阅读说明：本技术 草铵膦中间体及草铵膦的制备方法 (Glufosinate-ammonium intermediate and preparation method of glufosinate-ammonium ) 是由 周波 杨清 蒋海军 陈曙 杨苏军 程柯 尹英遂 于 2019-12-04 设计创作，主要内容包括：本发明提供了一种制备式草铵膦中间体及草铵膦的制备方法。本发明的方法将两种单独的计量料流S1和S2同时地加入反应器中,并且这些计量料流S1和S2具有以下组成：计量料流S1包含甲基膦化合物(I),计量料流S2包含不饱和酮化合物(II)和酸(III)。草铵膦中间体(IV)可经Strecker反应得到草铵膦。(The invention provides a preparation method of a glufosinate-ammonium intermediate and glufosinate-ammonium. The process of the present invention feeds two separate metering streams S1 and S2 simultaneously into the reactor, and these metering streams S1 and S2 have the following composition: metering stream S1 comprises methylphosphine compound (I), and metering stream S2 comprises unsaturated ketone compound (II) and acid (III). The glufosinate-ammonium Intermediate (IV) can be reacted by Strecker to obtain glufosinate-ammonium.)

1. A process for the preparation of a compound of formula (IV),

the method is characterized in that: the method comprises the following steps:

reacting a compound of formula (I) with a compound of formula (II) in the presence of an acid of formula (III),

wherein:

x and Y are each independently hydrogen, alkyl, alkenyl or aryl, R is hydrogen or C₁-C₄Alkyl, A is acyl;

wherein two separate metered streams S1 and S2 are fed simultaneously into the reactor and these metered streams S1 and S2 have the following composition: metering stream S1 comprises a compound of formula (I), metering stream S2 comprises a compound of formula (II) and an acid of formula (III).

2. A method according to claim 1, characterized in that: wherein two separate metering streams S1 and S2 are metered simultaneously into the reactor at such a rate that from 0.5 to 2mol of the compound of the formula (II) and from 0.5 to 2mol of the acid of the formula (III) are added simultaneously with 1mol of the compound of the formula (I).

3. A method according to claim 1 or 2, characterized in that: 0.8 to 1.2mol of compound of formula (II) and 0.8 to 1.2mol of acid of formula (III) are used per 1mol of compound of formula (I), preferably 0.9 to 1.1mol of compound of formula (II) and 0.9 to 1.1mol of acid of formula (III).

4. A method according to claims 1-3, characterized in that: a is C₁-C₆An acyl group.

5. Method according to claims 1-4, characterized in that: the alkyl group is C₁-C₁₈With one or more substituted alkyl groups and alkenyl is C₂-C₁₈The aryl group is phenyl, benzyl, substituted phenyl or substituted benzyl, wherein the substituent is halogen, nitro, sulfonyl, etheroxy, etherthio, ester group, thioester group or cyano.

6. A method according to claims 1-5, characterized in that: x, Y are each independently C₁-C₆An alkyl group;

r is hydrogen;

a is C₁-C₆An acyl group.

7. The method according to claim 6, characterized in that: x is ethyl, Y is ethyl, R is hydrogen, and A is acetyl.

8. A method according to claims 1-7, characterized in that: the metering streams S1 and/or S2 also comprise an organic solvent.

9. The method of claim 8, wherein: the organic solvent is an alcohol solvent or a benzene solvent.

10. A method according to claims 1-9, characterized in that: the reaction temperature is-80-50 ℃, preferably 10-42 ℃, and more preferably 20-30 ℃.

11. A method according to any one of claims 1 to 10, characterized in that: and after the addition of the metering materials S1 and S2 is finished, the method further comprises a heat preservation step, wherein the temperature of the heat preservation step is 20-30 ℃.

