JPH01125361A - Production of alpha-arylpropionitrile - Google Patents
Production of alpha-arylpropionitrileInfo
- Publication number
- JPH01125361A JPH01125361A JP28385187A JP28385187A JPH01125361A JP H01125361 A JPH01125361 A JP H01125361A JP 28385187 A JP28385187 A JP 28385187A JP 28385187 A JP28385187 A JP 28385187A JP H01125361 A JPH01125361 A JP H01125361A
- Authority
- JP
- Japan
- Prior art keywords
- reaction
- formula
- arylpropionitrile
- mol
- alcohol
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 6
- 150000004820 halides Chemical class 0.000 claims abstract description 14
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 10
- 125000005843 halogen group Chemical group 0.000 claims abstract description 6
- 125000003118 aryl group Chemical group 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims 3
- 238000006243 chemical reaction Methods 0.000 abstract description 33
- 150000001875 compounds Chemical class 0.000 abstract description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 abstract description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 abstract description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract description 4
- 230000002140 halogenating effect Effects 0.000 abstract description 4
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 abstract description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 150000004795 grignard reagents Chemical class 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000007818 Grignard reagent Substances 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000012279 sodium borohydride Substances 0.000 description 5
- 229910000033 sodium borohydride Inorganic materials 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- CRRUGYDDEMGVDY-UHFFFAOYSA-N 1-bromoethylbenzene Chemical compound CC(Br)C1=CC=CC=C1 CRRUGYDDEMGVDY-UHFFFAOYSA-N 0.000 description 3
- WAPNOHKVXSQRPX-UHFFFAOYSA-N 1-phenylethanol Chemical compound CC(O)C1=CC=CC=C1 WAPNOHKVXSQRPX-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- XPNGNIFUDRPBFJ-UHFFFAOYSA-N alpha-methylbenzylalcohol Natural products CC1=CC=CC=C1CO XPNGNIFUDRPBFJ-UHFFFAOYSA-N 0.000 description 3
- 125000006267 biphenyl group Chemical group 0.000 description 3
- -1 biphenylyl group Chemical group 0.000 description 3
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- JESIHYIJKKUWIS-UHFFFAOYSA-N 1-(4-Methylphenyl)ethanol Chemical compound CC(O)C1=CC=C(C)C=C1 JESIHYIJKKUWIS-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 2
- 238000006149 azo coupling reaction Methods 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical group CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 2
- DMQHFJJRWZJNLF-UHFFFAOYSA-N 1-(1-bromoethyl)-4-methylbenzene Chemical compound CC(Br)C1=CC=C(C)C=C1 DMQHFJJRWZJNLF-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- VELPKXLIEFPYNV-UHFFFAOYSA-N 2-(4-methylphenyl)propanenitrile Chemical compound N#CC(C)C1=CC=C(C)C=C1 VELPKXLIEFPYNV-UHFFFAOYSA-N 0.000 description 1
- NVAOLENBKNECGF-UHFFFAOYSA-N 2-phenylpropanenitrile Chemical compound N#CC(C)C1=CC=CC=C1 NVAOLENBKNECGF-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- HTRNHWBOBYFTQF-UHFFFAOYSA-N 4-bromo-2-fluoro-1-phenylbenzene Chemical group FC1=CC(Br)=CC=C1C1=CC=CC=C1 HTRNHWBOBYFTQF-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000005002 aryl methyl group Chemical group 0.000 description 1
- 238000003763 carbonization Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000007809 chemical reaction catalyst Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000007333 cyanation reaction Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- SYTBZMRGLBWNTM-UHFFFAOYSA-N flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 description 1
- 229960002390 flurbiprofen Drugs 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
【発明の詳細な説明】
（産業上の利用分野）
本発明は、一般式［Ｉ）
Ｈ３
Ａｒ−ＣＨＣＮ （１）（式中、Ａｒ
は置換基を有することもあるアリール基を表わす）
で示されるα−アリールプロピオニトリルの新規な製造
方法に関するものであり、更に詳しくは一般式（Ｉｌ、
）
Ｈ３
Ａ ｒ −ＣＨＯＨＣＩＩ ］
（式中、Ａｒは前記と同一の意味を表わす）で示される
１−アリールエタノール（以下、アルコール（ｎ）と称
する）をハロゲン化して、一般式（ｍ）
ＣＨ。DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to the general formula [I) H3 Ar-CHCN (1) (wherein Ar
represents an aryl group which may have a substituent.
