JPS63130578A - Organic selenium compound - Google Patents

Abstract

NEW MATERIAL:The organic selenium compound of formula I [Ar is (substituted)aryl or (substituted)heterocyclic group; the substituent group is lower alkyl, lower alkoxy, phenoxy, halogen, lower alkylthio, lower alkanoyl, benzoyl, benzoyloxy, lower alkanoyloxy, hydroxy, etc.]. EXAMPLE:1-Hydroxy-1-(4'-methylphenyl)-2-phenylselenopropane. USE:A synthetic intermediate for an alpha-aromatic-substituted propionic acid or its ester useful as a medicine having anti-inflammatory and analgesic actions (e.g. ibuprofen) or its intermediate. PREPARATION:The compound of formula I can be produced by reacting a compound of formula II with benzeneselenyl chloride in an inert solvent and reacting the resultant compound of formula III with a reducing agent such as lithium hydride.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel intermediate of α-aromatic group-substituted propionic acid or its ester, which is useful as a pharmaceutical having anti-inflammatory analgesic effect (eg, ibuprofen) or an intermediate thereof.

Conventional ■ and formula% formula% (In each formula, Ar' represents an unsubstituted or substituted aryl group, R1 and R2 represent alkyl or may be combined to form a cyclic acetal, and X is Halogen atom, hydroxy, alkylsulfonyloxy, arylsulfonyloxy.

A method for obtaining an α-aromatic group-substituted propionic acid derivative by subjecting a compound represented by phenylseleno and phenyltelluro to a rearrangement reaction is known (JP-A No. 59-163345, No. 56-135423, Same 59
-62545. 60-218332. 57-675
35. 6O-97927).

The rearrangement products in these methods are usually obtained as esters. When the target product is α-aromatic group-substituted propionic acid, an additional step of hydrolysis from the ester is required.

ICH3(1) (wherein, Ar is an unsubstituted or substituted group [the substituent is unsubstituted or substituted lower alkyl (the substituent is phenyl, a halogen atom, hydroxyl, amino or nitro]) ,
Lower alkoxy, phenoxy.

halogen atom, lower alkylthio, lower alkanoyl,
Henzoyl, Henzoyloxy, lower alkanoyloxy, hydroxy, amino7, nitro.

An organic selenium compound represented by cyano, cyclopentyl, cyclohexyl, methylenedioxy or ethylenedioxy, or an unsubstituted or substituted heterocyclic group [hereinafter referred to as compound (I)].

The same applies to other compounds with numbers 2].

Compound (1) is a useful intermediate for producing α-aromatic group-substituted coropionic acid derivatives.

In the definition of Ar in (1), aryl includes phenyl, naphthyl, and the like. In the definition of substituents of substituent ryl,
Lower alkyl includes straight chain or branched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, isobutyl, n-pentyl, n-hexyl, etc. Substituted lower alkyl In the group definition, the halogen atom is chlorine.

It includes fluorine, bromine, etc., and the number of substituents is usually 1.

In the definition of the substituents of substituted aryl, lower alkoxy includes linear or branched alkoxy having from I to 6 carbon atoms, such as methoxy, ethoxy, propoxy, n-butoxy, etc., and halogen atoms include chlorine, fluorine, bromine, etc. Lower alkylthio includes linear or branched alkylthio having 1 to 6 carbon atoms, such as methylthio, ethylthio, isopropylthio, n-butylthio, etc., and lower alkanoyl includes 1 to 6 carbon atoms. Straight-chain or branched alkanoyl, such as formyl, acetyl, n-propionyl,
It includes n-butyryl and the like, and lower alkanoyloxy includes linear or branched fluoryloxy having 1 to 6 carbon atoms, such as formyloxy, acetyloxy, n-propionyloxy and the like. The number of substituents in the substituent group can be 1 to 5, but 1 or 2 is suitable.

Unsubstituted or substituted heterocyclic groups are CH.

