JP2008230992A - PHOSPHORUS-CONTAINING SULFONE, SULFOXIDE DERIVATIVE AND METHOD FOR PRODUCING PHOSPHORUS-CONTAINING alpha-KETO ACID USING THE SAME AS INTERMEDIATE - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for efficiently producing 4-(hydroxymethyl-phosphonyl)-2-oxobutanoic acid of an intermediate for producing herbicide L-AMPB. <P>SOLUTION: The method for producing the 4-(hydroxymethyl-phosphonyl)-2-oxobutanoic acid uses a compound represented by formula (5) [wherein, R<SP>1</SP>is an aryl group; R<SP>2</SP>, R<SP>3</SP>and R<SP>4</SP>are each a 1-4C alkyl group; and n is an integer of 1 or 2]. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to 4- (hydroxymethylphosphinyl) -2, which is an intermediate for producing the herbicide L-2-amino-4- (hydroxymethylphosphinyl) -butanoic acid (hereinafter abbreviated as L-AMPB). -Relates to the production of oxobutanoic acid.

  4- (Hydroxymethylphosphinyl) -2-oxobutanoic acid is already known to be a synthetic intermediate of L-AMPB having herbicidal activity (JP-A-1-27485 (Patent Document 1), JP-A-2003-2003). -528572 (patent document 2), JP-A-59-184196 (patent document 3), J. Org. Chem., 56,1783-1788 (1991) (non-patent document 1)).

  To date, as a method for producing 4- (hydroxymethylphosphinyl) -2-oxobutanoic acid, the method of Bailey et al. Via (alkoxymethylphosphinyl) -propionic acid ester (Japanese Patent Laid-Open No. 56-92897 (Patent Document 4) )) Is only known, and establishment of a more efficient production method is desired.

  The sulfanylation reaction of active methylene is already known, but no example of application to a reaction with a compound having a polar substituent such as phosphorus has been reported (Synthesis, 420 (1997) (Non-patent Document 2). ).

As a method for synthesizing α-keto acid using an organic sulfur compound, a synthesis method using dithiane is known (J. Org. Chem., 28, 961 (1963) (Non-patent Document 3), J. Org). Chem., 36, 3553 (1971) (non-patent document 4), J. Org. Chem., 37, 505 (1972) (non-patent document 5)). However, there has been no report of an example applied to a reaction with a compound having a polar substituent such as phosphorus. Furthermore, there are few reports on the synthesis of α-keto acids using sulfone derivatives.
JP-A-1-27485 JP 2003-528572 A JP 59-184196 A JP 56-92897 J. Org. Chem., 56,1783-1788 (1991) Synthesis, 420 (1997) J. Org. Chem., 28, 961 (1963) J. Org. Chem., 36, 3553 (1971) J. Org. Chem., 37, 505 (1972)

  An object of the present invention is to provide a method for efficiently producing 4- (hydroxymethylphosphinyl) -2-oxobutanoic acid, which is an intermediate for producing L-AMPB, which is useful as a herbicide.

  The present inventor has found that a sulfonylacetate derivative easily undergoes a Michael addition reaction to methylvinylphosphinate in the presence of a base to produce 2-sulfonyl-4- (substituted oxymethylphosphinyl) -butanoate. As a result of examining the α-sulfanylation reaction of the heading and the obtained derivative, 2-sulfonyl-2-sulfanyl-4- (substituted oxymethylphosphinyl)-was easily reacted with thiosulfonate in the presence of a base. It was found that butanoic acid ester was formed. Subsequently, it was found that 4- (hydroxymethylphosphinyl) -2-oxobutanoic acid can be efficiently obtained by acid hydrolysis, and the present invention was completed.

  That is, the present invention is as follows.

  According to a first aspect of the present invention, there is provided a compound represented by the following formula (3) that is useful as an intermediate for producing 4- (hydroxymethylphosphinyl) -2-oxobutanoic acid.

[Wherein R ¹ represents a C _1-4 alkyl group, an aryl group, a substituted aryl group, an arylmethyl group, or a substituted arylmethyl group;
R ² represents a C _1-4 alkyl group, an arylmethyl group or a substituted arylmethyl group,
R ³ represents a C _1-4 alkyl group, an aryl group, a substituted aryl group, an arylmethyl group, or a substituted arylmethyl group, and n represents an integer of 1 or 2.
As a 2nd aspect, the compound represented by following formula (5) is provided.

