JPH0267250A - Production of 2,2-difluoro-3-hydroxycarboxylic acid derivative - Google Patents

Abstract

PURPOSE:To obtain the title compound useful as a synthetic intermediate for compounds of drugs, etc., by reacting a readily obtainable difluoroiodoacetic acid derivative as a starting raw material with a carbonyl compound in the presence of a metallic reagent. CONSTITUTION:1 equivalent difluoroiodoacetic acid derivative as a starting raw material is reacted with about 0.01-1 equivalent, especially about 0.1-0.5 equivalent carbonyl compound in the presence of a metallic reagent in a solvent such as acetonitrile at about -20 deg.C-60 deg.C, generally 0 deg.C-room temperature to give the aimed compound. A 0 valent metal or a combination of the 0 valent metal and on organic silyl compound is used as the metallic reagent. Zinc is especially preferable as the 0 valent metal. The amount of the 0 valent metal is about 1-3 equivalent based on 1 equivalent difluoroiodoacetic acid derivative and preferably about 1-1.5 equivalent when the 0 valent metal is combined with the organic silyl compound.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a 2,2-difluoro-3-hydroxycarboxylic acid derivative.

As a method for synthesizing 2-difluoro-3-hydroxycarboxylic acid derivatives, a method in which a bromodifluoroacetic acid derivative and a carbonyl compound are reacted in the presence of zinc powder is conventionally known ('Tetrahedron Lett
,” 25a, page 2301.

(1984), however, it is not easy to prepare the referent reagent from bromodifluoroacetic acid derivatives, and the addition reaction yield and selectivity are not high. development was desired.

The present invention seeks to overcome the aforementioned drawbacks of the prior art. That is, the present invention provides a novel manufacturing method for efficiently synthesizing 2,2-difluoro-3-hydroxycarboxylic acid derivatives using a difluoroiodo vinegar conductor easily obtained from tetrafluoroethylene as a starting material.

The present invention provides 2
．． The present invention relates to a method for producing a 2-difluoro-3-hydroxycarboxylic acid derivative, in which a difluoroiodoacetic acid derivative and a carbonyl compound are reacted in the presence of a metal reactant to produce a 2.2-difluoro-3-hydroxycarboxylic acid derivative having 3 or more carbon atoms.
-2,2-difluoro-3-, characterized in that it is converted into a derivative of difluoro-3-hydroxycarboxylic acid.
This is a method for producing hydroxycarboxylic acid derivatives.

As the difluoroiodoacetic acid derivative in the present invention, its ester form is particularly suitable. Suitable ester residues include, for example, alkyl groups, alkenyl groups, aryl groups, aralkyl groups, and those groups having substituents inert to the reaction in the present invention. Alkyl groups and benzyl groups are employed.

The alkyl group may be a linear alkyl group or a branched alkyl group.

Particularly preferred are lower alkyl groups having 1 to 4 carbon atoms such as methyl and ethyl groups.

The above difluoroiodoacetic acid derivatives are usually produced from difluoroiodoacetyl fluoride, but are not limited thereto.

Difluoroiodoacetyl fluoride is described, for example, in Japanese Patent Publication No. 60-56126. An ester is obtained by the reaction of such difluoroiodoacetyl fluoride and alcohol.

As the carbonyl compound in the present invention, various compounds having at least one aldehyde group or ketone group can be employed.

These compounds may have various characteristic groups that are inert to the reaction in the present invention, such as a hydroxyl group that may be protected, an ester group, a halogen atom, a sulfide group, a sulfonyl group, and a nitro group. group, nitrile group, protected amino group, imino group, etc.

The metal reactant in the present invention is a zero-valent metal or a zero-valent metal.
A combination of a valent metal and an organosilyl compound is used. 0
Examples of the valent metal include zinc, copper, magnesium, alkali metals, etc., and the use of zinc is particularly preferred.The zero-valent metal is usually used in the form of powder. Such a zero-valent metal can be used in the coexistence of a difluoroiodoacetic acid derivative and a carbonyl compound, or can be used by reacting one in advance and then reacting the product with the other, but side reactions may occur. It is preferable to use the latter method in order to suppress the reaction and increase the yield of the target product. When using the latter method, the difluoroiodoacetic acid derivative and the zero-valent metal are first reacted, and then the carbonyl compound is reacted. is preferred.

