1) for a residence time of t1. The resulting reaction solution was then continuously passed into a tubular reactor to react with the H3 solution and ammonia gas at the flow rates shown in Table 4 (reaction temperature T2) for a residence time of t2. The reaction solution exiting the tubular reactor was then heated to 90°C and maintained for 8 hours. Finally, it was hydrolyzed with hydrochloric acid at 100°C to obtain L-glufosinate hydrochloride.

[0157] Table 4

[0158]

[0159] Note: Each microchannel reactor has a volume of approximately 8.5 mL. The density of a 10% MDP solution is approximately 1.16 g / mL, a 25% MDP solution is approximately 1.19 g / mL, a 10% ethanol solution is 1.059 g / mL, a 20% ethanol solution is 1.03 g / mL, a 10% H3 solution is approximately 1.136 g / mL, and a 20% H3 solution is approximately 1.131 g / mL. The tubular reactor has a volume of 1.4 L.

[0160] D11 is reacted in the same way as D5 in Table 4 above, except that the ammonia gas used is replaced with the same number of moles of triethylamine. The flow rates, equivalence ratios, concentration ratios, reaction temperatures, residence times, and yields of each reactant are shown in Table 5.

[0161] Table 5

[0162]

[0163] D12 to D14 are reacted in the same way as D5 in Table 4 above, except that the ethanol used is replaced with the various alcohols listed in Table 6, where the flow rate of H3, the equivalence ratio of each reactant, the reaction temperature and the yield are listed in Table 6 below.

[0164] Table 6

[0165]

[0166] Example E: Preparation of L-Glufosinate Hydrochloride (Reaction Reactor Process)

[0167] A solution of 155 g of 10% MDP in chlorobenzene, a solution of 200 g of 10% H3 in chlorobenzene, and a solution of 61.12 g of 10% ethanol in chlorobenzene were prepared.

[0168] The 61.12 g of ethanol solution was added to the reaction vessel and cooled to -15°C. The 155 g of MDP solution was slowly added dropwise. After the addition was complete, the mixture was stirred for 5 min. Then, the 200 g of H3 solution and 32.2 g of triethylamine were added dropwise. After the addition was complete, the mixture was heated to 90°C for rearrangement reaction. After about 2 h, the mixture was desolvated under reduced pressure. Concentrated hydrochloric acid was added for hydrolysis to obtain L-glufosinate hydrochloride. The absolute yield of the product was 65.4%.

[0169] The above description is exemplary and not restrictive. Variations and modifications to the embodiments disclosed above will become apparent to those skilled in the art and do indeed fall within the scope of this disclosure. Therefore, the scope of legal protection afforded to this disclosure can only be determined by examining the appended claims.

[0170] The foregoing description of embodiments has been provided for illustrative and descriptive purposes. It is not intended to be exhaustive or limiting of this disclosure. Elements or features of a particular embodiment are generally not limited to that particular embodiment, but are interchangeable where applicable, and may be used in selected embodiments even if not specifically shown or described. They may also vary in many ways. Such variations should not be considered a departure from this disclosure, and all such modifications are intended to be included within the scope of this disclosure.

[0171] Exemplary embodiments are provided to make this disclosure thorough and to fully convey the scope to those skilled in the art. Numerous specific details, such as examples of specific components, apparatus, and methods, are set forth to provide a thorough understanding of embodiments of this disclosure. It will be apparent to those skilled in the art that specific details are not required, and that exemplary embodiments may be embodied in many different forms, none of which should be construed as limiting the scope of this disclosure. In some exemplary embodiments, well-known methods, well-known apparatus structures, and well-known techniques are not described in detail.

[0172] The terminology used herein is for the purpose of describing particular exemplary embodiments only and is not intended to be limiting. The terms “comprising,” “including,” and “having” are inclusive and therefore specify the presence of the said features, integers, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or combinations thereof. Unless expressly identified as an order of execution, the method steps, processes, and operations described herein should not be construed as requiring performance in the specific order discussed or exemplified. It should also be understood that additional or alternative steps may be employed.

