Throughout this application various publications are referenced. The disclosures of these documents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

TECHNICAL FIELD

The present subject matter relates to a process for preparing and using an alkyl phosphinic acid alkyl ester, an intermediate useful for preparing the herbicide glufosinate. One such process includes preparing and then alkylating the alkyl phosphinic acid ester in a non-polar solvent, without isolating the alkyl phosphinic acid ester prior to the alkylation step. In particular, the present subject matter provides a process for preparation of methyl phosphinic acid butyl ester by preparing and then alkylating butyl phosphinic acid ester in a non-polar solvent, without isolating the butyl phosphinic acid ester.

BACKGROUND

Glufosinate is a broad-spectrum systemic herbicide produced that function as Glutamine synthetase inhibitor which leads to accumulation of ammonium ions, and inhibition of photosynthesis.

The compound methyl phosphinic acid alkyl ester of formula (I)


is an important intermediate for preparing the herbicidal active ingredient Glufosinate, RS)-2-Amino-4-(hydroxy(methyl)phosphonoyl)butanoic acid, as described in U.S. Pat. Nos. 5,420,329 and 4,168,963.

Different manufacturing processes are known in the literature.

U.S. Pat. No. 5,734,072 describes preparing monoalkyl phosphinate from dichlorophosphines.

U.S. Pat. No. 9,035,083 describes a method for producing H-phosphonates while avoiding the use of chlorine. The method comprises the steps of: reacting hypophosphorous acid with an alcohol to produce a phosphinate and an excess of alcohol; and then reacting the phosphinate in the presence of the excess alcohol with a metal catalyst to produce an H-phosphonate.

CN102351900 describes a method for synthesizing monoalkyl phosphonate. The method is characterized in that alkyl phosphine dihalide is taken as a raw material that is subjected to a hydrolysis reaction to obtain alkyl phosphinic acid. The alkyl phosphinic acid undergoes a dehydrated esterification reaction with a compound possessing a structure of R2—OH to obtain the alkyl phosphonate, wherein R2is alkyl, nonsaturated alkylene, or aryl. The process route for preparing a halogen hydride by-product or its aqueous solution can be used as a normal industrialization production process. The esterification process reaction takes place under mild conditions and without requiring complex equipment, keeping the production cost low.

CN103435643 describes a preparation method of a monohydroxy dialkyl phosphinic acid metal salt fire retardant. The preparation method includes the step of reacting alkyl phosphonium dichloride and alcohol to obtain monoalkyl phosphonate.

U.S. Pat. No. 6,815,558 describes a preparation of (metal) salts of alkylphosphonous acids, comprising reaction of elemental yellow phosphorus with alkyl halides in the presence of a base selected from carbonates, bicarbonates, amides, alcoholates, amino bases and/or solid hydroxides.

U.S. Pat. No. 6,806,383 describes a process for the preparation of (metal) salts of alkylphosphonous acids, which comprises reacting elemental yellow phosphorus with halogen-free alkylating agents in the presence of at least one base. Also discussed is the use of the (metal) salts of alkylphosphonous acids prepared by this process.

However, there was a need to develop synthetic pathways where the reaction starts with commercial, easily handled material, in a process that is highly efficient, low-cost, and environmentally friendly. These advantages are not exhibited by prior art processes. The present subject matter provides such a process.

It is therefore a purpose of the present subject matter to provide a process that overcomes the disadvantages of the known art.

SUMMARY

The present invention provides a process for preparing the compound of the formula (II)


wherein
R is a C1-C6alkyl or benzyl, and R1is C1-C6alkyl comprising reacting in a non-polar solvent the compound of formula (I)


wherein
R is C1-C6alkyl or benzyl,
with an alkylating agent in the presence of base.

The present invention also provides a process for preparing the compound of the formula (II)


wherein
R is C1-C6alkyl or benzyl, and
R1is C1-C6alkyl,
comprising the steps of:
(a) reacting hypophosphorous acid with a C1-C6alkyl or benzyl alcohol in the presence of an acid under dehydrating conditions to give the compound of the formula (I),


wherein
R is C1-C6alkyl or benzyl; and
(b) reacting the compound of formula (I) obtained in step (a) with an alkylating agent in the presence of a base,
wherein each step is carried out in the same pot in a non-polar solvent, and wherein the product of step (a) is neither purified nor isolated prior to step (b).

The present invention further provides a process for preparing the compound of the formula (II)


wherein
R is C1-C6alkyl or benzyl, and R1is C1-C6alkyl, comprising the steps of:
(a) reacting hypophosphorous acid with a C1-C6alkyl or benzyl alcohol in the presence of an acid under dehydrating conditions in a non-polar solvent to obtain the compound of formula (I)


wherein R is C1-C6alkyl or benzyl;
(b) reacting the compound obtained in step (a) with a trialkyl orthoformate to obtain the compound of formula (IIIa):


c) reacting the compound obtained in step (b) with an alkylating agent in the presence of a base to obtain a compound of formula (IIIb):


wherein R is C1-C6alkyl or benzyl; R1is C1-C6alkyl; and R2is O-alkyl;
(d) reacting the compound obtained in step (c) with an acid to obtain a compound of formula (IV):


wherein R1is C1-C6alkyl;
(e) reacting the compound obtained in step (d) with an alkyl alcohol in the presence of an acid under dehydrating conditions in a non-polar solvent to obtain the compound of formula (II).

The present invention yet further provides a process for preparing compound of the formula (II):


wherein
R is C1-C6alkyl or benzyl, and R1is C1-C6alkyl, comprising the steps of:
(a) reacting hypophosphorous acid with a trialkyl orthoformate to obtain the compound of formula (IIIc):


wherein each R2is O-alkyl;
(b) reacting the compound obtained in step (a) with an alkylating agent in the presence of a base to obtain the compound of formula (IIId):


wherein R1is C1-C6alkyl or benzyl; and each R2is O-alkyl;
(c) reacting the compound obtained in step (b) with an acid to obtain the compound of formula (IV):


wherein R1is C1-C6alkyl;
(d) reacting the compound obtained in step (c) with a C1-C6alkyl alcohol or benzyl alcohol in the presence of an acid under dehydrating conditions in a non-polar solvent to obtain the compound of formula (IV).

The present invention also provides a process for preparing the compound of the formula (II)


wherein
R is C1-C6alkyl or benzyl, and R1is C1-C6alkyl, comprising the steps of:
(a) reacting hypophosphorous acid with a C1-C6alkyl or benzyl alcohol in the presence of an acid under dehydrating conditions to obtain the compound of formula (I)


wherein
R is C1-C6alkyl or benzyl; and
(b) reacting the compound obtained din step (a) with an alkylating agent in the presence of a base to give the compound of formula (II).

