JPS6058538A - Optical analysis reagent including fluorine - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a fluorine-containing optical analysis reagent, particularly a shift reagent for NMR (nuclear magnetic resonance analysis).

NMR shift reagents are widely used to determine the optical purity of organic compounds.

In shift reagents consisting of rank nido chelates such as europium chelate, the β-diketone ligand is an important compound that determines its performance, and those containing a large number of fluorine atoms are particularly effective. However, 1. All of these Schiff 1 reagents have a shifting effect only on reagents that have lone pairs of electrons due to heteroatoms such as oxygen atoms and nitrogen atoms in the molecule.
Therefore, it does not exhibit a shift effect on samples containing unsaturated bonds such as olefins or aromatic unsaturated bonds. Regarding shift reagents for olefins and hydrocarbon substrates having only aromatic substituents, Ln(rod)3C5F7C00Ag by Evans,
and Ln(f od), −Ag (t
f a) has been proposed, but there is only one report regarding the analysis of the optical isomers present in these systems (R, E, 5 iev
ivs et,al,, J,Am,Chem.

Soc, 104.382 388 (1982))
Not reported except for

The object of the present invention is to provide a novel and useful compound that exhibits sufficient optical analysis functions such as a shift effect even for samples with unsaturated bonds, contains a fluorine atom, and has an appropriate steric height. The present invention provides a fluorine optical analysis reagent.

That is, the present invention has the general formula: (+)- or (-)-RH\ (However, R↑ and R'5 are the same or different CF
5 ShiI'J is a valanthanide element. ) A fluoro-β-diketone lanthanide chelate compound represented by the general formula: % formula %) (where R? is an optically active or inactive fluorohydrocarbon group, M is a metal element, and n is an integer of 1 or more. This invention relates to a fluorine-containing optical analysis reagent characterized by comprising a metal salt of a fatty acid represented by:

A compound in which a chiral carbon tree C is present, such as the above-mentioned fluoro-β-diketone, which forms the fluorine-containing optical analysis reagent according to the present invention, is effective for forming a shift reagent consisting of a ranknido chelate such as europium chelate. It is. That is, the fluorine atoms (1) increase the electron-withdrawing property, activate the chelate, and increase the Lewis acidity as a shift reagent, resulting in an excellent shift effect even at low concentrations. 2) Since there are few hydrogen atoms that overlap with the substrate, the shift reagent becomes stable due to steric effects because the structure becomes symmetrical in terms of overlap with the signal of the substrate, and the chiral center (carbon) is
It can also hold l. Note that 3 or more chiral carbons may be present in each of River and R+.

In the above general formula, R [and bacteria are fluoroalkyl groups having 7 or less carbon atoms, such as -CF5, -C2F5°C
It may consist of 3F3, -C1,000F1, etc.

What should be noted in the present invention is that in combination with the rank nido chelate of the flumoro-β-diketone, the general formula:
(將Coo) n M A metal salt (particularly a silver salt) of a fatty acid is used. As described below, this metal salt effectively causes an interaction between the unsaturated compound such as olefin 4 and the rank nido chelate through the metal element, thereby causing the interaction between the rank nido chelate and the olefin. A complex compound is formed between the NMR
This is thought to cause a shift in the spectrum.

The analytical reagent of the present invention comprising the above-mentioned ranknidochelate-1.

In the above general formula of the metal salt, Rj is a fluoroalkyl group having 3 to 8 carbon atoms, for example, C3FT-1C4F1-1CrF11-1C/F+, in consideration of solubility in the solvent.
, - etc. are desirable. In addition, silver atoms are suitable for M, but
In addition, other metal atoms belonging to Groups 1, 2, 1V, 2 or 1 of the periodic table, such as mercury, hafnium,
Elements such as boronium and palladium are applicable,
Preferably, it is a transition metal.

Next, the fluoro-β-
Diketones will be specifically exemplified according to their manufacturing process.

Perfluorocarboxylic acid fluoride, such as perfluoro-2-propoxypropionic acid fluoride (CF5CF2
CF, 0CF-COF) is obtained by hexane flue. This perfluorocarboxylic acid fluoride soil is calculated by the following formula (
Diastereomer mixture 1 is produced by condensation with -)-α-phenylethylamine, which is separated using a column column and the resulting product is hydrolyzed. For example, it has been found that when a perfluoroisopropyl group is used as Rj in this perfluorocarboxylic acid soil, it is possible to optically resolve the compound very well based on the amount of the mixture. Among these, perfluoro-2-isopropoxypropionic acid is preferably obtained via a fluoride compound which was previously synthesized by the applicant according to the following reaction in Japanese Patent Application No. 155440/1982.

115 -CONH-CHPh CH.