) H3 Ar -CHOHCII ] (wherein Ar represents the same meaning as above) 1-arylethanol (hereinafter referred to as alcohol (n)) is halogenated to give the general formula (m) CH.
Ａ ｒ −ＣＨＸ （ｍ ）（式中
、Ａｒは前記と同一の意味を表わし、Ｘはハロゲン原子
を表わす）
で示される１−アリールエチルハライド（以下、ハロゲ
ン化物（ｍ）と称する）としたのち、このハロゲン化物
（ＩＩＩ）とシアン化アルカリとを反応させることから
なるα−アリールプロピオニトリルの製造方法に関する
。After forming 1-arylethyl halide (hereinafter referred to as halide (m)) represented by A r -CHX (m) (wherein Ar represents the same meaning as above and X represents a halogen atom), , relates to a method for producing α-arylpropionitrile, which comprises reacting this halide (III) with an alkali cyanide.
本発明で得られるα−アリールプロピオニトリルは、フ
ルルビプロフェンで代表される医薬品の中間体として有
用な化合物である。α-Arylpropionitrile obtained in the present invention is a compound useful as an intermediate for pharmaceuticals, typified by flurbiprofen.
（従来の技術および発明が解決すべき問題点）従来、α
−アリールプロピオニトリルの製造方法としては、アミ
ノハロベンゼンアセトニトリル類のジアゾカップリング
によりビフェニルアセトニトリル類を製造する方法（ア
メリカ特許第４，５３９，３９７号および第４，５４４
，５０９号）が開示されている。(Problems to be solved by conventional techniques and inventions) Conventionally, α
-A method for producing arylpropionitriles includes a method for producing biphenylacetonitriles by diazo coupling of aminohalobenzeneacetonitriles (U.S. Pat. Nos. 4,539,397 and 4,544).
, No. 509) is disclosed.
しかし、これらの方法は、プロピオニトリル基の導入さ
れたアニリン誘導体のジアゾカップリングによるビフェ
ニル誘導体のみを製造するものであり、本発明のごとき
アリール基に任意の置換基を有することもあるα−アリ
ールプロピオニトリルを工業的に製造する製造法は開示
されていない。However, these methods only produce biphenyl derivatives by diazo coupling of aniline derivatives into which a propionitrile group has been introduced, and α- No method for industrially producing arylpropionitrile is disclosed.
（問題点を解決するための手段）
本発明者らは、α−アリールプロピオニトリルを工業的
に容易に製造する方法について検討した結果、下記の反
応式で示すように、［■） ［ＩＩ［：ｌ
［１１（反応式中、Ａｒは前記と同一の意
味を表わし、Ｘはハロゲン原子を表わす）
アルコール［ＩＩＩをハロゲン化してハロゲン化物（Ｉ
ＩＩ）としたのち、ハロゲン化物（ｍ）をシアン化アル
カリによりシアノ化することにより一３＝
α−アリールプロピオニトリルが得られることを見い出
し、本発明を完成したものである。(Means for Solving the Problems) The present inventors investigated a method for industrially easily producing α-arylpropionitrile, and as a result, as shown in the reaction formula below, [■] [II [:l
[11 (In the reaction formula, Ar represents the same meaning as above, and X represents a halogen atom) Alcohol [III is halogenated to form a halide (I
II), and then cyanating the halide (m) with an alkali cyanide to obtain -3=α-arylpropionitrile, thereby completing the present invention.