Claims

1. A method for preparing glufosinate of formula (IV) or its analogues, characterized in that, The method includes: a) React the compound of formula (II), the alcohol of formula (III), and the compound of formula (V) b) Hydrolyze the product of the above reaction to obtain glufosinate or its analogues of formula (IV). R1 and R2 are each independently selected from C1-C 16 Alkyl, C6-C 12 Aryl, C3-C 10 cycloalkyl, C7-C 12 Alkyl and C7-C 12 Aryl groups, each of which is unsubstituted or substituted with C1-C6 alkyl, C1-C6 alkoxy, dialkyl or dialkylamino groups; Hal1 is a halogen. Hal 2 Halogen, PG is a hydrogen or amino protecting group. When PG is an amino protecting group, the method further includes removing the amino protecting group. X is either -OR3 or -NR3R4, where R3 is C1-C 16 Alkyl, C6-C 16 Aryl, C3-C 16 cycloalkyl, C7-C 16 Aryl or C7-C 16 Alkyl aryl, wherein each of the groups is unsubstituted or substituted with a C1-C6 alkyl group; R4 is hydrogen or as defined by R3; The molar ratio of compound (II) to alcohol of formula (III) is 1:(0.1-1.1).

2. The method according to claim 1, characterized in that, R1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, phenyl, benzyl, phenethyl, phenylpropyl, methylphenyl, ethylphenyl, and propylphenyl; and / or R2 is a C1-C8 alkyl group.

3. The method according to claim 1, characterized in that, R1 is C1-C 16 Alkyl, cyclohexyl, cyclopentyl or phenyl, wherein each group is unsubstituted or substituted by C1-C6 alkyl, C1-C6 alkoxy or dialkylamino; R2 is a C1-C6 alkyl group; Hal1 and Hal 2 Each can be fluorine, chlorine, bromine, or iodine independently.

4. The method according to claim 3, characterized in that, R1 is a phenyl or C1-C6 alkyl group.

5. The method according to claim 4, characterized in that, R1 is a C1-C4 alkyl group.

6. The method according to claim 4, characterized in that, R1 is methyl, ethyl, propyl, butyl, pentyl, or hexyl.

7. The method according to claim 6, characterized in that, R1 is methyl, ethyl, propyl, or butyl.

8. The method according to claim 3, characterized in that, R2 is a C1-C4 alkyl group.

9. The method according to claim 3, characterized in that, R2 is methyl, ethyl, propyl, butyl, pentyl, or hexyl.

10. The method according to claim 9, characterized in that, R2 is methyl, ethyl, propyl, or butyl.

11. The method according to any one of claims 1 to 10, characterized in that, R1 is methyl, R2 is ethyl, PG is hydrogen, and Hal1 and Hal 2 Each is chlorine independently.

12. The method according to claim 1, characterized in that, The compounds of formula (II) are dichloromethylphosphine, dichloroethylphosphine, dichloropropylphosphine, dichlorobutylphosphine, dichlorocyclohexylphosphine, dichlorophenylphosphine, dichloro-4-methoxyphenylphosphine, or dichloro-4-dimethylaminophenylphosphine.

13. The method according to claim 1, characterized in that, The alcohol in formula (III) is methanol, ethanol, n-propanol, isopropanol or n-butanol.

14. The method according to claim 13, characterized in that, The alcohol in formula (III) is ethanol, n-propanol, isopropanol or n-butanol.

15. The method according to claim 14, characterized in that, The alcohol in formula (III) is n-butanol or ethanol.

16. The method according to claim 15, characterized in that, The alcohol in formula (III) is ethanol.

17. The method according to any one of claims 1 to 10, characterized in that, Step a) is achieved in the following way: i) Mixing the compound of formula (II), the alcohol of formula (III), and the compound of formula (V) together with a solvent; or ii) Mix the compound of formula (II) with the alcohol of formula (III), and then mix the resulting product with the compound of formula (V); or iii) Mix the compound of formula (II) with the compound of formula (V), and then mix the resulting product with the alcohol of formula (III).

