JPS5965037A - Preparation of 4-acetyl-2-fluorobiphenyl - Google Patents

Abstract

PURPOSE:To prepare the titled compound useful as an intermediate of pharmaceuticals, in high yield, with easy purification of the intermediate, by using 1- bromo-2-nitro-4-ethylbenzene as a starting raw material, and finally oxidizing the benzyl site. CONSTITUTION:The compound of formula I and iodobenzene are subjected to Ullmann reaction and the resultant 4-ethyl-2-nitrobiphenyl of formula II is catalytically reduced at room temperature in an alcohol solvent using a Pd-C catalyst to obtain an amino derivative of formula III, which is converted to 4- ethyl-2-fluorobiphenyl of formula IV by Schiemann reaction. The compound of formula IV is made to react with N-chloro-(or bromo-)succinimide in a halogenated hydrocarbon solvent using a peroxide as a catalyst, and the obtained halide is oxidized in a dimethylsulfoxide-sodium bicarbonate system to obtain the objective compound of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 2-(2-fluor-4-
The present invention relates to a method for producing an acetophenone derivative represented by formula (6), which is an important intermediate in the production of biphegol propionic acid.

According to the present invention, the acetophenone derivative of formula (6) is produced by the method described below. That is, a biphenyl compound expressed by formula (9) (2) is obtained by using a bromide expressed by formula (1) O2 as a starting material and reacting it with iodobenzene.In this reaction, copper powder is used as a catalyst, and the -Temperature near the boiling point of dobenzene (185-19
The reaction is completed after stirring vigorously for 5 to 8 hours at 0°C.

Next, the reaction liquid is filtered after cooling, and the biphenyl compound can be obtained in high yield by distilling and purifying the F solution. This compound is then reduced to produce an amine compound represented by formula (3). For this reaction, a method of catalytic reduction using a palladium-carbon catalyst at room temperature in an alcoholic solvent such as ethyl alcohol,
Alternatively, the dinitro group can be reduced by a reduction method using a metal such as iron or tin and a mineral acid, but the catalytic reduction method as used in the present invention is a much superior method due to ease of post-treatment and high yield. be. The obtained amine compound can be converted into a fluoride represented by the formula (4) by performing the Dieman reaction. In this reaction, the amine compound formed by formula (3) is diazotized with hydrochloric acid, nitrous acid, and soda, then fluoroboric acid is added, and the precipitated boron fluoride diazonium salt is filtered out. Fluorine can be introduced by thermal decomposition after drying. In order to oxidize the side chain ethyl group of the obtained fluorinated hydrocarbon to lead to an acetophenone derivative, N-bromosuccinimide or N-chlorosuccinimide was peroxidized using a halogenated hydrocarbon in a carbon tetrachloride cap as a solvent. After reacting with a peroxide such as lauroyl as a catalyst to produce a halide represented by the formula (5) (wherein X is Ct and Br), dimethyl sulfoxide-sodium hydrogen carbonate is reacted. By reacting in a system at 60°C for 5 to 8 hours, the desired 4-acetyl-2-fluorobiphenyl represented by formula (6) is produced.

Conventional methods for producing 4-acetyl-2-fluorobiphenyl are described in JP-A-52-153932 and JP-A-53.
-84952 and JP-A-54-112842 are disclosed. One example is that 4-acetyl-1-bromo-2-nitrobenzene is used as a starting material and is subjected to an Ullmann reaction with iodobenzene, and the resulting 4-acetyl-2-nitrobiphenyl is reduced to an amine. There is a method for producing the target compound by introducing fluorine by subjecting it to a Dieman reaction.

Although this method seems to be a very good method with a small number of steps, the highly active acetyl group participates in various side reactions in each reaction step, producing many byproducts, and as a result, the purification step is very difficult. The disadvantage is that it is time-consuming and high yield cannot be expected.