The process of synthesizing compound (1) from a known compound and the process of producing an α-aromatic group-substituted probionic acid derivative from compound (1) can be expressed as a reaction formula as follows.

(III) (I) (In each formula, Ar has the same meaning as above, and R represents a hydrogen atom or lower alkyl) Does not participate in reactions such as tetrahydrofuran in the process of synthesizing compound (rV) from compound (I) When a solvent is used, compound (VI) is obtained as a carboxylic acid.

Next, each manufacturing process will be explained in detail.

Compound (n) is a generally known compound, and can be obtained by subjecting an aromatic compound and an acylating agent such as propionyl chloride to a Friedelkraff acylation reaction in the presence of a Lewis acid such as aluminum chloride [e.g. , Hartu
ng et al,,J,Am,Chem,Soc,+
Vines, 4149 (1931)).

Compound Cn[) can be obtained by reacting compound (II) and benzeneselenenyl chloride in an inert solvent. Benzene selenenyl chloride is a compound (I
It is used in an amount of 1 to 3 equivalents, preferably 1 to 1.5 equivalents, based on I). As an inert solvent, esters such as ethyl acetate,
Ethers such as tetrahydrofuran, methylene chloride,
Halogenated alkanes such as chloroform are preferably used. The reaction temperature can be selected within the range of 0 to 50°C,
Preferably around room temperature. The reaction time varies depending on the temperature, but is usually 10 to 20 hours at around room temperature.

High quality compound (1) can be obtained by purifying the reaction mixture by silica gel chromatography or the like.

Compound (I) can be obtained by reacting compound (III) with a reducing agent such as lithium aluminum hydride or sodium borohydride. The reducing agent is the compound (II
) is usually used in an amount of 1 to 2 equivalents.

When lithium aluminum hydride is used as the reducing agent, ether, tetrahydrofuran, etc. are preferable as the solvent, and when sodium borohydride is used as the reducing agent, the solvent is methanol.

Ethanol and mixtures thereof with water and the like are preferred. The reaction temperature is preferably -10 to 0°C, and in this case, the reaction time is usually 0.5 to 2 hours. After the reaction is completed, excess reducing agent is decomposed and then extracted with chloroform or the like to obtain compound (I).

If necessary, purify by silica gel chromatography or the like to obtain high quality compound (1).

Compound (1) thus obtained is peracetic acid.

By reacting with a peracid such as perbenzoic acid (2m-chloroperbenzoic acid), hydrogen peroxide, t-butyl hydroperoxide, etc., compound (IV) can be prepared by transfer of the Ar group and subsequent oxidation reaction. give. In this reaction, it is preferable to use 3 to 5 equivalents of peracid, etc., based on the amount of the compound. As a solvent, an organic solvent that does not participate in the reaction, such as ethyl ether.

When using ethers such as tetrahydrofuran and dimethoxyethane, halogenated lower alkanes such as methylene chloride, 1,2-dichloroethane, and chloroform, esters such as ethyl acetate, and aromatic hydrocarbons such as benzene and toluene, the compound (IV ) is obtained as a free carboxylic acid, and when a lower alkanol (having 1 to 6 carbon atoms) such as methanol or ethanol is used as a solvent, the compound (I
V) is obtained as an ester. The reaction temperature is -20~4
It can be selected within the range of 0°C, and is usually carried out at around room temperature. In this case, the reaction time is usually 10 to 24 hours.

High quality compound (IV) can be obtained by purifying the reaction mixture by silica gel chromatography or the like.

Carbonization Example 1 l-1) 3.83 g of 2-phenylseleno-4'-methylpropiophenone benzeneselenenyl chloride was dissolved in ethyl acetate 4
A solution of 2.96 g of 4'-methylpropiophenone dissolved in 40 ml of ethyl acetate was added to this solution, and the mixture was stirred at room temperature for 20 hours.

