JPH03112947A - Novel beta-hydroxy-beta,beta-bis(trifluoromethyl)amine derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> and R<2> are H, alkyl, aryl or aralkyl which may contain unsaturated bond, ether bond, halogen and OH) or formula II (R<2> is H, alkyl, aryl or aralkyl; n is 3 or 4). EXAMPLE:1,1,1-Trifuloro-2-trifluoromethyl-3((S)-1-phenylethyl)aminohex ane-2,6- diol-6-tetrahydropyranyl ether. USE:Intermediate for pharmaceuticals, agricultural chemicals or catalyst for organic syntheses. PREPARATION:The compound of formula I can be produced by reacting a compound of formula III (R<3> is group defined by R<1>) with a compound of formula R<2>NH2 in the presence of an acid acceptor and a phase transfer catalyst. The compound of formula II is produced by converting a part of R<1> of the compound of formula III to R<2>NH2 and subjecting to intramolecular reaction in the presence of an acid acceptor and a phase-transfer catalyst.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to β-hydroxy-β,β-bis(trifluoromethyl)amine derivatives and their Regarding the manufacturing method.

[Prior Art and Problems to Be Solved] Conventionally, many fluorine-containing organic compounds have unique properties and have been used for various purposes such as medicines, agricultural chemicals, resins, and functional materials.

However, fluorine-containing amino alcohols, especially amino alcohols having a tertiary alcohol whose acidity is increased by a perfluoroalkyl group, have not been known.

[Means for Solving the Problems] Under these circumstances, the present inventors have developed β-hydroxy-R9β- which can be easily obtained by reacting hexafluoroacetone with the carbanion generated by reacting sulfone with a strong base. The present invention was achieved by discovering that a novel fluorine-containing amino alcohol can be produced by reacting a bis(trifluoromethyl)sulfone derivative with an amine under various conditions.

That is, the present invention relates to the general formula (wherein R8 and R2 are each independently hydrogen, an alkyl group, an aryl group, or an aralkyl group, and may contain an unsaturated bond, an ether bond, a halogen atom, or a hydroxyl group) , ) β-hydroxy-β, β-
bis(trifluoromethyl)amine derivatives, and the general formula (where RI R3 is each independently hydrogen, an alkyl group, an aralkyl group, an unsaturated bond, a -U-thyl bond halogen β-hydroxy-β, which may contain an atom or a hydroxyl group, is represented by 〉
, β-bis(trifluoromethyl)sulfone derivative,
In the presence of an acid acceptor and a phase transfer catalyst, -S formula % formula % ([[) (wherein R2 is hydrogen, an alkyl group, an aryl group, an aralkyl group, an unsaturated bond, an ether bond, a halogen A method for producing the novel β-hydroxy-β,β-bis(trifluoromethyl)amine derivative described above, which is characterized by reacting the derivative with an amine derivative represented by ), which may contain an atom or a hydroxyl group, and β-hydroxy-β, β-bis(trifluoromethyl)amine derivative represented by the general formula (wherein R2 represents hydrogen, an alkyl group, an aryl group, or an aralkyl group, and n = 3.4), and - General formula (wherein RI R3 is each independently hydrogen, an alkyl group, an aryl group, an aralkyl group,
β-hydroxy-β, which is represented by unsaturated bond, ether bond), may contain a rogen atom, or a hydroxyl group;
The substituent R1 of the β bis(trifluoromethyl)sulfone derivative is II'' Nil group (wherein R2 is
After converting into hydrogen or an alkyl group, an aryl group, an aralkyl group, which may contain an unsaturated bond, an ether bond, a rogen atom, or a hydroxyl group, in the presence of an acid acceptor and a phase transfer catalyst, The present invention provides a method for producing the above-mentioned novel β-hydroxy-β,β-bis(trifluoromethyl)amine derivative, which is characterized by carrying out an intramolecular reaction.

