JPH0368546A - Preparation of substituted glycine derivative - Google Patents

Abstract

PURPOSE:To readily, safely and profitably prepare the subject compound useful as a raw material or intermediate for agricultural chemicals, medicines, polymers, etc., by reacting a specific thioglycine with a specified alcohol or amine as a raw material in the presence of a base. CONSTITUTION:A thioglycine of formula I (R<1> is alkyl or phenyl; R<2> is R1 or alkoxy; X is OH, alkoxy or amino) is reacted with an alcohol of formula II [R<3> is (substituted) alkyl, alkenyl or alkynyl] in the presence of a base in a solvent, if necessary, in the presence of water at -20 deg.C to the refluxing temperature of the reaction solution to provide the objective compound of formula III (Y is X). Or the thioglycine compound of formula I is reacted with an imino compound of formula IV [R<4> and R<5> are H, R<3>, phenyl or heterocyclic ring group, or R<4> and R<5> form together a heterocyclic ring] in an inert solvent, if necessary, in the presence of water and a base at -20 deg.C to the refluxing temperature of the reaction solution to provide the objective pts.wt. of formula V [Z is OH, alkoxy or (substituted)amino].

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a method for producing a substituted glycine derivative useful as a raw material or intermediate for agricultural chemicals, medicines, polymers, etc.

[Conventional technology]

Conventionally, methods for producing glycine derivatives in which the α-position is substituted with an oxy group include: ■ Reaction of α-halogenoglycine derivatives with alcohols (EP, 174-088-A), ■
Reaction between α-hydroxyhippuric acid and methanol (Tetr
ahedron vol 31, 863-866 (19
75), U, Z.

11er et al), (2) a method in which α-benzylthiohippuric acid is reacted with N-promosuccinimide (NBS) in methanol at -78°C (same as (2)), etc. are known.

In addition, as a method for producing a glycine derivative in which the α-position is substituted with an amino group, ■ a method in which an α-isopropylthioglycine derivative and a butyl carbamate are reacted in the presence of mercury chloride (J, Org, Chem, vol. 51°3718
-3720 (1986), Mark G, Huck
et al) are known.

[Problem to be solved by the invention]

However, method (2) is difficult to handle because α-halogenoglycine derivatives are unstable and irritating;
In addition, since method (2) uses a harmful mercury compound, it is not suitable as an industrial manufacturing method.

[Means for Solving the Problems] Firstly, the present invention has the following features: General formula (1) , X represents a hydroxyl group, an alkoxy group or an alkoxy group. ) and a compound represented by the general formula [11) % formula % () (in the formula, R8 represents an alkyl group, an alkenyl group, or an alkynyl group that may have a substituent), and a compound represented by the general formula General formula () % Formula % ([[) (wherein, R1 and R1 have the same meanings as above, and Y is a hydroxyl group or an alkoxy group) or which represents an amino group).

The reaction is carried out in an organic solvent at -20'C to reflux temperature in the presence of a base.As the reaction solvent, if the general formula (It) is a lower alcohol such as methanol or ethanol, the reaction itself can be used as a solvent. Bye.

In other cases, ether solvents such as THF, dimethoxyethane and dioxane, BTX solvents such as benzene and toluene, halogen solvents such as chloroform and methylene chloride,
Ester solvents such as ethyl acetate, acetonitrile, DM
F, DMSO, etc. can be used, and a mixed solvent thereof may also be used.

Alcohol 11 (II) is used in an amount equal to or more than the same mole relative to the compound (H, usually 1.0-
2.0 times the molar amount is used.

As a base, use alcoholade, sodium hydroxide, potassium hydroxide, DBU, sodium hydride, etc. for compound (1).
1.0 to 3.0 times the molar amount is appropriately used. Also,
When X is an alkoxy group, it is possible to hydrolyze it to a hydroxyl group, that is, a free carboxylic acid, simultaneously with the substitution reaction by making water present in the reaction system, for example, in a solvent.

The second aspect of the present invention is a compound represented by the general formula (1) (in which R1, R1, and X have the same meanings as above) and a compound represented by the general formula [■] (in the formula, R4 and R% represent hydrogen, an alkyl group, an alkenyl group, an alkynyl group, a phenyl group, an aryl group, or a heterocyclic group which may have a substituent, and R4 and R5 together form a heterocyclic group. It is characterized in that it is reacted with a compound represented by () in the presence of water and a base as necessary.

A method for producing a compound represented by general formula (V) (wherein Rt, R', and R3 have the same meanings as above, and 2-bar represents a hydroxyl group, an alkoxy group, or an optionally substituted amino group). be.

The reaction was carried out in an organic solvent at -20°C in the presence of a base if necessary.
~Performed at reflux temperature.

Reaction solvents include ethers such as THF, dimethoxyethane, and dioxane, BTXs such as benzene and xylene, halogens such as chloroform and methylene chloride, esters such as ethyl acetate, acetonitrile, DMF, and DMS.
O, etc. can be used, and a mixed solvent thereof may also be used.

Amine lfl (IV) is 1.0 for compound (1)
~ZO times the molar amount is used. As a base, a tertiary amine such as triethylamine, pyridine, or DBU can be used as a compound.
0.1 to 2.0 times the mole of (1) is used,
There is no need to use them in reactions with alkylar bags.

