JPH02270841A - Production of 2,2-difluoro-3,4,5-trihydroxycarboxylic acid derivative - Google Patents

Abstract

PURPOSE:To stereospecifically and effectively produce the anti-type compound useful as a medicine or agricultural chemical or as an intermediate thereof by reacting a difluorohaloacetic acid derivative with an alpha,beta-dihydroxyaldehyde derivative in the presence of a metal reagent. CONSTITUTION:A difluorohalo (preferably bromo or iodo) acetic acid derivative is reacted with a compound of formula I (R<1> is H or a hydrocarbon group capable of containing a specific group inert to the reaction; R<2> and R<3> are H or a protecting group for an OH group, respectively, or R<2> and R<3> together forms a protecting group for two OH groups) in the presence of a metal reagent, preferably a combination of a 0 valent metal (especially zinc) and an organic silicon compound or further a Lewis acid to selectively readily and stereospecifically provide the objective anti-type compound of formula II (R<4> is H or a protecting group for an OH group; R<5> is ester residue or H) useful as an intermediate for various nucleotides having antitumor activity and antiviral activity in a good yield.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing 2,2-difluoro-3,4,5-trihydroxycarboxylic acid derivatives.

Conventionally, anti-2,2-difluoro-3,4,5-
There is no known method for selectively producing hydroxycarboxylic acid derivatives.

Anti-type 2,2-difluoro-3,4,5-trihydroxycarboxylic acid derivatives have recently attracted attention for their antitumor and antiviral activities.
2-deoxypyranose derivatives and 2,2-difluoro-
It is an important intermediate for various nucleosides such as 2-deoxyfuranose derivatives (rTetrahedron L
ett, J 29, 3219, 1986).

Regarding the anti-stereochemistry, S, Masamu
ne et rAngew, Chem, Int, Ed, Eng
l, J vol. 19, p. 557 1980 and S. Mas.
amune et al rJ, Am, chem, soc, J 1
04, page 5521, 1982.

A general synthesis of 2,2-difluoro-3-hydroxycarboxylic acid derivatives, which are the constituent units of 2-difluoro-3,4,5-trihydroxycarboxylic acid, involves combining a bromodifluoroacetic acid derivative and a carbonyl compound with zinc. A method of reacting in the presence of powder (rTetrahedron
Lett, J Vol. 25, p. 2301, 1984), a method of reacting a difluoroiodoacetic acid derivative with a carbonyl compound in the presence of a metal reactant (Japanese Patent Application No. 63-2185
00), a method of reacting a chlorodifluoroacetic acid derivative and a carbonyl compound in the presence of zinc powder (rTetrah
edronLett, J vol. 29, p. 2943, 198
8 years). However, when these methods are applied to the production of 2,2-difluoro-3,4,5-trihydroxycarboxylic acid derivatives, the yield and selectivity are low;
In order to obtain the desired product, a very complicated separation and purification operation of isomers is required. So ant
There has been a strong desire to develop a selective and efficient method for producing i-type 2,2-difluoro-3,4,5-trihydroxycarboxylic acid derivatives.

The present invention seeks to overcome the aforementioned drawbacks of the prior art. That is, using a difluorohaloacetic acid derivative obtained from chlorotrifluoroethylene or tetrafluoroethylene as a starting material, anti-2,2-difluoro-3,4,5-)-lihydroxycarboxylic acid can be selectively and efficiently produced. The present invention provides a novel manufacturing method for synthesizing derivatives.

The present invention provides Reformats from α,β-dihydroxyaldehyde derivatives and the above-mentioned difluorohaloacetic acid derivatives.
ky-type reaction to produce 2,2-difluoro-3,4,
The present invention relates to a method for diastereoselectively producing a 5-trihydroxycarboxylic acid derivative, that is, a difluorohaloacetic acid derivative and a,β- represented by the following formula [1].
A dihydroxyaldehyde derivative is reacted in the presence of a metal reactant to form an anti
2, characterized in that it is converted into a derivative of 2,2-difluoro-3,4,5-trihydroxycarboxylic acid of type 2.
, a method for producing a 2-difluoro-3,4,5-trihydroxycarboxylic acid derivative.

R1 is a hydrogen atom, a hydrocarbon group, or a hydrocarbon group containing a characteristic group inert to the reaction, R1 and R1 are each a hydrogen atom or a protecting group for a hydroxyl group, or one protecting group that jointly protects two hydroxyl groups. represent.

R', R2, and R'' are the same as above. R' represents a hydrogen atom or a hydroxyl group-protecting group, and R5 represents an ester residue or a hydrogen atom, respectively.