The sulfone used as a raw material in the present invention is an alkylaryl sulfone, etc., and for example, by reacting an alkyl chloride with sodium P-)luenesulfinate,
Alternatively, it is obtained by reacting benzenethiol with alkyl chloride in the presence of a base and then oxidizing it. The alkyl chloride may contain an aryl group, an ether bond, etc. By reacting with hexafluoroacetone to generate a carbanion at the α-position, β-hydroxy-β, β
-bis(trifluoromethyl)sulfone derivatives can be obtained.

Examples of the strong base include butyllithium, lithium diisopropylamide, etc., and the reaction is preferably carried out at -20°C or lower using an ether such as tetrahydrofuran or a hydrocarbon medium such as hexane as the solvent.

β-hydroxy-β thus obtained.

The β-hydroxy-β,β-bis(
trifluoromethyl)amine derivatives can be obtained.

As the phase transfer catalyst, phosphonium salts and ammonium salts are preferred, such as amyltriphenylphosphonium bromide, butyltriphenylphosphonium bromide,
Examples include tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, benzyltriethylammonium chloride, etc. As acid acceptors, hydroxides such as sodium hydroxide, potassium hydroxide, etc. Alkali, alkali carbonates such as sodium carbonate and potassium carbonate, alkali hydrogen carbonates such as sodium bicarbonate and potassium hydrogen carbonate, etc. are used, and as the reaction medium, no solvent or an aromatic solvent such as toluene is used, and the temperature is 80 to 150°C.
The reaction can be carried out at a temperature of

Under the above conditions, the raw material β-hydroxy-β,
If a β-bis(trifluoromethyl)sulfone compound is reacted with an amine, a chain-like β-hydroxy-β,β-bis(trifluoromethyl)amine derivative can be obtained, and the substituents other than the sulfonyl group can be obtained using the above raw materials. After introducing an amino group into a part of the molecule, an intramolecular reaction occurs when a phase transfer catalyst and an acid acceptor are used to generate cyclic amine derivatives such as pyrrolidine and piperidine that have a bistrifluoromethylhydroxymethyl group. . In the introduction of the above-mentioned amino group, when the above-mentioned substituent has a hydroxyl group or an ether bond, the substitution reaction with the amine proceeds relatively easily.

The produced compounds have bis(trifluoromethyl) groups, so they have properties different from normal compounds, and various compounds using these compounds as intermediates are expected to have useful uses such as medicines and agricultural chemicals. In addition, optically active compounds are useful as catalyst intermediates in organic synthesis.

[Examples] Hereinafter, the present invention will be specifically explained with reference to Examples, but the present invention is not limited to these Examples.

Example 1 35.8 g of sodium iodide, 20.6 g of sodium p-toluenesulfinate tetrahydrate and 17.0 g of 4-chlorobutylbenzoate were dissolved in 50 ml of DMF and reacted at 70-80°C with stirring for 16 hours. After the 0 reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ether. The organic layer was washed with an aqueous sodium thiosulfate solution and then with water, washed with i*m, and diluted with 2N KOH (10
After refluxing and hydrolyzing for 1.5 hours in 0mg) and methanol (100ml), the mixture was concentrated under reduced pressure. After adding water to the residue, it was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 4-P to toluenesulfonyl-1-butanol 1.
7.2 g was obtained as a colorless oil. The yield was 94.6%.

Example 2 To a solution of 4.44 g of the product obtained in Example 1 in methylene chloride was added the catalyst para-toluenesulfonic acid and dihydrobilane 1.
．． 79 g was added, stirred for 2 hours under water cooling, and stirred for 2 hours under water cooling to obtain pyranyl ether. Separated and purified by silica gel column chromatography, 4.75 g of T
An HF form was obtained.

(Yield: 78.2%) 50mj! TH
A hexane solution of butyllithium (1.6M, 18.1a) was dissolved in F and cooled in a dry ice-acetone bath.
After stirring at the same temperature for 1 hour, hexafluoroacetone gas was introduced and the reaction mixture was allowed to react for another 1 hour. The reaction solution was poured into water, and after extraction with ether, the organic layer was dried over anhydrous magnesium sulfate. After concentration, silica gel column chromatography treatment yielded 1,1.1-)lifluoro-2-trifluoromethyl-3-(ρ-toluenesulfonyl)hexane-2°6-diol-6-tetrahydrobilanyl ether 6. .88g (Yield: 95.2%
) was obtained as a colorless oil.

