JP7018327B2 - Method for producing benzaldehyde derivative - Google Patents
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- JP7018327B2 JP7018327B2 JP2018018163A JP2018018163A JP7018327B2 JP 7018327 B2 JP7018327 B2 JP 7018327B2 JP 2018018163 A JP2018018163 A JP 2018018163A JP 2018018163 A JP2018018163 A JP 2018018163A JP 7018327 B2 JP7018327 B2 JP 7018327B2
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- 238000004519 manufacturing process Methods 0.000 title claims description 17
- 150000003935 benzaldehydes Chemical class 0.000 title description 5
- 239000011777 magnesium Substances 0.000 claims description 39
- 229910052749 magnesium Inorganic materials 0.000 claims description 38
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- -1 aromatic magnesium halide Chemical class 0.000 claims description 26
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 17
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 239000007795 chemical reaction product Substances 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 150000004795 grignard reagents Chemical class 0.000 description 6
- 239000007818 Grignard reagent Substances 0.000 description 4
- 150000001555 benzenes Chemical class 0.000 description 4
- 230000000977 initiatory effect Effects 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 0 *c1c(*)c(*)c(*)c(*)c1* Chemical compound *c1c(*)c(*)c(*)c(*)c1* 0.000 description 3
- JPHKMYXKNKLNDF-UHFFFAOYSA-N 3,4-difluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1F JPHKMYXKNKLNDF-UHFFFAOYSA-N 0.000 description 3
- 150000001299 aldehydes Chemical class 0.000 description 3
- 239000003849 aromatic solvent Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- YMQPKONILWWJQG-UHFFFAOYSA-N 4-bromo-1,2-difluorobenzene Chemical compound FC1=CC=C(Br)C=C1F YMQPKONILWWJQG-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 239000002808 molecular sieve Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 2
- 125000003107 substituted aryl group Chemical group 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- APQIUTYORBAGEZ-UHFFFAOYSA-N 1,1-dibromoethane Chemical compound CC(Br)Br APQIUTYORBAGEZ-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- SEVPHEDFUKVTBD-UHFFFAOYSA-N FC1=CC=C([Mg])C=C1F Chemical class FC1=CC=C([Mg])C=C1F SEVPHEDFUKVTBD-UHFFFAOYSA-N 0.000 description 1
- 238000003747 Grignard reaction Methods 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 241000209504 Poaceae Species 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000005844 autocatalytic reaction Methods 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000002374 hemiaminals Chemical class 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、ハロゲン化ベンゼン誘導体からベンズアルデヒド誘導体を高収率で製造する方法に関する。 The present invention relates to a method for producing a benzaldehyde derivative from a halogenated benzene derivative in a high yield.
非特許文献１、２または３に開示されているように、グリニャール試薬にＤＭＦのようなＮ，Ｎ－二置換ホルムアミドを付加させるとヘミアミナールが得られる。このヘミアミナールは加水分解してアルデヒドを生成する。
グリニャール試薬（有機マグネシウムハライド）は、ハロゲン化アルキルなどの有機ハライドと金属マグネシウムとを反応させることによって合成できる。ところが、金属マグネシウム表面を覆う酸化物被膜が、合成反応の開始を阻害するので、初期反応速度が低い。そこで、よう素、よう化メチル、臭化メチル、ジブロモエタンなどの活性化剤を添加したり、金属マグネシウムを窒素雰囲気下で強撹拌したりして、初期反応速度を高めている。また、グリニャール試薬の合成反応は、自触媒反応であると言われている。特許文献１や非特許文献４に記載のように、グリニャール試薬の合成反応において、事前に用意したグリニャール試薬を開始剤として添加することが提案されている。 Grignard reagents (organic magnesium halides) can be synthesized by reacting organic halides such as alkyl halides with metallic magnesium. However, the oxide film covering the surface of the metallic magnesium inhibits the start of the synthetic reaction, so that the initial reaction rate is low. Therefore, activators such as iodine, methyl iodide, methyl bromide, and dibromoethane are added, and metallic magnesium is strongly stirred in a nitrogen atmosphere to increase the initial reaction rate. Further, the synthetic reaction of Grignard reagent is said to be an autocatalytic reaction. As described in Patent Document 1 and Non-Patent Document 4, it has been proposed to add a Grignard reagent prepared in advance as an initiator in the synthesis reaction of the Grignard reagent.
本発明の目的は、ハロゲン化ベンゼン誘導体からベンズアルデヒド誘導体を高収率で製造する方法を提供することである。 An object of the present invention is to provide a method for producing a benzaldehyde derivative from a halogenated benzene derivative in a high yield.