12. A process for the preparation of a compound of formula (V),

the method is characterized in that: the method comprises the following steps:

wherein R is hydrogen or C₁-C₄Alkyl, wherein the compound of formula (IV),

optionally after hydrolysis to form a compound of formula (IV'),

wherein Z is OH or a mixture of OX or with ammonia and hydrocyanic acid, with ammonia/ammonium chloride and sodium cyanide or with a mixture of ammonia and hydrocyanic acid or with ammonia and hydrocyanic acid, optionally in the presence of ammonium chloride, under the conditions of the Strecker synthesis reaction to give alpha-aminonitriles of the formula (IV') or salts thereof

And (IV ") hydrolyzing the compound of formula (IV") under acidic or basic conditions to give a compound of formula (V), wherein X, Y, A, R is as defined in any one of claims 1 or 4 to 7, the compound of formula (IV) being prepared by a process according to any one of claims 1 to 11.

Technical Field

The invention relates to a glufosinate-ammonium intermediate and a preparation method of glufosinate-ammonium.

Background

Glufosinate is an important herbicide.

Patent CN1267305A is known to date disclosing a process for the preparation of glufosinate intermediate acetals of the formula,

(wherein X, Y, R independently of one another is H or C₁-C₁₈Alkyl, benzyl or phenyl, R is hydrogen or C₁-C₄Alkyl, A is acyl) and then further preparing glufosinate-ammonium by Strecker reaction and hydrolysis. In the method, four materials are required to be added when preparing the acetal, so that the material cost is high and the byproducts are more.

Patent CN1858054A discloses a method for preparing glufosinate by preparing effective intermediate of methyl phosphonate, and further by Strecker reaction and hydrolysis. When the method is used for preparing the effective intermediate of the methyl phosphonate, only three materials of methyl phosphinate, acrolein and carboxylic acid can be added, and the final product glufosinate-ammonium with the purity of 97.8 percent and the total yield of 96 percent can be obtained. However, it is only mentioned that the aforementioned glufosinate intermediate acetal may be one of the existing forms of methylphosphonate useful intermediates, and it is not mentioned how to efficiently prepare the glufosinate intermediate acetal. And the yield and the purity of the final product glufosinate-ammonium still have room for further improvement.

Disclosure of Invention

In order to solve the above problems, the present invention provides a process for preparing a compound of formula (IV) or a salt thereof,

the method comprises the following steps:

reacting a compound of formula (I) with a compound of formula (II) in the presence of an acid of formula (III),

wherein:

x andy is independently hydrogen, alkyl, alkenyl or aryl, R is hydrogen or C₁-C₄Alkyl, A is acyl;

wherein two separate metered streams S1 and S2 are fed simultaneously into the reactor and these metered streams S1 and S2 have the following composition: metering stream S1 comprises a compound of formula (I), metering stream S2 comprises a compound of formula (II) and an acid of formula (III).

Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.

Alkyl refers to a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 18 carbon atoms. Alkyl groups having 1 to 6 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.

Alkenyl refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl, and the like. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent may be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.

An aromatic group refers to a group having at least one aromatic ring structure. The aryl group is preferably a phenyl group or a benzyl group. The phenyl and benzyl groups may be substituted or unsubstituted, and when substituted, the substituents may be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.

Acyl is the residue of an organic acid, for example: residues of carboxylic acids and other acids derived therefrom, for example, residues of thiocarboxylic acids, optionally N-substituted iminocarboxylic acids, or carbonic monoesters, optionally N-substituted carbamic acids, sulfonic acids, sulfinic acids, phosphonic acids, phosphinic acids. For example: formyl, alkylcarbonyl, for example: (C)₁-C₄-alkyl) -carbonyl, phenylcarbonyl. Preferred A is the acyl radical of a carboxylic acid having 1 to 6 carbon atoms, especially the acetyl radical。

The compounds of formula (I) can be prepared according to known methods, for example as disclosed in CN1267305A and as mentioned in the literature. X, Y are preferably each independently C₁-C₆Alkyl, especially ethyl.

The compounds of the formula (II) and the acids of the formula (IIII) are known basic chemicals.