[Wherein R ¹ , R ² , R ³ and n represent the same meaning as defined in the formula (3),
R ⁴ represents a C _1-4 alkyl group, an aryl group, a substituted aryl group, an arylmethyl group, or a substituted arylmethyl group]
Moreover, this invention is a method of manufacturing the compound of said Formula (3), Comprising: following Formula (1)

[Wherein R ¹ , R ² and n represent the same meaning as defined in formula (3)], in the presence of a base, the compound represented by the following formula (2)

[Wherein R ³ represents the same meaning as defined in formula (3)] to provide a method for producing a compound of formula (3) by reaction.

  Another aspect of the present invention is a method for producing the compound of the formula (5), which is represented by the following formula (3):

[Wherein R ¹ , R ² , R ³ and n represent the same meaning as defined in the above formula (3)] and the following formula (4)

[Wherein R ⁴ represents the same meaning as defined in formula (5);
R ⁵ represents a C _1-4 alkyl group, an aryl group, a substituted aryl group, an arylmethyl group, or a substituted arylmethyl group], and a compound represented by the formula (5) is reacted with each other in the presence of a base. To provide a method of manufacturing

  Furthermore, the present invention provides the following formula (6)

A process for producing 4- (hydroxymethylphosphinyl) -2-oxobutanoic acid represented by the following formula (5)

[Wherein R ¹ , R ² , R ³ and n represent the same meaning as defined in the above formula (3), and R ⁴ represents the same meaning as defined in the above formula (5). A method is provided by acid-hydrolyzing a compound represented by the above formula and further deprotecting a hydroxyl group and an amino group moiety.

  4- (Hydroxymethylphosphinyl) -2-oxobutanoic acid, which is an intermediate for producing L-AMPB, which is useful as a herbicide, can be produced by the intermediates of the present invention and the production method using them. The production method of the present invention is excellent as a method that can be synthesized efficiently at a lower cost than conventional production methods.

In the compounds represented by formula (1) to formula (5), groups represented by R ¹ , R ² , R ³ , R ⁴ , and R ⁵ will be described.

The C _1-4 alkyl group on the group or group represented by R ¹ , R ² , R ³ , R ⁴ , and R ⁵ means a linear or branched alkyl group having 1 to 4 carbon atoms. Examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, 2-butyl group, isobutyl group and t-butyl group.

Examples of the group represented by R ¹ , R ² , R ³ , R ⁴ , and R ⁵ or the aryl group on the group include a phenyl group and a naphthyl group.

The arylmethyl group represented by R ¹ , R ² , R ³ , R ⁴ and R ⁵ means a methyl group substituted with 1 to 3 aryl groups, and more specifically, a benzyl group, diphenyl Examples thereof include a methyl group, a fluorenyl group, and a triphenylmethyl group.

The group represented by R ¹ , R ³ , R ⁴ , and R ⁵ or the substituted aryl group on the group is substituted with one or more hydrogen atoms, preferably 1 to 3 hydrogen atoms, on the benzene ring. Specific examples of the substituent include linear or branched groups such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, 2-butyl group, isobutyl group, and t-butyl group. And a C _1-4 alkyl group, a halogen atom such as a fluorine atom, a chloro atom and a bromine atom, and a C _1-4 alkoxy group such as a methoxy group. When R ² represents a substituted aryl group, the substituent is preferably one or more methoxy groups.

In the compound of the formula (1), R ¹ is preferably a C _1-4 alkyl group, an aryl group and a substituted aryl group, and R ² is preferably a C _1-4 alkyl group, an arylmethyl group and a substituted arylmethyl group, n is preferably 2.