On the other hand, it is known that el-toanione, which is obtained by iXI from terL-butyl acetate as shown in the following formula, is a useful reagent for obtaining the corresponding β-diketone from a carboxylic acid chloride.

CH bc, oc (CH u), + i-C+H7Mg
CI! .

↓ Therefore, the present inventor prepared, for example, (+)-perfluoro-2-propoxypropionic acid among the above-mentioned optically resolved perfluorocarboxylic acids by using phosphorus pentachloride to produce its acid chloride; (+) CF5CFeC wood CF.

The desired chiral β-diketone di(perfluoro-2-propoxypropionyl)-methane was synthesized. This diketone can be obtained in good yield (eg 90%).

Cj! MgCH2C0C(CK)>+(+) CF3C
F2CF20CFCOC7! ■CF.

C.F.

cr chicken MgCl ○ Thus obtained (+)-β-diketone di(bel+)-
Rank Nidochelate leads to the shadow. If this is the case, (-)-β-
The same applies to diketone di(perfluoro-2-propoxypropionyl)-methane.

Yu Blasphemy '3 C.F.

8 (Ln: Eu SPr s Yb,, HE, l-1o.

Sm, etc.) In addition, this ranknidochelate-1.1 can be expressed as follows when the above-mentioned perfluoro-2-isopropoxypropionic acid is used.

C-do.

On the other hand, the metal salts used in conjunction with this ranknido chelate, e.g. Synthesize by

C.F.

(+), () CFjCFzCF2-○-CF-Next -COOH+CHnCOOAg -1-→ (+), () CF5CF OtsuCF, -〇-■ Furthermore, the following silver salinities can also be synthesized.

C0OH+Ag to C4F→C+FgCOOAg+HN 059' Next, an example will be described in which the NMR shift reagent consisting of the rank nido chelate 1 obtained above and silver salinity is applied to enantiomeric analysis.

The most noteworthy aspect of the shift reagent of the present invention is the shift effect when a compound with a chiral center, for example, an olefin represented by the following general formula (having an asymmetric carbon at the allylic position) is used as a substrate. .

1 \Song dynasty CHCH=CH.

(However, R1%R1 is an alkyl group having 10 or less carbon atoms, such as a methyl group, an ethyl group, a propyl group, etc.) Specifically, this olefin is CH5Cl-12C
When analyzed with a shift reagent containing equimolar amounts of H2 salt, the first
This is a new and useful discovery that cannot be obtained using the 'HN MR spectrum reagents of olefins as shown in the figure, and makes it possible to determine the optical purity (and thus optical resolution) of chiral olefins, which was previously considered impossible. It is something to do. For this shift effect, the combination of (+) praseodymium chelate and (-) ill salt is effective, and for (-) praseodymium chelate, the combination of (+) silver salt is effective. has been confirmed.

As mentioned above, it is thought that the silver salt is the reason why the shift reagent of the present invention exerts its effect on olefins (substrates).

Therefore, the shift reagent according to the present invention has made it possible for the first time to determine the optical purity of chiral olefins even if no heteroatoms such as O or N are present in the molecule.

In addition, the olefin as a substrate can also be applied to those having a hetero atom other than those mentioned above. in this case,
Although C and 10- are too far apart, since -CH=CH- is adjacent to C, the interaction with the shift reagent increases and analysis by NMR becomes possible. Furthermore, in place of the above-mentioned olefin, a substrate consisting of an alkyne having a 1ζ carbon-carbon triple bond is also effective in shifting the non-equivalent protons of hydrocarbons, such as toluene, which determine optical purity in the same manner as described above. It has been confirmed that there is.

That is, the above-mentioned run length is 1.
(DPPM)5 and CAF as silver salt, COOΔg
When equimolar amounts of and were added to a toluene solution (/8 medium CHCfy), three non-equivalent types of protons (H',

It was found that it was possible to completely separate the components (Ho) in the NMR spectrum.

Next, the present invention will be explained in more detail with reference to examples.
It will be understood that the following embodiments can be modified in various ways without departing from the technical idea of the present invention.

Precipitation ■) Synthesis of optically active perfluoro-2-propoxypropionic acid: 13.28 g (40 mm on) of perfluoro-2-proboxyp I:J pionic acid fluoride was added in a water bath.
(-)-α-phenylethylamine 4.84g (40
m m o 1 ) and triethylamine 4.04 g
(40 m m o I!) in dichloromethane solution (50 m β).

After addition, the mixture was stirred for an additional 30 minutes at room temperature.

The reaction mixture was washed with water and 1N hydrochloric acid, and after drying, the solvent was removed to give an oily diastereomer mixture ((+)
-(-) and (-)-(-)) were obtained.

This mixture was separated using a silica gel column using a hexane-benzene mixed solvent (3:1).

