JPH0153661B2 - - Google Patents
Info
- Publication number
- JPH0153661B2 JPH0153661B2 JP17456782A JP17456782A JPH0153661B2 JP H0153661 B2 JPH0153661 B2 JP H0153661B2 JP 17456782 A JP17456782 A JP 17456782A JP 17456782 A JP17456782 A JP 17456782A JP H0153661 B2 JPH0153661 B2 JP H0153661B2
- Authority
- JP
- Japan
- Prior art keywords
- formula
- fluorobiphenyl
- represented
- reaction
- ethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- YCOXTKKNXUZSKD-UHFFFAOYSA-N as-o-xylenol Natural products CC1=CC=C(O)C=C1C YCOXTKKNXUZSKD-UHFFFAOYSA-N 0.000 claims description 5
- SNHMUERNLJLMHN-UHFFFAOYSA-N iodobenzene Chemical compound IC1=CC=CC=C1 SNHMUERNLJLMHN-UHFFFAOYSA-N 0.000 claims description 5
- ZLKQQDFLPVWFDT-UHFFFAOYSA-N 1-(3-fluoro-4-phenylphenyl)ethanone Chemical group FC1=CC(C(=O)C)=CC=C1C1=CC=CC=C1 ZLKQQDFLPVWFDT-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- GEBUSPQBSWYLBN-UHFFFAOYSA-N 4-ethyl-2-fluoro-1-phenylbenzene Chemical group FC1=CC(CC)=CC=C1C1=CC=CC=C1 GEBUSPQBSWYLBN-UHFFFAOYSA-N 0.000 claims description 2
- FZGLYBAYKWOVFZ-UHFFFAOYSA-N 5-ethyl-2-phenylaniline Chemical group NC1=C(C=CC(=C1)CC)C1=CC=CC=C1 FZGLYBAYKWOVFZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000006887 Ullmann reaction Methods 0.000 claims description 2
- MXBMKNNPFIPIBM-UHFFFAOYSA-N 1-bromo-4-ethyl-2-nitrobenzene Chemical compound CCC1=CC=C(Br)C([N+]([O-])=O)=C1 MXBMKNNPFIPIBM-UHFFFAOYSA-N 0.000 claims 1
- KXZHLITXFKZKJC-UHFFFAOYSA-N 4-ethyl-2-nitro-1-phenylbenzene Chemical group [O-][N+](=O)C1=CC(CC)=CC=C1C1=CC=CC=C1 KXZHLITXFKZKJC-UHFFFAOYSA-N 0.000 claims 1
- 230000026030 halogenation Effects 0.000 claims 1
- 238000005658 halogenation reaction Methods 0.000 claims 1
- -1 biphenyl compound Chemical class 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000000243 solution Substances 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003054 catalyst Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000000921 elemental analysis Methods 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 150000008062 acetophenones Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000007086 side reaction Methods 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- YIVJZNGAASQVEM-UHFFFAOYSA-N Lauroyl peroxide Chemical compound CCCCCCCCCCCC(=O)OOC(=O)CCCCCCCCCCC YIVJZNGAASQVEM-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 235000010290 biphenyl Nutrition 0.000 description 2
- 239000004305 biphenyl Substances 0.000 description 2
- 238000010531 catalytic reduction reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RYDDNTFGUBVICV-UHFFFAOYSA-N 1-(3-nitro-4-phenylphenyl)ethanone Chemical group [O-][N+](=O)C1=CC(C(=O)C)=CC=C1C1=CC=CC=C1 RYDDNTFGUBVICV-UHFFFAOYSA-N 0.000 description 1
- YFVOFFKNHQTQQE-UHFFFAOYSA-N 1-(4-bromo-3-nitrophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Br)C([N+]([O-])=O)=C1 YFVOFFKNHQTQQE-UHFFFAOYSA-N 0.000 description 1