In addition, when X is an alkoxy group, as in the case of the first invention, by using excess water or amines (IV) in the reaction system, hydrolysis or exchange with amines can be carried out simultaneously with the substitution reaction. It is also possible to carry out a reaction.

In addition, the compound represented by the general formula (1) % formula % ((in the formula, R', R'', and It can be easily synthesized as follows from a compound represented by the formula (Vl)R'5CHNHz (Vl) (in which R1 has the same meaning as above) (Japanese Patent Application No. 167738/1983).

R' 5CHNHz +R" COCl --
Zun・CN [Example] Next, the present invention will be further explained with reference to Examples.

N-benzoyl-α-phenylthioglycine, 2.87
12 g of a 10% caustic soda aqueous solution was added dropwise at 5°C into a solution of g (10 m+wol) and 30 M1 of ethanol. After the completion of the dropwise addition, the reaction was further carried out at the same temperature, and then the ethanol was distilled off under reduced pressure and water was added to the residue. was added and washed with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure,
The residue was washed with benzene to obtain 2.0 g of the target product.

Yield 90% m, p 129-131°C Example 2 N
-Benzoyl-α-(2-naphthylmethoxy)glycine N-benzoyl-α-7enylthioglycine, methyl ester, in a solution of 0.75 g (2,5 m++ ol) in 10 d of acetonitrile at room temperature in 2-naphthylmethanol 0th order ite DB with 0.79g (5a+mol) added
0.38 g (2,5+nol) of U was added and stirred at the same temperature overnight.

After the reaction was completed, the reaction solution was poured into water and treated in the same manner as in Example 1 to obtain 0.5 g of the desired product.

Yield 60% m, p 149-150'C Example 3
N-benzoyl-α-methoxyglycine N-benzoyl-α-phenylthioglycine acid Q, 5g (1,75
Old. The suspension was suspended in 5 d of methanol, and 0.41 g (2.1 ml) of 28% methylated methanol solution was added thereto at 0°C. Thereafter, the reaction was allowed to proceed at room temperature for 5 hours, and then the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and then ethyl acetate was distilled off under reduced pressure. The residue was washed with n-hexane to obtain 0.26 g of the target product.

Yield 71% m, p 130-132 °C Table I Synthesis: N-(4-chlorobenzoyl)-α-ethylthioglycine 0.5 g (1,8 m+Iol) in methanol 10
Add 2.9 g (7.3 m
mol) was added at room temperature.

After reacting at the same temperature for 5 days, the reaction mixture was treated in the same manner as in Example 1 to obtain 0.4 g of the desired product.

Yield 91% m, p 131-132°C Other examples are shown in Table-1.

Example 11 N-benzoyl-α-n-butylaminoglycine methyl ester 3.0 g (10 mm.l) of N-benzoyl-α-phenylthioglycine methyl ester was dissolved in 30 d of acetonitrile.
Dissolve n-butyl agone at room temperature.

46g (20ms◎1) was added. After reacting at the same temperature overnight, the reaction solution was poured into water and extracted with ethyl acetate.

The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and then ethyl acetate was distilled off under reduced pressure. The residue was purified by column chromatography to obtain 2.3 g of the target product.

Yield 96.5% n,! S1.5250 Example a 12
N-benzoyl-α-(N-methylaniline)glycine methyl ester rII+ 0.75 g (2.5 m5 aol) of methyl ester was dissolved in 10ffi of acetonitrile! Then, 0.54 g (5ms+ol) of N-methylaniline and DBU
o, 38 g (2,5+amof) were added at room temperature. After reacting at the same temperature overnight, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and then ethyl acetate was distilled off under reduced pressure.

The residue was purified by column chromatography to obtain 0.52 g of the desired product.

Yield 70% m, p 132-134°C Example 11
Examples of other compounds produced in the same manner as No. 12 are shown in Table 2.

N-benzoyl-α-phenylthioglycine* (N)
represents N in formula (I'll).

〔Effect of the invention〕

According to the present invention, substituted glycine derivatives are easily and safely produced by an industrially advantageous method.The derivatives of the present invention are agricultural chemicals,
It is useful as a raw material or intermediate for pharmaceutical polymers, etc.

Claims (2)

[Claims] (1) General formula [I] ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, R^1 is an alkyl group or phenyl group, R^2
represents an alkyl group, a phenyl group or an alkoxy group, and X represents a hydroxyl group, an alkoxy group or an amino group. ) and a compound represented by the general formula [II] R^3OH [II] (wherein R^3 represents an alkyl group, an alkenyl group, or an alkynyl group that may have a substituent). General formula [III] characterized by reacting in the presence of a base and adding water if necessary ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [III] (In the formula, R^2, R^3 are (has the same meaning as above, and Y represents a hydroxyl group, an alkoxy group, or an amino group). (2) General formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [I] (In the formula, R^1, R^2, and X have the same meanings as above.) Compounds and general formulas represented by [IV] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[IV] (In the formula, R^4, R^5 hydrogen, an alkyl group that may have a substituent, an alkenyl group, an alkynyl group, a phenyl group, or a hetero (representing a cyclic group, and R^4 and R^5 may be combined to form a heterocycle), in the presence of water and a base as necessary. shall be. General formula [V] ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [V] A method for producing a compound represented by (indicates an optional amino group).