As the difluorohaloacetic acid derivative in the present invention, bromodifluoroacetic acid derivatives and difluoroiodoacetic acid derivatives are suitable, and esters thereof are particularly suitable. Suitable ester residues are, for example, alkyl groups, alkenyl groups, aryl groups, aralkyl groups and those groups which have a 'substituent which is inert to the reaction according to the invention. Usually, an alkyl group having 1 to 10 carbon atoms or a benzyl group is employed. The alkyl group may be a linear alkyl group or a branched alkyl group, but lower alkyl groups having 1 to 4 carbon atoms such as a methyl group and an ethyl group are particularly preferred.

In the present invention, an α,β-dihydroxyaldehyde derivative represented by the following formula [1] is used.

R1 represents a hydrogen atom, a hydrocarbon group, or a hydrocarbon group containing a characteristic group inert to the reaction, and the characteristic groups include a hydroxyl group that may be protected, an ester group, a halogen atom, a sulfide group, and a protected amino group. etc. In particular, R1 is preferably a hydrogen atom, a methyl group, or a hydroxymethyl group which may be protected. R'' and R'' represent a hydrogen atom or a hydroxyl group-protecting group, respectively. Hydrocarbon groups such as methyl, benzyl, and allyl groups, trialkylsilyl groups, and acyl groups are used as protecting groups for hydroxyl groups, but in particular, cyclic groups in which R2゜R3 jointly protect two hydroxyl groups are used. Preferably, a hydroxy protecting group is formed. Specifically, isopropylidene acecul, cyclohexylidene acecul, methylene acetal, benzylidene acecul, ethylidene acetal, etc. are used.

As the metal reactant in the present invention, a combination of a zero-valent metal and an organosilicon compound or a combination of a zero-valent metal, an organosilicon compound, and a Lewis acid is used. Examples of zero-valent metals include zinc, copper, tin, lead, magnesium, alkali metals, etc., and use of zinc is particularly preferred. As the form of the zero-valent metal, powder is usually used. As an organosilicon compound, three same or different alkyl groups and one
A trialkylsilyl halide consisting of halogen atoms is used. Specific examples include triethylsilyl chloride, trimethylsilyl chloride, t-butyldimethylsilyl chloride, and ethyldimethylsilyl chloride.

When zinc powder and trialkylsilyl halide are applied to a difluorohaloacetic acid derivative, the following formula [[II]
It is thought that silylketene acecure as shown in Figure 1 is generated and added to the α,β-dihydroxyaldehyde derivative.

CF2= C(OR) (O3iR'a) ・
... [It13 However, R represents an ester residue of a difluorohaloacetic acid derivative, and R' represents three alkyl substituents on a silyl atom.

It has already been reported (Japanese Patent Application No. 63-213500) that in the Reformatsky type reaction, when silylketene acecool as shown in the above formula [] is used, the addition reaction proceeds in a high yield under mild conditions.

In the present invention, the addition reaction of difluorohaloacetic acid to α,β-dihydroxyaldehyde via [111] is the anti-2,2-difluoro-3,4,5
It has been found that this method is effective for efficiently synthesizing -trihydroxycarboxylic acid derivatives, and that anti-selectivity is improved by adding Lewis acid.

As the Lewis acid, salts of 4, typical metals and transition metals are used. Lewis acids are cited in books such as Nozaki et al. ``New Reactants for Organic Synthesis'' by Kagaku Doujin, Nozaki et al. ``Organometallics'' by Kagaku Doujin, Yoshinori Yamamoto, Yoshinori Narita ``Organometallic Chemistry'' by Maruzen), etc. compounds may be used, but are not limited to these. Specifically, B, Al.

Metal salts such as Mg, Si, Sn, Ti, and Zr are used, and titanium compounds are particularly preferred, with titanocene dichloride, titanium tetrachloride, and the like being preferred. In the method of the present invention, 2,2-
A difluoro-3,4,5-trihydroxycarboxylic acid derivative is obtained as the main product. For example, as an aldehyde, 2.3-0-inpropylidene-D-glyceraldehyde (in the formula [IVl, R'=H, R'=H, R8=
H) or 2.3-0-cyclohexylidene-D-glyceraldehyde (in formula [IV], R', R7=-(CH
2), -1R8=H), useful anti-isomers can be obtained with high selectivity from any aldehyde. (If a small amount of the syn form is produced as a by-product, the pure anti form can be easily obtained by converting it into an appropriate derivative and then recrystallizing it. These compounds are 2,2-difluoro-
It is a useful precursor for 2-deoxypyranose derivatives and 2,2-difluorofuranose derivatives. 2.2-difluoro-2-deoxypyranose derivatives and 2.2-difluoro-2-deoxyfuranose derivatives are important intermediates for various nucleoside derivatives that are attracting attention for their antitumor and antiviral activities.