- RILZRCJGXSFXNE-UHFFFAOYSA-N 2-[4-(trifluoromethoxy)phenyl]ethanol Chemical compound OCCC1=CC=C(OC(F)(F)F)C=C1 RILZRCJGXSFXNE-UHFFFAOYSA-N 0.000 description 1
- PYTPYXCFKXSEFK-UHFFFAOYSA-N 4-(1-bromoethyl)-2-fluoro-1-phenylbenzene Chemical group FC1=CC(C(Br)C)=CC=C1C1=CC=CC=C1 PYTPYXCFKXSEFK-UHFFFAOYSA-N 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 238000006350 Schiemann fluorination reaction Methods 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000001743 benzylic group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000008282 halocarbons Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- YAMWQJCABLEXQR-UHFFFAOYSA-M sodium;hydrogen carbonate;methylsulfinylmethane Chemical compound [Na+].CS(C)=O.OC([O-])=O YAMWQJCABLEXQR-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
【発明の詳細な説明】
本発明は、医薬として有用な２―（２―フルオ
ロ―４―ビフエニル）プロピオン酸製造の重要な
中間体である式(6)
であらわされるアセトフエノン誘導体の製造方法
に関する。DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of formula (6) which is an important intermediate for the production of 2-(2-fluoro-4-biphenyl)propionic acid, which is useful as a pharmaceutical. The present invention relates to a method for producing an acetophenone derivative represented by:
本発明によれば、式(6)のアセトフエノン誘導体
は以下に述べる方法により製造される。すなわち
式(1)
であらわされるブロマイドを出発原料とし、ヨー
ドベンゼンと反応させることにより式(2)
であらわされるビフエニル体を得る。この反応に
際しては、銅粉末を触媒とし、ヨードベンゼンの
沸点付近の温度（185〜190℃）で５時間ないし８
時間激しく撹拌すると反応は完結する。 According to the present invention, the acetophenone derivative of formula (6) is produced by the method described below. That is, equation (1) By using the bromide represented by as a starting material and reacting it with iodobenzene, the formula (2) is obtained. The biphenyl compound represented by is obtained. In this reaction, copper powder is used as a catalyst and the reaction is carried out at a temperature near the boiling point of iodobenzene (185-190℃) for 5 hours to 8 hours.
The reaction is completed after vigorous stirring for an hour.
つぎに反応液は、冷却後過し、液を蒸留精
製することにより高収率でビフエニル体を得るこ
とができる。ついでこの化合物を還元することに
より式(3)
であらわされるアミン体を生成する。この反応に
際しては、エチルアルコールなどのアルコール系
溶媒中で室温下にパラジウム―炭素触媒を用いて
接触還元する方法、あるいは鉄、錫などの金属と
鉱酸による還元法などによりニトロ基を還元でき
るが、本発明のように接触還元法が後処理の容易
さ、収率の良さなどではるかにすぐれた方法であ
る。得られたアミン体は、シーマン反応を行うこ
とにより式(4)
であらわされる弗化物とすることができる。この
反応に際しては、式(3)であらわされるアミン体を
塩酸および亜硝酸ソーダでジアゾ化した後、弗化
硼素酸を加え、析出する弗化硼素ジアゾニウム塩
を過して取り、これを乾燥後に加温分解するこ
とにより弗素を導入できる。得られた弗化炭化水
素の側鎖エチル基を酸化してアセトフエノン誘導
体に導くために、四塩化炭素等のハロゲン化炭化
水素を溶媒としてＮ―ブロムコハク酸イミドまた
はＮ―クロロコハク酸イミドを過酸化ラウロイル
などの過酸化物を触媒として、反応させて式(5)
（式中ＸはClまたはBrである）であらわされる
ハロゲン化物を生成させた後、ジメチルスルフオ
キシド―炭酸水素ナトリウムの系で60℃において
５〜８時間反応させることにより、式(6)
であらわされる目的の４―アセチル―２―フルオ
