JPS62212329A - Production of alpha-hydroxycarboxylic acid derivative - Google Patents

Abstract

PURPOSE:To produce the titled compound having physiological activity of plant hormone and useful as a synthetic intermediate for enalapril and its derivative, in high yield, by reacting a nucleophilic reagent to a glycidic acid derivative derivated from a serine derivative. CONSTITUTION:The objective alpha-hydroxycarboxylic acid derivative of formula III [e.g. (S)-2-hydroxy-4-phenylbutyric acid] can be produced by using a glycide derivative of formula II as a raw material and reacting the compound with a compound of formula RM [R is alkyl, alkenyl, phenyl, etc.; M is MgX (X is Cl, Br or I) or alkali metal]. The starting compound of formula II is obtained by converting the amino group of a serine derivative to halogen atom and treating the resultant compound of formula I [R<1> and R<2> are H, alkyl or phenyl; R<3> is OH, OR<4> (R<4> is alkyl, OH-protecting group, phenyl, etc.), etc.; Y is halogen] with a base.

Description

Detailed Description of the Invention Object of the invention α-hydroxycarboxylic acid derivatives are important intermediates in the synthesis of useful pharmaceuticals, such as enalapril and its derivatives, and α-hydroxycarboxylic acid has the physiological activity of a plant hormone. It is known. Therefore, the development of a practical method for synthesizing α-hydroxycarboxylic acids is desired. The inventors discovered a method for obtaining α-hydroxycarboxylic acid in good yield using a serine derivative as a starting material, and completed the present invention.

Structure of the Invention [In the formula, R1 and R2 are the same or different and represent a hydrogen atom, an alkyl group, or a phenyl group which may have a substituent, and R3 is a hydroxyl group.

OR' group (nA represents an alkyl group, a hydroxyl protecting group, a phenyl group which may have a substituent, a succinimide group or a -N:CH-C> group), an SR5 group (R5 is
It represents an alkyl group, a phenyl group which may have a substituent, or a 5j& or 6-membered heteroaryl group which may have a substituent. ), NR6B' group (R6 and R7 are
The same or different hydrogen atom, C1-C10 alkyl group, phenyl group which may have a substituent, aralkyl group which may have a substituent, or R6 and R7 taken together -(CH2)n - group (indicates n = 3.4.5)
, or NHNHR8 group (R8 represents a hydrogen atom, an alkyl group, or a phenyl group), and Y represents a halogen atom. ] is treated with a base to produce [wherein R', R2 and R3 have the same meanings as described above. ] and then give this compound the formula RM
(In formula 311m, R is an alkyl group, an alkenyl group 0, a phenyl group which may have a substituent, a benzyl group which may have a substituent, a 5-membered or sl group which may have a substituent) 5 which may have a heteroaryl group or a substituent
or 6-membered heteroarylmethyl group, M is MgX (Mg is magnesium, X is chlorine,
Indicates bromine or iodine. ) or alkali metal.

] [wherein R, R', R2 and R3 have the same meanings as described above. ] is a method for producing a compound having the following.

In the above description, the alkyl groups in R', R2, R', R5, R8 and R include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, S-butyl or t-butyl.

R', R2, R'# R5, R', 17 and the substituent of the phenyl group having a substituent in R are, for example, alkyl, alkoxy group, halogen atom, trifluoromethyl group, nitro group or cyano group. The alkyl group is, for example, a methyl, ethyl, propyl or isopropyl group, the alkoxy group is, for example, methoxy, ethoxy or propoxy, and the halogen atom is a fluorine, chlorine or bromine atom.

Examples of the 5-membered or 6-membered heteroaryl group in R5 and R include furyl, chenyl, thiazolyl, or pyridyl, and when these groups have a substituent, the substituent is the same as the substituent of the phenyl group described above. Same as the example.