In the present invention, as a result of considering the synthesis method with this point in mind, it is clear that the presence of an acetyl group is the main cause of side reactions, so we subjected the side chain to various reactions as an ethyl group and We developed a method to oxidize the benzylic position. Although this method requires a long process and seems uneconomical,
Since almost no side reactions occur in each step, the purity of the intermediate is high, purification is extremely easy, and the desired compound can be obtained in good yield.

Examples are described below.

Practical example 1 Synthesis of 4-ethyl-2-nitrobiphenyl 1-7' rom-4-ethyl-2-nitrobenzene (10
, 3t, 44.8 mmol) and iodobenzene (50
? , 245 mmol) and add copper powder C7 into this.
, Of, 110 mmol), 185-190
The mixture was stirred at ℃ for 6.0 hours. After cooling, it was filtered, the precipitate was washed with benzene (40 m), the P liquid and the washing liquid were combined and concentrated, the residue was distilled under reduced pressure, and then recrystallized with ethyl alcohol.8. Of (78,7%) of 4-ethyl-2-nitrobiphenyl was obtained.

b, p, 135~14'2@(4,0mmHg), m
, p, 41.6-42.0°C.

Engineering RνTnaz-cm-': 1550 (vs), 1
485(w), 1445(w).

1355 (m), 840 (w), 795 (m),
770 (m), 755 (m), 700 (m).

NMR (60MHz, CDCl2), δ1.26
(3H, t, , T = 7.0Hz), 2.71 (2H, q
, J=7.0Hz), ~7.30 (8H, m, aroma).

MSm/z (70eV) 227 (M+), 229(
M++2), 210, 199° Elemental analysis actual measurement A [: 73.91 5.75 6.14 Calculated value: 73.99 5.77 6.16 Example 2 Synthesis of 2-amino-4-ethylbiphenyl 4-ethyl- 2-Nitrobiphenyl (59, Of.

After dissolving 172 mmol) in ethanol (200d) and adding 596 Pd-C (4, Of) under an argon stream, the inside of Marken was replaced with hydrogen for hydrogenation.

When approximately 11.6 tons of hydrogen has been absorbed, the reaction is stopped, the catalyst is separated, the P liquid is concentrated, and the residue is distilled.30.
39 (89, Section 5) obtained 2-amino-4-ethylbiphenyl.

b, p, L48° ~ 153° (4, OmmHg), TI
D 1.6070゜ENGRJmBz・crn-':346
0(w), 5370(m), 1620(s), 1575
(m), 1560 (m), 1520 (w), 1450 (
w), 1425 (m).

1295(w), 1220(w), 101070(,1
01060(,101010(,86 width).

NMR (6ffMHz, CDCl2), δ1.23
(3H,t,,T=7.50Hz), 2.60(2H1
q, J=150H2), 3.60(2H1'br, 8.
-NF2), ~6.5-7.5 (8H, m, aroma).

Ms(70eV)n)/z, 197(M”).

Actual elemental analysis value: 85.26 7.68 7.20 Calculated value:
85.24 7.66 7.10 Example 3 Synthesis of 2-fluoro-4-ethylbiphenyl 2-amino-4-ethylbiphenyl (23, Of, 11
7 mmol), water (23.0 mg) and concentrated hydrochloric acid (23.0 mg)
Add sodium nitrite (20,0 mJ) dissolved in water (30,0
0.29 mol) was added dropwise at 5° C. or lower over about 40 minutes. Next, a 47% HBF4 solution (25.0 mg) was added, and after further stirring for 60 minutes, the precipitated crystals were filtered and dissolved in methanol (15d) and ether (50.0mg).
m/) and then dried.

When this crystal was left in a desiccator, it gradually decomposed and the decomposition was completed in about 24 hours. Distill the remaining oily substance to 1
3.29 (5El) of 2-fluoro-4-ethylbiphenyl was obtained.

b, p, 121-123° (5,0 mmHg).