ロビフエニルが製造される。 Next, the reaction solution is cooled and filtered, and the biphenyl compound can be obtained in high yield by distilling and purifying the solution. Then, by reducing this compound, formula (3) It produces an amine compound represented by In this reaction, the nitro group can be reduced by catalytic reduction using a palladium-carbon catalyst at room temperature in an alcoholic solvent such as ethyl alcohol, or by a reduction method using a metal such as iron or tin and a mineral acid. However, the catalytic reduction method as used in the present invention is a far superior method in terms of ease of post-treatment and good yield. The obtained amine compound is converted to the formula (4) by performing the Seeman reaction. It can be a fluoride represented by In this reaction, the amine compound represented by formula (3) is diazotized with hydrochloric acid and sodium nitrite, then fluoroboric acid is added, the precipitated boron fluoride diazonium salt is filtered off, and after drying, Fluorine can be introduced by thermal decomposition. 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 is converted to lauroyl peroxide using a halogenated hydrocarbon such as carbon tetrachloride as a solvent. Formula (5) is obtained by reacting with peroxide such as as a catalyst. After producing a halide represented by (wherein X is Cl or Br), the formula (6) is obtained by reacting in a dimethyl sulfoxide-sodium hydrogen carbonate system at 60°C for 5 to 8 hours. The desired 4-acetyl-2-fluorobiphenyl represented by is produced.
従来の４―アセチル―２―フルオロビフエニル
の製造方法については特開昭52−153932号、特開
昭53−84952号および特開昭54−112842号公報が
開示されている。その１例を掲げると、４―アセ
チル―１―ブロム―２―ニトロベンゼンを出発原
料としてヨードベンゼンとウルマン反応させ、得
られた４―アセチル―２―ニトロビフエニルを還
元してアミンとし、これをシーマン反応に付する
ことにより弗素を導入して目的化合物を製造する
方法がある。 Conventional methods for producing 4-acetyl-2-fluorobiphenyl are disclosed in JP-A-52-153932, JP-A-53-84952, and JP-A-54-112,842. One example is that 4-acetyl-1-bromo-2-nitrobenzene is used as a starting material and subjected to Ullmann reaction with iodobenzene, and the resulting 4-acetyl-2-nitrobiphenyl is reduced to an amine, which is then subjected to Schiemann reaction. There is a method of producing the target compound by introducing fluorine by subjecting the compound to .
この方法は、一見工程数が少なく大変良い方法
にみえるが、各反応工程で活性の高いアセチル基
が種々の副反応に関与して多くの副生成物を生
じ、その結果精製工程が大変困難で手間がかか
り、高収率は望めないという欠点を有する。 At first glance, this method seems to be a very good method with a small number of steps, but 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. It has the disadvantage that it is time consuming and high yield cannot be expected.
本発明においては、この点に留意して合成法を
検討した結果、アセチル基の存在が副反応の主要
因であることは明らかなことから側鎖をエチル基
のまま種々の反応に供し、最終的にベンジル位を
酸化する方法を開発した。本方法は工程が長くな
り、一見すると不経済にみえるが、各工程で副反
応がほとんど生じないために中間体の純度もよ
く、精製も極めて容易であり、好収率で目的化合
物を得られるという利点を有する。 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. This method requires a long process and appears uneconomical at first glance, but because almost no side reactions occur in each step, the intermediate is of good purity and purification is extremely easy, allowing the target compound to be obtained in good yield. It has the advantage of
以下に実施例を記載する。 Examples are described below.