本発明の原料であるアルコール（ＩＩ）は、−般式（Ｉ
Ｖ）
Ａｒ−ＭｇＸ （ＩＶ）
（式中、Ａｒは前記と同一の意味を、Ｘはハロゲン原子
を表わす）
で示されるグリニヤール試薬（以下、グリニヤール試薬
［ＩＶ）と称する）とアセトアルデヒドとを反応させて
アルコール〔■〕とする、または一般式（Ｖ）
Ａｒ−Ｃ−ＣＨ３（Ｖ）
（式中、Ａｒは前記と同一の意味を表わす）で示される
アリールメチルケトン（以下、ケトンＥＶ）と称する）
の還元反応によりアルコール〔■〕が得られる。本発明
で用いるアルコール（ＩＩ）のアリール基としてはフェ
ニル基、トリル基、キシリル基、ビフェニリル基等が例
示され、置換基としてアルキル基、アルキルオキシ基、
アルケニル基、ハロゲン原子、保護基を有してもよい水
酸基およびアミノ基などを有するものも含むものである
。グリニヤール試薬（ＩＶ）とアセトアルデヒドからア
ルコール〔■〕を得る反応は、非プロトン溶媒例えばジ
エチルエーテル、ジイソプロピルエーテル、ジブチルエ
ーテル、テトラヒドロフランなどのエーテル類、ｎ−ペ
ンタン、ｎ−ヘキサン、ベンゼン、トルエンなどの炭化
水素系の反応溶媒中で、グリニヤール試薬〔■〕１当量
に対して１〜１．５当量のアセトアルデヒドを反応させ
る。反応温度は０〜１００℃、好ましくは１０〜５０℃
が適しており、通常は１〜５時間で反応は完結する。ま
た、ケトン〔ｖ〕の犀元反応によりアルコール（ＩＩＩ
を得る反応は、還元剤として水素化リチウムアルミニウ
ムまたは水素化ホウ素ナトリウムを用いることにより容
易に進行する。水素化リチウムアルミニウムを用いた還
元反応は、ジエチルエーテル、テトラヒドロフランなど
のエーテル類を溶媒として行われ、反応温度Ｏ〜５０℃
、反応時間１〜５時間で還元反応は完結する。Alcohol (II), which is a raw material of the present invention, has the general formula (I
V) Reacting a Grignard reagent (hereinafter referred to as Grignard reagent [IV]) represented by Ar-MgX (IV) (wherein Ar has the same meaning as above and X represents a halogen atom) with acetaldehyde. alcohol [■], or aryl methyl ketone (hereinafter referred to as ketone EV) represented by the general formula (V) Ar-C-CH3(V) (wherein Ar represents the same meaning as above) )
Alcohol [■] is obtained by the reduction reaction. Examples of the aryl group of alcohol (II) used in the present invention include phenyl group, tolyl group, xylyl group, biphenylyl group, and substituents include alkyl group, alkyloxy group,
It also includes those having an alkenyl group, a halogen atom, a hydroxyl group which may have a protecting group, an amino group, and the like. The reaction to obtain alcohol [■] from Grignard reagent (IV) and acetaldehyde involves the carbonization of aprotic solvents such as ethers such as diethyl ether, diisopropyl ether, dibutyl ether, and tetrahydrofuran, and n-pentane, n-hexane, benzene, and toluene. In a hydrogen-based reaction solvent, one equivalent of Grignard reagent [■] is reacted with 1 to 1.5 equivalents of acetaldehyde. Reaction temperature is 0-100℃, preferably 10-50℃
is suitable, and the reaction is usually completed in 1 to 5 hours. In addition, alcohol (III
The reaction to obtain the compound easily proceeds by using lithium aluminum hydride or sodium borohydride as a reducing agent. The reduction reaction using lithium aluminum hydride is carried out using ethers such as diethyl ether and tetrahydrofuran as a solvent, and the reaction temperature is 0 to 50°C.
The reduction reaction is completed within a reaction time of 1 to 5 hours.
水素化ホウ素ナトリウムを用いた還元反応は、プロトン
性溶媒、例えば水またはメタノール、エタノール、イソ
プロピルアルコールなどのアルコール中で行われ、反応
温度Ｏ〜１００℃、反応時間１〜１０時間で還元反応は
完結しアルコール［ＩＩ］が得られる。The reduction reaction using sodium borohydride is carried out in a protic solvent such as water or an alcohol such as methanol, ethanol, or isopropyl alcohol, and the reduction reaction is completed at a reaction temperature of 0 to 100°C and a reaction time of 1 to 10 hours. Alcohol [II] is obtained.