When zinc powder is applied to a difluoroiodoacetic acid derivative, active InZn (CF2C
OOH) *-n [I] However, n is 0
Or 1. It is thought that R is generated as a type representing an ester residue of a difluoroiodoacetic acid derivative, and this is added to the carbonyl compound.

On the other hand, when it is necessary to enhance the stereocontrollability in such an addition reaction, an organic silyl compound is combined with the above zero-valent metal as a metal reactant to form a difluoroketenesilylacetal as shown in the following formula [■]. After converting,
Addition anti-CFg-C (OR) (O3iR'
[H] However, Ro represents three alkyl substituents on the silyl atom.

It is effective to have them take action. Here, the organic silyl compound has three same or different alkyl groups and one
A trialkylsilyl halide consisting of halogen atoms is used. Specifically, the difluoroketenesilylacetal shown in the formula [■], which includes triethylsilyl chloride, trimethylsilyl chloride, t-butyldimethylsilylsilyl chloride, etc., is the above formula [x]
It can be obtained by adding the above trialkylsilyl halide to the compound.

This compound can be produced in situ and directly reacted with a carbonyl compound without isolation, or more easily, it can be isolated and then reacted with a carbonyl compound in the presence of a Lewis compound such as zinc halide. The former method is commonly used, but in either method, a 2,2-difluoro-3-hydroxycarbon derivative in which the 3-hydroxyl group is trialkylsilylated is obtained as the main product.For example, as an aldehyde, D-glyceradehyde acetonide (in formula [m], Rl = hydrogen) and 4-
Deoxy-L-threose acetonide (in formula [m], R
l 1-methyl group), syn
Although the anti-isomer and the anti-isomer are produced in a ratio of about 1:2, the useful anti-isomer can be obtained from any aldehyde with high selectivity from [■]. As reference examples to be described later, examples of conversion of these compounds to 2,2-difluoro-2-deoxypyranose derivatives (compounds of formula [17]) will be shown.

2.2-Difluoro-2-deoxypyranose derivatives are important intermediates for various nucleoside derivatives that are attracting attention for their antitumor and antiviral activities ('Tetrahe
Dron Lett,” Volume 27, Page 3219, 19
(see 1986).

t"I) yn nti The amount of the carbonyl compound to be used per equivalent of the difluoroiodo vinegar #derivative is not particularly limited, but is approximately 0.01-1 equivalent or appropriate. Particularly preferably approximately 0.01-1 equivalent.
．． The amount of the metal reactant to be used is preferably 1 to 0.5 equivalents, and when a zero-valent metal is used, it is suitably about 1 to 10 equivalents, particularly about 1 to 3 equivalents, per equivalent of difluoroiodoacetic acid derivative. is preferred, and when an organic silyl compound is combined, it is suitably used in an amount of about 1 to 10 equivalents, particularly preferably about 1 to 1.5 equivalents, per equivalent of the difluoroiodoacetic acid derivative.

Although the reaction can be carried out without a solvent, it is preferable to use a solvent. Suitable solvents are those that can dissolve the raw materials and products and are non-reactive, such as acetonitrile, tetrahydrofuran, diethyl ether%1 , 4-dioxane, dimethoxyethane, dimethylformamide, dimethyl sulfoxide, benzene, etc. are used, but acetonitrile is particularly preferred. The reaction is preferably carried out at about -20 to 60°C, and usually 0°C to room temperature. .

The present invention has the following advantages: (1) The reaction is easy and the yield is high. (2) Since various carbonyl compounds can be used, it is possible to produce many 2,2-difluoro-3-hydroxycarboxylic acid derivatives. (3) A highly stereospecific addition reaction was achieved by using difluoroketenesilylacetal as a synthetic intermediate, making it useful as pharmaceutical compounds and their intermediates that often require strict stereocontrol. It has the first characteristic that a 2,2-difluoro-3-hydroxycarboxylic acid derivative can be obtained.

Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited to these Examples, and in particular, various compounds other than the Examples may be employed as the carbonyl compound.

(Example) Under an argon atmosphere, zinc powder (220@g, 3.3 mmo
To a suspension of 1) in acetonitrile (2.5 ml) was added methyl difluoroiodoacetate 1 (708 mg) under water cooling.