'Hnmr (CDC1a, TMS) δppm 7.6
1 (4H, ABq, J = 8.7) 1z) 4.48 (IH
, brs), 5.8 (IH, brs), 3.9-2.
9(5)1. m) 2.47 (3H, s), 1.9-1.
2 (108, m) Example 3 10 mj of 948 g of THP obtained in Example 2! ) (S)-[-]-]α-phenethylamine 0.
5 ml 20% Na0)1 aqueous solution 1.2 ml, tetrabutylammonium fluoride 0.5 mj! The reaction mixture was heated and refluxed for 5 hours to make it acidic with acetic acid, then made basic with aqueous ammonia, and extracted with ether. The extracted organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and treated with silica gel column chromatography (hexane-ethyl acetate-40:1).
1:1 diastereomer of 1-trifluoro-2-trifluoromethyl-3<(S)=1-phenylethyl)aminohexane-2,6-diol-6-tetrahydrobilanyl ether 618 mg was obtained as a colorless oil. After removing the THP protecting group, silica gel column chromatography was performed again (hexane-ethyl acetate-20:1) to obtain 107 mg of a low polar substance and 243 mg of a high polar substance.

Low polarity substance: 'Hnmr (CDC13, TMS) δp
p■7.36 (5H.

), 6.92 (IN, brs), 3.95<LH
, q, J=6.4Hz) 3.64(28°t, J=
6.0Hz), 3.11(18,d, J=8.8Hz
), 2.01 (LH, t, J=12.3Hz) 1.8-1.5 (4H, m), 1.4 (38, d, J=
6.5 Hz>Example 4 A catalytic amount of para-toluenesulfonic acid hydrate was added to a 20 ml methanol solution of 339 g of T)IPPI obtained in Example 2, and the mixture was stirred at room temperature for 30 minutes. After methanol was distilled off under reduced pressure, water was added, and after extraction with ether, the extracted organic layer was dried over anhydrous magnesium sulfate, and after further condensation, 2,
6-hexanediol 880 mg (yield: 76.
4%).

'Hnmr (CDCl2, T to S) δppm
7.64 (4H, ABq, J=8.3flz).

6.78 (18, brs), 3.61 (IH, d of
d, J=4.6Hz>.

3.44 (2H, s), 2.50 (3H, s), 2.1
7 (2H, m) 1.43 (LL-), 1.11 (LH,
m)”Fnsr (CDC13, BTF) δppm −
7,67(q, J=10Hz>11.23(Q,J=1
0Hz) Example 5 Pyridinium chlorochromate (P
CC) 530 mg of methylene chloride (30 m ti )
A methylene chloride solution of 413 mg of the diol obtained in Example 4 was added, and the mixture was stirred at room temperature for 1.5 hours. 50 ml of ether was added and stirred for 5 minutes, and anhydrous magnesium sulfate was added for 10 minutes. Stir for a minute. Filtration through silica gel and concentration under reduced pressure gave a 3:2 equilibrium mixture of aldehyde-lactol as a colorless viscous oil.

After making this into an ether solution, 2 g of anhydrous magnesium sulfate, 302.5 tag of (S)-(-)-α-phenethylamine and 7 ml of ether were added under water cooling under an argon atmosphere, and after stirring for 1 hour, the solid matter was filtered. Separated. Further, the filtrate was added dropwise under an argon atmosphere to an ether suspension of 93 mg of lithium aluminum hydride at -78°C, stirred for 1 hour, and then stirred for 30 minutes at 0°C. Ethyl acetate and aqueous ammonia were added to the reaction solution. After that, it was extracted with ether and dried over anhydrous magnesium sulfate.