本発明のアルコール（ＩＩ）のハロゲン化は、通常のハ
ロゲン化剤例えば三臭化リン、臭化水素、五塩化リン、
塩化水素などが用いられ、アルコール［ＩＩ）に対して
当モル以上のハロゲン化剤を反応させる。ハロゲン化剤
として三臭化リンを用いた臭素化は、ベンゼン、トルエ
ンなどの有機溶媒中で、反応温度０〜１０℃で反応する
のが好適であり、また臭化水素を用いた臭素化は、酢酸
溶媒中で反応温度３０〜１００℃で反応するのが好適で
ある。反応時間はいずれの場合も１〜１０時間で完結す
る。反応終了後、溶媒を留去し、更に蒸留等の手段によ
り生成したハロゲン化物
［Ｉ［１］を単離する。The halogenation of alcohol (II) in the present invention can be carried out using conventional halogenating agents such as phosphorus tribromide, hydrogen bromide, phosphorus pentachloride,
Hydrogen chloride or the like is used, and alcohol [II] is reacted with an equimolar or more amount of halogenating agent. Bromination using phosphorus tribromide as a halogenating agent is preferably carried out in an organic solvent such as benzene or toluene at a reaction temperature of 0 to 10°C, and bromination using hydrogen bromide is preferably carried out at a reaction temperature of 0 to 10°C. The reaction is preferably carried out in an acetic acid solvent at a reaction temperature of 30 to 100°C. The reaction time is 1 to 10 hours in all cases. After the reaction is completed, the solvent is distilled off, and the produced halide [I[1] is further isolated by means such as distillation.
ハロゲン化物Ｃｍ）のシアン化アルカリによるシアノ化
は、ハロゲン化物（Ｉ［ｒ］に対して当モル以上のシア
ン化アルカリを、極性溶媒例えばＮ、Ｎ−ジメチルホル
ムアルデヒド、ジメチルスルホキシド、アセトニトリル
、テトラヒドロフラン中で反応させる。シアン化アルカ
リとしてはシアン化ナトリウムやシアン化カリウムが用
いられる。反応温度は使用する溶媒により異なるが５０
〜１００℃が好適であり、溶媒や反応温度により異なる
が２〜７０時間で反応は完結する。なお、反応触媒とし
てトリアルキルアミン、クラウンエーテルなどを使用す
ることにより、反応時間を短縮することができる。反応
終了後、得られたα−アリールプロピオニトリルを精留
などの手段により精製し、アルコール〔■〕に対して８
０〜９０％の高収率でα−アリールプロピオニトリルを
得る。Cyanation of a halide Cm) with an alkali cyanide is carried out using an alkali cyanide in an amount equal to or more than the equivalent mole of the alkali cyanide relative to the halide (I[r]) in a polar solvent such as N,N-dimethylformaldehyde, dimethyl sulfoxide, acetonitrile, or tetrahydrofuran. React. Sodium cyanide or potassium cyanide is used as the alkali cyanide. The reaction temperature varies depending on the solvent used, but
The temperature is preferably 100° C. and the reaction is completed in 2 to 70 hours, depending on the solvent and reaction temperature. Note that the reaction time can be shortened by using trialkylamine, crown ether, or the like as a reaction catalyst. After the reaction is completed, the obtained α-arylpropionitrile is purified by means such as rectification, and the alcohol [■] is
α-Arylpropionitriles are obtained in high yields of 0-90%.
（発明の効果）
本発明は新規なα−アリールプロピオニトリルの製造方
法を提供するものであり、本発明の方法により、任意の
置換基を有するアリール基を導入したα−アリールプロ
ピオニトリルを工業的に容易な方法で得ることを可能と
したものである。(Effects of the Invention) The present invention provides a novel method for producing α-arylpropionitrile, and the method of the present invention can produce α-arylpropionitrile into which an aryl group having an arbitrary substituent is introduced. This makes it possible to obtain it by an industrially easy method.
（実施例および実験例） 以下、実施例および実験例により説明する。(Examples and Experimental Examples) This will be explained below using Examples and Experimental Examples.
実験例１
４−ブロモ−２−フルオロビフェニル１００．４ ｇと
マグネシウム１０．２ ｇから合成したグリニヤール試
薬（０，３６モル）を含むテトラヒドロフラン溶液に、
１００ｎ＋Ｑのトルエンに溶解したアセトアルデヒド１
９ ｇ （０，４３モル）を反応温度を１５〜２０℃に
保ちながら３０分を要して滴下した。Experimental Example 1 A tetrahydrofuran solution containing Grignard reagent (0.36 mol) synthesized from 100.4 g of 4-bromo-2-fluorobiphenyl and 10.2 g of magnesium,
Acetaldehyde 1 dissolved in 100n+Q toluene
9 g (0.43 mol) was added dropwise over 30 minutes while maintaining the reaction temperature at 15-20°C.