実施例 １
４―エチル―２―ニトロビフエニルの合成
１―ブロム―４―エチル―２―ニトロベンゼン
（10.3ｇ、44.8ミリモル）とヨードベンゼン（50
ｇ、245ミリモル）とを合わせ、この中へ銅粉末
（7.0ｇ、110ミリモル）を加えた後、185〜190℃
で6.0時間撹拌した。冷却後過し、沈殿をベン
ゼン（40ml）で洗浄し、液と洗浄液を合わせて
濃縮し、残渣を減圧蒸留した後エチルアルコール
で再結晶して8.0ｇ（78.7％）の４―エチル―２
―ニトロビフエニルを得た。Example 1 Synthesis of 4-ethyl-2-nitrobiphenyl 1-bromo-4-ethyl-2-nitrobenzene (10.3 g, 44.8 mmol) and iodobenzene (50
g, 245 mmol) and added copper powder (7.0 g, 110 mmol) thereto, and heated to 185-190℃.
The mixture was stirred for 6.0 hours. After cooling and filtering, the precipitate was washed with benzene (40 ml), the liquid and washing liquid were combined and concentrated, and the residue was distilled under reduced pressure and recrystallized with ethyl alcohol to obtain 8.0 g (78.7%) of 4-ethyl-2.
- Nitrobiphenyl was obtained.
b.p.135〜142゜（4.0mmＨｇ）、m.p.41.6〜42.0℃。b.p.135~142° (4.0mmHg), m.p.41.6~42.0℃.
IRνnax・cm-1：1530（vs）、1485（ｗ）、1445（ｗ）
、
1355（ｍ）、840（ｗ）、795（ｍ）、770（ｍ）、755
（ｍ）、700（ｍ）。IRν nax・cm -1 : 1530 (vs), 1485 (w), 1445 (w)
,
1355 (m), 840 (w), 795 (m), 770 (m), 755
(m), 700 (m).
NMR（60MHz、CDCl3）、δ1.26（3H、ｔ、Ｊ＝7.0
Hz）、2.71（2H、ｑ、Ｊ＝7.0Hz）、〜7.30（8H、
ｍ、アロマ）。NMR (60MHz, CDCl 3 ), δ1.26 (3H, t, J=7.0
Hz), 2.71 (2H, q, J = 7.0Hz), ~7.30 (8H,
m, aroma).
MS ｍ／ｚ（70eV）227（M+）、229（M+＋２）、
210、199。MS m/z (70eV) 227 (M + ), 229 (M + +2),
210, 199.
元素分析
Ｃ％ Ｈ％ Ｎ％
実測値： 73.91 5.75 6.14
計算値： 73.99 5.77 6.16
実施例 ２
２―アミノ―４―エチルビフエニルの合成
４―エチル―２―ニトロビフエニル（39.0ｇ、
172ミリモル）をエタノール（200ml）に溶解しア
ルゴン気流下に５％Pd―Ｃ（4.0ｇ）を加えた後、
マーゲン内を水素で置き換えて水添した。約11.6
の水素が吸収されたところで反応を停止し、触
媒を別し、液を濃縮後に残渣を蒸留して30.3
ｇ（89.5％）の２―アミノ―４―エチルビフエニ
ルを得た。Elemental analysis C% H% N% Actual value: 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 (39.0g,
After dissolving 172 mmol) in ethanol (200 ml) and adding 5% Pd-C (4.0 g) under an argon atmosphere,
Hydrogenation was carried out by replacing the inside of Marken with hydrogen. Approximately 11.6
The reaction is stopped when 30.3% of hydrogen has been absorbed, the catalyst is separated, the liquid is concentrated, and the residue is distilled to 30.3%.
g (89.5%) of 2-amino-4-ethylbiphenyl was obtained.
b.p.148゜〜153゜（4.0mmＨｇ）、n20.0 D1.6070。bp148°~153° (4.0mmHg), n 20.0 D 1.6070.
IRνnax・cm-1：3460（ｗ）、3370（ｍ）、1620（ｓ）
、
1575（ｍ）、1560（ｍ）、1520（ｗ）、1450（ｗ）、
1425（ｍ）、1295（ｗ）、1220（ｗ）、1070（ｗ）、
1060（ｗ）、1010（ｍ）、860（ｍ）。IRν nax・cm -1 : 3460 (w), 3370 (m), 1620 (s)
,
1575 (m), 1560 (m), 1520 (w), 1450 (w),
1425 (m), 1295 (w), 1220 (w), 1070 (w),
1060 (w), 1010 (m), 860 (m).