The residue concentrated under reduced pressure was treated with silica gel column chromatography to obtain 1,1.1-trifluoro2-trifluoromethyl-3-p-)luenesulfonylhexane-6.
282 mg of -((S)-1-phenylethyl)amino-6-hexanol was obtained. (Yield: 54%) 'Hnmr (CDCIs, TMS) δppm 7.3
5 (5H, a), 5.50 (2tl.

brs), 3.81 (2H, m), 2.58 (3H, s
), 2.35 (4H, Otori), 1.45 (3H, d, J=
7.5Hz), 1.4-0.8<28. m) Example 6 Aminohexanol of the product obtained in Example 5 178 m
0.3 ml of IM THF solution of tetrabutylammonium fluoride, 25% NaO in 4 ml of toluene solution of
After adding 1 ml of H aqueous solution and heating under reflux for 5 hours, the mixture was made acidic with acetic acid, then returned to basicity with aqueous ammonia, and extracted with ether. After extraction, it was dried over anhydrous magnesium sulfate, subjected to ifimmL under reduced pressure, and subjected to silica gel column chromatography (hexane-ethyl acetate = lO:1) to give 1-((S)-1-phenylethyl)-2-(hexafluoro- 98.21 g (yield: 80%) of 2-hydroxy-2-propyl)pyrrolidine was obtained as a colorless oil.

'Hnmr (CDCl2, TMS) δppm
7.41-7.25 (5H, m).

4.16 (0.5H, q, J=6.8Hz), 3.6
8(0,51(,d,J=8.8Hz).

3.37 (0,5H, d, J = 7.8Hz) Example 7 A THF solution of 3.17 g of an aldehyde-lactol equilibrium mixture obtained in the same manner as in Example 5 was mixed with R-(- )-Phenylglycitur (1.21 g) and anhydrous magnesium sulfate (4 g) were added dropwise to a THF (10 ml) mixture, and after stirring at room temperature for 30 minutes, an ethanol solution of 748 mg of cyanosodium borohydride and acetic acid solution were added, and the mixture was stirred at room temperature. The mixture was stirred for an additional 30 minutes. After adding ether, the solid matter was filtered off, water was added, and the mixture was extracted with ether. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was treated with silica gel column chromatography (methylene chloride-ether=
3:1) L,1,1.1-)rifluoro-2trifluoromethyl-3-P-toluenesulfonyl 6-((R)-
1.7 g of 1-phenyl-2-hydroxyethyl)amino-2-hexanol was obtained as a colorless oil. (Yield: 41.2%) 'Hrvr (CDC13, TMS) δ ppm
7.81 (2H, dd, J = 4.0Hz6.35Hz
), 7.18<28. d, J=6.35Hz), 7.3
2 (5B, w), 3.67 (IH, ddd, J=1
, 7Hz, 4.0Hz, 10.1Hz), 3.5
9 (IH, dd, J=8.22Hz, 4.0Hz
>, 3.53 (2H, hazy), 2.49 (1,5H, s)
2.48 (1,5H, s), 2.0-2.4 (2H,
s), 1.2-0.86(2H,m)"Fnmr
(CDCl2.BTF) δppm -8,00(q, J
= 8 Hz) 10.83 (Q, J = 10 Hz) Example 8 Aminohexanol (1.7 g) of the product obtained in Example 7
, 3.3+*mol) in toluene solution (30m 1
．． ) was added with 20% NaOH and tetrabutylammonium fluoride (3.3 ml) and heated under reflux for 5 hours.The reaction solution was made acidic with acetic acid, then returned to basicity with aqueous ammonia, and extracted with ether. After extraction, the extract was washed with brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride-ether = 50:1) to separate and purify the diastereomers. (2R,1'R)-bistrifluoromethyl-[1-(1'-phenyl-2°
-hydroxyethyl)pyrrolidinyl-2]methanol 4
62 mg and (25,1°R)-bistrifluoromethyl-[1-(1phenyl-2°-hydroxyethyl)pyrrolidinyl-2]methanol 592 mg in 1ess polar and l1ore pola, respectively.
Obtained as a colorless oil.