滴下終了後、４０℃で１時間加熱し反応を完結させた。After the dropwise addition was completed, the mixture was heated at 40° C. for 1 hour to complete the reaction.
反応終了後、４７％臭化水素酸７０ｇと水４００ ｇを
加えて加水分解したのち、分液し、水洗後濃縮して１−
（２−フルオロビフェニル）エタノール６８ ｇ （０
，３１モル）を得た。収率８６％。After the reaction was completed, 70 g of 47% hydrobromic acid and 400 g of water were added for hydrolysis, the liquid was separated, washed with water, and concentrated to give 1-
(2-fluorobiphenyl)ethanol 68 g (0
, 31 mol) was obtained. Yield 86%.
核磁気共鳴スペクトル（ＣＤＣＱ ３）δｐｐｍ＝７．
３〜７．８（ｍ、８Ｈ，ビフェニル基プロトン）５．１
（ｑ、ＩＨ，−ＣＨ−）
３．１ （ｓ、ＬＨ，−ＯＨ）
１．８ （ｄ、３Ｈ，−ＣＨ５）
マススペクトルｍ／ｅ ２１６（Ｍ”）実験例２
３−フルオロ−４−フェニルアセトフェノン２１．４
ｇ （０，１０モル）をイソプロピルアルコール３００
ｍＱに溶解し、水素化ホウ素ナトリウム１．２＆を加え
て３時間加熱還流下に反応した。反応終了後、酢酸Ｌｏ
ｇを加えて過剰の水素化ホウ素ナトリウムを分解し、溶
媒を減圧下に留去したのち、残渣にベンゼン、水を加え
て水洗、分液後濃縮して１−（２−フルオロビフェニル
）エタノール１９．９ ｇ （０，０９２モル）を得た
。Nuclear magnetic resonance spectrum (CDCQ 3) δppm=7.
3-7.8 (m, 8H, biphenyl group proton) 5.1
(q, IH, -CH-) 3.1 (s, LH, -OH) 1.8 (d, 3H, -CH5) Mass spectrum m/e 216 (M'') Experimental example 2 3-Fluoro-4- Phenylacetophenone 21.4
g (0.10 mol) in isopropyl alcohol 300
The mixture was dissolved in mQ, 1.2 mm of sodium borohydride was added, and the mixture was reacted under heating under reflux for 3 hours. After the reaction, acetic acid Lo
g to decompose excess sodium borohydride, and the solvent was distilled off under reduced pressure.Benzene and water were added to the residue, washed with water, separated, and concentrated to give 1-(2-fluorobiphenyl)ethanol19 .9 g (0,092 mol) was obtained.
収率９２％。Yield 92%.
核磁気共鳴スペクトル（ＣＤＣｆｌ 、 ）δｐｐｍ＝
７．３−７．８（ｍ、８Ｈ，ビフェニル基プロトン）５
．１ （（１，ＬＨ，−ＣＨ−）３．１
（ｓ、ＩＨ，−ＯＨ）
１．８ （ｄ、３Ｈ，−ＣＤ５）マススペクトル
ｍ／ｅ ２１６（Ｍ”）実験例３
クロロベンゼン４５ｇとマグネシウム１０．２ｇから合
成したグリニヤール試薬（０，３４モル）とアセトアル
デヒド１９ｇ（０，４３モル）とを、実験例１と同様に
反応したのち後処理を行い、残渣を減圧蒸留してα−メ
チルベンジルアルコール３５．３ ｇ （０，２９モル
）を得た。収率８５％。Nuclear magnetic resonance spectrum (CDCfl, )δppm=
7.3-7.8 (m, 8H, biphenyl group proton) 5
．． 1 ((1,LH,-CH-)3.1
(s, IH, -OH) 1.8 (d, 3H, -CD5) Mass spectrum m/e 216 (M") Experimental example 3 Grignard reagent synthesized from 45 g of chlorobenzene and 10.2 g of magnesium (0.34 mol) and 19 g (0.43 mol) of acetaldehyde were reacted in the same manner as in Experimental Example 1, followed by post-treatment, and the residue was distilled under reduced pressure to obtain 35.3 g (0.29 mol) of α-methylbenzyl alcohol. .Yield 85%.