The alkyl group of R6 and R7 is, for example, benzyl, 2
-Phenethyl, 1-phenethylmataha, 3-phenylpropyl, and the substituent of the aralkyl group having a substituent is the same as the above-mentioned examples of the substituent of the phenyl group.The substituent of the benzyl group having a substituent of R are the same as the examples of substituents for the phenyl group described above. The heteroaryl group of the heteroarylmethyl group of R is the same as the above-mentioned heteroaryl group, and the substituent of the heteroarylmethyl group having a substituent is the same as the above-mentioned substituent of the phenyl group. be.

The hydroxyl retaining group of R4 is, for example, t-butyl, allyl, tetrahydropyranyl, tetrahydrothiopyranyl,
Substituted methyl groups (such substituents include, for example, methoxy, ethoxy or chloromethymethylthio, phenylsulfonylmatahanitrophenylthio), aralkyl groups which may have substituents (such as benzyl, diphenylmethyl, or triphenylmethyl, and the substituent is, for example, methyl, ethyl, methoxy or ethoxy), -C(O19)
5 groups (R9 represents an alkyl group such as methyl, ethyl, propyl or isopropyl) or a trisubstituted silyl group (the substituents may be the same or different, for example, methyl, ethyl, propyl, butyl, t-butyl) , phenyl, methoxy, ethoxy, propoxy or butoxy).

The C1-C1° alkyl group of R6 and R7 is, for example, methyl, ethyl, propyl, inpropyl, phthyl,
Mention may be made of t-butyl, pentyl, S-pentyl, hexyl, heptyl, octyl, nonyl or decyl.

Examples of the alkenyl group for R include vinyl or allyl.

Examples of the alkali metal M include lithium, sodium or potassium.

Examples of the halogen atom of Y include chlorine, bromine, or iodine.

The reaction formula of the production method of the present invention is as follows.

[In the formula, R', R2, Y, R and M have the same meanings as described above. ] A compound obtained by converting the 7-mino group of the serine conductor to a halogen atom (11) is treated with a base to form a glycidic acid derivative (2) (first step), and this compound is treated with a nucleophilic reagent (3). ) is reacted (second step) to obtain an α-hydroxycarboxylic acid derivative (41).

1st step: This reaction is carried out using 2 equivalents or more, preferably z1 to 3 equivalents, of Bases (e.g. potassium hydroxide, sodium hydroxide, lithium hydroxide, calcium hydroxide,
Mention may be made of sodium carbonate, sodium hydrogen carbonate, triethylamine, N-methylmorpholine or 1.8-diazabicyclo(S, 4.0)undec-γ-ene. )
In the presence of Q, 5~ at room temperature from 06~! Do time. * (e.g. potassium hydrogen sulfate, sodium hydrogen sulfate,
Examples include sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, trifluoroacetic acid, trichloroacetic acid, monochloroacetic acid, methanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid. ), and after neutralization, extract with a solvent (for example, a solvent that is immiscible with water among the solvents used in the reaction in the first step) to obtain the glycidic acid derivative (21). Compound (2) can be purified by recrystallization or chromatography if necessary, but can also be used in the next reaction without being purified.

The second step two-step reaction is carried out in ether or tetrahydrofuran at -78° to 50°C, preferably at -201: to room temperature.
It is carried out for 0 minutes to 5 hours, preferably 0.5 to 2 hours. Compound (3) is 1 to 5 equivalents relative to compound (2).

It is preferably 1 to 3 equivalents, and when compound (3) is a Grignard reagent, halogenated steel (for example, cuprous chloride, cuprous bromide, or cuprous iodide) is used in this reaction.
When 0.1 to 0.3 equivalents are added to the Grignard reagent, the yield of the target product is improved.

After completion of this reaction, the desired product (4) can be obtained by processing according to conventional methods, and if necessary, by recrystallization or chromatography! #Can be made.

Effects of the Invention Nucleophilic reagent (31) reacts regioselectively with glycidic acid derivative (2) to form α-hydroxycarbon ravj conductor (
4) and conduct this reaction using a glycidic acid derivative derived from an optically active serine life conductor, stereoselectively optically active α-hydroxycarboxylic acid (41) can be obtained in good yield.