The absolute configuration was determined by X-ray crystal analysis of more polar optically active crystal pycnolate (melting point: 153-156°C).

1ess polar 'Hnmr(CHCl3,
TMS) δppm 7.39-7.20 (5H, m),
4.22 (IH, dd, J=10.7Hz, 10Hz)
, 3.99(1)1. dd, J=10.7Hz,
4.9)1z) , 4.12(18,dd, J=
9.2Hz.

J=4.9Hz>, 4.00 (IH, m),
3.05 (211, m), 2.07 (IH, m)
.

1.77 (3H, ■) I9Fnmr (CHCl3, BTF) δp
pm -13,4 (q, J=11.2Hz) -8,8
7 (q, J=11.2Hz) MS (El) m/z 358 (M”+ 1), 32
6(M”-C)120H) HRMS Calculated value CI4
H14F6NIOXM+-CH20H) 326.09
78 actual value 326.0978 [α]:'=-11.68°(C-1,411t6.C
HCl3) more polar 'Hnmr(C
DC13, TMS) δppm 7.407.23 (
5B, a), 4.16 (IH, s), 4.11 (1) 1
．． d, J=9.3Hz>.

3.95 (IH, dd, J=10.3Hz, 3.4Hz
), 3.85 (LH, d, J=5.6)1z), 3.
12 (111, m), 2.89 (2H, m), 2.08
(IH, m), 1.68 (2H, m), 1.38 (
IH, m)” Fnmr (CDC13, BTF)
δppm -8,67 (q, J=12Hz>13.07
(q, J=101(z) [α]%'=-38,92°(C=2.03. CH
Ch) [Effects of the Invention] According to the present invention, by using a sulfone having β-hydroxy-β, β-bis(trifluoromethyl) group as a raw material and reacting it with an amine, a chain having the above-mentioned substituent group can be prepared. A novel fluorine-containing amine with a shape or a ring shape is produced, and the above-mentioned compound is an extremely important compound as an intermediate for medicines, agricultural chemicals, a catalyst in organic synthesis, etc.

Claims (4)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) (However, in the formula, R_1 and R^2 are each independently hydrogen, an alkyl group, an aryl group, an aralkyl group,
It may contain an unsaturated bond, an ether bond, a halogen atom, or a hydroxyl group. ) β-hydroxy-β,
β-bis(trifluoromethyl)amine derivative. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (II) (However, in the formula, R^1 and R^3 are each independently hydrogen, an alkyl group, an aryl group, an aralkyl group,
It may contain an unsaturated bond, an ether bond, a halogen atom, or a hydroxyl group. ) β-hydroxy-β,
A β-bis(trifluoromethyl)sulfone derivative is treated with the general formula R^2NH_2(III) in the presence of an acid acceptor and a phase transfer catalyst (wherein R^2 is hydrogen, an alkyl group, an aryl group, an aralkyl group). The novel β-hydroxy-β according to claim (1), characterized in that it is reacted with an amine derivative represented by: β-bis(
A method for producing a trifluoromethyl)amine derivative. (3) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (IV) (However, in the formula, R^2 represents hydrogen, an alkyl group, an aryl group, an aralkyl group, and n = 3, 4) β
-Hydroxy-β,β-bis(trifluoromethyl)amine derivative. (4) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) (However, in the formula, R^1 and R^3 are each independently hydrogen, an alkyl group, an aryl group, an aralkyl group,
It may contain an unsaturated bond, an ether bond, a halogen atom, or a hydroxyl group. ) β-hydroxy-β,
A part of the substituent R^1 of the β-bis(trifluoromethyl)sulfone derivative is replaced by a -R^2NH group (however, R^2 in the formula
is hydrogen, an alkyl group, an aryl group, or an aralkyl group, and may contain an unsaturated bond, an ether bond, a halogen atom, or a hydroxyl group. ) The novel β-hydroxy-β according to claim (3), characterized in that it is subjected to intramolecular reaction in the presence of an acid acceptor and a phase transfer catalyst.
A method for producing a β-bis(trifluoromethyl)amine derivative.