上記目的を達成するために検討した結果、以下の形態を包含する本発明を完成するに至った。 As a result of studies for achieving the above object, the present invention including the following embodiments has been completed.
〔１〕 芳香族マグネシウムハライドの存在下、溶媒中で、式(1)で表される化合物と金属マグネシウムとを反応させて有機マグネシウムハライドを得、
次いで、有機マグネシウムハライドとＮ，Ｎ－ジメチルホルムアミドとを反応させることを含む、
式(2)で表される化合物の製造方法。
[1] In the presence of aromatic magnesium halide, the compound represented by the formula (1) is reacted with metallic magnesium in a solvent to obtain an organic magnesium halide.
It then comprises reacting the organic magnesium halide with N, N-dimethylformamide.
A method for producing a compound represented by the formula (2).
〔２〕 溶媒が、トルエンとテトラヒドロフランとの混合物である、〔１〕に記載の製造方法。
〔３〕 トルエン／テトラヒドロフランの重量比が５５／４５～９５／５である、〔２〕に記載の製造方法。
[2] The production method according to [1], wherein the solvent is a mixture of toluene and tetrahydrofuran.
[3] The production method according to [2], wherein the weight ratio of toluene / tetrahydrofuran is 55/45 to 95/5.
〔４〕 芳香族マグネシウムハライドが式(3)で表される化合物である、〔１〕～〔３〕のいずれかひとつに記載の製造方法。
〔５〕 有機マグネシウムハライドとＮ，Ｎ－ジメチルホルムアミドとの反応を行った後、その反応生成物と塩酸とを混ぜ合わせ、次いで分液することをさらに含む、〔１〕～〔４〕のいずれかひとつに記載の製造方法。
[4] The production method according to any one of [1] to [3], wherein the aromatic magnesium halide is a compound represented by the formula (3).
[5] Any of [1] to [4], which further comprises mixing an organic magnesium halide with N, N-dimethylformamide, then mixing the reaction product with hydrochloric acid, and then separating the liquids. The manufacturing method described in one.
本発明の製造方法によると、ハロゲン化ベンゼン誘導体からベンズアルデヒド誘導体を高収率で製造することができる。 According to the production method of the present invention, a benzaldehyde derivative can be produced from a halogenated benzene derivative in a high yield.
本発明は、芳香族マグネシウムハライドの存在下、溶媒中で、式(1)で表される化合物と金属マグネシウムとを反応させて有機マグネシウムハライドを得（第一工程）、次いで、有機マグネシウムハライドとＮ，Ｎ－ジメチルホルムアミドとを反応させる（第二工程）ことを含む、式(2)で表される化合物の製造方法である。 In the present invention, in the presence of aromatic magnesium halide, the compound represented by the formula (1) is reacted with metallic magnesium in a solvent to obtain organic magnesium halide (first step), followed by organic magnesium halide. It is a method for producing a compound represented by the formula (2), which comprises reacting with N, N-dimethylformamide (second step).
Ｒ1、Ｒ2、Ｒ3、Ｒ4、およびＲ5におけるアルキル基としては、例えば、メチル基、エチル基、ｎ－プロピル基、ｉ－プロピル基、ｎ－プチル基、ｓ－ブチル基、ｉ－ブチル基、ｔ－ブチル基、ｎ－ペンチル基、ｎ－ヘキシル基などのＣ１～６アルキル基を挙げることができる。 Alkyl groups in R 1 , R 2 , R 3 , R 4 , and R 5 include, for example, methyl group, ethyl group, n-propyl group, i-propyl group, n-ptyl group, s-butyl group, i. -C1-6 alkyl groups such as butyl group, t-butyl group, n-pentyl group and n-hexyl group can be mentioned.
芳香族マグネシウムハライドは、ＡｒＭｇＸで表される化合物である。Ａｒは、無置換若しくは置換アリール基または無置換若しくは置換ヘテロアリール基、好ましくは無置換若しくは置換アリール基である。Ｘは塩素原子、臭素原子またはヨウ素原子である。芳香族マグネシウムハライドは、最も好ましくは、式(3)で表される化合物である。 Aromatic magnesium halide is a compound represented by ArMgX. Ar is an unsubstituted or substituted aryl group or an unsubstituted or substituted heteroaryl group, preferably an unsubstituted or substituted aryl group. X is a chlorine atom, a bromine atom or an iodine atom. The aromatic magnesium halide is most preferably the compound represented by the formula (3).