Specific examples of the compound represented by the formula (1) include
Methylsulfonylacetic acid methyl ester,
Ethylsulfonylacetic acid ethyl ester,
Phenylsulfonylacetic acid methyl ester,
Phenylsulfonylacetic acid ethyl ester,
p-toluenesulfonylacetic acid methyl ester,
p-toluenesulfonylacetic acid ethyl ester,
Methylsulfonylacetic acid benzyl ester,
Ethylsulfonylacetic acid benzyl ester,
Phenylsulfonylacetic acid benzyl ester,
Phenylsulfonylacetic acid benzyl ester,
p-toluenesulfonylacetic acid benzyl ester p-toluenesulfonylacetic acid benzyl ester methylsulfinylacetic acid methyl ester,
Ethyl sulfinyl acetate ethyl ester,
Phenylsulfinyl acetic acid methyl ester,
Phenylsulfinyl acetic acid ethyl ester,
p-toluenesulfinyl acetic acid methyl ester,
p-toluenesulfinyl acetic acid ethyl ester,
Methylsulfinyl acetic acid benzyl ester,
Ethyl sulfinyl acetic acid benzyl ester,
Phenylsulfinyl acetic acid benzyl ester,
Phenylsulfinyl acetic acid benzyl ester,
p-toluenesulfinyl acetic acid benzyl ester, or
p-Toluenesulfinyl acetic acid benzyl ester is exemplified, and phenylsulfonylacetic acid ethyl ester is preferable.

  Compounds of formula (1) are described in ActaChem. Scand., B32, 193, (1978), Synthesis, 420 (1997), Tetrahedron lett., 3997 (1974), Tetrahedron lett., 2841 (1975), Chem. Rev. , 78, 363 (1978).

In the compound of formula (2), R ³ is preferably a C _1-4 alkyl group. Specific examples of the compound represented by the formula (2) include
Methyl vinylphosphinic acid methyl ester,
Methyl vinylphosphinic acid ethyl ester,
Methyl vinylphosphinic acid propyl ester,
Methyl vinylphosphinic acid isopropyl ester,
Methyl vinylphosphinic acid butyl ester,
Methyl vinylphosphinic acid phenyl ester or
And methyl vinylphosphinic acid benzyl ester.

  The compound of formula (2) was synthesized by the method described in (Angew. Chem. Int. Ed. Engl., 20, 223 (1981), Bull. Chem. Soc. Japan, 60, 1761 (1987)). can do.

In the compound of formula (3), R ¹ is preferably a C _1-4 alkyl group, an aryl group and a substituted aryl group, and R ² is preferably a C _1-4 alkyl group, an arylmethyl group and a substituted arylmethyl group, R ³ is preferably a C _1-4 alkyl group, and n is preferably 2.

  Specific examples of the compound represented by the formula (3) include

Is mentioned. In specific examples, Ph represents a phenyl group.

In the compound of formula (4), R ⁴ is preferably a C _1-4 alkyl group, a phenyl group or a benzyl group, and R ⁵ is preferably a C _1-4 alkyl group or a phenyl group.

Specific examples of the compound represented by the formula (4) include
S-methyl methylthiosulfonate,
S-ethyl methylthiosulfonate,
S-phenyl methylthiosulfonate,
S-benzyl methylthiosulfonate,
S-methyl ethyl thiosulfonate,
S-methyl phenylthiosulfonate,
S-methyl benzyl osulfonate,
S-ethyl phenylthiosulfonate,
S-phenyl phenylosulfonate or
S-benzyl phenylosulfonate is mentioned.

In the compound of formula (5), R ¹ is preferably a C _1-4 alkyl group, an aryl group and a substituted aryl group, and R ² is preferably a C _1-4 alkyl group, an arylmethyl group and a substituted arylmethyl group, ³ is preferably a C _1-4 alkyl group, R ⁴ is preferably a C _1-4 alkyl group, a phenyl group and a benzyl group, and n is preferably 2.

  Specific examples of the compound represented by the formula (4) include

Is mentioned. In specific examples, Ph represents a phenyl group.

  Solvents used in the method for producing the compound of formula (3) from the compound of formula (1) and the compound of formula (2) include halogenated hydrocarbon solvents such as methylene chloride and chloroform, and aromatics such as benzene and toluene. Aromatic hydrocarbon solvents, ether solvents such as tetrahydrofuran, dimethoxyethane and dioxane, aprotic polar organic solvents such as N, N-dimethylformamide and dimethyl sulfoxide, or alkanol solvents having 1 to 4 carbon atoms such as methanol Preferred are tetrahydrofuran, toluene, N, N-dimethylformamide.