The reaction solution was washed twice with 30 nl of 20% brine, and the resulting ethyl acetate layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 6.49 g of a yellow oil as a residue. This was subjected to column chromatography [silica gel (2
00m&'), ethyl acetate:n-hexane=1:
20 (v/v), purified at 1j2) to 4.45
g of 2-phenylseleno-4'-methylpropiophenone was obtained as a yellow oil (yield 73.5%).6 The physicochemical properties of the product are as follows.

NMR (CDCI! 3): δ1.64 (3H, d
, J=7Hz).

2.41 (3H, s), 4.67 (LH, q,
J=711z), 7.15-7.96 (9H, m)
Elemental analysis (%) Calculated value as C+JL60Se:
C, 63, 37; H, 5, 32 measurement value: C, 63, 7
0; H, 5,481-2) 1-hydroxy-1-(
0.10 g of lithium aluminum hydride (4'-methylphenyl)-2-phenylselenopropane was suspended in 3mf of diethyl ether, and 2-phenylseleno-4
A solution of 0.49 g of '-methylpropiophenone dissolved in 3 mA of diethyl ether was added at -10°C. −
The mixture was stirred at 10 to 0°C for 2 hours, then 0.5 ml of a 4N aqueous sodium hydroxide solution was added, and the mixture was further stirred for 3 hours.

The precipitate was removed by filtration, the filtrate was washed twice with 5 mQ of 20% brine, and the ether layer obtained by separation was dried over anhydrous magnesium sulfate. Distill the solvent under reduced pressure to 0.3
9 g of a yellow oil was obtained as a residue. This was subjected to column chromatography [silica gel (40mβ), ethyl acetate:n-hexane-1:20 (ν/v), 250mβ
61 to obtain 0.29 g of 1-hydroxy-1=(
4'-Methylphenyl)-2-phenylselenopropane was obtained as a pale yellow oil (yield 59.4%). The physicochemical properties of the product are as follows.

NMR (CDC1,): δ1.20 (3H, d,
J=711z).

2.32 (3H,s), 3.14 (IH
, broad, s).

3.40 (IH, m), 4.35 (IH, d,
J=7)1z), 7.00~7.68 (9H
, m) I R(neat): 3420cm-'Elemental analysis (%) Calculated value as C+bll+aO3e:
C,62,95; H,5,94 Measured value: C,63,2
6; H, 6,02 Example 2 2-1) 2-Phenylseleno-4'-bromopropiophenone 3.83 g of benzeneselenenyl chloride was dissolved in 40 ml of ethyl acetate, and 4'-bromopropyl chloride was dissolved in 40 ml of ethyl acetate. A solution of 4.26 g of piophenone dissolved in 40 ml of ethyl acetate was added, and the mixture was stirred at room temperature for 20 hours.

After the reaction, the mixture was washed twice with 30 ml of 20% saline, and the resulting ethyl acetate layer was dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure to obtain 7.89 g of yellow oil as a residue. This was subjected to column chromatography [silica gel (200ml), ethyl acetate:jl-hexane-1
: 20 (v/v), 1 (Purified using 1'J to obtain 5.05 g of 2-phenylseleno-4'-bromopropiophenone as a yellow oil (yield 68.6%)
). The physicochemical properties of the product are as follows.

NMR (CDCl3): δ1.64 (3H, d,
J=7Hz).