芳香族マグネシウムハライドは、式(1)で表される化合物と金属マグネシウムとの反応を開始させる段階に存在させることが好ましい。反応開始段階における芳香族マグネシウムハライドの存在量は、反応開始段階における溶媒１００重量部に対して、好ましくは０．００１～１０重量部、より好ましくは０．１～５重量部である。芳香族マグネシウムハライドを反応開始段階に存在させると、金属マグネシウムの活性を高めることができ、式(1)で表される化合物と金属マグネシウムとの反応をすみやかに開始させることができる。 The aromatic magnesium halide is preferably present at the stage of initiating the reaction between the compound represented by the formula (1) and the metallic magnesium. The abundance of aromatic magnesium halide in the reaction initiation stage is preferably 0.001 to 10 parts by weight, more preferably 0.1 to 5 parts by weight, based on 100 parts by weight of the solvent at the reaction initiation stage. When the aromatic magnesium halide is present at the reaction initiation stage, the activity of the metallic magnesium can be enhanced, and the reaction between the compound represented by the formula (1) and the metallic magnesium can be promptly initiated.
第一工程の反応に使用される溶媒は、エーテル系溶媒と芳香族系溶媒との混合物が好ましい。エーテル系溶媒としては、ジエチルエーテル、テトラヒドロフラン、１、４－ジオキサン、ジブチルエーテル、ｔ－ブチルメチルエーテルなどを挙げることができる。芳香族系溶媒としては、トルエン、キシレンなどを挙げることができる。エーテル系溶媒は、金属マグネシウムを分散させる液媒体として、好ましく使用される。芳香族系溶媒は、式(1)で表される化合物を溶解させる液媒体として、好ましく使用される。
本発明においては、トルエンとテトラヒドロフランとの混合物が特に好ましく用いられる。トルエン／テトラヒドロフランの重量比は、好ましくは５５／４５～９５／５である。使用される溶媒はでき得る限り水分を除去した方が好ましいが、工業的に入手可能な溶媒に含まれている程度の水分は、本発明の製造方法の実施に差ほどの支障はないので、工業的に入手可能な溶媒はそのまま使用することもできる。
The solvent used in the reaction of the first step is preferably a mixture of an ether solvent and an aromatic solvent. Examples of the ether solvent include diethyl ether, tetrahydrofuran, 1,4-dioxane, dibutyl ether, t-butyl methyl ether and the like. Examples of the aromatic solvent include toluene, xylene and the like. The ether solvent is preferably used as a liquid medium for dispersing metallic magnesium. The aromatic solvent is preferably used as a liquid medium for dissolving the compound represented by the formula (1).
In the present invention, a mixture of toluene and tetrahydrofuran is particularly preferably used. The weight ratio of toluene / tetrahydrofuran is preferably 55/45 to 95/5. It is preferable to remove water as much as possible from the solvent used, but the amount of water contained in the industrially available solvent does not hinder the implementation of the production method of the present invention so much. The industrially available solvent can be used as it is.
金属マグネシウムとしては、グリニャール反応において通常使用される公知の形状のマグネシウムがそのまま使用できる。 As the metallic magnesium, magnesium having a known shape usually used in the Grignard reaction can be used as it is.
第一工程において生成する有機マグネシウムハライドは、式(3)で表される化合物と同じ構造を有する化合物である。よって、第一工程において生成した有機マグネシウムハライドの一部を抜き出して、次の第一工程に使用される芳香族マグネシウムハライドとして使用することができる。第一工程における反応温度は、好ましくは－１０～６０℃、より好ましくは０～４５℃、さらに好ましくは０～４０℃である。 The organic magnesium halide produced in the first step is a compound having the same structure as the compound represented by the formula (3). Therefore, a part of the organic magnesium halide produced in the first step can be extracted and used as the aromatic magnesium halide used in the next first step. The reaction temperature in the first step is preferably −10 to 60 ° C., more preferably 0 to 45 ° C., still more preferably 0 to 40 ° C.
第二工程に用いられるＮ，Ｎ－ジメチルホルムアミドは、でき得る限り水分を除去した方が好ましいが、工業的に入手可能なＮ，Ｎ－ジメチルホルムアミドに含まれている程度の水分は、本発明の製造方法の実施に差ほどの支障はないので、工業的に入手可能なＮ，Ｎ－ジメチルホルムアミドはそのまま使用することもできる。第二工程における反応温度は、好ましくは－１０～５０℃、より好ましくは０～２０℃である。 It is preferable to remove as much water as possible from the N, N-dimethylformamide used in the second step, but the amount of water contained in the industrially available N, N-dimethylformamide is the present invention. Since there is no significant difference in the implementation of the production method of N, N-dimethylformamide, which is industrially available, the industrially available N, N-dimethylformamide can be used as it is. The reaction temperature in the second step is preferably −10 to 50 ° C., more preferably 0 to 20 ° C.