IRvmaz-rrn-': 1625(w), 16
05(w), 1580(m), 1560(m), 152
0 (m), 1490 (m), 1450 (w), 1420
(m).

1270 (m), 1230 (m), 1150 (w), 1
111-30(,101010(,915(m),87
0 (m), 830 (m), 765 (m), 730 (m)
.

700(s).

NMR (60MHz + CDCZ 5 ) δ1.2
3 (3H, t, , T = 7.0Hz), 2.62 (2H.

q, J=7.0Hz), 6.70-7.70
(8H, m, aroma).

MS (70eV)rn/z, 200(M+), 18
5(M”-Me).

Actual elemental analysis value: 84.04 6.35 Calculated value: 85.97 6.54 Example 4 Synthesis of 4-(1-bromoethyl)-2-fluorobiphenyl 4-ethyl-2-fluorobiphenyl (10,02, 5
0 mmol) and N-bromosuccinimide (17,8F
, 100 mmol) in carbon tetrachloride (120 m/), and after adding a small amount of lauroyl peroxide as a catalyst, 8
The mixture was heated under reflux for 0 hours.

After cooling, it is filtered, the solution is washed with water, and then sequentially washed with sodium thiosulfate solution, saturated water, saturated sodium chloride, and water, dried (CaC42), concentrated, and the residue is reconstituted with ethanol. 4-(1-) of 11.849 (84,9 section)
Bromoethyl)-2-fluorobiphenyl was obtained.

m, p, 54.2-55.0°C I Rv max""-': 1585 (m),
1565(w), 1420(m), 1380(m
).

1275 (m), 1225 (m), 1190 (m), 1
140(m), 101090(,101050(,10
1020(,980(w),915(m),880(m
), 840(m).

NMR (60MHz, CDC1,3), 62.00
(3H, +1, J=7.OH2), 5.15(I
H.

q, J=l OH2) r ~7.30 (8HT
m + aroma).

MS (70eV) m/z, 27B (M÷-2), 2
76 (M+-2).

Actual elemental analysis value: 60.20 4.25 Subtraction value: 60.24 4.55 Example 5 Synthesis of 4-acetyl-2-fluorobiphenyl 4-(1-bromoethyl)-2-fluorobiphenyl (
20011 g, 0.72 mmol) and sodium bicarbonate (130 g, 1.54 mmol) were dissolved in dimethyl sulfoxide (5.0 mg) and stirred at 60°C for 5 hours. The reaction solution was poured into water (50-), extracted with inpropyl ether (20 m/x twice), the extracted organic layers were combined, washed sequentially with water and saturated brine, and dried (M
gSOa) and concentrated, and the residual liquid was recrystallized from isopropyl ether to obtain 140 parts (91,3 parts) of 4-acetyl-2-fluorobiphenyl.

m, p, 95.2-96.0°C.

Max-cm-': 1680 (vs), 1415
(θ), 1280(θ), 890(e), 770(s)
.

NMR (60MHz, CDCl2) δ2.60(I
H,s), ~7.45~(8H,m.

aroma).

elemental analysis C Chi H% Actual value: 78.32 5.11 Division value = 78.49 5.18 Patent applicant: Nisshin Seifun Co., Ltd. Same as Nisshin Chemical Co., Ltd.

Claims (1)

[Scope of Claims] 1-bromo-2-nido-4-ethylbenzene represented by the formula (1) is reacted with iodobenzene to obtain the formula (2).
) to give 4-ethyl-2-nitrobiphenyl, which is then reduced to give 2-amino-4-ethylbiphenyl, which is given by formula (3), and further converted to di-manganese. The reaction produces 4-ethyl-2-fluorobiphenyl represented by formula (4), which is then halogenated to form 4 represented by formula (5).
-(1-haloethyl)-2-fluorobiphenyl (X is Ct or Br), and oxidizing this, a method for producing 4-acetyl-2-fluorobiphenyl (6) .