JPH0211547A - Preparation of 4-lower alkyl-2,4-hexadinenic acid amide - Google Patents
Preparation of 4-lower alkyl-2,4-hexadinenic acid amideInfo
- Publication number
- JPH0211547A JPH0211547A JP63164524A JP16452488A JPH0211547A JP H0211547 A JPH0211547 A JP H0211547A JP 63164524 A JP63164524 A JP 63164524A JP 16452488 A JP16452488 A JP 16452488A JP H0211547 A JPH0211547 A JP H0211547A
- Authority
- JP
- Japan
- Prior art keywords
- lower alkyl
- compound
- salt
- acid amide
- formula
- 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.)
- Granted
Links
- 150000001408 amides Chemical class 0.000 title 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 8
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 2
- 150000001875 compounds Chemical class 0.000 abstract description 25
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 abstract description 8
- 206010002383 Angina Pectoris Diseases 0.000 abstract description 3
- 125000001475 halogen functional group Chemical group 0.000 abstract 2
- AHIHJODVQGBOND-UHFFFAOYSA-N propan-2-yl hydrogen carbonate Chemical compound CC(C)OC(O)=O AHIHJODVQGBOND-UHFFFAOYSA-N 0.000 abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000000034 method Methods 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 235000010288 sodium nitrite Nutrition 0.000 description 2
- 150000003512 tertiary amines Chemical class 0.000 description 2
- JNXGEGMYGREXAA-SIZYMYPJSA-N (2e,4e)-4-ethylhexa-2,4-dienamide Chemical compound CC\C(=C/C)\C=C\C(N)=O JNXGEGMYGREXAA-SIZYMYPJSA-N 0.000 description 1
- ONRFQULGRIAPJL-SIZYMYPJSA-N (2e,4e)-4-ethylhexa-2,4-dienoic acid Chemical compound CC\C(=C/C)\C=C\C(O)=O ONRFQULGRIAPJL-SIZYMYPJSA-N 0.000 description 1
- BZEUYEFVVDTLOD-SNAWJCMRSA-N (e)-hex-2-enamide Chemical compound CCC\C=C\C(N)=O BZEUYEFVVDTLOD-SNAWJCMRSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- -1 amine salts Chemical class 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 238000007664 blowing 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
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- IVRIRQXJSNCSPQ-UHFFFAOYSA-N propan-2-yl carbonochloridate Chemical compound CC(C)OC(Cl)=O IVRIRQXJSNCSPQ-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/52—Improvements relating to the production of bulk chemicals using catalysts, e.g. selective catalysts
Landscapes
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
この発明は、狭心症治僚剤等として有用な一般式
％式％
（式中Ｒは低級アルキル基を意味する）で示される２−
ヒドロキシイミノ−４−低級アルキルー５−ニトロ−３
−ヘキセンアミドもしくはその塩を製造する為の中間体
として有用な、一般式
％式％
（式中Ｒは前と同じ意味）
で示される４−低級アルキルー２，４−へキサジエン酸
アミドを収率良く製造する方法に関するものである。Detailed Description of the Invention [Industrial Application Field] The present invention provides a 2-
Hydroxyimino-4-lower alkyl-5-nitro-3
- Yield of 4-lower alkyl-2,4-hexadienoic acid amide, which is useful as an intermediate for producing hexenamide or its salt, and is represented by the general formula % (wherein R has the same meaning as before). It relates to a method of manufacturing well.
［従来の技術］
一般式（ＩＩＩ ）で示される化合物は、例えばヨーロ
ツバ特許公開公報第０１１３１０６号に記載される様に
平滑筋弛緩作用（例えば冠状血管拡張作用等）や血圧降
下作用等を有し、従って例えば狭心症治療剤等の医薬品
としての利用が期待されている。[Prior Art] The compound represented by the general formula (III) has a smooth muscle relaxing effect (e.g. coronary vasodilator effect), a blood pressure lowering effect, etc., as described in, for example, European Patent Publication No. 0113106. Therefore, it is expected to be used as a pharmaceutical agent, such as a therapeutic agent for angina pectoris.
化合物（■■）を製造する方法は上記ヨーロッパ特許公
開公報に記載されており、それによれば、化合物（ＩＩ
）に亜硝酸ナトリウムを反応させることによって製造す
ることかできる。そして上記反応の原料物質である化合
物（１■）については、一般式
％式％（）
（式中Ｒは前と同じ意味）
で示される４−低級アルキルー２．４−へキサジエン酸
もしくはその塩にクロル炭酸エチルの存在下アンモニア
を反応させることによって製造される雪間公報に記載さ
れている。The method for producing compound (■■) is described in the above-mentioned European Patent Publication, and according to it, compound (II
) can be produced by reacting sodium nitrite with sodium nitrite. Regarding compound (1), which is a raw material for the above reaction, 4-lower alkyl-2,4-hexadienoic acid or its salt represented by the general formula % (in which R has the same meaning as above) It is described in the Yukima publication that it is produced by reacting ammonia with ethyl chlorocarbonate.