The dosing disclosed in CN1858054A is a drop-wise addition of the acrolein-weak acid mixture to diethyl methylphosphonite. The applicant has found, through experimental and mechanistic studies, that if the opposite dosing regime is adopted, i.e. diethyl methylphosphonite is added dropwise to the acrolein-weak acid mixture, side reactions occur in large amounts, due to the effect of the excess acid, with a target acetal content of less than 60%. In addition, the number and the content of impurities in the reaction liquid are greatly increased, and particularly, a large amount of impurities with the following structures are generated, and the content of the impurities can reach more than 10 percent:

therefore, an excess of diethyl methylphosphonite is advantageous in suppressing the occurrence of side reactions, which is also consistent with the dosing disclosed in CN 1858054A. Surprisingly, however, when diethyl methylphosphonite and an acrolein-weak acid mixture are simultaneously fed into a reactor for reaction, not only the target acetal content is significantly increased, but also the number and content of impurities in the reaction solution are significantly reduced, as compared with the aforementioned feeding method in which diethyl methylphosphonite is fed in an excess amount,

in addition, while a number of methylphosphonate useful intermediates are disclosed in CN1858054A, they are believed to have similar functions in subsequent reactions. However, the applicant has unexpectedly found in the actual production of glufosinate-ammonium that the yield and purity of glufosinate-ammonium has a significant positive correlation with the target acetal content in the reaction solution in the process for preparing glufosinate-ammonium by preparing a methylphosphonate efficient intermediate.

Therefore, the method can be used for preparing the reaction liquid with high target acetal content, thereby effectively improving the production efficiency of subsequent reaction.

The highly concentrated aldolisation reaction solution prepared in the present invention can be prepared by the known literature methods without any or with suitable workup by continuing the reaction to obtain glufosinate-ammonium, such as the method described in CN1267305A, especially the strecker method.

In a further preferred embodiment, wherein two separate metering streams S1 and S2 are metered simultaneously into the reactor at such a rate that 0.5 to 2mol of the compound of the formula (II) and 0.5 to 2mol of the acid of the formula (III) are added simultaneously over the course of 1mol of the compound of the formula (I). To achieve simultaneous metering, the techniques known in the art can be used, for example, using the existing devices such as constant pressure dropping funnels, metering pumps, etc.

Further, 0.8 to 1.2mol of the compound of the formula (II) and 0.8 to 1.2mol of the acid of the formula (III), preferably 0.9 to 1.1mol of the compound of the formula (II) and 0.9 to 1.1mol of the acid of the formula (III) are used per 1mol of the compound of the formula (I).

Further, A is C₁-C₆An acyl group.

Further, the alkyl group is C₁-C₁₈With one or more substituted alkyl groups and alkenyl is C₂-C₁₈The aryl group is phenyl, benzyl, substituted phenyl or substituted benzyl, wherein the substituent is halogen, nitro, sulfonyl, etheroxy, etherthio, ester group, thioester group or cyano.

Preferably, X, Y are each independently C₁-C₆An alkyl group; r is hydrogen; a is C₁-C₆An acyl group.

More preferably, X is ethyl, Y is ethyl, R is hydrogen and a is acetyl.

In the process of the present invention, the aforementioned metered streams S1 and/or S2 may comprise suitable organic solvents, such as alcoholic solvents or benzene-based solvents. Surprisingly, the presence of ethanol in the process of the present invention rather reduces the target acetal content in the reaction solution, as compared to the alcohol-assisted effect of the CN1267305A process, and the more ethanol, the lower the target acetal content.

The reaction temperature of the method can be-80-50 ℃, preferably 10-42 ℃, and more preferably 20-30 ℃.

Compared with the feeding mode of CN1858054A, the reaction is basically completed after the raw materials are dripped. As a further preference, after all the reaction raw materials have been metered simultaneously, i.e. after the addition of the aforementioned metered streams S1 and S2 is completed, a step of heat preservation is included, wherein the temperature of the heat preservation is 20-30 ℃ so as to obtain a reaction liquid with higher target acetal content.