第二工程において得られた反応生成物と塩酸とを混ぜ合わせて、反応させる（第三工程）。この反応によってＭｇ残渣が主に水相に分配され、式(2)で表される化合物が主に有機相に分配される。第三工程における反応温度は、好ましくは－１０～５０℃、より好ましくは０～２０℃である。 The reaction product obtained in the second step and hydrochloric acid are mixed and reacted (third step). By this reaction, the Mg residue is mainly distributed to the aqueous phase, and the compound represented by the formula (2) is mainly distributed to the organic phase. The reaction temperature in the third step is preferably −10 to 50 ° C., more preferably 0 to 20 ° C.
３，４－ジフルオロベンズアルデヒドの製造
窒素置換した３００ｍｌの４頚フラスコに、モレキュラシーブス４Ａで乾燥させたＴＨＦ３０ｍｌ、および金属マグネシウム３．８３ｇを加え撹拌した。これに臭化（３，４－ジフルオロフェニル）マグネシウム６９０ｍｇを加え５分間撹拌した。温度が０．７℃上昇した。これに、１－ブロモ－３，４－ジフルオロベンゼン２９．５４ｇをトルエン６０ｍｌに溶解させた溶液を、滴下ロートで１時間かけて加え、３０℃±０．５℃で１時間反応させて、有機マグネシウムブロマイドを含む液を得た。
この液を１０℃に冷却し、この液にモレキュラシーブス４Ａで乾燥させたＤＭＦ１１．５１ｇを１０℃～１２℃で３０分間かけ滴下ロートで加え、１０℃～１５℃で１時間反応させて、反応生成液を得た。
５００ｍｌの４頚フラスコに１２．５ｗｔ％塩酸１２０ｇを調製した。これを１０℃に冷却し、そこに前記反応生成液を、窒素雰囲気下、カニューレを用いて１０℃±０．５℃で２５分間かけ滴下し、１０℃～１５℃で１時間反応させた。
得られた液を分液して、３，４－ジフルオロベンズアルデヒドのトルエン溶液９８．４９ｇ（濃度２０．９５ｗｔ％、収率９６．２ｍｏｌ％）を得た。
To a 300 ml 4-necked flask substituted with nitrogen, 30 ml of THF dried with Molecular Sives 4A and 3.83 g of metallic magnesium were added and stirred. To this, 690 mg of brominated (3,4-difluorophenyl) magnesium was added, and the mixture was stirred for 5 minutes. The temperature rose by 0.7 ° C. A solution prepared by dissolving 29.54 g of 1-bromo-3,4-difluorobenzene in 60 ml of toluene was added to this over 1 hour with a dropping funnel, and the mixture was reacted at 30 ° C. ± 0.5 ° C. for 1 hour to make it organic. A solution containing magnesium bromide was obtained.
This liquid was cooled to 10 ° C., and 11.51 g of DMF dried with Molecular Sieves 4A was added to this liquid at 10 ° C. to 12 ° C. for 30 minutes with a dropping funnel, and the mixture was reacted at 10 ° C. to 15 ° C. for 1 hour to react. A product solution was obtained.
120 g of 12.5 wt% hydrochloric acid was prepared in a 500 ml 4-necked flask. This was cooled to 10 ° C., and the reaction product solution was added dropwise at 10 ° C. ± 0.5 ° C. over 25 minutes using a cannula under a nitrogen atmosphere, and the reaction was carried out at 10 ° C. to 15 ° C. for 1 hour.
The obtained liquid was separated to obtain 98.49 g (concentration: 20.95 wt%, yield: 96.2 mol%) of a toluene solution of 3,4-difluorobenzaldehyde.