EXAMPLES The present invention will be specifically explained with reference to Examples below.

Example 1゜L-7 tss, of ni (lk sulfur m 210
A mixture of 2,350ml of water was added and the mixture was cooled to -5°C.

After adding 65401 F of potassium bromide to this, a solution of 3 g of sodium nitrite dissolved in 560 g of water was added dropwise.

After stirring at room temperature for 1 hour, nitrogen monoxide gas in the solution was removed by passing nitrogen through the solution. The product was extracted with 1 J of ethyl acetate, and then extracted 4 times with 500 ml of ethyl acetate, and the organic layers were combined and ampered under reduced pressure to obtain (S)-α-promo β-hydroxypropproone @2rJS, 41. . This was soaked in 600ml of water and cooled to 0~5''C.
A solution prepared by dissolving 102 g of caustic soda in water Boost was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was cooled to 0 to 5°C, and 30% potassium hydrogen sulfate aqueous solution 860 ml was added, extracted with 81 ml of ethyl acetate, and the aqueous layer was diluted with 5 ml of ethyl acetate.
After extraction with J twice, the organic layer was concentrated under reduced pressure to obtain colorless oil 1054f (yield 9T, 8%).

NMR (CDCj3) δppm: 3.00 (2H, d, J=3Hz),
3.50 (IH, LJ==3Hz), 11
．． 15 (S, IH)IR: y:! 7: 304
0.1730.126G, so.

mp, 43'c (recrystallized from benzene-hexane) [α
) D+30.4 ((=1.5. CH3CN) Example 2 Using D-Seri y10f as a starting material, the same operation as in Example 1 was carried out to obtain 6.5 g of the target product as an oily substance.

NMR (cncj5) δpprtt: 3,05 (
2)1. d, J = = a'Hz ) - L57 (IH, t
, J=3)iz), 11.10 (IH,s)
neat.

IRν, 3020.1715.1250(:r' [α] o 30.0 (C=1.0 ICH3C
N) Example 1 (R) -2-Hydroxy-4-phenylbutyric acid Under a nitrogen atmosphere, benzylmagnesium chloride (IM/j-tetrahydrofuran, hereinafter abbreviated as THF) 18.1- was converted to -1
Cooled to 0°C. To this was added 1.491 g of cupric iodide, and the mixture was stirred at the same temperature for 10 minutes. To this (R
2.291 of )-glycidic acid was dissolved in T)IF 20-, and the solution was slowly poured into a 100% potassium aqueous solution while maintaining the temperature at -10"C, and extracted twice with 100% ethyl acetate. Saturate the layer 1 with 100 m of water
The aqueous layer was extracted twice, the pH of the aqueous layer was adjusted to 1.5 with hydrochloric acid, and the mixture was extracted three times with ethyl acetate (100ml). Dry over anhydrous magnesium sulfate, remove the solvent under reduced pressure, and recrystallize from toluene to obtain the desired (R)-2-8mD115.
~116℃ [αAyu=-8,s (c=1.gtolNMR(c
ncj3) δppm: 1.83 to 2.35 (2
H0m).

2.79 (2H, t, J=7Hz), 4.23
(IH, dd.

J=7.5H2), 7.00 (2)I, br,
8), 7.20 (SR, 8) Example 4 Using (S)-glycidic acid and benzylmagnesium chloride and operating in the same manner as in Example 3, (S)-2-hydroxy-4-phenyl acetic acid Obtained in a yield of 8896.

[α]. +8.3 ((=l, gtolExample 5゜Using (R8)-glycidic acid and benzylmagnesium chloride, the same procedure as in Example 3 was carried out until (R8)-2-hydroxy-4-phenylbutyric acid was 90% was obtained in a yield of .

