JPH03251551A - Fluorine-containing polyfunctional ketone compound and method for substitution with fluorine in production thereof - Google Patents

Abstract

NEW MATERIAL:A fluorine-containing polyfunctional ketone compound expressed by formula I (R<1> and R<2> are H, aromatic group or 1-10C alkyl; X is sulfenyl, sulfinyl, sulfonyl, NO2 or halogen). EXAMPLE:Ethyl 2-fluoro-2-nitro-3-oxobutyrate. USE:An intermediate useful for, e.g. synthesis and asymmetric synthesis of optical isomers derived from polyfunctional carbon structures and synthesis, etc., of organic compounds as fluorine-containing synthons. PREPARATION:A compound expressed by formula 1 is nitrated or sulfenylated and then fluorinated to provide a compound expressed by formula 4 or 5 in formula I. Furthermore, if perchloryl fluoride is used as a fluorinating agent in the process, fluorination can be nearly quantitatively carried out in an ultrahigh yield at times. The compound expressed by formula 1 is fluorinated under conditions of, e.g. F2/N2 and then sulfonylated or halogenated to afford a compound expressed by formula 7 or 8 in formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel fluorine-containing compound, particularly a fluorine-containing multifunctional ketone compound, and a method for fluorine substitution during its production.

[Problem to be solved by the invention]

The study of compounds containing a carbon atom to which three or more different functional groups, including fluorine atoms, are directly attached is of great interest in the field of organic synthesis. These compounds can be used, for example, in the synthesis of optical isomers derived from multifunctional carbon structures;
It is useful for asymmetric synthesis and the synthesis of organic fluorine compounds as fluorine-containing synthons.

An object of the present invention is to provide a novel fluorine-containing compound having multifunctional carbon, and to provide a production method capable of increasing its yield.

[Means and effects for solving the problems] The fluorine-containing multifunctional ketone compound of the present invention has the general formula 0 11 F-C-C-R'C0OR" (wherein R1 and R2 are hydrogen or aromatic X represents a sulfenyl group, a sulfinyl group, a sulfonyl group, a nitro group, or a halogen group.

The compounds of the present invention have carbonyl groups, sulfenyl groups, sulfinyl groups, sulfonyl groups, nitro groups, and halogen functional groups, such as synthesis of optical isomers derived from multifunctional carbon structures, asymmetric synthesis It is useful for applications such as the synthesis of organic fluorine compounds as fluorine-containing synthons.

In addition, the ketone group of the compound of the present invention is reduced to diastereomers of secondary alcohols, and the mechanistic study of asymmetric induction derived from this, asymmetric synthesis, synthesis of organic fluorine compounds as fluorine-containing synthons, etc. Useful for applications such as Furthermore, when X is a nitro group, the nitro group is reduced and then protected to form an amino group or an amide group;
A fluorine-containing amino acid derivative can be produced from the compound of the present invention by hydrolyzing the ester group to form a carbonyl group.

In the above formula, the alkyl group for R1 and R1 has 1 to 10 carbon atoms, such as methyl, ethyl, propyl, etc.
In addition to alkyl groups having straight or side chains, W such as halogen or hydroxyl group is added to the carbon of these alkyl groups.
It may have a substituent. Furthermore, suitable aromatic groups include phenyl, chlorophenyl, tolyl, xylyl, naphthyl, and the like.

Examples of the substituent for χ include a sulfenyl group, a sulfinyl group, a sulfonyl group, a nitro group, and halogens such as fluorine, chlorine, bromine, and iodine.

The compounds of the present invention are, for example, R'-Co-CHl-GOO
It can be advantageously obtained by nitrating or sulfenylating a difunctional compound represented by R'' and then fluorinating it. For example, by nitrating this difunctional compound,
Next, to explain the case where this is obtained by fluorination, the above bifunctional compound is nitrated by a conventional method,
This is then fluorinated under, for example, FCIOs/NaH conditions to obtain the desired compound as shown in the following formula.