4.59 (LH, q, J=7Hz), 7.1
2-7.80 (9H, m) Elemental analysis (%) Calculated value as C+sH+3BrO3e: C, 48,94; H, 3,56 Measured value: C,
49,16; H, 3,962-2) 0.15 g of 1-hydroxy-1-(4'-bromophenyl)-2-phenylselenopropane lithium aluminum hydride was dissolved in 4 mA' of diethyl ether! Add 0.86 of 2-phenylseleno-4'-bromopropiophenone to this cloudy A.
g dissolved in 3 ml of diethyl ether.
Added at °C. -10-0"C for 2 hours, then 4 hours.
A specified aqueous sodium hydroxide solution (0.8 mA) was added, and the mixture was further stirred for 3 hours. 20% of the filtrate removed by filtering the precipitate
5mjl of salt water! The ether layer obtained by washing twice and separating the layers was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.76 g of yellow oil as a residue. This was subjected to column chromatography [silica gel (4
0ml), ethyl acetate:n-hexane=1:20(ν/
ν), 300 ml] to obtain 0.41 g of 1-hydroxy-1-(4'-7' romophenyl)-2-phenylselenopropane as a pale yellow oil (yield: 4
7.3%). The physicochemical properties of the product are as follows.

NMR (CDC13): δ1.21 (3H,
d, J=7H2).

3.26 (LH, d, J=2Hz), 3.
37 (IH.

dq, J=8Hz, 7Hz), 4.33
(LH, dd.

J = 8H2,2i(z), 7.08~7.
60 (9H, m)I R(neat):
3 4 1 0cm-'Elemental analysis (%) C+s)l
Calculated value as +5BrO5e: C, 48, 67, H, 4
,08 Measured value: C,49,02iH,4,40 Example 3 3-1) Dissolve 2.35 g of 2-phenylseleno-4'-phenylpropiophenone benzene selenenyl chloride in 20 ml of ethyl acetate, and dissolve this solution. A solution of 2.10 g of 4'-phenylpropiophenone dissolved in 20II11 of ethyl acetate was added to the mixture, and the mixture was stirred at room temperature for 20 hours.

After the reaction, the solvent was distilled off under reduced pressure, and 50% of n-hexane was added to the residue.
ml was added and stirred at room temperature for 1 hour. The solid was filtered, washed with 10 mf of n-hexane, and dried to obtain pure 2
-Phenylseleno-4'-phenylpropiophenone 3
．． 18 g was obtained as pale yellowish white crystals (yield 87.0%).
),.

The physicochemical properties of the product are as follows.

Melting point 124.2°C NMR (CDCe 3): δ1.72 (3H, d,
J=7flz).

4.75 (L H, q, J = 7Hz),
7.20-8.08 (14H, m) Elemental analysis (%) Calculated value as CzlHra O5e: C, 69,04; H, 4,97 Measured value: C, 69,2
6; H, 5,033-2) 1-hydroxy-1-(
0.32 g of lithium aluminum hydride (4-biphenylyl)-2-phenylselenopropane was suspended in 10 ml of tetrahydrofuran, and 1.83 g of 2-phenylseleno-4'-phenylpropiophenone was dissolved in 10 rall of tetrahydrofuran. solution to 10
Added at °C. Stir for 2 hours at -1O~O℃, then add 1.6mN of 4N sodium hydroxide aqueous solution and further stir for 3 hours.
Stir for hours. The precipitate was removed by filtration, and the solvent was distilled off under reduced pressure. 20 ml of ethyl acetate was added to the residue, washed twice with 20% brine 10+17, separated, and the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.63 g of yellow oil. This was subjected to column chromatography [silica gel (80ml).

Ethyl acetate:n-hexane=1:20 (v/v
).

480 ml] to obtain 1.20 g of 1-hydroxy-1-(4-biphenylyl)-2-phenylselenopropane as a viscous pale yellow oil (yield: 65.3
%). The physicochemical properties of the product are as follows.

NMR (CDCl3): δ1.28 (3H, d,
J=7Hz) 3.28 (LH, d, J=2Hz), 3
．． 46 (LH.

dq, J=8Hz, 7Hz), 4.33 (IH, dd
.