(-)-(-)amide as the first fraction
．． 23g (72%) obtained. This amide is m, p, 5
5.5-56.5°C, [α), -82,0° (cl
, 00, .CgHO. Also, (+) −(
-) 6.06 g of amide as the second fraction (
70%). This is m.

p, 83-83.5°C, (α)';-88,0' (C
1,OO,C,H,).

In their IR spectra, both exhibited characteristic absorptions of NH and C-0 at the 3300 mark and 1700 cm, respectively. 'HNMR (tn CC/J also,
Both showed exactly the same pattern (61.53(Me
), 5.12 (CH), 6.72 (NH)
, 7.27 (in the chemical shift of (-) −
(-) amide is more 91 than (+) −(-) amide.
It turns out that it can appear in the 1Z low magnetic field. Since there is a difference in retention time between the two in gas chromatography, the purity can be determined by FNMR and gas chromatography.

Pure (+)-(-)amide 4.33g (10m
m o (1>) was added to an ethanol-water mixed solvent (40 mA) containing 10% sodium hydroxide, and 16
The mixture was heated to reflux for an hour. The reaction solution was neutralized with hydrochloric acid, and the chemically formed carboxylic acid was extracted with ether. After drying the extract over magnesium sulfate, the ether was removed and the residue was distilled under reduced pressure to obtain 2.28 g (69%) of (+)-perfluoro-2-propoxypropionic acid. (α, +2
6.50° (neat, jl = 1)).

Similarly, from (-)-(-)amide, 2.38 g of (-)-perfluoro-2-propoxypropionic acid (
72%) was obtained (α. -26,30° (neat, β
=1)).

The physical property values and IR-NMR spectra of both are shown below.

b, r,: 93-b I R (film): 3200 (OH), 178
0 (C=O) cmlHNMR (CDC7!,): δ
10.3ppm”F NMR (neat): δ2
．． 7 (IF), 5.43 <3F), 6.3
(3F), 10.0 (IF), 53.0 (2F)
, 54.8 (IF) ppm (external standard CF.

CO□H) 2) Synthesis of (+)-perfluoro-2-propoxypropionic acid chloride: (+)-perfluoro-2-propoxypropionic acid 3
．． 30 g (2 phosphorus pentachloride in a 10 mm rice bath)
．． 50 g (12 mm off) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 10 minutes and carefully distilled to obtain 3.24 g (93%) of acid chloride. This bp73-74℃, α, +8.66° (ne
at, jl = 1).

3) Synthesis of (+)-di(perfluoro-2-propoxypropionyl)methane: Isoprobylmagnesium chloride (40mmol
n) was synthesized in diethyl ether (20 ml!). To this was added 4.64 g of tert-butyl acetate (40
The solution was added dropwise at room temperature. The reaction was exothermic and propane gas was rapidly evolved. The rate of addition was adjusted so that the ether self-refluxed. After the dripping is finished,
Sarani 1 Time P1. After W, 6.54 g of (+)-perfluoro-2-propoxypropionic acid chloride (
18 mmol was added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 15 minutes and then quenched with dilute hydrochloric acid. After separating the organic layer, it was dried with magnesium sulfate. After distilling off the ether and excess reagent, a small amount of p-1-luenesulfonic acid was added and the mixture was heated at 120° C. for 15 minutes.

The residue was distilled to obtain the desired product. Physical properties of this product,
The spectrum was as follows.

Yield: 5.20g (90%) bp: 94-96℃/110mmHg [α), : +34.88° (neat, jl
= 1) IR (film): 1600cm (C=
O) 1HNM R(CC4): 13.67.5.9
7ppm”F NMR (CC6+): δ1.65
(IF), 4.00 (.

3F), 4.77 (3F), 6.55 (IF)
, 51.73 (2F) , 57.50 (L F)
ppm (external standard CF.

C0zH) 4)(-)-1-Lis[di(perfluoro-2-propoxypropionyl)metathi 1~]praseodymium (Il
Synthesis of l): praseodymium nitrate hexahydrate (566 mg, 1.3 m
The solution was dissolved in methanol (1mj2). 6N sodium hydroxide 50% methanol solution (0.5rn I
A solution of (-)-di(perfluoro-2-propoxypropionyl)methane (2.40 g, 3.9 mmol) was added to the previously prepared praseodymium nitrate solution and stirred at room temperature for 2 hours. Then, distilled water (5 ml)
) was added, and the separated oil was extracted with methylene chloride.

The extract was washed with a large amount of distilled water and treated with MgSO.

It was dried. After completely distilling off methylene chloride under reduced pressure, it was placed in a desiccator containing phosphorus pentoxide under reduced pressure every 2 days.
Dry. We obtained pure praseodymium chelate. (
Yield 1.91 g (72%)).