沸点 ９８〜ｂ
核磁気共鳴スペクトル（ＣＤＣｆｌ ３）δｐｐｍ＝７
．３（ｓ、５Ｈ，フェニル基プロトン）４．８（ｑ、Ｌ
Ｈ，−ＣＨ−）
１．９（ｓ、ＩＨ，−ＯＨ）
１．５（ｄ、３Ｈ，−ＣＤ５）
マススペクトルｍ／ｅ １２２（Ｍ”）実験例４
アセトフェノン１２．０ ｇ （０，１０モル）のイソ
プロピルアルコール溶液に水素化ホウ素ナトリウム１．
２ｇを加え、実験例２と同様に反応したのち後処理を行
い、残渣を減圧蒸留してα−メチルベンジルアルコール
１１．６ ｇ （０，０９５モル）を得た。収率９５％
。Boiling point 98-b Nuclear magnetic resonance spectrum (CDCfl 3) δppm=7
．． 3 (s, 5H, phenyl group proton) 4.8 (q, L
H, -CH-) 1.9 (s, IH, -OH) 1.5 (d, 3H, -CD5) Mass spectrum m/e 122 (M”) Experimental example 4 Acetophenone 12.0 g (0,10 sodium borohydride in an isopropyl alcohol solution of 1.
2 g was added, and the reaction was carried out in the same manner as in Experimental Example 2, followed by post-treatment, and the residue was distilled under reduced pressure to obtain 11.6 g (0,095 mol) of α-methylbenzyl alcohol. Yield 95%
.
沸点 ９８〜ｂ
核磁気共鳴スペクトル（ＣＤＣＱ 、 ）δｐｐｍ＝７
．３（ｓ、５１（、フェニル基プロトン）４．８（ｑ、
ＩＨ，−ＣＨ−）
１．９（ｓ、ＩＩ（、−０）１ ）
１．５（ｄ、３Ｈ，−Ｃ）Ｉ３）
マススペクトルｍ／ｅ １２２（Ｍ”）実施例１
実験例１で得た１−（２−フルオロビフェニル）エタノ
ール２１．６ ｇ （０，１０モル）を３０％臭化水素
酢酸溶液３００ ｇに溶解し、反応温度４０℃で５時間
加熱攪拌し反応を行った。反応終了後濃縮し、残渣を減
圧蒸留して１−（２−フルオロビフェニル）エチルプロ
ミド２５．４ ｇ （０，０９１モル）を得た。収率９
１％。Boiling point 98-b Nuclear magnetic resonance spectrum (CDCQ, ) δppm=7
．． 3(s, 51(, phenyl group proton) 4.8(q,
IH, -CH-) 1.9 (s, II (, -0) 1 ) 1.5 (d, 3H, -C) I3) Mass spectrum m/e 122 (M") Example 1 In Experimental Example 1 21.6 g (0.10 mol) of the obtained 1-(2-fluorobiphenyl)ethanol was dissolved in 300 g of a 30% hydrogen bromide acetic acid solution, and the mixture was heated and stirred at a reaction temperature of 40° C. for 5 hours to carry out a reaction. After the reaction was completed, it was concentrated, and the residue was distilled under reduced pressure to obtain 25.4 g (0,091 mol) of 1-(2-fluorobiphenyl)ethyl bromide. Yield: 9
1%.
沸点 １３９〜ｂ
核磁気共鳴スペクトル（ＣＤＣＱ ３）δｐｐｍ＝７．
４−７．８（ｍ、８Ｈ，フェニル基プロトン）５．４
（＋１．ＬＨ，−ＣＨ−）２．４ （ｄ、３Ｈ
，−ＣＨ，）
マススペクトルｍ／ｅ ２８０（Ｍ”、＠１Ｂｒ）２７
８（Ｍ”、” Ｂｒ）
次いで、１−（２−フルオロビフェニル）エチルプロミ
ド１２．６ ｇ （０，０４５モル）、シアン化カリウ
ム４．４ ｇ （０，０６８モル）、トリエチルアミン
０．３ｇをアセトニトリル５０ｍＱに溶解し、加熱還流
下に２４時間反応を行った。反応終了後濃縮し、残渣を
シリカゲルクロマトで精製して、白色結晶のα−（２−
フルオロビフェニル）プロピオニトリル９．３ ｇ （
０，０４１モル）を得た。収率９１％〔対１−（２−フ
ルオロビフェニル）エチルプロミド〕。Boiling point 139-b Nuclear magnetic resonance spectrum (CDCQ 3) δppm=7.