A solution of 31 tsol) in acetonitrile (21) was added dropwise over 5 minutes, and 3-phenylpropionaldehyde (200 g, 1
．． After stirring for 2 hours, 1% hydrochloric acid was added to the reaction mixture and extracted with ether. 5% ether extract
After washing with an aqueous sodium bicarbonate solution and a saline solution, it is dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (hexane-ethyl acetate 5:1) to obtain 289+ag (yield 79%) of the title compound.

(Colorless oily substance) obtained.

IR(CHCI:+) cra-' :3590,33
80,1765°'If-NMR (CDCh) δ: 2.
0G (21 quantity, m), 2.50 (IH, ds).

2.8:1 (2H, m), 3.87 (3H, s), 3.
90-4.30 (IH, ■).

7, :10 (511, bs).

凰'F-NM11 (CDC13) 1hi: -51,0pp
m(dd, Jr-r-26:1llz.

Ju-r"7.5H2), -60.0ppm (dd, J
r-rs26ko11z.

Ju-r-14Hri.

MS m/e: 224 (M”), 226 (M”-HzO
), 206 (M''-HzO-IIF).

(*"F-MNR uses benzaldehyde as the internal standard and the high magnetic field side is indicated by a minus sign.) By the same operation as in the previous example, 1 (944 mg, 4.0 mmol) and zinc powder (340 mg, 5.2 mmol) were added. Acetonitrile (6
1), and then 3-phenyl-2-propenal (264 mg, 2.0 mol) was added and stirred at room temperature for 30 minutes. Perform similar post-treatment and purification to obtain 3
30 g (yield 68%, colorless oil) was obtained.

IR (CDCI3): 3590, 1765, 1760
゜IH-NMR (CDCI3) δ: 2.85 (IH, b
r), : 1.90 (311, s).

4.50-4.95 (IH, m), 6.23 (18, d
d, J-4, 16+1z).

7.27-7.50 (5H, False).

"F-N111R (CDC13) Knee SG, 7ppm (
dd, J, -r=263tlz.

J,, -8,6Hz), -59,0ppm (dd, Jr.
-rm263Hz.

Jn-r-14Hz).

Similarly, 1 (850g, 3.6■■0■), zinc powder (2
70mg.

4.14 mmol) in acetonitrile (51), D-glyceraldehyde acetonide (260 mg,
2.2 mmol) was added thereto, and the mixture was stirred for 2 hours under water cooling.

After similar work-up, the diastereomer mixture was prepared in 26 sl.
g (yield 58%) methylene chloride-methanol 80:1) on a silica gel column, the syn isomer was converted to 72s+
g (yield 15%), 144 mg (yield 30%) of the anti body was obtained.

Anti body: colorless crystal pho p4, 5°C IR (CtlCh) cm-': 3550, 3425.
1775, 1765°') I-NMR (CDC13)
δ: 1.38 (38, j), 1.42 (Has)
C2,92 (IH, brs), 3.80-3.91 (1
8, m).

3.89 (3H, s), 3.97 (IH, ddd, Jn
-u-3,8H2゜Jo-r=5.8,16.3Hz)
, 4.13 (IH, dd, J-6, 6° 8.411z)
,4. :+7 (IH, dt, J-3, 7, 6, 1lz)
.

1'F-NMR ((:De13) knee 49.3p9@C
dd, Jr-W-264NZ.

JII-r-5,8112), -60,0ppm (dd
, Jr-r-26411z.

Ju-r-16, 2tlZ).

MS m/e (CI): 251 (M◆◆1), 225,
183° syn body: colorless oily substance IR (C11CI:+) cm-': 3:15G, 342
5,1775,1765゜') I-NMR (CDC13
) δ: 1.38 (38, s), 1.42 (3H, s).

2.92 (IH, brs), 3.130-3.91 (I
H, m).

3.89 (3H, s), 3.97 (1) 1. ddd, J
nu-3,8゜Jn-r-5,8,16,314Z)
,4.13(111,dd,J-6,6Hz)-凰'
F-NMR (CDCI 3) knee 49.3 ppm (dd
, Jr-r=264Hz.

Ju-r-5,88Z), -60,0ppm (dd,
Jr-r-264Hz.

Jn-r-16,2jlz).

