JPS62129243A - 2-fluoro-4-biphenylylacetic acid derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I (Y is OH, halogen, mercapto, lower alkylthio, arylthio, amino, lower alkylamino or dilower alkylamino; R is H or lower alkyl). EXAMPLE:alpha-Chloromethyl-(2-fluoro-4-biphenylyl)acetic acid. USE:A raw material for producing flurbiprofen [=2-(2-fluoro-4-biphenylyl)propionic acid] which is an anti-inflammatory and analgesic agent. PREPARATION:A novel compound expressed by formula II (R' is R other than H) is reduced with NaBH4, etc., in a polar solvent to afford the aimed compound expressed by formula I (R is R'; Y is OH), which is then subjected to halogen substitution reaction with thionyl chloride, etc., to give the aimed compound expressed by formula I (R is R'; Y is halogen). Furthermore, the resultant compound is reacted with H2S or lower alkylamine, etc., in an organic solvent to afford the aimed compound expressed by formula I [R is R'; Y is Y' (Y' is NH2, lower alkylamino, etc.)].

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention has an anti-inflammatory and analgesic effect and is important as a pharmaceutical.
The present invention relates to novel intermediates which can lead to 2-fluoro-4-biphenylyl)furopionic acid and its derivatives.

Prior Art and Problems 2- Many proposals have already been made regarding methods for producing (2-fluoro-4-biphenylyl)propionic acid and its derivatives. Among them, a method using a 2=fluoro-4-biphenylylacetic acid derivative as a raw material is a method in which 2-fluorobiphenylylacetic acid ester is changed to the corresponding malonic acid ester, and then alkylation, hydrolysis, and decarboxylation are carried out ( Tokuko Sho 44-25076) or 2
- A method of converting fluoro-4-biphenylylacetonitrile to 2-carbalkoxy-2-fluoro-4-biphenylylacetonitrile, followed by alkylation, hydrolysis, and decarboxylation (such as JP-A-53-116352) is known. Both of these methods require a large number of steps, and the former method requires a high-temperature reaction of 190°C, while the latter method requires the use of raw material acetonate, which is difficult to handle industrially when producing the IJ compound. If you don't use cyanide.

Means for Solving the Problems The present invention is based on the formula (1) (wherein Y is a hydroxy group, a halogen atom, a mercapto group, a lower alkylthio group, an arylthio group, an amino group,
A lower alkylamino group or a di-lower alkylamino group,
R represents a hydrogen atom or a lower alkyl group. 2-fluoro-4-biphenylylacetic acid derivative represented by (hereinafter sometimes referred to as compound (I)). The same applies to compounds with other formula numbers.

Regarding the definition of Y in compound (I), the halogen atom is chlorine,
Includes fluorine, bromine atoms, etc. The lower alkylthio group is a straight or branched alkylthio group having 1 to 6 carbon atoms,
Examples include methylthio, ethylthio, isopropylthio, and the like. Arylthio groups include phenylthio and the like. The lower alkylamino group includes linear or branched alkylamino groups having 1 to 6 carbon atoms, such as methylamino and ethylamino groups. The lower alkyl group referred to in the di-lower alkylamino group means a straight or branched alkyl group having 1 to 6 carbon atoms, and examples of the di-lower alkylamino group include dimethylamino, diethylamino, and diisopropylamino groups.

Regarding the definition of R in compound (I), the lower alkyl group includes straight or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, isopropyl, and the like.

Compound (1) can be produced by the following steps.

(1-3) ([-4) [wherein,
R' is R other than hydrogen, Hal is)\rogen atom, Y
/ represents SH, lower alkylthio or arylthio group,
Y' represents NH2, lower alkylamino or di-lower alkylamino group. Also, compounds (I-1), (I-2)
. etc. are compounds included in compound (I). ] First, compound (I[) is reduced to obtain compound (1-1). As the reduction method, chemical reduction using sodium borohydride, aluminum amalgam, etc. or catalytic reduction using Raney nickel or the like as a catalyst is used. For example, when using sodium borohydride, the amount of sodium borohydride in a polar solvent such as water or lower alkanol (methanol, ethanol, etc.) is 1 to 10 equivalents, preferably 1 to 2 equivalents, based on compound (If). The reaction temperature ranges from 0°C to the reflux temperature of the solvent, preferably from 0°C to room temperature.