4-7.8 (m, 8H, phenyl group proton) 5.4
(+1.LH, -CH-)2.4 (d, 3H
, -CH,) Mass spectrum m/e 280 (M”, @1Br) 27
8 (M", "Br) Next, 12.6 g (0,045 mol) of 1-(2-fluorobiphenyl)ethyl bromide, 4.4 g (0,068 mol) of potassium cyanide, and 0.3 g of triethylamine were added to 50 mQ of acetonitrile. The mixture was dissolved and reacted under heating under reflux for 24 hours. After the reaction was completed, it was concentrated, and the residue was purified by silica gel chromatography to obtain white crystals of α-(2-
fluorobiphenyl)propionitrile 9.3 g (
0,041 mol) was obtained. Yield: 91% [vs. 1-(2-fluorobiphenyl)ethyl bromide].
融点 ７０〜７３℃
核磁気共鳴スペクトル（ＣＣＬ）
δｐｐｍ＝７．５〜８．０（ｍ、８Ｈ，ビフェニル基プ
ロトン）４．８ （ｑ、ＩＨ，−ＣＨ−）１．９
（ｄ、３Ｈ，−ＣＤ５）赤外スペクトル（ｖＣ
Ｎ） ２２５０ｃｍ−”マススペクトルｍ ／ ｅ １
．３１． （Ｍ ” ）実施例２
実験例４の方法で得たα−メチルベンジルアルコール１
２．２ ｇ （０，１０モル）を３０％臭化水素酢酸溶
液３００ ｇに溶解し、反応温度４０℃で５時間加熱攪
拌し反応を行った。反応終了後濃縮し、残渣を減圧蒸留
してα−メチルベンジルプロミド１７．２ ｇ （０，
０９３モル）を得た。収率９３％。Melting point 70-73°C Nuclear magnetic resonance spectrum (CCL) δppm=7.5-8.0 (m, 8H, biphenyl group proton) 4.8 (q, IH, -CH-) 1.9
(d,3H,-CD5) Infrared spectrum (vC
N) 2250 cm-”mass spectrum m/e 1
．． 31. (M'') Example 2 α-Methylbenzyl alcohol 1 obtained by the method of Experimental Example 4
2.2 g (0.10 mol) was dissolved in 300 g of a 30% hydrogen bromide acetic acid solution, and the mixture was heated and stirred at a reaction temperature of 40° C. for 5 hours to carry out a reaction. After the reaction was completed, it was concentrated, and the residue was distilled under reduced pressure to obtain 17.2 g of α-methylbenzyl bromide (0,
093 mol) was obtained. Yield 93%.
沸点 ７８〜ｂ
核磁気共鳴スペクトル（ＣＤＣＱ３）
δｐｐｍ＝７．３（ｍ、５Ｈ，フェニル基プロトン）５
．２（ｑ、 ＬＨ，−ＣＨ−）
２．０（ｄ、３Ｈ，−ＣＤ５）
マススペクトルｍ／ｅ １８６（Ｍ”、８１Ｂｒ）１８
４（Ｍ”、” Ｂｒ）
次いで、α−メチルベンジルプロミド１８．５ｇ （０
，１０モル）、シアン化カリウム４．４ ｇ （０，０
６８モル）、トリエチルアミン０．３ｇをアセトニトリ
ル５０ｍＱに溶解し、加熱還流下に２４時間反応を行っ
た。反応終了後濃縮し、残渣を減圧蒸留して無色透明液
体のα−フェニルプロピオニトリル１２．４ ｇ （０
，０９５モル）を得た。収率９５％（対α−メチルベン
ジルプロミド）。Boiling point 78-b Nuclear magnetic resonance spectrum (CDCQ3) δppm=7.3 (m, 5H, phenyl group proton) 5
．． 2 (q, LH, -CH-) 2.0 (d, 3H, -CD5) Mass spectrum m/e 186 (M'', 81Br) 18
4 (M", "Br) Then, 18.5 g of α-methylbenzyl bromide (0
, 10 mol), potassium cyanide 4.4 g (0,0
68 mol) and 0.3 g of triethylamine were dissolved in 50 mQ of acetonitrile, and the mixture was reacted under heating under reflux for 24 hours. After the reaction was completed, the residue was concentrated and distilled under reduced pressure to obtain 12.4 g of α-phenylpropionitrile (0
,095 mol) was obtained. Yield 95% (vs. α-methylbenzyl bromide).