In general, the reaction time of the present invention can be generally 0.5 to 48 hours, preferably 0.5 to 18 hours, depending on the reaction temperature, batch size, nature of reactants, and solvent (if any).

Depending on the nature of the starting materials and the reaction conditions, diethyl methylphosphonite is flammable at high temperatures, and to increase the safety in production, inert gases or noble gases, such as nitrogen, can be added to the reaction.

On the basis of the above, the present invention also provides a process for preparing a compound of formula (V) or a salt thereof,

the method comprises the following steps:

wherein R is hydrogen or C₁-C₄Alkyl, wherein the compound of formula (IV),

optionally after hydrolysis to form a compound of formula (IV'),

wherein Z is OH or a mixture of OX or with ammonia and hydrocyanic acid, with ammonia/ammonium chloride and sodium cyanide or with a mixture of ammonia and hydrocyanic acid or with ammonia and hydrocyanic acid, optionally in the presence of ammonium chloride, under the conditions of the Strecker synthesis reaction to give alpha-aminonitriles of the formula (IV') or salts thereof

And (IV) hydrolyzing the compound of formula (IV ") under acidic or basic conditions to provide a compound of formula (V), wherein X, Y, A, R is as defined above, the compound of formula (IV) being prepared according to the methods described above.

Detailed Description

Example 1

Diethyl methylphosphonite (136.13g/mol, 20g, 0.147mol) was charged to an isopiestic dropping funnel as feed A; to another constant pressure dropping funnel was added a mixture of acrolein (56.06g/mol, 8.24g, 0.147mol) and acetic acid (60.05g/mol, 8.8g, 0.147mol) as feed B. Under the protection of nitrogen, the materials A and B are simultaneously dripped into a reaction flask, the reaction is started under magnetic stirring, the dripping speeds of the two materials are controlled, and the system temperature is controlled at 20-30 ℃. After the two materials are simultaneously dripped, the mixture is continuously stirred and reacts for 30min at room temperature (25 ℃) to obtain an acetal mixture, and the acetal main peak content is 86.03 percent by GC detection.

The acetal mixture was added dropwise to a 50mL25 wt% aqueous ammonia solution of sodium cyanide (49.01g/mol, 7.2g, 0.147mol), ammonium chloride (53.49g/mol, 15.73g, 0.294mol) and stirred for 2h after the addition to give the cyanamide mixture.

The cyanamide mixture was added dropwise to 200mL of 37 wt% hydrochloric acid and heated under reflux for 3.5 h. The water was drained to give a viscous material, which was dissolved in 125mL of methanol and filtered to remove ammonium chloride solids. After the filtrate is concentrated and desolventized by methanol, 15mL of distilled water is added, and the pH is adjusted to 3.0-3.5 by using 5mol/L NaOH solution. Methanol was added for recrystallization to precipitate 26.6g of white crystals of glufosinate-ammonium (181.13g/mol), the purity of glufosinate-ammonium was 98.5%, and the yield was 98.4% (based on the molar amount of diethyl methylphosphite).

Example 2

According to the method of example 1, the reaction temperature was changed to 10 to 20 ℃ (i.e., the temperature during the dropwise addition control), the acetal main peak content was 85.47% by GC detection, 26.3g of white glufosinate-ammonium crystals were precipitated, the purity of glufosinate-ammonium was 98.5%, and the yield was 97.3%.

Example 3

According to the method of the embodiment 1, the reaction temperature is changed to 38-42 ℃, the acetal main peak content is 84.75% by GC detection, 26.2g of glufosinate-ammonium white crystals are precipitated, the purity of glufosinate-ammonium is 98%, and the yield is 96.4%.

Example 4

According to the method of the embodiment 1, the reaction temperature is changed to 48-50 ℃, the acetal main peak content is 77.24% by GC detection, 24.4g of white glufosinate-ammonium crystals are precipitated, the purity of glufosinate-ammonium is 97%, and the yield is 88.9%.