MS m/e (CI): 251 (il”+1), 225
, 183° under argon atmosphere, zinc powder (: 113mg,
4. A solution (3 ml) of 1 (944 g * 4.0 svol) in acetonitrile (3 ml) was added dropwise to a suspension of 1 (944 g * 4.0 svol) of acetonitrile (31) over 5 minutes while cooling with water. After further stirring for 10 minutes at the same temperature, triethylsilyl chloride (
Add benzaldehyde (212 mg, 4.4 mmol) and stir for 5 minutes, then add benzaldehyde (212 mg, 2.0 mmol) and stir for 20 minutes.The reaction mixture was diluted with ether (10 sl). After adding a 2.5% aqueous sodium bicarbonate solution, the precipitate is filtered off, and the polar liquid is extracted with ether. Wash the ether extract with saline and dry (magnesium sulfate)
The residue was purified by silica gel column chromatography (hexane-ethyl acetate 200:l) to obtain 536-g of the desired product (yield 81%, colorless oil).
Obtained.

IR (CHCI:+) cm-": 1775, 1765°'H-NMR (CDCI+) δ: 0.33-1.0
0 (15H, m).

3.82 (3H, s), 5.10 (IH, dd, J”7
．． 5, 16.5Hz).

7.35 (511, brs).

"F-NMR (CDCl2) knee 48.3 ppm (dd
, Jr-r=259Hz.

Ju-y-7,5Hz), -60,3ppm (dd, J
r-r-259Hz.

J□-, -16,5Hz).

MS m/e: 301 (M”-CJs), 221 (M
”-CO*CH:+).

By the same operation as before, l (944mg, 4.0ss
ol), zinc dust (313mg, 4.8ssol), triethylchlorosilane (0.73ml1.4.4ssol)
) and 3-phenylpropionaldehyde, 55hg of 8 (yield 77%, colorless oil) was obtained.

IR(COCl2)Cl@-':1765.

'If-NMR (CDCI+) δ:0.3O-
1.10 (15H, ■).

1, 98 (211, m), 2.70 (2H, m), 3.
83 (3H, s).

4, 13 (IH.-), 7.23 (5H, brs).

Otori'F-NMR (CD(:I*) knee 4.93ppm(
dd, Jr-r-259Hz.

Jn-r=11Hz), -5
5 - 3 p p m (dd t J r -
y-2 5 9 Hz *Jn-r-118ri.

igs ■/e: 329 (M”-CJs), 249 (M
”-COJe).

By the same operation as before, 1 (946g, 4.0 ssol)
, zinc dust (313mg, 4.8ms+ol) and triethylchlorosilane (0.73ml, 4.4++mol)
After reacting l) in acetonitrile (6 ml), cyclohexanone (196 g, 2.0 sw+ol)
Add and stir at room temperature for 5 hours. After similar post-treatment, 134 mg of triethylsiloxy compound (yield 21%) was obtained.
), 117 mg (yield 21%) of the hydroxy compound was obtained.

Hydroxy form: Colorless oily substance IR (CHCh) C-': 3595,3420.
1765.

"H-NMR (CDCl2) δ: 1.0-1.
9 (1011, layer).

2, 13 (IH, s): 1.8 g (38, s).

Otori'F-NMR (CDC I+): -5 7.0p
pm(s).

MS m/e: 2G9 (M”+1), 191 (M”-O
ll), 171,99.

Triethylsiloxy compound: colorless oily substance IR(CuCl2)CI-”: 1760.

"H-NMR (CDC1i) δ: 0.47-1.15 (
15H, 11).

1, 20-1.85 (IOH, Oboro), 3.85 (3H,
s).

”F-NMR knee 52.7ppm(s)-MS m/e
:323(M"+1), 293(M◆-C,H.),
213.

1 (9441g, 4.o gaol
), zinc powder (313mg, 4.8+smol),
) ethylchlorosilane (0.7:1ml, 4.4ss
ol) in acetonitrile (61), then D
-Glyceraldehyde acetonite (26G+*g,2
．． Add 0■zen o1) and stir for 1 hour under water cooling. After the same post-treatment as before, 54 mg of syn body (yield 7.6%)
, 465 mg (yield 66%) of the anti body was obtained.

ant i form: colorless oily substance IR ((:lIc13)C11-': 1775,17
65.

"H" NMR (CDCh) δ: 0.62-0.7
0 (611, Otori).