Example 6 A solution of phenylmagnesium bromide (2M/j-THF) was prepared by adding 600η of cupric oxide at -10"C to 17d.
K was added thereto, and the mixture was stirred for 30 minutes under a nitrogen atmosphere. To this (B)-
The internal temperature of a solution of 1 g of glycidic acid in 'rHF10-10~
Add the skin while keeping it at -5'c, and after stirring for 1 hour at the same temperature,
Stirring was continued for an additional hour at room temperature. Cool the reaction solution with water for 30 minutes.
Pour into a 5Q aqueous solution of potassium hydrogen sulfate, then extract twice with ethyl acetate, and add the extract to a 50% aqueous solution of potassium hydrogen sulfate.
The aqueous layer was extracted with amic acid and extracted three times with ethyl acetate (51). Dry over magnesium sulfate, evacuate through R, and evaporate the solvent under reduced pressure to obtain the desired product as white crystals. 1.719 (yield 90*) was obtained.

[α] D + 29-32 ((==l * CH3
0N) NMR (CDCj3 + d'-0M80)
δppm: 2.113 to 3.17 (2H*rn)
a 433 (IH# dd, J==7.5Hz
).

7.23 (5H,s), 7.50 (2H,brJ
) Example T.

(S)-β-Phenyl lactic acid <S>-Glycidic acid and phenylmagnesium bromide were used in the same manner as in Example 1 to obtain (8)-β-Phenyl lactic acid in a yield of 91%.

[α)'Ij -29,50 (C=1.CH3CN)
Example 8゜(R)-3-t-glylactic acid t-butylmagnesium chloride 17.3gZ (25
% ether solution) was cooled to -10°C and diluted with cuprous chloride (30%).
After adding 0 Q and stirring at the same temperature under nitrogen stream for 30 minutes,
A solution of (R)-glycidic acid 1fI in 'i')iF1Gml was added dropwise while maintaining the internal temperature at -10 to -s'c, and then stirring was continued for 1 hour and 30 minutes at room temperature. Post-treatment was carried out in the same manner as in Example 3, and 147jl (yield: 88%) of the target product was obtained as white crystals.

[α], +5.35 (c==0.986.CH
,CN)NMR(CDCj5+d'-DM80)δ
” 1.03 (9)t-8)jpm e 1.30~1-69 (2H-m)-4,10(1He
dd, J=7.5Hz), 8.30 (IH, b
r, s) Example 9゜(8) -3-t-Butyl lactic acid (8) Using the same procedure as in Example 8 using (8)-glycidic acid and t-butylmagnesium chloride, (S)-3-t-butyl Lactic acid was obtained with a yield of 85%.

[α]0-5. s (C: 1. CH, CN) Example 1
A THF bath solution of 4-fluoropenzylmagnesium bromide prepared with 5.63 f of 4-fluorobenzyl bromide and 1.11 h of magnesium was cooled to -10'C, and 600 g of cupric iodide was added to the solution. (2) was added and stirred at the same temperature for 30 minutes. TI of (R)-glycidic acid 1.031 (
F t (l s/, added dropwise to the bath liquid while keeping it at -10 to -5°C, then returned to room temperature, stirred for 1 hour, and then post-treated in the same manner as in Example a to obtain 1 liter of the target product (yield 92%). ) was obtained.

NMIL (CI)3COCD, )299m; 1
．． 66-150 (2H, m).

2.80 (2H, t, J=7Hz), 4.19
(IH, dd.

J=4.5)tz), 6.80~7.48 (4)t
, m), T, TG (2H1br, 8) Example 11 3-Methylbenzylmagnesium chloride and (R)-glycidic acid were treated in the same manner as in Example 3 in the coexistence of cuprous chloride to achieve the objective. was obtained with a yield of 87%.