(Left below) Ox 02 (3) Ox 02 (3)
I 03 /NaH) Ph C-C0OR" By the way, as a result of intensive study, the present inventors have found that when perchloryl fluoride is used as a fluorinating agent in the reaction of replacing hydrogen atoms on this asymmetric carbon with fluorine atoms. , we found that fluorination can be achieved in very high yields, sometimes almost quantitatively.

For example, sodium hydride is added to a non-aqueous solvent such as anhydrous tetrahydrofuran, then the substance to be fluorinated is added and stirred for a while, and then fluorinated perchloryl gas is introduced to perform fluorination.

The insoluble matter produced by this fluorination is filtered and the filtrate is concentrated to obtain the desired fluorinated product.

The fluorinated perchloryl gas used in this case can be obtained, for example, by chemically reacting fluorosulfonic acid and potassium perchlorate by mixing and heating the mixture. Of course, any fluorinated perchloryl gas may be used for this fluorination in the present invention.

Moreover, the amount of fluorinated perchloryl gas in this case is preferably 0.5 to 30 times equivalent, most preferably 1.0 to 15 times equivalent, relative to the substance to be fluorinated.

In addition, as another method for obtaining the target compound, for example, after fluorinating a bifunctional compound represented by R'-CO-CH, -COOR, sulfonylation or halogenation may be performed. That is, first, this bifunctional compound is fluorinated under, for example, h/To conditions, and then sulfonylated or halogenated by a conventional method to obtain the desired compound as shown in the following formula.

(1) (6) (8) In this method, various reactions other than sulfonylation and halogenation are possible in the second stage reaction after fluorination, and other functional groups can be introduced. The present invention does not impose any restrictions on the type of functional group.

In the present invention, the above reaction is preferably carried out in an organic solvent. The compound of the present invention can be isolated and purified by known means such as extraction, concentration, distillation, recrystallization, gas chromatography, and column chromatography. I can do it.

〔Effect of the invention〕

The compound according to claim 1 is extremely useful for, for example, the synthesis of optical isomers derived from a multifunctional carbon structure, asymmetric synthesis, and the synthesis of organic fluorine compounds as fluorine-containing synthons.

According to the method according to claim 2, a very high yield is obtained,
Sometimes it has the effect of being able to fluorinate almost quantitatively.

〔Example] Next, embodiments of the present invention will be described in detail.

Synthesis of ethyl 2-nitro-3-oxobutyrate (compound 2. R'=Me, R''=Et) on charcoal. Nitration with nitroacetic acid) [Journal
of Organic Chemistry (Journal
of Organic Chemistry) 1975
Compound 2 was synthesized in a yield of 86χ according to the following procedure.

Disaster kML3-oxy2-(phenylthio)#1 ethyl acid (compound 3, R'=Me, R2=Et) (7
) Anhydrous tetrahydrofuran (100 ml
l) and sodium hydride (720mg, 18mm+ol
) and replace the inside of the container with argon gas. Ethyl 3-oxobutyrate (compound 1, R'-Me,
A tetrahydrofuran solution (10 ml) of R''=Et) (1.95 g, 15 m+wol) was added dropwise using a syringe, and the excess benzenesulfenyl chloride was added through the dropping funnel with stirring at room temperature for 20 minutes. Add until it can be confirmed by thin layer chromatography. Distill off the solvent, add water (5 axis l) and boil at 1o
After making the reaction solution acidic with χ hydrochloric acid, it is extracted with ether (20 ml x 3), the ether layer is dried over anhydrous magnesium sulfate, and the solvent is distilled off to obtain a yellow oil. This was carried out using silica gel column chromatography (
Solvent: hexane/chloroform = 2/1) to obtain the target product 3 as a yellow transparent oil (2.88 g, 81
χ).

60 MHz') l-NMR spectrum (CDCl3
．． TMS) δppm1.17(3)1. t, J=
7 Hz, CLCL), 2.33 (3H,s, C
0CHs), 4.16 (2H9q, J=7Hz, C
Hz), 7.0 to 7.4 (58, L Ph).