18. The method according to any one of claims 1 to 10, characterized in that, When the reaction in step a) occurs in a microchannel reactor, the reaction in step a) is carried out at a reaction temperature of -30°C to 50°C; or when the reaction in step a) occurs in a reactor consisting of a microchannel reactor and a tubular reactor or in a reaction vessel, the reaction in step a) is carried out at a reaction temperature of -30°C to 50°C.

19. The method according to claim 18, characterized in that, When the reaction in step a) occurs in a microchannel reactor, the reaction in step a) is carried out at a reaction temperature of -10°C to 30°C; or when the reaction in step a) occurs in a reactor consisting of a microchannel reactor and a tubular reactor or in a reaction vessel, the reaction in step a) is carried out at a reaction temperature of -20°C to 10°C.

20. The method according to claim 19, characterized in that, When the reaction in step a) occurs in a microchannel reactor, the reaction in step a) is carried out at a reaction temperature of -5°C to 30°C; or when the reaction in step a) occurs in a reactor consisting of a microchannel reactor and a tubular reactor or in a reaction vessel, the reaction in step a) is carried out at a reaction temperature of -15°C to 5°C.

21. The method according to any one of claims 1 to 10, characterized in that, The molar ratio of the compound of formula (II), the alcohol of formula (III), and the compound of formula (V) is 1:(0.1-1.1):(0.1-2).

22. The method according to claim 21, characterized in that, The molar ratio of the compound of formula (II), the alcohol of formula (III), and the compound of formula (V) is 1:(0.5-1.1):(0.5-1).

23. The method according to claim 22, characterized in that, The molar ratio of the compound of formula (II), the alcohol of formula (III) and the compound of formula (V) is 1:(0.9-1.1):(0.7-1).

24. The method according to any one of claims 1 to 10, characterized in that, Hal 2 It is chlorine; PG is H, -C(O)-R5, -SO2-R6, -CHC(O)O-R7 or -C(O)OR8, where R5 is C6-C 16 Aryl, C7-C 16 Aryl or C7-C 16 Alkyl aryl; R6 is C6-C 16 Aryl, C7-C 16 Aryl or C7-C 16 Alkyl aryl; R7 and R8 are each independently C1-C 16 Alkyl, C6-C 16 Aryl, C3-C 16 cycloalkyl, C7-C 16 Aryl or C7-C 16 Alkyl aryl; and X is -OR3, where R3 is a C1-C8 alkyl or C7-C 10 Aryl group.

25. The method according to claim 24, characterized in that, R5 is C6-C 12 Aryl, C7-C 13 Aryl or C7-C 13 Alkyl; R6 is C6-C 12 Aryl, C7-C 13 Aryl or C7-C 13 Alkyl; R7 and R8 are each independently C1-C8 alkyl, C6-C 12 Aryl, C3-C 10 cycloalkyl, C7-C 12 Aryl or C7-C 12 alkylaryl; and / or R3 is a C1-C6 alkyl or a C7-C9 aralkyl.

26. The method according to claim 25, characterized in that, R5 is phenyl, tolyl, benzyl, or phenethyl; R6 is phenyl, tolyl, benzyl, or phenethyl; R7 and R8 are each independently methyl, ethyl, propyl, butyl, phenyl, benzyl, phenethyl, tolyl, ethylphenyl, cyclopropyl, cyclobutyl, or cyclopentyl; and / or R3 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or benzyl.

27. The method according to claim 26, characterized in that, R5 is a phenyl group; R6 is tolyl; and / or R7 and R8 are each an independent isomer of methyl, ethyl, propyl, or butyl.

28. The method according to any one of claims 1 to 10, characterized in that, The hydrolysis is either acid hydrolysis or alkaline hydrolysis, wherein the acid hydrolysis is carried out using an inorganic acid or an organic acid, and the alkaline hydrolysis is carried out using an inorganic base or an organic base.