NMR (d'-DM80+CDCj5) 299m
;1. a1~2-40 (2H-m)-2,30(
3, a) -2,65 to 3.05 (2) I, m),
4.20 (1) I, dd, J near, 5H2)6
．． 85-7.35 (4H, m), 8.90 (21
,br, 8) Example 12゜SirIAW1 Using (S)-glycidic acid and 3-methylbenzylmagnesium chloride, the same procedure as in Example 11 was carried out to prepare (S).
-4-(3-)lyl)-2-noydroxybutyric acid is 85
% yield.

Example 13 2-Trifluoromethylbenzylmagnesium bromide and (R)-glycidic acid were operated in the same manner as in Example 3 in the presence of cuprous bromide to obtain the desired product in a yield of 93%. .

NMR (CDCj, +d6-DM80) 299m;
1.80-2.50 (2H, m), 170-3.2
1 (21 (, m), 4.31 (IHs dd*
J=Ts5Hz) #7-10~1-B2 (
4H-m) -11, IQ (2)t, br, 'a
).

Example 14 (8)-4-(2-) Lifluoromethylphenyl)
-2-nohydroxyacetic acid was obtained with a yield of 86%.

Example 15゜2-methoxybenzylmagnesium bromide and (R)-
The desired product was obtained in a yield of 86% using glycidic acid in the same manner as in Example 6 in the presence of cuprous bromide.

NMR(CD(J3+d6-DMSO) δI)pm
: 1.77~2.40 (2H, m), 2.71~
3.04 (2H, m), 3.76 (3H, s),
4.25 (IH, dd, J=7.5H2)1
6.51 ~7.52 (4H, m), 7.95
(2)1. br, s) Example 16 2-Methylbenzylmagnesium chloride and (R)-glycidic acid were treated in the same manner as in Example 3 in the presence of cuprous chloride to obtain the desired product with a yield of 90%. Obtained. .

NMR (d'-0M80) 209m: 1
．． 75-2.35 (2H.

m), 2.21 (3H, S), 2.65-101
(2H, m).

4.22 (IH, dd, J=7.5Hz), 7
．． 1(4nns)*7.91 (2H, br, s) Example 17゜Siri6 acid (S)-glycidic acid and 2-methylbenzylmagnesium chloride were used in the same manner as in Example 16, and (S)
-4-(2-tolyl)-2-hydroxybutyric acid was obtained with a yield of 85%.

Example 1B.

2-Chlorobenzylmagnesium chlorideto(R)-glycidic acid was operated in the same manner as in Example 3 in the presence of cuprous chloride to obtain the desired product in a yield of 93%.

NMR (CDCI5+d'-DMSO) δppm; 1.
85-2.51 (2H, m), 175-L18 (2
H, m), 4.30 (IH, dd, J=7,5Hz
), 6.91-7.52 (4H, m).

7.65 (2H, br, s) Example 19 Using the same procedure as in Example 18 using (S)-glycidic acid and 2-chlorobenzylmagnesium chloride, (s) -
4-(2-chlorophenyl)-2-hebutroxyfadic acid was obtained with a yield of 85%.

Example 20゜3-methoxybenzylmagnesium bromide and (R)-
The desired product was obtained in a yield of 86% using glycidic acid in the same manner as in Example 3 in the presence of cuprous bromide.

NMR (CDCJ5+d6-0M80) δppm:
1.82-2.42 (2H=mL 170-3.07
(2Hs mL 3-74 (3H.

S), 4.15 (IH, dd, r, 5uz),
6.62-7.46 (4HI m) I 9.20 (2
HI br, r) Example 21゜4-Methoxybenzylmagnesium chloride and (R)-
The desired product was obtained in a yield of 88% using glycidic acid in the same manner as in Example 3 in the presence of cupric iodide.

NMR (CDCj5+d6-0M80) δppm;
1.76-2.311 (2H, m), 2.66-3
．． 02 (2H, m), 3.50 (3H.

s), 4.11 (IH, dd, J=7.5Hz
), 6.75 (2H.

d, J==8Hz), 7.15 (2H, d, J==
8Hz) e 9.20 (2H, br, s) Example 22゜4-bromobenzylmagnesium bromide and (R)-glycidic acid were treated in the same manner as in Example 3 in the presence of cuprous bromide to achieve the objective. was obtained with a yield of 87%.