Example 5

A mixture of diethyl methylphosphonite (20g, 0.147mol) and ethanol (6.77g, 0.147mol) was added to an isopiestic dropping funnel as feed A; to another constant pressure dropping funnel was added a mixture of acrolein (8.24g, 0.147mol) and acetic acid (8.8g, 0.147mol) as feed B. Under the protection of nitrogen, the materials A and B are simultaneously dripped into a reaction flask, the reaction is started under magnetic stirring, the dripping speeds of the two materials are controlled, and the system temperature is controlled at 20-30 ℃. After the two materials are added simultaneously, the stirring reaction is continued for 30min at room temperature (25 ℃), and the acetal main peak content is 83.35% by GC detection.

From the acetal mixture to the cyanamide mixture and further to white crystals of glufosinate-ammonium according to the preceding example procedure. 25.8g of white glufosinate-ammonium crystals are finally precipitated, the purity of glufosinate-ammonium is 98%, and the yield is 95.0%.

Example 6

According to the method of example 5, the amount of ethanol added was changed to 0.75 equivalent, the acetal main peak content was 85.42% by GC assay, 26.1g of white crystals of glufosinate-ammonium was precipitated, the purity of glufosinate-ammonium was 98.5%, and the yield was 96.6%.

Example 7

A solution of diethyl methylphosphonite in trimethylbenzene (50g, containing 10g of the methyl diester, 0.074mol) was added to a constant pressure dropping funnel as feed A; to another isopiestic dropping funnel was added a mixture of acrolein (4.12g, 0.074mol) and acetic acid (4.4g, 0.074mol) as feed B. Under the protection of nitrogen, the materials A and B are simultaneously dripped into a reaction flask, the reaction is started under magnetic stirring, the dripping speeds of the two materials are controlled, and the system temperature is controlled at 20-30 ℃. After the two materials are added simultaneously, the stirring reaction is continued for 30min at room temperature (25 ℃), and the acetal main peak content is 79.01% by GC detection.

From the acetal mixture to the cyanamide mixture and further to white crystals of glufosinate-ammonium according to the preceding example procedure. 25.0g of white glufosinate-ammonium crystals are finally precipitated, the purity of glufosinate-ammonium is 97%, and the yield is 91.1%.

Example 8

According to the method of the embodiment 7, the reaction temperature is changed to 14-16 ℃, the acetal main peak content is 75.94% by GC detection, 24.1g of white glufosinate-ammonium crystals are precipitated, the purity of glufosinate-ammonium is 97%, and the yield is 87.8%.

Example 9

According to the method of the embodiment 7, the reaction temperature is changed to 35-45 ℃, the acetal main peak content is 72.62% by GC detection, 23.5g of glufosinate-ammonium white crystals are precipitated, the purity of glufosinate-ammonium is 96%, and the yield is 84.7%.

Comparative example 1

Diethyl methylphosphonite (20g, 0.147mol) was added to a four-necked flask as feed A; a mixture of acrolein (8.24g, 0.147mol) and acetic acid (8.8g, 0.147mol) was added to the isopiestic dropping funnel as feed B. And (3) under the protection of nitrogen, dropwise adding the material B into the material A, starting reaction under magnetic stirring, and controlling the dropwise adding speed of the material B and the system temperature to be 20-30 ℃. After the dropwise addition, the reaction was continued for 30min under stirring at room temperature (25 ℃), and the acetal main peak content was 81.53% by GC detection.

From the acetal mixture to the cyanamide mixture and further to white crystals of glufosinate-ammonium according to the preceding example procedure. 24.8g of white glufosinate-ammonium crystals are finally precipitated, the purity of glufosinate-ammonium is 98%, and the yield is 91.3%.