29. The method according to claim 28, wherein the inorganic acid is hydrochloric acid or sulfuric acid.

30. The method according to any one of claims 1 to 10, characterized in that, Step a) is carried out in the absence of a solvent or in an inert solvent, wherein the inert solvent is any one or more of amide solvents, hydrocarbon solvents, sulfone or sulfoxide solvents, ether solvents or ester solvents.

31. The method according to any one of claims 1 to 10, characterized in that, Step a) is carried out in the absence of a solvent or in an inert solvent, wherein the inert solvent is a benzene-based solvent or a halogenated hydrocarbon solvent.

32. The method according to any one of claims 1 to 10, characterized in that, Step a) is carried out in the absence of solvent or in an inert solvent selected from one or more of chlorobenzene, thiol, 1,4-dioxane, 1,2-dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate.

33. The method according to any one of claims 1 to 10, characterized in that, The base is added at the start of the reaction in step a), during the reaction, and / or after the reaction.

34. The method according to claim 33, characterized in that, After the reaction in step a), an alkali is added.

35. The method according to claim 33, wherein the base is an organic base or ammonia.

36. The method of claim 33, wherein the base is ammonia.

37. The method according to claim 35, characterized in that, The organic base is an organic amine.

38. The method according to claim 37, characterized in that, The organic amine is triethylamine, pyridine, or a pyridine derivative having 1 to 3 substituents attached to one or more carbon atoms of the heterocycle, or a piperidine derivative having 1 to 3 substituents attached to one or more carbon atoms of the heterocycle.

39. The method according to any one of claims 1 to 10, characterized in that, Step a) is carried out in the following manner: (i) the compound of formula (II) is simultaneously introduced into a first reactor with the alcohol of formula (III) and the compound of formula (V) to react in the presence of a solvent, and then the resulting product is introduced into a second reactor with a base; or (ii) the compound of formula (II) is simultaneously introduced into a first reactor with the alcohol of formula (III) to react in the presence of a solvent or in the absence of other solvents, and then the resulting product is introduced into a second reactor with the compound of formula (V), and finally the resulting product is introduced into a third reactor with a base to react; or (iii) the compound of formula (II) is simultaneously introduced into a first reactor with the compound of formula (V) to react in the presence of a solvent or in the absence of other solvents, and then the resulting product is introduced into a second reactor with the alcohol of formula (III), and finally the resulting product is introduced into a third reactor with a base to react; or (iv) the compound of formula (II) is simultaneously introduced into a first reactor with the alcohol of formula (III) to react in the presence of a solvent or in the absence of other solvents, and then the resulting product is introduced into a second reactor with the compound of formula (V) and a base to react.

40. The method according to claim 39, characterized in that, The first reactor, the second reactor, and / or the third reactor are each independently selected from microchannel reactors, tubular reactors, tubular packed reactors, stirred tank reactors, or any combination thereof.

41. The method according to claim 40, characterized in that, The first reactor, the second reactor, and / or the third reactor each independently consist of one or more microchannel continuous flow reactors, or each independently consists of one or more microchannel continuous flow reactors and one or more tubular reactors.

42. The method according to claim 39, characterized in that, Step a) is carried out in the following manner: (i) the compound of formula (II) is simultaneously introduced into a first microchannel reactor with the alcohol of formula (III) and the compound of formula (V) to react in the presence of a solvent, and then the resulting product is introduced into a second microchannel reactor with a base; or (ii) the compound of formula (II) is simultaneously introduced into a first microchannel reactor with the alcohol of formula (III) to react in the presence or absence of a solvent, and then the resulting product is introduced into a second microchannel reactor with the compound of formula (V), and finally the resulting product is introduced into a third microchannel reactor with a base to react. (iii) The compound of formula (II) and the compound of formula (V) are simultaneously introduced into the first microchannel reactor to react in the presence or absence of solvent, and the resulting product is then introduced into the second microchannel reactor with the alcohol of formula (III), and finally the resulting product is introduced into the third microchannel reactor with the base to react; or (iv) The compound of formula (II) and the alcohol of formula (III) are simultaneously introduced into the first microchannel reactor to react in the presence or absence of solvent, and the resulting product, the compound of formula (V), and the base are then introduced into the tubular reactor to react.