J = 8Hz, 2) 1z), 7.08~? ,6
0 (9H, m) [R (neat): 3420
am-' elemental analysis (%) Calculated value as Cz+HzoO3e: C, 68, 67; H, 5, 49 Measured value: C, 6
8,47;H,5,52 Example 4 4-1) 4'-isobutylphenyl-2-phenylselenopropiophenone 2.35 g of benzeneselenenyl chloride was dissolved in 20 ml of ethyl acetate, and 4'- A solution of 1.90 g of isobutylpropiophenone dissolved in 20 ml of ethyl acetate was added. After stirring for 20 hours at room temperature, 20ml of 20% saline solution
Washed twice with l. After drying the obtained ethyl acetate layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3.69 g of a yellow-red oil as a residue. This was subjected to column chromatography [silica gel (200 m#), ethyl acetate; n-hexane = 1:30 (v/v),
900ml) to obtain 2.44 g of 4'-isobutylphenyl-2-phenylselenopropiophenone as a viscous yellow oil (yield 70.6%). The physicochemical properties of the product are as follows.

NMR (CDCl: δ0.89 (6H, d, , J
=6Hz).

1.88 (IH, m), 1.61 (3H, d, J
=782), 2.50 (2H, d, J=
6Hz>, 4.66 (IH, Q, J=7H
z), 6.9 to 8.0 (9 summers).

m) Elemental analysis (%) Calculated value as CI911220Se: C
, 66,08; H, 6, 42 measurement value: C, 66, 50;
H,6,584-2) 1-hydroxy-1-(4'
-isobutylphenyl)-2-phenylselenopropane 0.32 g of lithium aluminum hydride was dissolved in diethyl ether 9+nl', and 4'-isobutylphenyl-2-phenylselenopropiophenone 1.
A solution of 73 g dissolved in 10 ml of diethyl ether was added at -10°C. Stir at -10°C to Q'C for 2 hours, then 1.6ml of 4N aqueous sodium hydroxide solution.
# was added and further stirred for 3 hours.

The precipitate was removed by filtration, and the filtrate was washed twice with 5 m/' of 20% saline. After drying the obtained ether layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a yellow oil.
68 g were obtained as a residue. This was subjected to column chromatography (silica gel <50 mn).

Ethyl acetate; n-hexane = 1:20 (v/v).

Purification at 300 mff3 gave 0.72 g of 1-hydroxy-1-(4'-isobutylphenyl)-2-phenylselenopropane as a pale yellow oil (yield 4).
5%). The physicochemical properties of the product are as follows.

NMR (COCp3): δ0.89 (6H, d,
J=611z).

1.21 (3H, d, , J-7tlz),
1.84 (III.

m), 2.46 (2H, d, J = 61
iz), 3.16 (IH, br s), 3.40
<iH, dq, J-811z, 711z),
4.37 (IN, d, ,,T=8H
z).

7.00~7.64 (9H, m) IR (near): 3420 cm-' Elemental analysis (%) Calculated value as C1qHz40Se: C,6
5,70;L! ,'i,96 measurement value: C,66,02;
H,7,15 Example 5 5-1) 2-phenylselenopropiophenone 4'
-Methylpropiophenone2. Instead of 9 6 g,
Propiophenone 2. Actual h% example 1 using 68 g
The same reaction and shallow treatment as in 1) were performed. Target product 2-phenylselenopropiophenone 4. 7 4 g
was obtained as a yellow oil (yield 82%).

The physicochemical properties of the product are as follows.

NMR (CD(: e 1): δ1.5 3 (3H
, d. J=711z).

4,50 (IH, q, J = 7Hz)
, 6.9 0 to 7.35 (8H, m),
7.5 0~7.8 0 (2H, m) Elemental analysis (%
) CISHI4 0Se Toshi”'C Calculated value: C.
62.29; H, 4.88 measured value: C. 62.3
9; H, 4.975-2) I-H (J-1-phenyl-2-phenylselenopropane) 0.32 g of lithium aluminum hydride was suspended in 10 ml of diethyl ether, and 2-phenylselenopropyl 1.45 g of phenone to 1 portion of diethyl ether
0m7! was added at -10°C. After stirring at the same temperature for 2 hours, the same post-treatment as in Example 4-2) was performed, and 1. 05 g of 1-hydroxy-1-phenyl-2-phenylselenopropane was obtained as a pale yellow oil (yield 72%). The physicochemical properties of the product are as follows.

