JPS603070B2 - Method for producing 1-hydrazinophthalazine - Google Patents
Method for producing 1-hydrazinophthalazineInfo
- Publication number
- JPS603070B2 JPS603070B2 JP10324975A JP10324975A JPS603070B2 JP S603070 B2 JPS603070 B2 JP S603070B2 JP 10324975 A JP10324975 A JP 10324975A JP 10324975 A JP10324975 A JP 10324975A JP S603070 B2 JPS603070 B2 JP S603070B2
- Authority
- JP
- Japan
- Prior art keywords
- hydrazinophthalazine
- producing
- phthalonitrile
- hydrazine
- acidic conditions
- 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
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 title claims description 27
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 10
- XQZYPMVTSDWCCE-UHFFFAOYSA-N phthalonitrile Chemical compound N#CC1=CC=CC=C1C#N XQZYPMVTSDWCCE-UHFFFAOYSA-N 0.000 claims description 10
- 229920006391 phthalonitrile polymer Polymers 0.000 claims description 8
- 230000002378 acidificating effect Effects 0.000 claims description 7
- 238000010531 catalytic reduction reaction Methods 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000000034 method Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 3
- 229910000564 Raney nickel Inorganic materials 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 238000006722 reduction reaction Methods 0.000 description 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 229960002474 hydralazine Drugs 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000007142 ring opening reaction Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001301224 Onesia Species 0.000 description 1
- 241000269851 Sarda sarda Species 0.000 description 1
- XRYSDRCNTMEYFH-UHFFFAOYSA-N [acetyloxy(phenyl)methyl] acetate Chemical compound CC(=O)OC(OC(C)=O)C1=CC=CC=C1 XRYSDRCNTMEYFH-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- ZUXNZUWOTSUBMN-UHFFFAOYSA-N hydralazine hydrochloride Chemical compound Cl.C1=CC=C2C(NN)=NN=CC2=C1 ZUXNZUWOTSUBMN-UHFFFAOYSA-N 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000003317 industrial substance Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- IJAPPYDYQCXOEF-UHFFFAOYSA-N phthalazin-1(2H)-one Chemical compound C1=CC=C2C(=O)NN=CC2=C1 IJAPPYDYQCXOEF-UHFFFAOYSA-N 0.000 description 1
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【発明の詳細な説明】
本発明は血圧降下剤として有用な１ーヒドラジ／フタラ
ジン（０）の新規な製造法にか）わるものであり、さら
に詳しくはフタロニトリル（１）をヒドラジンの存在下
接触還元および開環させることを特徴とする１−ヒドラ
ジノフタラジン（ロ）の製造法である。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing 1-hydrazi/phthalazine (0), which is useful as an antihypertensive agent. This is a method for producing 1-hydrazinophthalazine (b), which is characterized by reduction and ring opening.
。本発明の骨子は次の反応式によって示される。１−ヒ
ドラジノフタラジン（ロ）の製造法は、従来、多くの報
告があるが、その主なものはｉ）１ーフタラジノンをク
ロル化後ヒドラジノ化する方法（Ｈｅｌｖ．Ｃｈｉｍ．
Ａｃね．，３４１９５（１９５１）；日本特許第１８７
０１３号（特公昭２５一４３７９）、五）１．４ージフ
タラジノンをジクロル化後、選択的にモノヒドラジノ化
を行ない、さらに接触還元する方法（ドイツ特許公開番
号２３１１５１０（１９７２））、誼）○ーシアノベン
ズアルデヒドジアセテートとヒドラジンを反応せしめる
方法（英国特許７１９１斑（１９払））等がある。. The gist of the present invention is shown by the following reaction formula. There have been many reports on the production method of 1-hydrazinophthalazine (b), but the main one is i) chlorination of 1-phthalazinone followed by hydrazination (Helv. Chim.
Ac. , 34195 (1951); Japanese Patent No. 187
No. 013 (Special Publication No. 25-4379), 5) A method of dichlorinating 1,4-diphthalazinone, selectively monohydrazinating it, and further catalytically reducing it (German Patent Publication No. 2311510 (1972)), y) -cyano There is a method of reacting benzaldehyde diacetate with hydrazine (British Patent No. 7191 (Payment 19)).