［発明が解決しようとする課題］
化合物（ＩＩ）は化合物（ＩＩＩ ）を製造する為の重
要な中間体として位置付けられるものであるが、上述の
ヨーロッパ特許公開公報に記載されている方法、即ち化
合物（Ｉ）にクロル炭酸エチルを反応させる方法の収率
はそれほど高いものではなく、化合物（ＩＩＩ ）の製
造コストを押し上げる要因となっている。[Problems to be Solved by the Invention] Compound (II) is positioned as an important intermediate for producing compound (III), but the method described in the above-mentioned European Patent Publication, that is, the compound The yield of the method of reacting (I) with ethyl chlorocarbonate is not so high, which is a factor that increases the production cost of compound (III).
この発明者は上記の様な事情を憂慮し、化合物（１）か
ら化合物（ＩＩ）をより高収率に製造することのできる
方法を開発する目的で種々研究を行なった。Concerned about the above-mentioned circumstances, the inventor conducted various studies for the purpose of developing a method capable of producing compound (II) from compound (1) at a higher yield.
［課題を解決する為の手段］
上記課題を解決することのできたこの発明は、化合物（
１）にハロ炭酸イソプロピルの存在下アンモニアを反応
させる点に要旨が存在するものである。[Means for Solving the Problems] This invention that has solved the above problems is based on a compound (
The gist of 1) is that ammonia is reacted in the presence of isopropyl halocarbonate.
［作用］
化合物（Ｉ）および化合物（ＩＩ）においてＲで示され
る低級アルキル基としては、メチル、エチル、プロピル
、イソプロピル、ブチル、イソブチルなどが非限定的に
例示される。化合物（Ｉ）および（■りは２重結合の存
在によって２以上の幾何異性体をとり得るが、これらは
全てこの発明の技術的範囲に含まれる。化合物（Ｉ）の
塩としては、トリエチルアミン塩、ピリジン塩等の第３
級アミン塩が使用される。[Function] Examples of the lower alkyl group represented by R in compound (I) and compound (II) include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and the like. Compounds (I) and (I) may have two or more geometric isomers depending on the presence of a double bond, but all of these are included within the technical scope of this invention. As the salt of compound (I), triethylamine salt , pyridine salt etc.
grade amine salts are used.
ハロ炭酸イソプロピルにおけるハロゲンとは弗素、塩素
、臭素、沃素である。この発明の反応で使用されるアン
モニアはガス状であっても溶液状であっても良いが、特
に使い易いのはアンモニアガスであり、反応混合液中に
吹込むことによって反応が進行する。The halogens in isopropyl halocarbonate are fluorine, chlorine, bromine, and iodine. The ammonia used in the reaction of this invention may be in the form of a gas or a solution, but ammonia gas is particularly easy to use, and the reaction proceeds by blowing it into the reaction mixture.
反応は溶媒の存在下に行なうのが一般的であり、溶媒と
しては塩化メチレン、テトラヒドロフラン、ジオキサン
、水、あるいはこれらの混合液、その他この反応の進行
に悪影響を与えない溶媒が利用される。また反応温度は
特に限定されないが、冷却ないし室温程度の緩和な条件
下に行なわれる。The reaction is generally carried out in the presence of a solvent, such as methylene chloride, tetrahydrofuran, dioxane, water, a mixture thereof, or any other solvent that does not adversely affect the progress of the reaction. Although the reaction temperature is not particularly limited, the reaction is carried out under mild conditions such as cooling or room temperature.
この発明の反応ではまず化合物（Ｉ）とハロ炭酸イソプ
ロピルの反応が進行して化合物（１）の活性状態（非対
称酸無水物）となり、この過程において前記トリエチル
アミンやピリジン等の第３級アミンが併存すると、これ
らが脱ハロゲン化水素剤として作用し、化合物（１）の
活性化が効率良く進行する。化合物（１）は塩の状態で
使用することが好まれるが、遊離のカルボン酸として反
応に供するとぎは、前記第３級アミン或は水酸化ナトリ
ウムや炭酸ナトリウム等の無機塩基の存在下に反応を行
なうことが推奨される。In the reaction of this invention, the reaction between compound (I) and isopropyl halocarbonate first proceeds to form compound (1) in an active state (asymmetric acid anhydride), and in this process, tertiary amines such as triethylamine and pyridine coexist. Then, these act as a dehydrohalogenating agent, and the activation of compound (1) proceeds efficiently. Compound (1) is preferably used in the form of a salt, but if it is used in the reaction as a free carboxylic acid, it may be reacted in the presence of the tertiary amine or an inorganic base such as sodium hydroxide or sodium carbonate. It is recommended that you do this.