The reaction time is usually 10 minutes to 30 hours.

The resulting compound (I-1) can be converted to compound (1-2) by using a conventional halogen substitution reaction from a hydroxy group. For example, thionine chloride or thionine bromide can be treated with no solvent or with a solvent inert to the reaction, such as chloroform.
The corresponding chloride or bromide can be obtained by reacting in a halogenated lower alkane such as methylene chloride at 0° C. to the boiling point temperature of the solvent for 30 minutes to 30 hours. Alternatively, it is also possible to use phosphorus halides such as phosphorus pentachloride, phosphorus tribromide, and phosphorus triiodide to form the corresponding chloride, bromide, and iodide.

When the obtained compound (I-2) is reacted with hydrogen sulfide or lower alkyl or aryl mercaptan in an organic solvent alone or in a water-organic solvent two-phase system, compound (1-3) is obtained.
is obtained. Organic solvents include benzene, toluene, xylene, lower alkanols (methanol, ethanol, etc.), and the like.

The reaction temperature is -10 to 50°C, and the reaction is usually completed in 30 minutes to 30 hours. Similarly, compound (I-2) and ammonia,
Compound (I-4) is obtained by reacting a lower alkylamine or a di-lower alkylamine in an organic solvent alone or in a two-phase water-organic solvent system. A soluble 'JX includes benzene, toluene, xylene, lower alkanols (methanol, ethanol, etc.) and the like. The reaction temperature is -10~5
0°C is suitable, and the reaction is usually completed in 30 minutes to 30 hours.

In the case of compounds (I-1), (I-3), and (I-4), they can be hydrolyzed with a base such as sodium hydroxide or potassium hydroxide to lead to the corresponding carboxylic acid according to a conventional method. In the case of compound (I-2), it can be hydrolyzed to the corresponding carboxylic acid under acidic conditions, for example, using hydrochloric acid, hydrobromic acid, etc., according to a conventional method.

Compound (n) is also a new compound, which is obtained by condensing a compound represented by formula (III) (wherein R' has the same meaning as above) and a lower alkyl formic acid ester, such as ethyl formate, in the presence of a strong base. This can be obtained by Preferably, 1 to 5 of the compound (I (I) + metal)
Using 1 to 50 equivalents of ethyl formate, the reaction is usually carried out at 0° C. to room temperature for 1 to 30 hours (see Reference Example 1).

In compound (I), the compound represented by formula (I-5) (wherein Y has the same meaning as above) is converted to 2-(2-fluoro-4-biphenylyl)propionic acid by reduction. be able to. This compound is an anti-inflammatory painkiller called flurbiprofen. As the reduction method, any of chemical reduction, catalytic reduction, and electrolytic reduction can be used. For example, when Y is a chlorine, bromine or iodine atom, chemical reduction using zinc-acetic acid or the like or catalytic reduction using palladium, nickel or the like as a catalyst may be used. Practically, in the presence of a base such as an alkali metal hydroxide, for example, potassium hydroxide or sodium hydroxide, 5% palladium-carbon is used in an amount of 10 to 40% based on compound (1-5), and the temperature is 0 to 100°C. The catalytic reduction is preferably performed at a hydrogen pressure of 20 to 20 atmospheres (see Reference Example 2).

When Y is a mercapto group, a lower alkylthio group or an arylthio group, an alkali metal-lower amine or the like is used. Chemical reduction, catalytic reduction using Raney nickel as a catalyst, etc. are applied. When Raney nickel is used, the purpose can be achieved by using water, alcohol, dioxane, acetone, benzene, etc. alone or in combination, and reacting at a temperature ranging from room temperature to the boiling point of the solvent (Reference Example 3).

For example, a catalytic reduction method is also used when Y is a hydroxy group, an amino group, a lower alkylamino group or a di-lower alkylamino group. In the case of a hydroxy group, a catalyst such as nickel-diatomaceous earth is used, and in the case of an amino group, lower alkylamino group or di-lower alkylamino group, palladium-carbon or the like is used.