The amount of carbonyl compound used per equivalent of difluorohaloacetic acid derivative is not particularly limited, but is about 0.
．． 01 to 1 equivalent is suitable.

Particularly preferred is about 0.1 to 0.5 equivalents. Regarding the amount of the metal reactant used, the amount of the zero-valent metal to be used is approximately 1 to 10 equivalents, particularly preferably 1 to 3 equivalents, per equivalent of the difluorohaloacetic acid derivative. The organosilicon compound is suitably used in an amount of about 1 to 10 equivalents, particularly preferably 1 to 15 equivalents, per equivalent of the difluorohaloacetic acid compound. For Lewis acids, it is appropriate to use about 0.01 to 1 equivalent per equivalent of difluorohaloacetic acid derivative,
Particularly preferred is about 0.1 to 0.6 equivalents. Although the reaction can be carried out without a solvent, it is preferable to use a solvent.

Suitable solvents are those that dissolve the raw materials and products and are non-reactive, such as acetonitrile, tetrahydrofuran, diethyl ether, 1,4-dioxane, dimethoxyethane, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, Benzene and the like are used, with acetonitrile or tetrahydrofuran being particularly preferred.

The reaction is preferably carried out at -100°C to 60°C, and usually -40°C to room temperature.

The present invention provides (1) easy reaction, high yield, and high selectivity;
2) Since various α,β-dihydroxyaldehyde derivatives can be used, many 2,2-difluoro-3,4,5-
It is possible to produce trihydroxycarboxylic acid derivatives. (3) It is a very stereospecific reaction, so it is useful as medicines and agrochemicals that often require stereospecificity, and their intermediates. 2.2- It has the characteristics that a difluoro-3,4,5-1-lihydrokylecarboxylic acid derivative can be obtained.

Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples, and in particular α,
As the β-dihydroxyaldehyde derivative, various compounds other than the examples may be used.

Example 1 Methyl (3R,4R)-2,2-difluoro-4,5-〇-isopropylidene-3-triethylsiloxypentanoate In an argon atmosphere, zinc powder (H+7 mg, 2.4 mm)
Methyl difluoroiodoacetate (472 mg, 2.0 m
mol) in acetonitrile (1.5 ml) was slowly added dropwise. After stirring at the same temperature for 10 minutes, triethylsilyl chloride (0.37ml, 1.2.2 mmol) was added, stirred for 5 minutes, and then cooled to -40°C. 2.3
-0-isopropylidene-D-glyceraldehyde (1
30mg, 1. Ommol) of acetonitrile (1,
ml) solution followed by titanocene dichloride (
274 mg, 1.1 mmol) was added. After stirring at -40°C for 1.5 hours, the temperature was gradually raised to room temperature and stirred for 12 hours. The reaction mixture was diluted with ether (10 ml), 2.5% aqueous sodium chloride solution (10 ml) was added, and the mixture was stirred. The precipitate was filtered through Celite, and the filtrate was extracted with ether. The ether extract was washed with brine, dried (magnesium sulfate), and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 100:1) to obtain 330 mg of the desired product (yield 84%, colorless oil). I got it.

IR(CHCIs)cm-': 1775.1765
'H-NMR (CDC1,) δ: 0.62-0.7
0 (6H, m), 0.92-1.00 (9H, m),
1.31 (3H, s), 1.38 (3H, s), 3.8
5 (3H, s), 3.93 (IH, dd, J=5.2.
8.6Hz), 4.04 (LH, ddd, Jl, 5.5
．． 2.8Hz), 4.17-4.27 (2H, m) 1QF-NMR (CDCII, CFCl, standard): 1
13ppm (dd, Jr-p=261Hz, J...
, =7.5Hz), 122ppm (dd, Jr-p"
261Hz, J++-r16.2H2) Example 2 (3R,4R)- and (3S,4.R)-2,2-difluoro-〇-cyclohexylidene-3-triethylsiloxypentanoate dithyl zinc powder under argon atmosphere (1,
57 g, 24 mmol) of acetonitrile (30 ml
) Ethyl bromodifluoroacetate (2,56 ml
．． 20 mmol) was added dropwise at room temperature. After stirring at room temperature for 10 minutes, triethylsilyl chloride (3,69
After dropping ml (1.22 mmol) and stirring for 5 minutes, -
After cooling to 40 °C, 2,3-0-cyclohexylidene-D-glyceraldehyde (1,70 g, 10 mm
ol) in acetonitrile (10 ml) was added, followed by titanocene dichloride (0.25 g, 1.0 ml).
mol) was added. After stirring at -40°C for 2 hours, the temperature was gradually raised to room temperature and stirred for 12 hours. After the same post-processing as before, the 10=1 mixture of anti and sys forms was reduced to 2.9
4 g (yield 72%, colorless oil) was obtained.