NMR (cpcJ3+a'-DMSO) δppm;
1.65-2.33 (2I(,m), 2.55-3
．． 02 (2H, m), 4.17 (II(.

dd, J=7.5Hz), 7.03 (2H,d,
J:8H2).

7.35 (2Hs d= J=8Hz), 8.96
(IHlbr-s) Example 23゜4-Nitrobenzylmagnesium chloride and (R)-glycidic acid were operated in the same manner as in Example 3 in the coexistence of cuprous bromide to obtain the desired product with a yield of 93%. It was done.

NMR (d6-DMSO) 299m; 1.85-2
．． 52 (2H, m)e2.71~3.22 (2H,
m) s m, 28 (IH, dd, 5=-7,5H
z), 7.4Q (2H, d, J=:91(z)
.

8.11 (+2H,,d, J=9Hz), 9.
70 (2H, br, s) Example 24 The same operation as in Example 3 was carried out using 2-t-butyldimethylsilyloxypenzylmagnesium chloride and (R)-glycidic acid in the coexistence of ferrous steel bromide. The desired product, 2-t-butyldimethylsilyl, was obtained in a yield of 90%. The desired product was obtained by treating this with tetrabutylammonium fluoride or potassium fluoride in a conventional manner.

NMR (d'-DMSO+CDCJ5) 299m;
1.55-2.04 (2H, m), 'L72~3.
05 (2H, m), 4.22 (IH.

dd, J near, 5Hz), 6.45-7.40 (
41 (, m) s9.66 (3H, br, s) Example 2 1f/(R)-β-phenyllactic acid (R)-glycidic acid was dissolved in 10 liters of THF and cooled to -30"cK. Dissolution of phenyllithium*
12.6 ml (2M/J-cyclohexane-diethyl ether) was added dropwise and stirred at -5 to 5°C for 2 hours.
20 ml of N-hydrochloric acid was added and then extracted with 50 t of ethyl acetate. Extract with 30 ml of saturated deuterated aqueous water, add ethyl acetate Sod and 5 d of concentrated hydrochloric acid to the aqueous layer for extraction, dry the organic layer over magnesium sulfate, filtrate with sulfur chloride, and extract the desired product.
% yield. The physical data for this item is Example 6
matched those of .

Example 26゜(R)-glycid(4-methoxy)anilide 1 da was TH
Dissolve in FIO-, add 10 t of ethylmagnesium bromide (3M/j-ether) and 10 t of THF.
ml and 0.6 g of cupric iodide at -20℃~
It was added dropwise at -10°C. After stirring at 0°C for 1 hour, the reaction solution was poured into an ice-cooled 30% aqueous solution of potassium hydrogen sulfate.
Extracted 3 times with 50% ethyl acetate, dried over magnesium sulfate, passed through f and distilled off the solvent under reduced pressure to obtain the desired product (0.92 f).
80% yield) was obtained as a white powder.

NMR (CDCj5) δE'pm; Q, 70~'L
30 (7H*rn)-3,75(SL sL 3.
90 (IHs br-5) e4, QO ~ 4.40 (
IH, m), 6.78 (2H, d, J=9Hz)
, 7.40 (2H, d, J=9H2), 8.5
0 (IH.

br, s) Example 27゜(R)-glycid(4-methoxy)anilide 11 it
The solution was dissolved in 1G ml of THF and added dropwise to a mixed solution of benzylmagnesium chloride IJf/THF 2G- and cupric iodide a, 3y while maintaining the internal temperature at -20 to -10°C. After the dropwise addition and stirring at room temperature for 2 hours,
The mixture was poured into 30 d of 30% aqueous potassium hydrogen sulfate solution, extracted twice with 60 W 1 t of ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 1.19 g (yield: 81 g6) of the desired product.