IR spectrum J neat, I/saw) c
m-' 3000 (CH) + 1720, 1630 (C
o), 1585 (C-C).

Mass spectrum (m/e) 238 (M'), 19
3 (M'-0ut).

109 (SPh).

1 example of "-2-fluoro-2-nitro-3-oxoacetic acid, ethyl (compound 4, R'=Me, R"=Et
Anhydrous tetrahydrofuran (30 ml) was added to a 50-1 round-bottomed two-headed colben equipped with a synthetic balloon and a rubber septum.
and sodium hydride (96mg2.4+n+ol)
, replace the inside of the container with argon gas, and cool it in a water bath. Among these, ethyl 2-nitro-3-oxobutyrate (
Compound 2. R'=Me.

R"=Et) (420 mg, 2.4 vsol) was added dropwise using a syringe, the water bath was removed, and the mixture was stirred at room temperature for 2 hours. Into this solution, fluorosulfonic acid (
Fluorinated perchloryl gas generated by mixing and heating 18 ml) and potassium perchlorate (3 g) was introduced under a water bath for 2 hours. Insoluble matter is filtered and the filtrate is concentrated to obtain the desired fluorinated compound 4 as a pale yellow oil (463B, 100χ).

270 MHz 'H-NMR spectrum (CDCIs
, TMS) δppm1.38 (38,t, J=7.
1 Hz, CHzCHs).

2.45 (3H, d, J=2.7 Hz, C0CH
5) 14.45 (2H1q, J=7.11(z, C
Hz).

254 MHz 'Lee NMR spectrum (CDC13
, CFCl2) δppm 128.5 (br s).

TI? Spectrum (neat, l'5ax) C1l
-' 2950 (CI).

1760, 1710 (Co), 1585 (N(h).

Mass spectrum (s/e) 194 (M”+ 1>,
178 (M”-cHs), 150 (M”-cocos
).

92-Fluoro-3-oxyethyl 2-(phenylthio)acetate (Compound 5, R'=Me.

Anhydrous tetrahydrofuran (25 ml) was added to a 50 ml round-bottomed double-headed colben equipped with a synthetic balloon of R''=Et and a rubber septum.
and sodium hydride (38+sg.

0.95 vwol), the inside of the container was replaced with argon gas, and the reaction solution was stirred until it became homogeneous.

In this solution, ethyl 3-oxo-2-(phenylthio)acetate (compound 3. R'=Me, R"=Et) (
153mg.

0.64 mmol) in tetrahydrofuran solution (1 ml
) was added dropwise using a syringe and stirred at room temperature for 2 hours. Fluorinated perchloryl gas is introduced into this reaction solution in the same manner as in Example 3, and the same post-treatment is performed to obtain a yellow oil. This is purified by silica gel column chromatography (solvent: hexane/ether = 4/1) to obtain the desired fluorinated compound 5 as a colorless transparent oil (14
2mg, 871).

270 MHz 'H-NMR spectrum < CDCl1
．． TMS) δpp+m1.21(31(,t, J=
7.1 Hz, CLCI(z)2.2H31(,d,
J=3.4 fez, C0C)Is)4.20(2
Lq, J=7.1 Hz, CL), 7.32~
7.61 (5H, m, Ph).

254 MHz “F-NMR spectrum (CDCIf
f, TMS) δppm135.3 (q, J=3.4
Hz).

IR spectrum (neat, v saw) cm-
' 3000 (CI+) 1760, 1740 (Co)
, 1580 (Ph).

Mass spectrum (m/e) 256 (M”L 109 (
SPh).

43 (COCH3).