'H-NMR (CDC1m) δ: 0.64-0.70
(6H, m), 0, 92-1.00 (9H, m), 1
．． 36 (3H, t, J=7.1Hz), 1.30-
1.60 (IOH, m), 3.90 (IH, dd, J=5.5.8.41 (Z),
4, 01-4.04 (11(, m), 4.19-4.
35(41(,m)”F-NMR(CDC1,,CFC
l, standard): D anti body knee 113 ppm (dd, Jr-r”26
0H2,J,I-r”7.5Hz)-122ppm(d
d, JF-r=260Hz, Jo-r:15.81(z
) sys body knee 110 ppm (dd, Jr-p=26
0H2, Jo-r=7.9H2)-119ppm(dd
, Jr-y=260Hz, JH-F=11.9Hz) Example 7 (3R,4R)- and (3S,4R)-2,2-difluoro-4,5-0-cyclohexylidene-3-trimethyl Ethyl siloxypentanoate In the same manner as above, ethyl bromodifluoroacetate (0,
256m1.2. Ommol), zinc powder (157mg,
2.4 mmol), trimethylsilyl chloride (0
, 279 m1゜2, 2 mmol) in acetonitrile (3
2.3-0-cyclohexylidene-D-glyceraldehyde (170 mg, 1.O
mmol), titanocene dichloride (25 mg, O,
1 mmol) was added at -40°C, and 1.5 mmol was added at -40°C.
After stirring for an hour, the temperature was gradually raised to room temperature and stirred overnight.

After the same post-treatment as before, 178 mg' (49% yield, colorless oil) of a 9=1 mixture of anti and sys forms was obtained.

'H-NMR (CDCl2) δ: 1.33-1
．． 59 (IOH, m), 1, 36 (3H, t, J=
7.3Hz), 3.82 (IH, dd, J: 5.9.
8.4Hz), 4,0'O-4,02(1)1. m)
, 4.21 - 4.33 (4H, m)"F-NMR (
CDC1, CFCl, standard): anti body knee 115
ppm (dd, Jr-r=260Hz, JM-r=9.
9Hz)-120ppm(dd, Jr-p=260Hz
, J++-p=14.9Hz) sys body knee 111pp
m(dd, Jy-r=260Hz, L+-y near, 2Hz) 7121ppm(dd, JF-F"260
H2, JM-r=14.3 Hz) Examples 3 to 6.8 The desired products were synthesized by the same method as in the above example, changing the type of metal reactant and the solvent.

The results are shown in Table 1 below along with Examples 1 and 2.7. In addition, in Table 1, C1)2TIC12 represents titanocene dichloride.

Claims (5)

[Claims] (1) A difluorohaloacetic acid derivative and an α,β-dihydroxyaldehyde derivative represented by the following formula [I] are reacted in the presence of a metal reactant to form an anti-aldehyde derivative represented by the following formula [II]. 2,2-difluoro-3,
2,2-difluoro-3,4,5, characterized in that it is converted into a derivative of 4,5-trihydroxycarboxylic acid.
- A method for producing a trihydroxycarboxylic acid derivative. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] R^1 is a hydrogen atom, a hydrocarbon group, or a hydrocarbon group containing a characteristic group inert to the reaction, R^2 and R^3 are each hydrogen Represents a protecting group for an atom or a hydroxyl group, or one protecting group that jointly protects two hydroxyl groups. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[II] R^1, R^2, R^3 are the same as above. R^4 represents an elementary atom or a protecting group for a hydroxyl group, and R^5 represents an ester residue or a hydrogen atom, respectively. (2) the difluorohaloacetic acid derivative is a bromodifluoroacetic acid derivative or a difluoroiodoacetic acid derivative,
The manufacturing method according to claim 1. (3) The production method according to claim 1, wherein the metal reactant is a combination of a zero-valent metal and an organosilicon compound, or a combination of a zero-valent metal, an organosilicon compound, and a Lewis acid. (4) The manufacturing method according to claim 3, wherein the zero-valent metal is zinc. (5) The production method according to claim 3, wherein the organosilicon compound is a trialkylsilyl halide.