NMR (CDC Il.3): δ1.20 (3H
, d, J=711z).

3, 2 2 (I H, d, J=2Hz),
3.4 0 (IH.

d q, J =8tlz. 711z),
4.3 9 (1N, d d.

J=8Hz), 7.1 5 ~ 7.3 5
(8H.m).

7, 5 2-7.6 4 (2 H, rn) J R
(neat): 3 4 4 0cm-'Elemental analysis (%) Calculated value as CISI1160Se: C
, 61.86; Old 5.54 measurement value: C, 61.94;
Toho 5.68 Reference Example 1 ■-Hydroxy-1-(4'-isobutylphenyl)-
2-Phenylselenopropane! ．． 39g methanol 2
m-chloroperbenzoic acid dissolved at 0 mA. 4 5
g was added thereto, and the mixture was stirred at room temperature for 2 hours. Then 10%
Sodium thiosulfate water m i'i'i 30 m /
After stirring well, the mixture was extracted twice with 50 ml of ethyl acetate.

The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography [n-hexane-l ether (10:1) to (5:
4? 290 mg of 2-(,1'-isobutylphenyl)propionic acid (yield 35%)
I got it.

Reference example 2 ■-Hydroxy-1-(4'-isobutylphenyl)-
2-phenylselenopropane 1.39g methanol 2
0 mρ, 3.45 g of m-chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 24 hours.

The same post-treatment as in Reference Example 1 was carried out, and 790 rPg of methyl 2-(4'-isobutylphenyl)propionate (yield 90%) and 2-(4'-isobutylphenyl) were obtained.
83 .mu. (1 tllO%) of propionic acid was obtained.

Reference Example 3 0.261 g of 1-hydroquine-1-phenyl-2-phenylselenopropane was dissolved in 9 ml of methanol, and m-
0.97 g of chloroperbenzoic acid was added at room temperature and stirred.

After stirring at room temperature for 2 hours, add 100 ml of 10% sodium thiosulfate aqueous solution! The reaction solution was poured into the flask and extracted with 100 ml of diethyl ether. The organic layer was washed with IN/aqueous sodium hydroxide solution and dried over anhydrous magnesium sulfate. Analysis of this solution by gas chromatography revealed that methyl 2-phenylpropionate was 131m
61!g (production rate 89%). I could recognize it. In addition, the above sodium hydroxide washing solution was acidified with hydrochloric acid, extracted with diethyl ether, and further methyl esterified with diazomethane according to a conventional method. Production was confirmed by gas chromatography.

Gas chromatography conditions Column OV 101 0.24mmX30m Column temperature 120-260℃ (5℃/m1n) Internal standard
Effects of biphenyl invention Compounds that are new compounds using known compounds as starting materials (
By subjecting 1) to a novel rearrangement reaction, useful compound (IV) can be obtained under generally mild conditions and in high yield. In the conventional rearrangement reaction, the compound (
IV) was obtained only as an ester, but in the present invention it is obtained as a carboxylic acid.

Claims (1)

[Claims] Formulas include mathematical formulas, chemical formulas, tables, etc. (where Ar is unsubstituted or substituted aryl [substituent is unsubstituted or substituted lower alkyl] or nitro),
Lower alkoxy, phenoxy, halogen atom, lower alkylthio, lower alkanoyl, benzoyl, benzoyloxy, lower alkanoyloxy, hydroxy, amino, nitro, cyano, cyclopentyl, cyclohexyl,
methylenedioxy or ethylenedioxy], or an unsubstituted or substituted heterocyclic group).