  Examples of the base include sodium hydride, potassium hydride, sodium methoxide, potassium t-butoxide, and lithium diisopropylamide, preferably sodium hydride. The amount of the base used is 1 to 1.2 equivalents based on the amount of the compound of formula (1). The amount of the compound represented by formula (2) is preferably used in an equimolar amount based on the amount of the compound of formula (1). The reaction temperature is 0 to 50 ° C., preferably 10 to 30 ° C. The reaction time is usually 10 minutes to 2 hours, preferably 30 minutes to 1 hour.

  Solvents used in the method for producing the compound of formula (5) from the compound of formula (3) and the compound of formula (4) include halogenated hydrocarbon solvents such as methylene chloride and chloroform, and aromatics such as benzene and toluene. Aromatic hydrocarbon solvents, ether solvents such as tetrahydrofuran, dimethoxyethane and dioxane, aprotic polar organic solvents such as N, N-dimethylformamide and dimethyl sulfoxide, or alkanol solvents having 1 to 4 carbon atoms such as methanol Preferably, it is dimethyl sulfoxide. Examples of the base include sodium hydride, potassium hydride, sodium methoxide, potassium t-butoxide, and lithium diisopropylamide, preferably sodium hydride. The amount of the base used is 1 to 1.2 equivalents based on the amount of the compound of formula (3). The amount of the compound represented by the formula (4) is preferably used in an equimolar amount based on the amount of the compound of the formula (3). The reaction temperature is 0 to 50 ° C., preferably 10 to 30 ° C. The reaction time is usually 10 minutes to 2 hours, preferably 30 minutes to 1 hour.

  Examples of the acid used in the method for producing the compound (6) by acid hydrolysis from the compound of the formula (5) include hydrochloric acid and sulfuric acid, and examples of the solvent include water. The concentration of the acid is usually 6 to 12N when hydrochloric acid is used, and 2 to 18N when sulfuric acid is used. The reaction temperature is in the range of 20 to 150 ° C., preferably 50 to 120 ° C., and the reaction time is in the range of 2 to 12 hours, preferably 4 to 8 hours.

  Compound (6) can be isolated and purified using, for example, an ion exchange resin (BIO-RAD (registered trademark) Ag 1X2, eluent 1% trifluoroacetic acid aqueous solution).

  EXAMPLES Next, although an Example is given and this invention is demonstrated concretely, this invention is not limited to these Examples. Ethyl phenylsulfonyl acetate was commercially available from Tokyo Kasei. Methyl vinylphosphinic acid methyl ester was synthesized according to the method described in Bull. Chem. Soc. Japan, 60, 1761 (1987). S-methyl methanethiosulfonate was commercially available from Aldrich.

Example 1 Preparation of ethyl 2-phenylsulfonyl-4- (methoxy (methyl) phosphinyl) -butanoate To a solution of 90 mg of 60% sodium hydride suspended in 6 ml of tetrahydrofuran, 519 mg of ethyl phenylsulfonylacetate was added under ice cooling. And stirred at room temperature for 30 minutes. Next, 300 mg of methyl vinylphosphinic acid methyl ester was added and stirred at room temperature for 15 hours. To the reaction solution, 0.8 ml of a saturated aqueous ammonium chloride solution was added, and the solvent was concentrated under reduced pressure. Chloroform was added to the residue and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol 20: 1) to obtain 314 mg of the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.13 (t, J = 7.0 Hz); 1.13 (t, J = 7.0 Hz) (3H in total), 1.47 (d, J = 13.6 Hz); 1.48 (d, J = 13.6Hz) (3H combined), 1.78-1.88 (2H., M), 2.26-2.43 (2H, m), 3.69 (d, J = 11.0Hz); 3.70 (d, J = 10.7Hz) (adjusted 3H), 4.05-4.15 (3H, m), 7.57-7.61 (2H, m), 7.68-7.73 (1H, m), 7.88-7.91 (2H, m).
APIMASS: m / z 349 [M + H] ⁺ .