The analytical data for this chelate were as follows.

(α), = +74.20° (C, 0,29, CF
2ctlCFIC62) T R (film): 1630cm (C=O)1
530cm' (C=C) 'HNMR(CF2O(! CF CIle> :δ1
．． 67ppm (broad) 1'lFNMR (): δ5,83 (6F), 6.17 (2F), 53.67 (2F
), 60.00 (IF) ppm (external standard CF
, CO2H) 5) Synthesis of silver salt of (+)-perfluoro-bionic acid: (+)-perfluoro-ionic acid (1.651!, 5 mrno(1) and silver acetate (1.008, 5 mmo6) The mixture was added to diethyl ether (10 m R ). It was stirred for 4 hours with the light blocked. Then, 200 mβ of diethyl ether was added to completely dissolve the product. After filtering to remove insoluble matter, diethyl ether was added. and by-product acetic acid were distilled off under reduced pressure.

It was dried for 2 days under reduced pressure in a desiccator containing phosphorus pentoxide. Thus, almost pure (→−)-perfluoro-
Silver 2-propoxypropionate was obtained (yield: 2.12 g)
(97%)).

"FNMR (acetone): 62.5 (IF), 4, 0
(3F), 4.9 (3F), 6.5 (IF), 4
6.7 (I F), 51.7 (2 F) ppm
(External standard C F5 C OzH ) 6) 'HNMR analysis of olefin Next, (-)-1-lis[di(perfluoro-2-propoxypropionyl)methanate] praseodymium (III) obtained above and (+) - Varian E consisting of silver perfluoro-2-propoxypropionate
Measurements were performed using M390 90MIIzNMR. α
-Methylhexene (sample) is a liquid and is 10m! was measured and weighed. The solvent used was 0.3 ml of chloroform.

The above analytical reagent contains praseodymium chelate in 1.1.2
Equimolar amounts of -trichlorotrifluoroethane dissolved at 20 wt % and silver salt (crystals) were gradually added to the sample solution, and changes in the spectrum were observed. The results were as shown in Figure 2. In this iHNMR analysis, the silver salt obtained in 5) above was used as it was, but 10 m
Recrystallization of Il from carbon tetrachloride (-10°C, 1 day)
It was also possible to make it from fR.

In place of α-methylhexene in Example 1, the following heteroatom (oxygen atom)-containing olefin was used.

CH.

This olefin exhibited a 'HN MR spectrum as shown in FIG. 4 (r/, 3=O). However, using this olefin as a substrate, the following praseodymium chelate-1.
As a result of adding a reagent consisting of silver salt and silver salt, the HNMR spectrum became as shown in FIG. 5, and a sufficient chemical shift occurred (r/, -0,064).

F3 Testing 1 Weigh out 10 ml of toluene as a substrate (8 medium is chloroborm), add praseodymium chloride-1 from Example 1 to 1.
When equimolar amounts of 1.2-trifluoroethane dissolved in 20 wt % and a silver salt consisting of g of C+FM COOA were added to the sample solution and the spectrum was observed, it was found that the third
An NMR spectrum as shown in the figure was obtained, and the non-equivalent pro-1-one of toluene was completely separated.

[Brief explanation of drawings]

The drawings are for explaining the present invention, and FIG. 1 is an NMR spectrum diagram of a chiral olefin, FIG. 2 is an NMR spectrum diagram of a chiral olefin when using the shift reagent according to the present invention, and FIG. The figure shows an NMR spectrum of toluene when the shift reagent according to the present invention is used. Figure 4 is an NMR spectrum diagram of a chiral heteroatom-containing olefin. Figure 5 shows a chiral heteroatom-containing olefin when the shift reagent according to the present invention is used. It is an NMR spectrum diagram of an atom-containing olefin. Agent Patent attorney Hiroshi Aisaka (and 1 other person) 11th Yokoto 2 torso @enemy: Shift is also an alternative: (+)-70 "Fuseon Mukilate + (-)-Kansashi Salt"

Claims (1)

[Claims] ■, General formula: (+)- or (=)-\ (+)- or (-)-R1 (However, R1 and R1 are the same or different fluorohydrocarbon groups, or a fluoro-β-diketone lanthanide chelate compound represented by the following formula: % formula %) (wherein R1 is a fluorohydrocarbon group, M is a metal element, and n is an integer of 1 or more). . 2. The first claim, wherein RP is a perfluoroalkyl group represented by the general formula: % formula %), which has an ether bond in the chain and has a chiral center (C). Fluorine-containing optical analysis reagents described in section. 3. In any one of claims 1 or 2, where M is a metal atom belonging to Group 1, Group Ⅰ, Group 1V, Group Vl, or Group 1 of the periodic table. The described fluorine-containing optical analysis reagent.