Comparative example 2

Diethyl methylphosphonite (20g, 0.147mol) was added to a four-necked flask as feed A; to a constant pressure dropping funnel was added a mixture of acrolein (8.24g, 0.147mol) and acetic acid (8.8g, 0.147mol) as material B; to another constant pressure dropping funnel was added ethanol (6.77g, 0.147mol) as feed C. Under the protection of nitrogen, materials B and C are simultaneously dripped into the material A, the reaction is started under magnetic stirring, the dripping speeds of the two materials are controlled, and the system temperature is controlled at 20-30 ℃. After the two materials are added simultaneously, the stirring reaction is continued for 30min at room temperature (25 ℃), and the acetal main peak content is 81.65% by GC detection.

From the acetal mixture to the cyanamide mixture and further to white crystals of glufosinate-ammonium according to the preceding example procedure. 25g of white glufosinate-ammonium crystals are finally separated out, the purity of glufosinate-ammonium is 98%, and the yield is 92%.

Comparative example 3

A mixture of 20g of diethyl methylphosphonite, 0.147mol) and ethanol (6.77g, 0.147mol) was added to a four-necked flask as feed A; a mixture of acrolein (8.24g, 0.147mol) and acetic acid (8.8g, 0.147mol) was added to the isopiestic dropping funnel as feed B. And (3) under the protection of nitrogen, dropwise adding the material B into the material A, starting reaction under magnetic stirring, and controlling the dropwise adding speed of the material B and the system temperature to be 20-30 ℃. After the dropwise addition, the reaction was continued for 30min under stirring at room temperature (25 ℃), and the acetal main peak content was 76.60% by GC detection.

From the acetal mixture to the cyanamide mixture and further to white crystals of glufosinate-ammonium according to the preceding example procedure. 24.3g of white glufosinate-ammonium crystals are finally precipitated, the purity of glufosinate-ammonium is 97%, and the yield is 88.5%.

Comparative example 4

According to the method of comparative example 3, the amount of ethanol added was changed to 0.75 equivalent, the acetal main peak content by GC assay was 78.77%, 24.4g of white crystals of glufosinate-ammonium (181.13g/mol) were precipitated, the purity of glufosinate-ammonium was 97.5%, and the yield was 89.3%.

Comparative example 5

A solution of diethyl methylphosphonite in trimethylbenzene (50g, containing 10g of diethyl methylphosphonite, 0.074mol) was added to a four-necked flask as feed A; a mixture of acrolein (4.12g, 0.074mol) and acetic acid (4.4g, 0.074mol) was added to the isopiestic dropping funnel as feed B. And (3) under the protection of nitrogen, dropwise adding the material B into the material A, starting reaction under magnetic stirring, and controlling the dropwise adding speed of the material B and the system temperature to be 20-30 ℃. After the dropwise addition, the reaction was continued for 30min under stirring at room temperature (25 ℃), and the acetal main peak content was 74.51% by GC detection.

From the acetal mixture to the cyanamide mixture and further to white crystals of glufosinate-ammonium according to the preceding example procedure. 23.6g of white glufosinate-ammonium crystals are finally precipitated, the purity of glufosinate-ammonium is 97%, and the yield is 86.0%.

Comparative example 6

A solution of diethyl methylphosphonite in trimethylbenzene (50g, containing 10g of methyl diester, 0.074mol) was added to a four-necked flask as feed A; acrolein (4.12g, 0.074mol) was added to a constant pressure dropping funnel as feed B; to another isopiestic dropping funnel was added acetic acid (4.4g, 0.074mol) as feed C. Under the protection of nitrogen, materials B and C are simultaneously dripped into the material A, the reaction is started under magnetic stirring, the dripping speeds of the two materials are controlled, and the system temperature is controlled at 20-30 ℃. After the two materials are added simultaneously, the stirring reaction is continued for 30min at room temperature (25 ℃), and the acetal main peak content is 77.67% by GC detection.

From the acetal mixture to the cyanamide mixture and further to white crystals of glufosinate-ammonium according to the preceding example procedure. 24.1g of white glufosinate-ammonium crystals are finally precipitated, the purity of glufosinate-ammonium is 97%, and the yield is 87.8%.