! Synthesis of ethyl 2-fluoro-3-oxy-3-phenylpropionate (Compound 6. R'=PhR1=Et) Ethyl 3-oxo-3-phenylpropionate (Compound 1. R'=Ph, R"-Et) fluorinated using 10×7° elementary gas (nitrogen gas) [Journal of Organic Chemistry (Journal of Organic Chemistry)]
Compound 6 was synthesized in a yield of 79χ.

a 2-(benzenesulfonyl)-2-fluoro-3
-Ethyl oxobutyrate (compound 7゜R'=Me, R"=
Synthesis of Et) Anhydrous tetrahydrofuran (20m+) and sodium hydride (66-g, 1.7-o1) were placed in a 501 double-headed round-bottomed colben equipped with a balloon and a rubber septum, and the inside of the container was flushed with argon gas. Replace. At room temperature, ethyl 2-fluoro-3-oxobutyrate (compound 6. R'=M
A solution (21) of tetrahydrofuran (e, R”=Et) (163 mg, 1.1 vwol) was added dropwise using a syringe and stirred for 30 minutes. Into this, benzenesulfonyl chloride (0.14ml 1.1.1+wmol) was added using a syringe. The mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure, water (10 ml) was added, and the mixture was extracted with ether (5 ml).
ml×3), and after drying the extract with anhydrous magnesium sulfate,
The solvent is distilled off to obtain an oily mixture. This is purified by silica gel column chromatography (solvent: benzene) to obtain the target compound 7 as a colorless transparent oil (
263 mg, 83χ).

270 MHz 'H-NMR spectrum (CDCIs
, TMS) δppm1.31(3)1. t, J,
7.1 Hz, CH2CH2).

2.44(3)1. d, J=4.6 Hz, C0
CHs).

4.24(2H,q, ,b7.I Hz, (Jlz
), 7.55~B, 0O (5H, s, Ph).

254 MHz “F-NMR spectrum (CDCIs
, CFCl2) δpp+s −132,9(q,
J = 4.6 Hz).

IR spectrum (neat, v smJcIl-'
2950 (CI) 1760, 1735 (Co),
1385.1180 (Soa).

Mass spectrum (m/e) 289 (M”+1),
216 (M”11-COOEt), 141 (So□P
h).

ffl engineering 2-bromo-2-fluoro-3-oxygen 3
Synthesis of ethyl phenylpropionate (compound 8, p'gph, R''=Et) 2-Fluoro-3 -Ethyl oxo-3-phenylpropionate (compound 6.
R'=Ph, R''=gt) (92611g, 4.4
++nol) and carbon tetrachloride (15s+1),
Flow nitrogen gas into the container. Using a syringe, use bromine (
0.23ml (1.4.4+5sol) was added dropwise and stirred at room temperature for 1 hour. Add water (20 ml), separate the organic layer, and extract the aqueous layer with methylene chloride (20 ml x 2).
. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain a yellow oil. This was purified by silica gel column chromatography (solvent: benzene),
Obtain target product 8 as a colorless and transparent oil (1.205g, 95
χ).

270 MHz 'H-NMR spectrum (CDCh,
TMS) δppm1.28 (3H,t, J=7.1
Hz, CHs), 4.37 (2H, q, J=7
．． 1 Hz, CHz), 7.45~8°10 (5H
, m, Ph).

254 MHz “F-NMR spectrum (CDCh,
CFCIs)δl1l)II 118.9
(s).

IR spectrum (neat, I/@AX) CM-
' 3000 (CB) 11770, 1715 (GO),
1600 (Ph).

Mass spectrum (m/e) 289,291 (M”+
1).

243.245 (M”-0Et), 215,217 (M
”-COOEt), 105 (PhCO).

Claims (1)

[Claims] 1. General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R^1 and R^2 represent hydrogen, an aromatic group, or an alkyl group having 1 to 10 carbon atoms, and is a fluorine-containing multifunctional ketone compound represented by a sulfenyl group, a sulfinyl group, a sulfonyl group, a nitro group, or a halogen. 2. In the production of the above-mentioned organic fluorine compound, as a method for introducing fluorine, perchloryl fluoride is used as a fluorinating agent,
A method for fluorine substitution during the production of a fluorine-containing multifunctional ketone compound, which comprises substituting hydrogen on an asymmetric carbon with fluorine.