沸点 ９２〜ｂ
核磁気共鳴スペクトル（ＣＤＣＱ ３）δｐｐｍ＝７．
３（ｓ、５Ｈ，フェニル基プロトン）３．９（ｑ、 Ｌ
Ｈ，−ＣＨ−）
１．６（ｄ、３１１．−ＣＯ３）
赤外スペクトル（ｖｃＮ） ２２５０ａｎ−”マススペ
クトルｍ／ｅ １３１（Ｍ”）実施例３
ｌ−（２−フルオロビフェニル）エタノールの代わりに
１−（ｐ−トリル）エタノールを用いたほかは実施例１
と同様の反応を行って得られた１−（ｐ−トリル）エチ
ルプロミドを、実施例１と同様にシアン化カリウムによ
るシアノ化を行い収率８３％〔対１−（ｐ−トリル）エ
チルプロミド〕でα−（ｐ−トリル）プロピオニトリル
を得た。Boiling point 92-b Nuclear magnetic resonance spectrum (CDCQ 3) δppm=7.
3 (s, 5H, phenyl group proton) 3.9 (q, L
H, -CH-) 1.6 (d, 311.-CO3) Infrared spectrum (vcN) 2250an-"Mass spectrum m/e 131 (M") Example 3 l-(2-fluorobiphenyl) instead of ethanol Example 1 except that 1-(p-tolyl)ethanol was used for
1-(p-tolyl)ethyl bromide obtained by the same reaction as in Example 1 was cyanated with potassium cyanide in the same manner as in Example 1 to give α- (p-tolyl)propionitrile was obtained.
沸点 １２３°Ｃ／１２ＴｏｒｒBoiling point: 123°C/12Torr
Claims (1)
表わす） で示される１−アリールエタノールをハロゲン化して、 一般式〔III〕 ▲数式、化学式、表等があります▼〔III〕 （式中、Ａｒは前記と同一の意味を表わし、Ｘはハロゲ
ン原子を表わす） で示される１−アリールエチルハライドとし、次いで１
−アリールエチルハライドとシアン化アルカリとを反応
させて一般式〔 I 〕 ▲数式、化学式、表等があります▼〔 I 〕 （式中、Ａｒは前記と同一の意味を表わす）で示される
α−アリールプロピオニトリルを得ることを特徴とする
、α−アリールプロピオニトリルの製造方法。[Claims] 1. General formula [II] ▲ Numerical formulas, chemical formulas, tables, etc. are available▼ [II] (In the formula, Ar represents an aryl group that may have a substituent.) 1-aryl represented by Ethanol is halogenated to form 1-, which is represented by the general formula [III] ▲Mathematical formulas, chemical formulas, tables, etc.▼[III] (In the formula, Ar represents the same meaning as above, and X represents a halogen atom.) arylethyl halide, then 1
-By reacting arylethyl halide and alkali cyanide, α- is expressed by the general formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[I] (In the formula, Ar represents the same meaning as above) A method for producing α-arylpropionitrile, the method comprising obtaining arylpropionitrile.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28385187A JPH01125361A (en) | 1987-11-09 | 1987-11-09 | Production of alpha-arylpropionitrile |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP28385187A JPH01125361A (en) | 1987-11-09 | 1987-11-09 | Production of alpha-arylpropionitrile |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH01125361A true JPH01125361A (en) | 1989-05-17 |
Family
ID=17670988
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP28385187A Pending JPH01125361A (en) | 1987-11-09 | 1987-11-09 | Production of alpha-arylpropionitrile |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH01125361A (en) |
-
1987
- 1987-11-09 JP JP28385187A patent/JPH01125361A/en active Pending
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