Compound (I[I) is a known compound and is
It can be manufactured by the method described in No. 5076.

Compounds (1) and (II) can be isolated and purified by conventional methods, such as concentration, extraction, column chromatography, and crystallization.

The present invention will be explained in more detail by showing Examples and Reference Examples below.

Example 1 11.06 g of α-formyl-(2-fluoro-4-biphenylyl)acetic acid ethyl ester in 73 ml of methanol
1.48 g of sodium borohydride in a solution of 20°C
I added it. After stirring at 20°C for 4.5 hours, methanol was distilled off under reduced pressure, 20 Qml of water was added to the residue, and 3 ml of ethyl acetate was added.
Extracted with 0 Qml. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give α-hydroxymethyl-(2-fluoro-4-biphenylyl)acetic acid ethyl ester 8.6
2 g was obtained as a pale yellow oil (yield 76.7%).

An analytical sample was obtained by purifying this with column chromatography (silica gel, n-hexane/ethyl acetate, 9:1).

NMR (CDCj23): δ1.27 (3H, t,
J=7)lz).

2.60 (IJI, br), 3.8-4.6 (3H
, m), 4.24 (2H, Q.

J=7Hz), 7.0-7.6(8H,m)C,tH
,,FO,calculated value: C,? 0.82; H, 5,94% Measured value: C, 71,14; H, 5,72% Example 2 α-Hydroxymethyl-(2-fluoro-4-biphenylyl) obtained in Example 1 Acetate ethyl ester 0.2
To 9 g, 2 ml of a 1N hydroxide solution and 2 ml of ethanol were added, and the mixture was stirred at room temperature for 2 hours. After the reaction, 1Qml of ethyl acetate was added for extraction, and the aqueous layer was diluted with 2N hydrochloric acid.
The mixture was adjusted to H1 and extracted with 20 ml of ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 0.
．． 24 g α-hydroquinemethyl-(2-fluoro-4
-biphenylyl)acetic acid (yield 92.2%). It was further purified by column chromatography (silica gel, chloroform/methanol 19:1) to obtain deliquescent white crystals.

NMR (d' DMSO): δ3.42-4.08 (3
H, m).

7.02-7.62 (8L m) Calculated value as C15H1,FO3: C, 69,22; H, 5,04% Measured value:
C, 69,40; H, 5,22% Example 3 α-Hydroxymethyl-(2-fluoro-4-biphenylyl)acetic acid ethyl ester 6.0 g methylene chloride 21
5.0 g of thionyl chloride was added to the solution of m1, and the mixture was heated under reflux for 5 hours. Add 10 ethyl acetate to the residue after concentration under reduced pressure.
Add Qml and add water (100ml) and saturated heavy sodium water (10ml).
After washing with water (100 ml), the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 5.59 g of α-chloromethyl-(2fluoro-4-biphenylyl).
Acetic acid ethyl ester was obtained as a viscous oil (yield 8
6.8%).

An analytical sample was obtained by purifying this with column chromatography (silica gel, n-hexane/ethyl acetate, 9:1).

NMR (CDCj!3): δ 1.20 (3H, t,
J=7flz).

3.8-4.6 (3H, m), 4.70 (2H, q,
J = 7 Hz), 6.9-7.6 (81 (, m) C,, H,, CI Calculated value as FO2: C, 66,56; H, 5, 26% Measured value:
C, 66, 20; H, 5, 51% Example 4 4 ml of acetic acid and 1 ml of concentrated hydrochloric acid were added to 0.61 g of α-chloromethyl-(2-fluoro-4-biphenylyl)acetic acid ethyl ester, and the mixture was heated at 80°C for 2 hours. Stirred.

After the reaction, add 45 ml of ethyl acetate and wash with water (30 ml x 2
), the ethyl acetate layer was dried with anhydrous sodium sulfate,
Concentrate under reduced pressure to obtain 0.38 g of α-chloromethyl-(2-
Fluoro-4-biphenylyl) acetic acid'f-obtained as a viscous oil (yield 68.9%).