0, 92-1.00 (9H, m), 1.31 (311,
s), 1.38 (311, s).

3, 85 (3H, s), 3.93 (IH, dd, J”5
．． 2,8.6Hz).

4, 04 (IH, ddd, J ■ 1.5, 5.2.8Hz
), 4.17-4.27 (2H, 謹).

"F-NMR (CDCl2) knee 50.0 ppm (dd
, Jr-r-261Hz.

JH-rsa7.5Hz), -59.3ppm (dd,
Jr-r-261Hz.

Ju-r-16.2Hz).

11S m/e: 355 (M”+1), 339 (M”
- CD Co).

325 (M◆-CJs), 267.

High resolution MS calculated value: CsJ*sF*OsSi(M”-C113)
.

339, 1437.

Observed value: 339.1422.

[a] “Knee, 8.19 (c-0.854, CI
ICI3).

syn body: colorless oily substance NatsuR (CllCI3) cm-”: 1775,1760
.

Otori 11-N11R (CDCl2) δ: 0.55-0.7
3 (611, ■).

0, 85-1.03 (91, m), 1.35 (311,
s), 1.39 (koH, s).

3, 77 (IH, t, J-8.5Hz), 4.08 (
III, dd, J-7.0.

8.5Hz), 4.14 (IH, dt, J-12, 5,
8.5Hz).

4.21 (ill, dt, J-7,0,8,5Hz).

"F-NMR (CDCI3) knee 48.01) I) II
(dd, Jr-r-263Ilz.

Ju-rs8.5Hz), -57.3ppm (dd, J
r-r*263Hz.

JH-F”112Hz).

MS Otori/e: 355 (M”◆l), 339 (M”-
CD5).

325 (M order - CJi), 267° high resolution MS calculated value: (:s<fltsFloasi(M◆-C11
3).

339.1437° Observed value: 339.1448° [α] ”: 5.42 (c-0,70,C11C1+)
.

1 (2.89g, 12.0
gaol), zinc powder (863 mg, 13.2 smol)
, triethylylrollosilane (2,t+++1.14
．． After reacting 3 sets o1) in acetonitrile (20 ml), a hydrate of (2R,33),-dihydroxybutanal acetonide (4861 g, 3 gaol)
and stir for 40 minutes while cooling with water.

After similar post-treatment, the diastereomer mixture was
g (anti:syn W 1:2 yield 7.5%)
Then, 905 g (yield: 82%) of the anti body was obtained.

Anti body: colorless oily substance IR(C)1c13)Cm-凰:1773,1765゜''II-NMrl(CDCI:+)δ:0.6G-0.
78 (6114).

0.90-1.05 (9H, s), 1.30 (31
1,s).

1.35 (311, d, J = 6, 4) 1z), 1. :1
7(:III, s).

3.65 (111, dd, J=6.2, 7.5) 1z)
, 3.83 (3H, s).

4.09 (IH, dq, J-6, 2, 6, 4 Hz).

4.20 (IH, ddd, JH-8m7.5H2, JH
-ra6.1.1811z).

Otori'F-NMR (CDCI 3) knee 48.3ppm (
dd, Jr-r-26311z.

Jn-r"6.4H1), -62.8ppm (dd,
Jr-r*26311z.

Joy-y-18H2).

MS Il/Q (CI): 369 (M”+1), 35
3 (M”-C113).

311.281゜syn body "H-NMR (CDCh) δ: 3.a5 (311,s)
.

"F-NMR (CDCI3) knee 48.71) pm (d
d, Jr-r-263HzsJH-rmll, 3Hz)
, -54.3ppm (dd, Jr-rm263Hz.

Jll Imura 2.4Hz).