NMR（60MHz、CDCl3）、δ1.23（3H、ｔ、Ｊ＝
7.50Hz）、2.60（2H、ｑ、Ｊ＝7.50Hz）、3.60
（2H、br、ｓ、−NH2）、〜6.5〜7.5（8H、ｍ、
アロマ）。NMR (60MHz, CDCl 3 ), δ1.23 (3H, t, J=
7.50Hz), 2.60 (2H, q, J = 7.50Hz), 3.60
(2H, br, s, -NH2 ), ~6.5~7.5 (8H, m,
aroma).
MS（70eV）ｍ／ｚ、197（M+）。MS (70eV) m/z, 197 (M + ).
元素分析
Ｃ％ Ｈ％ Ｎ％
実測値： 85.26 7.68 7.20
計算値： 85.24 7.66 7.10
実施例 ３
２―フルオロ―４―エチルビフエニルの合成
２―アミノ―４―エチルビフエニル（23.0ｇ、
117ミリモル）に水（23.0ml）と濃塩酸（23.0ml）
とを加え、撹拌しながら５℃以下に冷却してこの
中へ水（30.0ml）に溶解した亜硝酸ソーダ（20.0
ｇ、0.29モル）を５℃以下で約40分間かけて滴下
した。次いで47％HBF4溶液（25.0ml）を加え、
さらに30分間撹拌した後、析出した結晶を過
し、結晶をメタノール（15ml）およびエーテル
（50ml）で洗浄後に乾燥した。デシケータ中にこ
の結晶を放置すると徐々に分解して約24時間で分
解が完了した。残つた油状物を蒸留して13.2ｇ
（58％）の２―フルオロ―４―エチルビフエニル
を得た。Elemental analysis C% H% N% Actual 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 (23.0g,
117 mmol), water (23.0 ml) and concentrated hydrochloric acid (23.0 ml)
Add sodium nitrite (20.0
g, 0.29 mol) was added dropwise over a period of about 40 minutes at a temperature below 5°C. Then add 47% HBF 4 solution (25.0ml),
After stirring for an additional 30 minutes, the precipitated crystals were filtered, washed with methanol (15 ml) and ether (50 ml), 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 13.2g.
(58%) of 2-fluoro-4-ethylbiphenyl was obtained.
b.p.121〜123゜（5.0mmＨｇ）。b.p.121~123° (5.0mmHg).
IRνnax・cm-1：1625（ｗ）、1605（ｗ）、1580（ｍ）
、
1560（ｍ）、1520（ｍ）、1490（ｍ）、1450（ｗ）、
1420（ｍ）、1270（ｍ）、1230（ｍ）、1150（ｗ）、
1130（ｍ）、1010（ｍ）、915（ｍ）、870（ｍ）、830
（ｍ）、765（ｍ）、730（ｍ）、700（ｓ）。IRν nax・cm -1 : 1625 (w), 1605 (w), 1580 (m)
,
1560 (m), 1520 (m), 1490 (m), 1450 (w),
1420 (m), 1270 (m), 1230 (m), 1150 (w),
1130 (m), 1010 (m), 915 (m), 870 (m), 830
(m), 765 (m), 730 (m), 700 (s).
NMR（60MHz、CDCl3）、δ1.23（3H、ｔ、Ｊ＝7.0
Hz）、2.62（2H、ｑ、Ｊ＝7.0Hz）、6.70〜7.70
（8H、ｍ、アロマ）。NMR (60MHz, CDCl 3 ), δ1.23 (3H, t, J=7.0
Hz), 2.62 (2H, q, J = 7.0Hz), 6.70-7.70
(8H, m, aroma).