Example 2 Preparation of ethyl 2-methylsulfanyl-2-phenylsulfonyl-4- (methoxy (methyl) phosphinyl) -butanoate
To a solution obtained by suspending 32 mg of 60% sodium hydride in 5 ml of dimethyl sulfoxide, 250 mg of the compound obtained in Example 1 was added and stirred at room temperature for 30 minutes. Subsequently, 109 mg of S-methyl methanethiosulfonate was added and stirred at room temperature for 3.5 hours. To the reaction solution, 0.4 ml of a saturated aqueous ammonium chloride solution was added, and the solvent was concentrated under reduced pressure. Chloroform was added to the residue and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform: methanol 20: 1) to obtain 171 mg of the title compound.
¹ H-NMR (CDCl ₃ ) δ: 1.18 (t, J = 7.1 Hz); 1.19 (t, J = 7.1 Hz) (3H in total), 1.52 (d, J = 13.6 Hz); 1.52 (d, J = 13.6Hz) (3H combined), 1.84-1.87 (1H., M), 1.89-2.05 (1H, m), 2.27 (3H, s), 2.38-2.45 (1H, m), 2.71-2.80 (1H , m), 3.73 (d, J = 10.9Hz); 3.73 (d, J = 11.0Hz) (3H combined), 4.09-4.20 (2H, m), 7.54-7.58 (2H, m), 7.68-7.72 (1H, m), 7.92-7.94 (2H, m).
FABMASS: m / z 395 [M + H] ⁺ .

Example 3 Production of 4- (hydroxymethylphosphinyl) -2-oxobutanoic acid 164 mg of the compound obtained in Example 2 was dissolved in 4.5 ml of concentrated hydrochloric acid and heated to reflux for 6 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified with BIO-RAD Ag1X2 (1% aqueous trifluoroacetic acid solution) to obtain 47 mg of the title compound.
¹ H-NMR (DMSO-d ₆ ) δ: 1.30 (3H, d, J = 14.2Hz), 1.78 (2H, dt, J = 14.2, 7.8Hz), 2.98 (2H, dt, J = 10.2, 7.8Hz ).
LCMASS: m / z 181 [M + H] ⁺ .

Claims (5)

Compound represented by the following formula (3):

[Wherein R ¹ represents a C _1-4 alkyl group, an aryl group, a substituted aryl group, an arylmethyl group, or a substituted arylmethyl group;
R ² represents a C _1-4 alkyl group, an arylmethyl group or a substituted arylmethyl group,
R ³ represents a C _1-4 alkyl group, an aryl group, a substituted aryl group, an arylmethyl group, or a substituted arylmethyl group, and n represents an integer of 1 or 2. Compound represented by the following formula (5):

[Wherein R ¹ , R ² , R ³ and n represent the same meaning as defined in formula (3) according to claim 1,
R ⁴ represents a C _1-4 alkyl group, an aryl group, a substituted aryl group, an arylmethyl group or a substituted arylmethyl group]. A process for producing a compound of formula (3) according to claim 1, wherein

[Wherein R ¹ , R ² and n represent the same meaning as defined in formula (3)], in the presence of a base, the compound represented by the following formula (2)

[Wherein R ³ represents the same meaning as defined in formula (3)] to produce a compound of formula (3). A process for producing a compound of formula (5) according to claim 2, comprising the following formula (3)

[Wherein R ¹ , R ² , R ³ and n represent the same meaning as defined in formula (3) according to claim 1] and the following formula (4)

[Wherein R ⁴ represents the same meaning as defined in formula (5);
R ⁵ represents a C _1-4 alkyl group, an aryl group, a substituted aryl group, an arylmethyl group, or a substituted arylmethyl group], and a compound represented by the formula (5) is reacted with each other in the presence of a base. Manufacturing method. Formula (6)

A process for producing 4- (hydroxymethylphosphinyl) -2-oxobutanoic acid represented by the following formula (5)

[Wherein R ¹ , R ² , R ³ and n represent the same meaning as defined in the formula (3) described in claim 1, and R ⁴ represents the formula (5 described in claim 2). Represents the same meaning as defined in the above)] by hydrolyzing the compound represented by [3] and further deprotecting the hydroxyl group and amino group moiety.