Reference Example Methyl (3R,4R)-2,2-difluoro-3,4,5-trihydroxypentanoate under argon atmosphere 4.
5-acetonide-3-triethylsilyl ether (35
Diisobutylaluminum hydride (1M hexane solution, 1.1ml) was added to a solution of 45g, 1.0mmol) of ether (31) under dry ice-acetone cooling, and after stirring for 5 minutes, 1% hydrochloric acid was added to acidify the ether (31). Extract with The ether extract was washed with a 5% aqueous sodium bicarbonate solution and saturated brine, dried, and then condensed to 1 liter under reduced pressure. The residual solution was stirred in water cooling (2 ml) and trifluoroacetic acid (21) for 2 hours and then at room temperature for 30 minutes, then toluene (51) was added and concentrated under reduced pressure. Triethylamine (4
tl), N,N-Dimethyl-4-aminopyridine (20 g) and anhydrous acid (2 g) were added and stirred for 30 min. The reaction mixture was made acidic by adding 3% hydrochloric acid and
Extract with a mixed solution of ether-ethyl acetate (1:1). The organic layer was washed with a 5% aqueous sodium bicarbonate solution and saturated brine, dried, and concentrated under reduced pressure. The remaining liquid was purified by silica gel column chromatography (hexane-ethyl acetate 4:1). 243 g (yield 82%) of the target product was obtained.
The IR spectrum shows that it is a 4:1 mixture of anomers. When a mixed solution of ether-pentane (1:1) is added to the product to collect crystals, the main product, α-
The anomer was obtained as a colorless crystalline material.

[α 3 zt any 43.4 (csl, 62.Cl
IC1+).

111-NMR (CD(:l)δ:2.14(3tl
,s).

2.19 (311, s), 3.88 (IH, dd, J
=2.6,13. :1llz).

4.10 (111, dd, J=2,1:1.3Hz),
5. :17(II, m).

5.46 (IH, ddd, Jun-4-0, Ju-r
“2.li, 5.711li.

Acetyl: +4-Go-diacetyl-26-dideoxy-2,2-difluorolixopyranosyl(:lR,4R
,5S)-2,2-difluoro-3,4,S,-)-methyl lihydroxyhexanoate-4,5,-acetonide-
3-triethylsilyl ether (37011g).

1.0 mmol) and DIBAL-H in the same manner as above.
After reduction and deprotection, pyridine (41) and acetic anhydride (2
1) Stir for 1 hour under water cooling and then for 30 minutes at room temperature. Extraction was performed and the product was subjected to silica gel column chromatography to obtain 180 g (yield: 58%) of the desired product from the fraction eluted with hexane-ethyl acetate (4:l). 'H-NMR spectrum shows a mixture of α:β=2=1. Further, 80 mg (yield: 30%) of diacetyl compound was obtained from the hexane-ethyl acetate (1:l) eluted portion. The diacetyl compound was quantitatively converted into the title compound by stirring lysine (21)-acetic anhydride (11) for 2.5 hours in a room temperature source. The α-anomer was obtained as a crystalline substance by standing in an ether-pentane (1:1) mixed solvent.

(mp128°C).

[α]” Knee 127 (c-0,87, CllCl:
+) “IR(CHCI:1)C11-’:1760-
1740°”H-NMII (CHCI3) δ:1.
20 (311, d, J-6, 511z).

2.10 (3H, s), 2. f7(3H,s)2.18
(311,s)4.31(IH,dq,J-0,9,6
, 5+1z), 5.32(Ill, m).

5.42(1)1. ddd, Jun-4, 0, Ju-
r-5, 2, 22, 8Hz).

6.20 (IH, d, J=7.2Hz).

"F-NMR (CDC1+) Knee 56.7ppm (d
d, J=5.5,2211z).

-57,2ppm (d, J-7,2)1z).

MS m/e: 251 (M”-0Ac).

*β-anomer integrated (analyzed from mixture with 16-α form) “84M11 (CHCI3) δ: 1.26 (3H, d,
J-6,411z).

4.05 (IH, q, J = 6.4Hz), 5.23 (l
If, Ju-u-4,5Hz, Jnur-4
,5,'21Hz), 5.27(ill,m).

5.78 (IH, d, JH-F-15, 6H2).

” 'F-NMR (CD C13): -5
9-3 p p m * (d d * J u -ke 4
-5 Hz eJ,, m244Hz), -71,0p
pm, (ddd, J,, -, s15.6.

21Hz, Jr-r=244Hz).

Claims (2)

[Claims] (1), characterized in that a difluoroiodoacetic acid derivative and a carbonyl compound are reacted in the presence of a metal reactant to convert them into a derivative of 2,2-difluoro-3-hydroxycarboxylic acid having 3 or more carbon atoms. A method for producing a 2,2-difluoro-3-hydroxycarboxylic acid derivative. (2) The manufacturing method according to claim 1, wherein the metal reactant is a zero-valent metal or a combination of a zero-valent metal and an organic silyl compound.