MS（70eV）ｍ／ｚ、200（M+）、185（M+−Me）。MS (70eV) m/z, 200 (M + ), 185 (M + −Me).
元素分析
Ｃ％ Ｈ％
実測値： 84.04 6.35
計算値： 83.97 6.54
実施例 ４
４―（１―ブロムエチル）―２―フルオロビフ
エニルの合成
４―エチル―２―フルオロビフエニル（10.0
ｇ、50ミリモル）とＮ―ブロムコハク酸イミド
（17.8ｇ、100ミリモル）とを四塩化炭素（120ml）
に溶解し、触媒として過酸化ラウロイルを少量加
えた後、8.0時間加熱還流した。放冷後、過し、
液を水洗し、そしてチオ硫酸ソーダ溶液、飽和
重曹水、飽和食塩そして水で順次洗浄した後に乾
燥（CaCl2）および濃縮して残渣をエタノールで
再結する。11.84ｇ（84.9％）の４―（１―ブロ
ムエチル）―２―フルオロビフエニルを得た。Elemental analysis C% H% Actual value: 84.04 6.35 Calculated value: 83.97 6.54 Example 4 Synthesis of 4-(1-bromoethyl)-2-fluorobiphenyl 4-ethyl-2-fluorobiphenyl (10.0
g, 50 mmol) and N-bromosuccinimide (17.8 g, 100 mmol) in carbon tetrachloride (120 ml).
After adding a small amount of lauroyl peroxide as a catalyst, the mixture was heated under reflux for 8.0 hours. After cooling, strain
The solution is washed with water and successively with sodium thiosulfate solution, saturated aqueous sodium bicarbonate, saturated salt and water, then dried (CaCl 2 ) and concentrated, and the residue is reconsolidated with ethanol. 11.84 g (84.9%) of 4-(1-bromoethyl)-2-fluorobiphenyl was obtained.
m.p.54.2〜55.0℃
IRνnax・cm-1：1585（ｍ）、1565（ｗ）、1420（ｍ）
、
1380（ｍ）、1275（ｍ）、1225（ｍ）、1190（ｍ）、
1140（ｍ）、1090（ｍ）、1050（ｍ）、1020（ｗ）、
980（ｗ）、915（ｍ）、880（ｍ）、840（ｍ）。mp54.2～55.0℃ IRν nax・cm -1 : 1585 (m), 1565 (w), 1420 (m)
,
1380 (m), 1275 (m), 1225 (m), 1190 (m),
1140 (m), 1090 (m), 1050 (m), 1020 (w),
980 (w), 915 (m), 880 (m), 840 (m).
NMR（60MHz、CDCl3）、δ2.00（3H、ｄ、Ｊ＝7.0
Hz）、5.15（1H、ｑ、Ｊ＝7.0Hz）、〜7.30（8H、
ｍ、アロマ）。NMR (60MHz, CDCl 3 ), δ2.00 (3H, d, J=7.0
Hz), 5.15 (1H, q, J = 7.0Hz), ~7.30 (8H,
m, aroma).
MS（70eV）ｍ／ｚ、278（M+−２）、276（M+−
２）。MS (70eV) m/z, 278 (M + -2), 276 (M + -
2).