こうして活性化された化合物（１）は、ＪｌＬｌ！ｌｌ
もしくは単離せずにアンモニアとの反応に供せられ化合
物（ＩＩ）が収率良く製造される。Compound (1) thus activated is JlLl! ll
Alternatively, the compound (II) is produced in good yield by being subjected to a reaction with ammonia without isolation.
［発明の効果］
この発明によれば化合物（！りを収率良く製造すること
ができ、前述のヨーロッパ特許公開公報では３１２７％
の収率が上げられたに止まるのに対し、後述の実施例で
は、８９．２％もの高収率で化合物（＋りを製造するこ
とができた。[Effect of the invention] According to this invention, it is possible to produce the compound (!) with a high yield, and in the European Patent Publication mentioned above, the yield is 3127%.
However, in the example described below, the compound (+) was able to be produced with a high yield of 89.2%.
［実施例］
実施例１
（Ｅ、Ｅ）−４−エチル−２，４−へキサジエン酸（７
０ｇ）とトリエチルアミン（６９，７ｍ１）を塩化メチ
レン（５００＋ｍｌ）に加え、この混合物にクロル炭酸
イソプロピル（５６，８■ｌ）を−５〜−１０℃に冷却
しながら２０分を要して加えた。[Example] Example 1 (E,E)-4-ethyl-2,4-hexadienoic acid (7
0 g) and triethylamine (69.7 ml) were added to methylene chloride (500+ ml), and to this mixture was added isopropyl chlorocarbonate (56.8 μl) over 20 minutes while cooling to -5 to -10°C. .
反応混合物を同温度で１時間攪拌した後、乾燥アンモニ
アガスを１時間に亘フて吹込んだ０反応終了後、反応混
合物を水（５００ｍｌ）に注ぎ、塩化メチレン（５００
＋＋１）を加えて抽出した有機層を分取し、５％水酸化
ナトリウム水溶液及び水で順次洗浄した後乾燥した。溶
媒を留去すると、（Ｅ、Ｅ）−４−エチル−２，４−へ
キサジエン酸アミド（６２ｇ）が得られた。After the reaction mixture was stirred at the same temperature for 1 hour, dry ammonia gas was blown in for 1 hour. After the reaction was completed, the reaction mixture was poured into water (500 ml), and methylene chloride (500
The organic layer extracted by adding ++1) was separated, washed successively with a 5% aqueous sodium hydroxide solution and water, and then dried. When the solvent was distilled off, (E,E)-4-ethyl-2,4-hexadienoic acid amide (62 g) was obtained.
Claims (1)
もしくはその塩にハロ炭酸イソプロピルの存在下アンモ
ニアを反応させて、一般式 ▲数式、化学式、表等があります▼ （式中Ｒは前と同じ意味） で示される４−低級アルキル−２，４−ヘキサジエン酸
アミドを得ることを特徴とする４−低級アルキル−２，
４−ヘキサジエン酸アミドの製造法。[Scope of Claims] 4-lower alkyl-2,4-hexadienoic acid or its salt represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (R in the formula means a lower alkyl group) halocarbonate Reacting ammonia in the presence of isopropyl to obtain 4-lower alkyl-2,4-hexadienoic acid amide represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (R in the formula has the same meaning as before) 4-lower alkyl-2, characterized by
Method for producing 4-hexadienoic acid amide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63164524A JPH07107035B2 (en) | 1988-06-30 | 1988-06-30 | Process for producing 4-lower alkyl-2,4-hexadienoic acid amide |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63164524A JPH07107035B2 (en) | 1988-06-30 | 1988-06-30 | Process for producing 4-lower alkyl-2,4-hexadienoic acid amide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0211547A true JPH0211547A (en) | 1990-01-16 |
| JPH07107035B2 JPH07107035B2 (en) | 1995-11-15 |
Family
ID=15794802
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63164524A Expired - Lifetime JPH07107035B2 (en) | 1988-06-30 | 1988-06-30 | Process for producing 4-lower alkyl-2,4-hexadienoic acid amide |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07107035B2 (en) |
-
1988
- 1988-06-30 JP JP63164524A patent/JPH07107035B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH07107035B2 (en) | 1995-11-15 |
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