43. The method according to claim 42, characterized in that, The alkali is ammonia.

44. The method according to claim 42, characterized in that, In scheme (i), the temperature in the first microchannel reactor and / or the second microchannel reactor is independently between -30°C and 50°C, wherein the above temperatures may be the same or different; in scheme (ii), the temperature in the first microchannel reactor, the second microchannel reactor, and / or the third microchannel reactor is independently between -30°C and 50°C, wherein the above temperatures may be the same or different; in scheme (iii), the temperature in the first microchannel reactor, the second microchannel reactor, and / or the third microchannel reactor is independently between -30°C and 50°C, wherein the above temperatures may be the same or different; in scheme (iv), the temperature of the first microchannel reactor is between -30°C and 50°C, and / or the temperature of the tubular reactor is between -30°C and 50°C.

45. The method according to claim 44, characterized in that, In scheme (i), the temperature inside the first microchannel reactor and / or the second microchannel reactor is independently between -10°C and 30°C, wherein the above temperatures may be the same or different; In scheme (ii), the temperature in the first microchannel reactor, the second microchannel reactor and / or the third microchannel reactor is independently between -10°C and 30°C, wherein the above temperatures are the same or different; In scheme (iii), the temperature in the first microchannel reactor, the second microchannel reactor and / or the third microchannel reactor is independently between -10°C and 30°C, wherein the above temperatures may be the same or different; In scheme (iv), the temperature of the first microchannel reactor is -25°C to 5°C, and / or the temperature of the tubular reactor is -25°C to 10°C.

46. ​​The method according to claim 45, characterized in that, In scheme (i), the temperature inside the first microchannel reactor and / or the second microchannel reactor is independently between -5°C and 30°C, wherein the above temperatures may be the same or different; In scheme (ii), the temperature in the first microchannel reactor, the second microchannel reactor and / or the third microchannel reactor is independently between -5°C and 30°C, wherein the above temperatures are the same or different; In scheme (iii), the temperature in the first microchannel reactor, the second microchannel reactor and / or the third microchannel reactor is independently between -5°C and 30°C, wherein the above temperatures are the same or different; In scheme (iv), the temperature of the first microchannel reactor is -20°C to -10°C, and / or the temperature of the tubular reactor is -20°C to 5°C.

47. The method according to claim 39, characterized in that, In step a), when the reactor consists only of microchannel reactors, the total residence time in all reactors is from 0.1 seconds to 300 seconds; or when the reactor consists of microchannel reactors and tubular reactors, the total residence time in all reactors is from 1 minute to 20 minutes.

48. The method according to claim 47, characterized in that, In step a), when the reactor consists only of microchannel reactors, the total residence time in all reactors is 1 second to 50 seconds; or when the reactor consists of microchannel reactors and tubular reactors, the total residence time in all reactors is 5 minutes to 18 minutes.

49. The method according to any one of claims 48, characterized in that, In step a), when the reactor consists only of microchannel reactors, the total residence time in all reactors is 10 to 40 seconds; or when the reactor consists of microchannel reactors and tubular reactors, the total residence time in all reactors is 9 to 14 minutes.

50. The method according to any one of claims 1 to 10, characterized in that, Step b) is carried out by heating the reaction product of step a) to a temperature of 30°C to 130°C and holding it therefor 1 to 24 hours, and then hydrolyzing it with acid at a temperature of 50°C to 120°C.

51. The method according to claim 50, characterized in that, Step b) is implemented in the following manner: The reaction product of step a) is heated to a temperature of 60°C to 120°C; Heat to the specified temperature and maintain it for 2 to 10 hours; Then hydrolyze with acid at a temperature of 80°C to 120°C; and / or The acid is hydrochloric acid.

52. The method according to claim 51, characterized in that, Step b) is implemented in the following manner: The reaction product of step a) is heated to a temperature of 90°C to 100°C; Heat to the specified temperature and maintain for 5 to 8 hours; and / or Then it is hydrolyzed with acid at a temperature of 100°C to 110°C.

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