元素分析
Ｃ％ Ｈ％
実測値： 60.20 4.25
計算値： 60.24 4.33
実施例 ５
４―アセチル―２―フルオロビフエニルの合成
４―（１―ブロムエチル）―２―フルオロビフ
エニル（200mg、0.72ミリモル）と炭酸水素ナト
リウム（130mg、1.54ミリモル）とをジメチルス
ルホキシド（5.0ml）に溶解しそして60℃で５時
間撹拌した。反応液は水（50ml）にあけ、イソプ
ロピルエーテル抽出（20ml×２回）し、抽出した
有機層を合わせ、これを水および飽和食塩水で順
次洗い、乾燥（MgSO4）および濃縮し、そして
残渣をイソプロピルエーテルで再結晶して1.40mg
（91.3％）の４―アセチル―２―フルオロビフエ
ニルを得た。Elemental analysis C% H% Actual value: 60.20 4.25 Calculated value: 60.24 4.33 Example 5 Synthesis of 4-acetyl-2-fluorobiphenyl 4-(1-bromoethyl)-2-fluorobiphenyl (200 mg, 0.72 mmol) and Sodium bicarbonate (130 mg, 1.54 mmol) was dissolved in dimethyl sulfoxide (5.0 ml) and stirred at 60°C for 5 hours. The reaction solution was poured into water (50 ml), extracted with isopropyl ether (20 ml x 2), the extracted organic layers were combined, washed sequentially with water and saturated brine, dried (MgSO 4 ) and concentrated, and the residue Recrystallize with isopropyl ether to obtain 1.40mg
(91.3%) of 4-acetyl-2-fluorobiphenyl was obtained.
m.p.95.2〜96.0℃。m.p.95.2~96.0℃.
IRνnax・cm-1：1680（vs）、1415（ｓ）、1280（ｓ）
、
890（ｓ）、770（ｓ）。IRν nax・cm -1 : 1680 (vs), 1415 (s), 1280 (s)
,
890(s), 770(s).
NMR（60MHz、CDCl3）、δ2.60（1H、ｓ）、〜7.45
〜（8H、ｍ、アロマ）。NMR (60MHz, CDCl3 ), δ2.60 (1H, s), ~7.45
~ (8H, m, aroma).
元素分析 Ｃ％ Ｈ％ 実測値： 78.32 5.11 計算値： 78.49 5.18Elemental analysis C% H% Actual value: 78.32 5.11 Calculated value: 78.49 5.18
Claims (1)
チルベンゼンとヨードベンゼンとをウルマン反応
させて式(2) であらわされる４―エチル―２―ニトロビフエニ
ルとなし、これを還元することにより式(3) であらわされる２―アミノ―４―エチルビフエニ
ルとなし、さらにこれをシーマン反応に付するこ
とにより式(4) であらわされる４―エチル―２―フルオロビフエ
ニルとなし、これをハロゲン化して式(5) であらわされる４―（１―ハロエチル）―２―フ
ルオロビフエニル（ＸはClまたはBrである）と
なし、そしてこれを酸化することを特徴とする、
４―アセチル―２―フルオロビフエニル(6) の製造方法。[Claims] 1 Formula (1) The Ullmann reaction of 1-bromo-2-nitro-4-ethylbenzene and iodobenzene expressed by the formula (2) By reducing this to 4-ethyl-2-nitrobiphenyl represented by formula (3) By further subjecting this to 2-amino-4-ethylbiphenyl represented by Formula (4) 4-ethyl-2-fluorobiphenyl represented by the formula (5) is obtained by halogenation. 4-(1-haloethyl)-2-fluorobiphenyl (X is Cl or Br), and oxidizes this.
4-acetyl-2-fluorobiphenyl(6) manufacturing method.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17456782A JPS5965037A (en) | 1982-10-06 | 1982-10-06 | Preparation of 4-acetyl-2-fluorobiphenyl |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP17456782A JPS5965037A (en) | 1982-10-06 | 1982-10-06 | Preparation of 4-acetyl-2-fluorobiphenyl |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5965037A JPS5965037A (en) | 1984-04-13 |
| JPH0153661B2 true JPH0153661B2 (en) | 1989-11-15 |
Family
ID=15980816
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP17456782A Granted JPS5965037A (en) | 1982-10-06 | 1982-10-06 | Preparation of 4-acetyl-2-fluorobiphenyl |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS5965037A (en) |
-
1982
- 1982-10-06 JP JP17456782A patent/JPS5965037A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5965037A (en) | 1984-04-13 |
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