比較例
窒素置換した１００ｍｌの３頚フラスコに、モレキュラシーブス４Ａで乾燥させたＴＨＦ１０ｍｌ、および金属マグネシウム０．３８５ｇを加え撹拌した。これに臭素少量を加え５分間撹拌した。これに、１－ブロモ－３，４－ジフルオロベンゼン３．００ｇをＴＨＦ５ｍｌに溶解させた溶液を、滴下ロートで１時間かけて加え、３０℃±０．５℃で１時間反応させて、有機マグネシウムブロマイドを含む液を得た。
この液を１０℃に冷却し、この液にモレキュラシーブス４Ａで乾燥させたＤＭＦ１．１３ｇをＴＨＦ５ｍｌに溶解させた溶液を１０℃～１２℃で３０分間かけ滴下ロートで加え、１０℃～１５℃で１時間反応させて、反応生成液を得た。
２００ｍｌの４頚フラスコに１２．５ｗｔ％塩酸４０ｇを調製した。これを１０℃に冷却し、そこに前記反応生成液を、窒素雰囲気下、カニューレを用いて１０℃±０．５℃で２５分間かけ滴下し、１０℃～１５℃で１時間反応させた。
得られた液を分液して、３，４－ジフルオロベンズアルデヒドのトルエン溶液（収率６３ｍｏｌ％）を得た。
Comparative example
To a 100 ml 3-necked flask substituted with nitrogen, 10 ml of THF dried with Molecular Sives 4A and 0.385 g of metallic magnesium were added and stirred. A small amount of bromine was added thereto, and the mixture was stirred for 5 minutes. A solution prepared by dissolving 3.00 g of 1-bromo-3,4-difluorobenzene in 5 ml of THF was added thereto with a dropping funnel over 1 hour, and the mixture was reacted at 30 ° C. ± 0.5 ° C. for 1 hour to produce organic magnesium. A solution containing bromide was obtained.
This solution was cooled to 10 ° C., and a solution of 1.13 g of DMF dried with Molecular Sieves 4A in 5 ml of THF was added to this solution at 10 ° C to 12 ° C for 30 minutes with a dropping funnel, and at 10 ° C to 15 ° C. The reaction was carried out for 1 hour to obtain a reaction product solution.
40 g of 12.5 wt% hydrochloric acid was prepared in a 200 ml 4-necked flask. This was cooled to 10 ° C., and the reaction product solution was added dropwise at 10 ° C. ± 0.5 ° C. over 25 minutes using a cannula under a nitrogen atmosphere, and the reaction was carried out at 10 ° C. to 15 ° C. for 1 hour.
The obtained liquid was separated to obtain a toluene solution of 3,4-difluorobenzaldehyde (yield 63 mol%).
以上のとおり、本発明の製造方法によると、ハロゲン化ベンゼン誘導体からベンズアルデヒド誘導体を高収率で製造することができる。 As described above, according to the production method of the present invention, a benzaldehyde derivative can be produced from a halogenated benzene derivative in a high yield.
Claims (3)
溶媒中での式(1)で表される化合物と金属マグネシウムとの反応を継続して有機マグネシウムハライドを得、
次いで、有機マグネシウムハライドとＮ，Ｎ－ジメチルホルムアミドとを反応させることを含み、
溶媒がトルエンとテトラヒドロフランとの混合物であり、
トルエン／テトラヒドロフランの重量比が５５／４５～９５／５である、
式(2)で表される化合物の製造方法。
The reaction between the compound represented by the formula (1) in a solvent and metallic magnesium was continued to obtain an organic magnesium halide.
It then involves reacting the organic magnesium halide with N, N-dimethylformamide.
The solvent is a mixture of toluene and tetrahydrofuran,
The weight ratio of toluene / tetrahydrofuran is 55/45 to 95/5 .
A method for producing a compound represented by the formula (2).
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| JP2009184976A (en) | 2008-02-07 | 2009-08-20 | Central Glass Co Ltd | Method for producing 1-bromo-3-fluoro-5-difluoromethylbenzene |
| JP2011521994A (en) | 2008-06-06 | 2011-07-28 | エフ．ホフマン−ラ ロシュ アーゲー | Method for producing halogenated benzoic acid derivative |
| CN104926633A (en) | 2015-05-06 | 2015-09-23 | 江西力田维康科技有限公司 | Preparation method for 3-alkoxybenzaldehyde |
| WO2016071920A2 (en) | 2014-11-07 | 2016-05-12 | Excel Industries Ltd. | A process for preparation of 3,4-dimethylbenzaldehyde |
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| JP2009184976A (en) | 2008-02-07 | 2009-08-20 | Central Glass Co Ltd | Method for producing 1-bromo-3-fluoro-5-difluoromethylbenzene |
| JP2011521994A (en) | 2008-06-06 | 2011-07-28 | エフ．ホフマン−ラ ロシュ アーゲー | Method for producing halogenated benzoic acid derivative |
| WO2016071920A2 (en) | 2014-11-07 | 2016-05-12 | Excel Industries Ltd. | A process for preparation of 3,4-dimethylbenzaldehyde |
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