Samples for analysis are subjected to column chromatography (IJ
It was obtained by purification using Kakeru and chloroform/methanol (8:2).

NMR (CDCβ, ): δ3.78-4.68(3)l
, m).

6.9 ~ 7.5 (811, m> C, 5H, 2Cff Calculated value as F○2・C, 64, 64; ) (, 4, 34% Measured value: C, 64, 72: H, 4, 50% Example 5 1.og of α-chloromethyl=(2-fluoro-4-biphenylyl)acetic acid ethyl ester was dissolved in 7 ml of benzene, and 1.0 g of methyl mercaptan sodium aqueous solution (15%) was dissolved.
．． 7g, tetrabutylammonium bromide 0.05
g was added thereto, and the mixture was stirred at room temperature for 2 hours. After the reaction, add 30ml of 1N hydrochloric acid. Add 30ml of ethyl acetate and separate the liquids. The upper layer was washed with 30 ml of water. Anhydrous sulfuric acid was dried over IJum and concentrated under reduced pressure to obtain 0.86 g of α-methylthiomethyl-(2-fluoro-4-biphenylyl)acetic acid ethyl ester as a viscous oil (yield: 82.3 %)
.

An analytical sample was obtained by purifying this with column chromatography (silica gel, n-hexane/ethyl acetate, 9:1).

NMR (CDCj!3): δ 1.25 (3H, t,
J=7tlz).

2.10 (3H, s), 2.90 (LH, m), 3
．． 20 (LH, m).

3.80 (ltl, m), 4.20 (2H, q, J
=7Hz), 7.0-7.6 (8N, m) Calculated value as CIIIH19FO2S: C, 67,90; H, 6,02% Measured value:
C, 68,34; H, 6,30% Example 6 α-Methylthiomethyl-(2-fluoro-4-biphenylyl)acetic acid ethyl ester obtained in Example 5 0.21
g of 1N sodium hydroxide 1.3ml, ethanol 1
ml was added and stirred at room temperature for 3 hours.

After the reaction, the pH was adjusted to 1.0 with 4N hydrochloric acid and ethyl acetate (
10ml x 2). The ethyl acetate layer was diluted with water (20
After washing with anhydrous sulfuric acid (ml) and drying with IJum,
Concentrate under reduced pressure to obtain 0.19 g of α-methylthiomethyl-(
2-Fluoro-4-biphenylyl)acetic acid was obtained as a viscous oil (yield 99.2%).

NMR (CDCN3); δ2.04 (3) 1. s>,
2.82 (IH, m), 3.18 (1N, m),
3.78 (18, m), 6.9~7.5 (8N,
m), LQ, 68 (11(,br)C+e H+s
Calculated value as F 02 S: C, 78,59; H, 5,2196 Measured value: C, 78,64; H, 5,30% Example 7 α-chloromethyl-(2-fluoro-4-biphenylyl) 1.0 g of ethyl acetate was dissolved in 7 ml of benzene, 0.59 g of a 50% dimethylamine aqueous solution and 0.05 g of tetrabutylammonium bromide were added, and the mixture was stirred at room temperature for 2 hours. After the reaction, 30 ml of 1N base and 30 ml of ethyl acetate were added, and the aqueous layer obtained by separation was adjusted to pH 8.0 with a 5N aqueous sodium hydroxide solution. Extract with ethyl acetate (30171L twice), dehydrate the ethyl acetate layer with anhydrous magnesium sulfate, and concentrate under reduced pressure to give 0.81
g of α-dimethylamine methyl-(2-fluoro-4-
Biphenylyl)acetic acid ethyl ester was obtained as a viscous oil (77.9% yield).

NMR (CD (J'3): δ 1.25 (3H, t,
J=7)1z).

2.30 (6H, s), 2.50 (1) l, m),
3.10 (IH, m), 3.80 (1N, m),
4.10(2)1. q, J=IHz>, 6.9
5-7.60 (8H, m) C,, Calculated value as 822FNO2: C,? 2.35, )4.7.03;N
, 4.44% Measured value: C,? 2.70; H, 7
J3;N, 4.3696 Example 8 α-dimethylaminomethyl-(2-
Fluoro-4-biphenylyl)acetic acid ethyl ester 0.
(1N hydroxide to 26 g) IJium aqueous solution 1.5 m
1 and 1 ml of ethanol were added, and the mixture was stirred at room temperature for 3 hours.