NMR (CDCj5+d'-DMSO) 299m;
t, 70-2.30 (in 2, m), 2.50-4.
QO(2H,m), S, T2 (3)I.

s), 4.30-4.55 (11, m), 5.2
0 (IH, br.

S), 6.82 (2H, d, J=9)IZ),
7.20 (5H,S).

Claims (1)

[Claims] 1) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 and R^2 are the same or different,
It represents a hydrogen atom, an alkyl group, or a phenyl group which may have a substituent, and R^3 is a hydroxyl group, an OR^4 group (R^4
indicates an alkyl group, a protecting group for a hydroxyl group, a phenyl group which may have a substituent, a succinimide group, or a ▲ mathematical formula, chemical formula, table, etc. ▼ group. ), SR^5 groups (R^5
represents an alkyl group, a phenyl group which may have a substituent, or a 5- or 6-membered heteroaryl group which may have a substituent. ), NR^6R^7 groups (R^6 and R
^7 is the same or different and is a hydrogen atom, C_1 to C_
1_0 alkyl group, phenyl group that may have a substituent, aralkyl group that may have a substituent, or R^6 and R
^7 together form -(CH_2)_n- group (n=3,
4 and 5 are shown. ), ▲Mathematical formulas, chemical formulas, tables, etc.▼
A group or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Indicates a group. ) or NHNHR^8 group (R^8 represents a hydrogen atom, an alkyl group, or a phenyl group). ] to a compound having the formula RM [wherein R is an alkyl group, an alkenyl group, a phenyl group which may have a substituent, a benzyl group which may have a substituent, a benzyl group which may have a substituent It represents a 5- or 6-membered heteroaryl group or a 5- or 6-membered heteroarylmethyl group that may have a substituent, and M is MgX (Mg
represents magnesium, and X represents chlorine, bromine or iodine. ) or alkali metal. ] There are formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by reacting compounds having the following ▼ [In the formula, R, R^1, R^2 and R^3 have the same meanings as above . ] A method for producing an α-hydroxycarboxylic acid derivative having the following. 2) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1 and R^2 are the same or different,
It represents a hydrogen atom, an alkyl group, or a phenyl group which may have a substituent, and R^3 is a hydroxyl group, an OR^4 group (R^4
indicates an alkyl group, a protecting group for a hydroxyl group, a phenyl group which may have a substituent, a succinimide group, or ▲a mathematical formula, a chemical formula, a table, etc.▼. ), SR^5 group (R^5 represents an alkyl group, a phenyl group that may have a substituent, or a 5- or 6-membered heteroaryl group that may have a substituent.), NR^ 6R^7 groups (R^6 and R^
7 is the same or different and is a hydrogen atom, C_1 to C_1
_0 alkyl group, phenyl group which may have a substituent,
Aralkyl group which may have a substituent or R^6 and R^
7 together form -(CH_2)_n- group (n=3, 4
, 5 is shown. ), ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ groups or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ Indicates groups. ) or NHNHR^8 group (R^8 represents a hydrogen atom, an alkyl group or a phenyl group), and Y represents a halogen atom. ] Treated with a base, a compound having the formula ▲ has a mathematical formula, a chemical formula, a table, etc. ▼ [In the formula, R^1, R^2 and R^3 have the same meanings as described above. ] and then convert this compound into a compound having the formula RM [wherein R is an alkyl group, an alkenyl group, a phenyl group which may have a substituent, a benzyl group which may have a substituent, a substituent represents a 5- or 6-membered heteroaryl group which may have a substituent, or a 5- or 6-membered heteroarylmethyl group which may have a substituent; M is MgX (Mg
represents magnesium, and X represents chlorine, bromine or iodine. ) or alkali metal. ] There are formulas ▲ mathematical formulas, chemical formulas, tables, etc. that are characterized by reacting compounds having the following ▼ [In the formula, R, R^1, R^2 and R^3 have the same meanings as above . ] A method for producing a compound having the following.