しかしながら、これらの製造法は、それぞれに工業的製
造法の観点から種々の問題が指摘される。すなわち、ｉ
）、五）の方法は、共に素原料からの製造工鰹が長く前
者に於いては酸化、ハロゲン化等の繁雑な反応工程を要
し、また後者に於いてもハロゲン化の他高価なパラジウ
ム触媒を使用する等の難点がある。また、両）の方法に
至っては、低収率であると共に、素原料の供鰍縞斜こ鱗
があるため実用的製造法として採用されている形跡はな
い。本発明者等は、工業薬品として容易にかつ安価に入
手し得る素原料フタロニトリル（１）を効率的に目的化
合物（０）に導く製造法について研究の結果（１）から
直接（０）を製造し得る方法を見出し本発賜を完成した
。However, each of these production methods has various problems from the viewpoint of industrial production methods. That is, i
) and 5) both involve long processes for producing bonito from raw materials, and the former requires complicated reaction steps such as oxidation and halogenation, and the latter also requires expensive palladium in addition to halogenation. There are drawbacks such as the use of catalysts. In addition, there is no evidence that methods (both) have been adopted as a practical production method because the yield is low and the raw material is striped and oblique. The present inventors have directly obtained (0) from the results of research on a manufacturing method for efficiently converting the raw material phthalonitrile (1), which is easily and inexpensively available as an industrial chemical, into the target compound (0). We found a method to manufacture this product and completed this project.
本発明は、フタロニトリルとヒドラジンを酸性条件下で
接触還元処理およびこれと同時にまたは続いて酸性条件
処理による閉環を行なうことにより１−ヒドラジノフタ
ラジンを製造する方法である。酸性条件で接触還元を行
なうとフタロニトリルの一方のシア／基のみが還元され
るが、この酸性条件下では続いて閉環反応が起り、１−
ヒドラジノフタラジンが生成する。The present invention is a method for producing 1-hydrazinophthalazine by subjecting phthalonitrile and hydrazine to a catalytic reduction treatment under acidic conditions and simultaneously or subsequently performing ring closure under acidic conditions. When catalytic reduction is carried out under acidic conditions, only one sia/group of phthalonitrile is reduced, but under these acidic conditions, a ring-closing reaction subsequently occurs, resulting in
Hydrazinophthalazine is formed.
そのためには、酢酸等の有機塩類または塩酸、硫酸、リ
ン酸等の糠機酸類を加えればよいが、場合によってはヒ
ドラジン酸塩の形で用いて酸性条件とすることもできる
。還元と開環を一挙に行なうには、高温または高圧の条
件を選べばよいが、還元が過度に進行しないように留意
して条件を設定する必要がある。温度としては、室温乃
至後に示す溶媒の沸点付近が適当であるが、通常は３０
〜７ぴ０で行なう。温度が低い場合には閉濠反応の進行
が遅いので加熱するのが有利であり、最も一般的な条件
の一つとして接触還元を常温常圧下で行ない、次いでア
ルコール中で加熱還流する例を挙げることができる。副
原料のヒドラジンはヒドラジンヒドラートまたは無機も
しくは有機塩類の型で用いることができ、フタロニトリ
ルに対し２〜５倍モル程度用いるのが適当である。For this purpose, organic salts such as acetic acid or bran acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc. may be added, but in some cases, acidic conditions may be achieved by using them in the form of hydrazine salts. In order to carry out reduction and ring opening all at once, high temperature or high pressure conditions may be selected, but the conditions must be set with care so that the reduction does not proceed excessively. The appropriate temperature is room temperature or around the boiling point of the solvent shown below, but it is usually 30°C.
~Do it at 7pi0. When the temperature is low, the closed-moat reaction progresses slowly, so it is advantageous to heat it.One of the most common conditions is to carry out catalytic reduction at room temperature and normal pressure, followed by heating to reflux in alcohol. be able to. The auxiliary raw material hydrazine can be used in the form of hydrazine hydrate or inorganic or organic salts, and is suitably used in an amount of about 2 to 5 times the molar amount of phthalonitrile.
反応溶媒としては、低級アルコール類、水またはこれら
の混合溶媒を適宜用いればよい。As the reaction solvent, lower alcohols, water, or a mixed solvent thereof may be used as appropriate.
接触還元に用いる触媒は通常ラネーニッケル、ラネーコ
バルト等のラネー触媒が用いられ、場合により若干の処
理をほどこし、触媒活性を調整したものも用いうる。以
上の如き条件下で反応を行なった後、生成した目的化合
物（０）を常用の手段で反応系から取り出し、稀塩酸と
処理することにより１−ヒドラジノフタラジン（０）の
塩酸塩（ヒドララジン）を得ることが出釆る。Raney catalysts such as Raney nickel and Raney cobalt are usually used as catalysts for catalytic reduction, and those which have undergone some treatment to adjust the catalytic activity may also be used. After carrying out the reaction under the above conditions, the generated target compound (0) was taken out from the reaction system by a conventional means and treated with dilute hydrochloric acid to obtain the hydrochloride of 1-hydrazinophthalazine (0) (hydralazine ) can be obtained.
本発明の方法は、以上の如く、安価な原料化合物を用い
、緩和な反応条件下甑単な操作でフタロニトリル（１）
から直後１ーヒドラジノフタラジン（０）を製造するこ
とを可能ならしめた工業的に有利な製造法である。As described above, the method of the present invention uses inexpensive raw material compounds and can produce phthalonitrile (1) under mild reaction conditions and with simple operations.
This is an industrially advantageous production method that makes it possible to immediately produce 1-hydrazinophthalazine (0) from
以下実施例により本発明を説明する。実施例
フタロニトリル１．２８夕、８５％ヒドラジンヒドラー
ト２．拠夕「酢酸２．４２をメタノール５０の‘に溶解
し、ラネーニッケル触媒２私を加え、常圧下２０〜２５
℃で水素気流中接触還元する。The present invention will be explained below with reference to Examples. Example Phthalonitrile 1.28% hydrazine hydrate 2. Dissolve 2.42 parts of acetic acid in 50 parts of methanol, add 2 parts of Raney nickel catalyst, and dissolve 2.42 parts of acetic acid in 50 parts of methanol.
Catalytic reduction in a hydrogen stream at ℃.
水素約２３０の‘を吸収後波過、ラネーニッケル触媒を
除き、滋液を酢酸でｐＨ２〜３に維持しながら８時間還
流する。冷後不溶物を猿去し、源液を濃縮後シリカゲル
カラムクロマト（溶媒クロロホルム、クロロホルムーメ
タノール）で分離し、１−ヒドラジノフタラジン区分を
とり、これを稀塩酸で処理することにより１−ヒドラジ
ノフタラジンの塩酸塩（ヒドララジン）０．５７夕を得
る。融点２ね〜２７３℃（分解）。本品は、標品とｍ、
ＭＭ旧スペクトルが完全に一致した。After absorbing about 230% of hydrogen, the Raney nickel catalyst was removed by filtration, and the solution was refluxed for 8 hours while maintaining the pH at 2-3 with acetic acid. After cooling, insoluble matter was removed, and the source solution was concentrated and separated using silica gel column chromatography (solvent: chloroform, chloroform-methanol) to separate 1-hydrazinophthalazine, which was treated with dilute hydrochloric acid to obtain 1-hydrazinophthalazine. 0.57 g of hydrazinophthalazine hydrochloride (hydralazine) is obtained. Melting point: 2-273°C (decomposition). This product is standard and m,
The MM old spectra matched perfectly.
Claims (1)
還元処理およびこれと同時にまたは続いて酸性条件処理
による閉環を行なうことを特徴とする１−ヒドラジノフ
タラジンの製法。1. A method for producing 1-hydrazinophthalazine, which comprises subjecting phthalonitrile and hydrazine to a catalytic reduction treatment under acidic conditions and simultaneously or subsequently ring-closing the phthalonitrile and hydrazine under acidic conditions.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10324975A JPS603070B2 (en) | 1975-08-26 | 1975-08-26 | Method for producing 1-hydrazinophthalazine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP10324975A JPS603070B2 (en) | 1975-08-26 | 1975-08-26 | Method for producing 1-hydrazinophthalazine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5227787A JPS5227787A (en) | 1977-03-02 |
| JPS603070B2 true JPS603070B2 (en) | 1985-01-25 |
Family
ID=14349157
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP10324975A Expired JPS603070B2 (en) | 1975-08-26 | 1975-08-26 | Method for producing 1-hydrazinophthalazine |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS603070B2 (en) |
-
1975
- 1975-08-26 JP JP10324975A patent/JPS603070B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5227787A (en) | 1977-03-02 |
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