After the reaction, adjust the pH to 3.1 with 4N hydrochloric acid and add ethyl acetate.
Extracted with Qml. The aqueous layer was adjusted to pH 5.8 with a 2N aqueous sodium hydroxide solution, and lyloform (20ml x
5 times). The chloroform layer is diluted with anhydrous sulfuric acid)
and concentrated under reduced pressure to give 0.17 g of α-dimethylamine methyl-(2-fluoro-4-biphenylyl).
Acetic acid was obtained as white crystals (yield: 71.3%).

Melting point 143.9℃ NMR (d' DMSO) ・δ2.40 (6H,
s), 2.70 (LH, m), 3.12 (IH,
m), 3.78 (IH, m), 6.90-7.50
(8H, m) Calculated value as CI78IIIFNO2: C,? 1. Q6; H, 6, 31, N,
4.88% measured value: C, 71,22; H, 6,50
, N, 4.92% Reference Example 1 2-Fluoro-4-biphenylylacetic acid methyl ester 8
．． Add 3.31 g of metallic sodium (wire form) to a solution of 90 g of ethyl formate (72 ml) and add 6.5 g of sodium metal (wire form) at room temperature.
Stir for hours. After the reaction, ethyl formate was distilled off and the residue was mixed with 2 ml of water.
00 ml was added thereto, the pH was adjusted to 2 with 2N hydrochloric acid, and the mixture was extracted with 303 ml of ethyl acetate. Anhydrous sulfuric acid) was dried over IJum and concentrated under reduced pressure to give 9.79 g of α-formyl (
2-Fluoro-4-biphenylyl)acetic acid ethyl ester was obtained as a viscous oil (yield 95.0%).

NMR (CDCj2s): δ1.29 (3H, t,
J=7Hz).

4.26 (2H, q, J=7Hz), 6.90
~7.56 (9N, m).

12.0(18,d, J=12Hz)C,9H,5
Calculated value as FO3: C, 73, 54'; H, 4, 87% Measured value: C,? 3.86; H, 4,91% Reference Example 2 In a solution of 0.13 g of α-chloromethyl-(2-fluoro-4-biphenylyl)acetic acid dissolved in 5 ml of 10% potassium hydroxide-methanol solution Q, 0.04 g of % palladium-carbon was added, and reduction was carried out in an autoclave at 60° C. and under a hydrogen pressure of 5 atm for 6 hours. After the reaction, the reaction solution was filtered to remove the catalyst, the p solution was concentrated, 2 ml of water was added to the resulting residue, and the pH of the solution was adjusted to 2 by adding 4N hydrochloric acid. The extract was extracted with ether (<5 mL twice), washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain 0.10 g of 2-(2-fluoro-4-biphenylyl)propionic acid. The melting point of the product recrystallized from n-hexane was 113-114°C.

Reference Example 3 Raney nickel 2IT11 was added to a solution of 0.15 g of α-methylthiomethyl-(2-fluoro-4-biphenylyl)acetic acid in 2 ml of methanol, and the mixture was heated under reflux for 9 hours. The catalyst was removed by filtration, and the resulting residue was recrystallized from n-hexane to yield almost pure 2-(
2-Fluoro-4-biphenylyl)propionic acid was obtained. Melting point 113-114°C.

Effects of the Invention According to the method of the present invention which involves intermediates, useful final substances can be obtained under mild conditions and with safe and easy operations.

Patent applicant (102) Kyowa Hakko Kogyo Co., Ltd.
Continued amendment January 73, 1986

Claims (1)

[Claims] Formulas include mathematical formulas, chemical formulas, tables, etc. (wherein Y is a hydroxy group, a halogen atom, a mercapto group, a lower alkylthio group, an arylthio group, an amino group,
A lower alkylamino group or a di-lower alkylamino group,
R represents a hydrogen atom or a lower alkyl group. ) A 2-fluoro-4-biphenylylacetic acid derivative represented by: