JPS62207264A - Production of nitrogen-containing heterocyclic derivative - Google Patents
Production of nitrogen-containing heterocyclic derivativeInfo
- Publication number
- JPS62207264A JPS62207264A JP61048583A JP4858386A JPS62207264A JP S62207264 A JPS62207264 A JP S62207264A JP 61048583 A JP61048583 A JP 61048583A JP 4858386 A JP4858386 A JP 4858386A JP S62207264 A JPS62207264 A JP S62207264A
- Authority
- JP
- Japan
- Prior art keywords
- group
- formula
- nitrogen
- containing heterocyclic
- iii
- 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 12
- 239000002904 solvent Substances 0.000 claims abstract description 31
- 150000001336 alkenes Chemical class 0.000 claims abstract description 22
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 14
- -1 nitrogen-containing heterocyclic compound Chemical class 0.000 claims abstract description 11
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 8
- 125000003118 aryl group Chemical group 0.000 claims abstract description 7
- 125000000962 organic group Chemical group 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000002560 nitrile group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims 4
- 150000001875 compounds Chemical class 0.000 abstract description 21
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 abstract description 8
- 125000002030 1,2-phenylene group Chemical group [H]C1=C([H])C([*:1])=C([*:2])C([H])=C1[H] 0.000 abstract description 6
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 abstract description 3
- 238000007259 addition reaction Methods 0.000 abstract description 3
- 150000002825 nitriles Chemical class 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 abstract description 2
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 2
- 239000003905 agrochemical Substances 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 229910052736 halogen Inorganic materials 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
- 239000011737 fluorine Substances 0.000 description 4
- OEPOKWHJYJXUGD-UHFFFAOYSA-N 2-(3-phenylmethoxyphenyl)-1,3-thiazole-4-carbaldehyde Chemical compound O=CC1=CSC(C=2C=C(OCC=3C=CC=CC=3)C=CC=2)=N1 OEPOKWHJYJXUGD-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VXNZUUAINFGPBY-UHFFFAOYSA-N 1-Butene Chemical compound CCC=C VXNZUUAINFGPBY-UHFFFAOYSA-N 0.000 description 2
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical class CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- HTDSQRRFFROEDP-UHFFFAOYSA-N 3-(trifluoromethyl)-2h-1,4-benzoxazine Chemical compound C1=CC=C2OCC(C(F)(F)F)=NC2=C1 HTDSQRRFFROEDP-UHFFFAOYSA-N 0.000 description 1
- QRAOZQGIUIDZQZ-UHFFFAOYSA-N 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1,4-benzoxazine Chemical compound C=1C=C2N(C)CCOC2=CC=1B1OC(C)(C)C(C)(C)O1 QRAOZQGIUIDZQZ-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 150000001555 benzenes Chemical class 0.000 description 1
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000007789 gas Substances 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
- 239000000543 intermediate Substances 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 150000004950 naphthalene Chemical class 0.000 description 1
- 229940037525 nasal preparations Drugs 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 1
- 230000001443 photoexcitation Effects 0.000 description 1
- 230000002250 progressing effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Abstract
Description
【発明の詳細な説明】
本発明は特定の含窒素複素環系誘導体を光反応により製
造する方法に関するものである。DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a specific nitrogen-containing heterocyclic derivative by photoreaction.
光を用いた有機合成は無公害プロセスや他手法では困難
な化合物も容易に合成できることなど実用価値の高い合
成技術である。この光反応の例としてオレフィン類の光
付加反応が知られている。その１つとして、本発明者は
含窒素複素環の−Ｎ−Ｃ＜結合へのオレフィン類の光付
加反応を検討した。しかし、通常この光付加反応はほと
んど起こらず、目的とする付加反応生成物はほとんど得
られない、しかしながら、さらに検討を行なった結果、
この−Ｎ−Ｃ＜結合の炭素原子にトリフルオロメチル基
が存在している場合に限り、この結合への光付加反応は
極めて容易に起こることを見い出した。しかも、オレフ
ィン類の１位の水素原子はトリフルオロメチル基が結合
している炭素原子のみに付加し、窒素原子には付加しな
いことより、選択性の高い付加反応であることも見い出
した。Organic synthesis using light is a synthetic technology with high practical value, as it is a non-polluting process and can easily synthesize compounds that are difficult to synthesize using other methods. A photoaddition reaction of olefins is known as an example of this photoreaction. As one of the methods, the present inventor investigated the photoaddition reaction of olefins to the -N-C< bond of a nitrogen-containing heterocycle. However, this photoaddition reaction rarely occurs, and the desired addition reaction product is hardly obtained.However, as a result of further investigation,
It has been found that the photoaddition reaction to this bond occurs extremely easily only when a trifluoromethyl group is present on the carbon atom of this -N-C< bond. Moreover, it has been found that the addition reaction is highly selective because the hydrogen atom at position 1 of olefins is added only to the carbon atom to which the trifluoromethyl group is bonded, and not to the nitrogen atom.
一方、従来フッ素化学関連分野において、光反応の研究
は単純な含フツ素化合物の光励起下での挙動を調べるな
どの基礎的な研究に限られており、応用上有用と思われ
る含フツ素化合物の合成に光反応を用いた例はほとんど
知られていない、また、近年医薬や農薬などにおいて、
フッ素原子に基づく薬効、安定性、その他の特異な特性
を利用した含フツ素化合物の検討が進んでいるが、含フ
ツ素化合物の合成手段は比較的限られており、新しい合
成手段の開発が望まれていた。On the other hand, in the field of fluorine chemistry, research on photoreactions has traditionally been limited to basic research such as investigating the behavior of simple fluorine-containing compounds under photoexcitation; There are almost no known examples of using photoreactions in the synthesis of
Studies are progressing on fluorine-containing compounds that take advantage of their medicinal efficacy, stability, and other unique properties based on the fluorine atom, but the means for synthesizing fluorine-containing compounds are relatively limited, and the development of new synthetic means is still in progress. It was wanted.
本発明は、トリフルオロメチル基を宥する前記含窒素複
素環を有する化合物とオレフィン類との光付加反応によ
って、トリフルオロメチル基を有する含窒素複素環系誘
導体を製造する下記製造法である。生成含窒素複素環系
誘導体は、医薬、鼻薬その他の用途に用いられるトリフ
ルオロメチル基含有化合物の合成中間体として有用であ
ると考えられる。The present invention is the following production method for producing a nitrogen-containing heterocyclic derivative having a trifluoromethyl group by a photoaddition reaction between a compound having the nitrogen-containing heterocycle that accommodates a trifluoromethyl group and an olefin. The produced nitrogen-containing heterocyclic derivatives are considered to be useful as intermediates for the synthesis of trifluoromethyl group-containing compounds used for pharmaceuticals, nasal preparations, and other uses.
下記式［Ｉ］で表わされる含窒素複素環化合物と下記式
［■］で表わされるオレフィン類とを反応性溶媒あるい
は非反応性溶媒中光の存在下に反応させて下記式［ＩＩ
Ｉ−ａ］あるいは［ＩＩＩ−ｂ］で表わされる含窒素複
素環系誘導体を製造することを特徴とする含窒素複素環
系誘導体の製造法。A nitrogen-containing heterocyclic compound represented by the following formula [I] and an olefin represented by the following formula [■] are reacted in the presence of light in a reactive or non-reactive solvent to form the following formula [II].
A method for producing a nitrogen-containing heterocyclic derivative, which comprises producing a nitrogen-containing heterocyclic derivative represented by [I-a] or [III-b].
Ａ；芳香核（ただし、ＮとＺは隣接部
位［即ち、０位に結合］に結合）
ｚ ： −ｏ−、−Ｎ（Ｒ）−（ただし、Ｒは水素原子
あるいは１価の有機基）
１１７１ 、 Ｒ２：同一あるいは異なり、それぞれ水
素原子、ハロゲン原子、ニト
リル基、またはアルキル基、アル
コキシ基、アルコキシカルボニル
基、あるいはその他の価の有機基
［ＩＩＩ −ａ ］ ［ＩＩＩ −ｂ ］
Ａ：上記式［Ｉ］に同じ、
Ｒ１、Ｒ２：上記式［ＩＩ］に同じ、
Ｒ３、Ｒ４、Ｒ５：Ｒ１あるいはそれに起因する残基、
Ｒ２あるいはそれに起因する
残基、および反応性溶媒に起因す
る残基の組み合せ（Ｒ３、Ｒ４，Ｒ５の内の２つが共同
して１つの酸素原
子を表わす場合を含む）
まず、式［Ｉ］で表わされる化合物から説明スル、この
式において、Ａはベンゼン核、ヒリジン核、ナフタレン
核、その他の芳香核を表わし、その芳香核はハロゲン原
子、アルキル基、アルコキシ基、あるいはその他のこの
光反応に不活性な置換基を有していてもよｌ／）、好ま
しくは、置換基を有するか有しないベンゼン核である。A: aromatic nucleus (however, N and Z are bonded to adjacent sites [i.e., bonded to the 0-position]) z: -o-, -N(R)- (however, R is a hydrogen atom or a monovalent organic group) 1171, R2: the same or different, each a hydrogen atom, halogen atom, nitrile group, or alkyl group, alkoxy group, alkoxycarbonyl group, or other valent organic group [III-a] [III-b]
A: Same as the above formula [I], R1, R2: Same as the above formula [II], R3, R4, R5: R1 or a residue derived therefrom,
A combination of R2 or a residue resulting from it, and a residue resulting from a reactive solvent (including the case where two of R3, R4, and R5 jointly represent one oxygen atom) First, in formula [I] In this formula, A represents a benzene nucleus, hyridine nucleus, naphthalene nucleus, or other aromatic nucleus. It is preferably a benzene nucleus with or without substituents, which may have active substituents.
この芳香核に結合するＮとＺは、芳香核の隣接部位［即
ち０位］に結合している。たとえば、芳香核がフェニレ
ン基の場合、それは０−フェニレン基である。Ｚは、−
〇−（エーテル結合）であるか、−Ｎ（Ｒ）−（（置換
）イミノ結合）である、Ｒは水素原子であるか１価の有
機基であり、１価の有機基としては特に低級の（炭素数
４以下をいう）のアルキル基である。Ｒは特に水素原子
であることが好ましい０式［Ｉ］で表され０−ヒドロキ
シ芳香族ジアミンに６７フ化プロピレンオキシドを反応
させることによって得られる。この６フツ化プロピレン
オキシドの反応は公知であり、たとえば石川らの報文［
Ｂｕ ｌ １ 。N and Z bonded to this aromatic nucleus are bonded to adjacent sites (ie, position 0) of the aromatic nucleus. For example, when the aromatic nucleus is a phenylene group, it is an 0-phenylene group. Z is -
〇-(ether bond) or -N(R)-((substituted) imino bond), R is a hydrogen atom or a monovalent organic group, especially lower monovalent organic groups is an alkyl group (having 4 or less carbon atoms). R is particularly preferably a hydrogen atom, represented by the formula [I], and is obtained by reacting an 0-hydroxy aromatic diamine with 67-fluorinated propylene oxide. This reaction of hexafluorinated propylene oxide is known, for example, in the report of Ishikawa et al. [
Bu l 1.
Ｃｂｅｍ、Ｓｏｃ、Ｊｐｎ、 、５０．２１８４（１９
７７）］に記載されている。 式［１１］で表わされる
オレフィン類としては種々のものを使用しうる。Ｒ１、
Ｒ２はそれぞれ、前記の内水素原子、アルキル基、アル
コキシ基およびアルコキシカルボニル基であることが好
ましく、特に一方が水素原子あるいは低級アルキル基で
あり、他方が低級アルキル基、低級アルコキシ基、ある
いは低級アルコキシカルボニル基であることが好ましい
、具体的なオレフィン類としては、たとえば、エチレン
、プロピレン、イソブチン、１−ブテン、エチルビニル
エーテル、ブチルビニルエーテル、メタクリル酸メチル
、メタクリル酸エチル、アクリル酸ブチル、酢酸ビニル
、塩化ビニル、塩化ビニリデン、アクリロニトリルなど
がある。Cbem, Soc, Jpn, , 50.2184 (19
77)]. Various olefins can be used as the olefin represented by formula [11]. R1,
Each of R2 is preferably a hydrogen atom, an alkyl group, an alkoxy group, or an alkoxycarbonyl group, particularly one of which is a hydrogen atom or a lower alkyl group, and the other is a lower alkyl group, a lower alkoxy group, or a lower alkoxy group. Specific olefins that are preferably carbonyl groups include, for example, ethylene, propylene, isobutyne, 1-butene, ethyl vinyl ether, butyl vinyl ether, methyl methacrylate, ethyl methacrylate, butyl acrylate, vinyl acetate, and chloride. Examples include vinyl, vinylidene chloride, and acrylonitrile.
上記２種の化合物を溶媒中で光の存在下で反応させる。The above two compounds are reacted in a solvent in the presence of light.
照射する光としては約２００〜５００ｎ＋ｓの波長の光
が好ましく、特に約３００ｎｍ以上の光が好ましい、溶
媒としては、非反応性溶媒は勿論反応性溶媒も使用しう
る。溶媒としては、芳香族炭化水素溶媒などの炭化水素
類、ハロゲン化炭化水素類、アルコール類、エステル類
、ケトン類、ニトリル類、エーテル類、その他の溶媒を
使用しうる。具体的には、たとえば、ベンゼン、トルエ
ン、メタノール、エタノール、酢酸エチル、アセトン、
ジエチルケトン、アセトニトリル、エチルエーテルなど
がある。この内、アルコール類、ケトン類、ニトリル類
などは、式ＣＩ］で表わされるオレフィン類の種類によ
っては反応性溶媒となり易い、この反応は主として付加
反応により形成される４員環が引！Ｊ続いて開裂し、そ
のときに反応性溶媒に起因する残基が開裂した炭素原子
に導入されるものと考えられる。この場合、前記オレフ
ィン類のＲ１やＲ２ちまた反応性溶媒残基の導入に伴い
他の基に変換されることもある。たとえば、アルコール
類を溶媒として用いるとアルコキシ基が導入され、アセ
トニトリルを用いるとアルデヒド基が生成する場合があ
る。また、オレフィン基として塩化ビニリデンを用いた
場合には２つの塩素原子が脱離してオキソ基が生成し、
このときアルコール溶媒を用いた場合はさらにアルコキ
シ基が導入されてアルコキシカルボニル基が生成するこ
とがある。従って、反応性溶媒を用いた場合には生成す
る化合物は反応性溶媒に起因する基は勿論、用いたオレ
フィン類のＲ１やＲ２の変換や脱離によりそれらに起因
する基もまた含む場合がある。また、非反応性溶媒の区
別は相対的なものであり、同じ溶媒を用いてもオレフィ
ン類の種類によっては非反応性溶媒にも反応溶媒にもな
りうるものである。なお、反応における前記２種の化合
物の使用割合は特に限定されるものではないが、式［Ｉ
］で表わされる化合物に対し式［ＩＩ］で表わされるオ
レフィン類は大過剰に用いることが好ましく、好ましく
は約３０倍モル以上、特に約５０倍モル以上の使用が好
ましい。The light to be irradiated is preferably light with a wavelength of about 200 to 500 nm+s, particularly preferably light of about 300 nm or more.As the solvent, not only non-reactive solvents but also reactive solvents can be used. As the solvent, hydrocarbons such as aromatic hydrocarbon solvents, halogenated hydrocarbons, alcohols, esters, ketones, nitriles, ethers, and other solvents can be used. Specifically, for example, benzene, toluene, methanol, ethanol, ethyl acetate, acetone,
Examples include diethyl ketone, acetonitrile, and ethyl ether. Among these, alcohols, ketones, nitriles, etc. can easily become reactive solvents depending on the type of olefin represented by formula CI. It is believed that J is subsequently cleaved, at which time residues due to the reactive solvent are introduced into the cleaved carbon atom. In this case, R1 and R2 of the olefins may be converted into other groups along with the introduction of reactive solvent residues. For example, when an alcohol is used as a solvent, an alkoxy group may be introduced, and when acetonitrile is used, an aldehyde group may be generated. In addition, when vinylidene chloride is used as the olefin group, two chlorine atoms are eliminated to form an oxo group,
If an alcohol solvent is used at this time, an alkoxy group may be further introduced to form an alkoxycarbonyl group. Therefore, when a reactive solvent is used, the resulting compound may not only contain groups caused by the reactive solvent, but also groups caused by conversion or elimination of R1 and R2 of the olefins used. . Furthermore, the distinction between non-reactive solvents is relative, and even if the same solvent is used, it can serve as both a non-reactive solvent and a reaction solvent depending on the type of olefin. Incidentally, the ratio of the two types of compounds used in the reaction is not particularly limited, but if the formula [I
] It is preferable to use the olefin represented by formula [II] in large excess, preferably about 30 times or more, particularly about 50 times or more by mole, relative to the compound represented by formula [II].
上記のように、反応生成物は４員環を有する化合物とそ
の４員環が開裂した化合物の２種類となる。多くの場合
、この２種の内一方のみが、選択的に生成するが、場合
によっては両者の混在物が得られることもある。４員環
を有する化合物は前記式［ＩＩＩ−ａ］で表わされる含
窒素複素環系化合物である。この式［Ｉ［１−ａ］で表
わされる化合物は、主としてオレフィン類のＲ１とＲ２
かいずれも比較的安定な基である場合に生成する。たと
えば、オレフィン類のＲ１とＲ２かいずれも水素原子、
アルキル基、あるいはアルコキシカルボニル基から選ば
れる基である場合に生成し易い、特に、Ｒ１とＲ２かい
ずれも水素原子あるいはアルキル基から選ばれる基であ
る場合、たとえアルコール類などの反応性の高い溶媒を
使用しても、この式［ＩＩＩ−ａ］で表わされる化合物
が生成する。一方、前記式［ＩＩＩ−ｂ］で表わされる
生成物は、たとえ式［Ｉ］で表わされる化合物と式［Ｉ
ＩＩで表わされるオレフィン類とが同一の組み合せであ
っても反応性溶媒の種類により異なるものとなる場合が
ある。特に、オレフィン類のＲ１とＲ２のいずれか１つ
がアルコキシ基やハロゲン原子などの場合には反応性溶
媒残基の導入やＲ１やＲ２の他の基への変換が起こり易
い、たとえば、オレフィン類がエチルビニルエーテルの
場合、メタノール溶媒を使用するとメトキシ基が導入さ
れ、Ｒ３とＲ４はそれぞれエトキシ基とメトキシ基にな
る（Ｒ５は水素原子）。As mentioned above, the reaction products are of two types: a compound having a 4-membered ring and a compound in which the 4-membered ring is cleaved. In many cases, only one of these two types is selectively produced, but in some cases a mixture of both may be obtained. The compound having a 4-membered ring is a nitrogen-containing heterocyclic compound represented by the above formula [III-a]. The compound represented by the formula [I[1-a] is mainly composed of olefins R1 and R2.
Both of these are relatively stable groups. For example, both R1 and R2 of olefins are hydrogen atoms,
This is likely to occur when the group is selected from an alkyl group or an alkoxycarbonyl group, especially when R1 and R2 are both hydrogen atoms or groups selected from an alkyl group, even when highly reactive solvents such as alcohols are used. Even when using this formula [III-a], a compound represented by the formula [III-a] is produced. On the other hand, the product represented by the formula [III-b] can be obtained even if the compound represented by the formula [I] and the product represented by the formula [I]
Even if the combination of olefins represented by II is the same, the combination may differ depending on the type of reactive solvent. In particular, when either one of R1 and R2 of the olefin is an alkoxy group or a halogen atom, introduction of reactive solvent residues or conversion of R1 or R2 to other groups is likely to occur. In the case of ethyl vinyl ether, when a methanol solvent is used, a methoxy group is introduced, and R3 and R4 become an ethoxy group and a methoxy group, respectively (R5 is a hydrogen atom).
また、エチルビニルエーテルをアセトニトリル中で反応
させた場合には、変換が起こってオレフィン類として塩
化ビニリデンを使用しメトキシカルボニル基（ＪＯＯＣ
Ｈ３）となる、好ましい式［ＩＩＩ−ｂ］で表わされる
化合物中のＲ３，Ｒ４゜Ｒ５は、Ｒ１，Ｒ２および反応
性溶媒の残基であるアルコキシ基の組み合せ、特に水素
原子、低級アルコキシ基および反応性溶媒の残基である
低級アルコキシ基の組み合せ、またはＲ３、Ｒ４、Ｒ５
のいずれか２つが共同して１つの酸素原子であり他の１
つが水素原子あるいはアルコキシ基であるあるかアルコ
キシカルボニル基である組み合せ）が好ましく、またこ
のアルコキシカルボニル基は、低級アルコキシ基を含む
ものであることが好ましい、なお、生成物は立体異性体
、光学異性体、その他の異性体混合物であってもよい。Also, when ethyl vinyl ether is reacted in acetonitrile, a conversion occurs and vinylidene chloride is used as the olefin, resulting in a methoxycarbonyl group (JOOC).
R3, R4゜R5 in the compound represented by the preferred formula [III-b], which is H3), is a combination of R1, R2 and an alkoxy group that is a residue of a reactive solvent, particularly a hydrogen atom, a lower alkoxy group, and A combination of lower alkoxy groups that are residues of reactive solvents, or R3, R4, R5
Any two of these are jointly one oxygen atom and the other one
is a hydrogen atom or an alkoxy group, or an alkoxycarbonyl group), and the alkoxycarbonyl group preferably contains a lower alkoxy group.The product may be a stereoisomer, an optical isomer, Other isomer mixtures may also be used.
以下に、本発明を実施例により具体的に説明するが１本
発明はこれら実施例に限られるものではない。EXAMPLES The present invention will be specifically explained below with reference to Examples, but the present invention is not limited to these Examples.
［実施例］
実施例１
１−メトキシカルボニル−１−メチル−２ａ−トリフル
オロメチル−３−オキソ−１，２，２ａ、３−テトラヒ
ドロ−４Ｈ−アセト［１，２−ａ］−キノキサリン（弐
ｃｍ−ａ］中、Ａ！ｏ−フェニレン基、Ｚ＝ＮＨ，Ｒ１
−ＣＯ２Ｍｅ 、 Ｒ２ｍＮｅ） ノ製造。[Example] Example 1 1-Methoxycarbonyl-1-methyl-2a-trifluoromethyl-3-oxo-1,2,2a,3-tetrahydro-4H-aceto[1,2-a]-quinoxaline (2 cm-a], A!o-phenylene group, Z=NH, R1
-CO2Me, R2mNe) production.
トリフルオロメチルキノキサリン−２−（１１）−オン
［式［Ｉ］においてＡ＝ｏ−フェニレン基、Ｚ＝ＮＨ］
（１，０ｍｍｏｌ、 ２１４１ｇ）のメタノール溶
液（２００鳳Ｑ）に、メタクリル酸メチル（１０層Ｑ）
を加え、アルゴン気流下１時間光照射（３００ｎｍ以上
、以下においても同様）する、減圧下溶媒を留去し、残
渣をシリカゲルカラムクロマトグラフィー（溶出液：ヘ
キサンー酢酸エチル）で精製すると純粋なｅ！Ｏ体及び
ｅｎｄｏ体が得られた。 ａ！ｏ体：収量１７８ｍｇ（
収率５７ｘ）、融点１８４．５−１６５℃； ＩＨ−Ｎ
ＮＲ（ＣＤＣｈ）、δ１．４２（３１，Ｓ）。Trifluoromethylquinoxalin-2-(11)-one [In formula [I], A=o-phenylene group, Z=NH]
(1,0 mmol, 2141 g) in methanol solution (200 Otori Q), methyl methacrylate (10 layer Q)
was added and irradiated with light (at least 300 nm, the same applies below) for 1 hour under an argon stream. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain pure e! O-form and endo-form were obtained. a! o body: Yield 178 mg (
Yield 57x), melting point 184.5-165°C; IH-N
NR(CDCh), δ1.42(31,S).
元素分析値 Ｃ５３，７５，Ｈ４，０５，Ｎ ８．７Ｂ
（計算値 ０５３．５１． ）１４．１？、 Ｎ ８．
９１ ）ｅｎｄａ体：収量１３５Ｂ （収率４３駕）
、融点１４５−１４７℃： ＩＨ−ＮＭＲ１δ１．７９
（３Ｈ，Ｓ）。Elemental analysis value C53.75, H4.05, N 8.7B
(Calculated value 053.51.) 14.1? , N8.
91) Enda body: yield 135B (yield 43 units)
, melting point 145-147°C: IH-NMR1δ1.79
(3H, S).
元素分析値 Ｃ５３，７４； ）Ｉ ４．０７； Ｎ
８Ｊ２（計算値 Ｃ５３，５１； Ｈ４，１７，Ｎ ８
．９１ ）実施例２
２ａ−トリフルオロメチル−３−オキソ−１，２，２ａ
。Elemental analysis value C53,74; )I 4.07; N
8J2 (calculated value C53,51; H4,17,N 8
．． 91) Example 2 2a-trifluoromethyl-3-oxo-1,2,2a
.
３−テトラヒドロ−４Ｈ−アセト［１，２−ａ］−キノ
キサリン（式［ＩＩＩ−ａ］中、Ａ＝ｏ−フェニレン基
、Ｚ＝ＮＨ，Ｒ１−Ｒ２−Ｈ）の製造。Production of 3-tetrahydro-4H-aceto[1,2-a]-quinoxaline (in formula [III-a], A=o-phenylene group, Z=NH, R1-R2-H).
３−トリフルオロメチルキノキサリン−２−（ＩＨ）−
オン（１，０＋ｓｍｏｌ、 ２１４ｍｇ）のベンゼン溶
液（２００＋ＩＱ）に、エチレンガスを導通しながら２
時間光照射する。実施例１と同様の処理を行なうことに
より表題化合物４１ｍｇ（収率１７τ原料の回収率を考
慮す６ ト４３％）？：得た。融点１８Ｂ−１８７℃。3-Trifluoromethylquinoxaline-2-(IH)-
(1,0+smol, 214mg) in benzene solution (200+IQ) while passing ethylene gas.
Irradiate with light for a period of time. By carrying out the same treatment as in Example 1, 41 mg of the title compound (yield 17τ43% considering the recovery rate of the raw material) was obtained. :Obtained. Melting point 18B-187°C.
元素分析値 Ｃ５４，３８； Ｈ３，５５； Ｎ １１
．１３１（計算値 Ｃ５４，５５； Ｈ３，７５； Ｎ
１１．５７）実施例３
１．１−ジメチル−２ａ−トリフルオロメチル−３−オ
キソ−１，２，２ａ、３−テトラヒドロ−４Ｈ−アセト
［１，２−ａ］−キノキサリン（式［１］Ｉ−ｃｌ中、
Ａ＝ｏ−７エニレン基、Ｚ ＝ＮＨ，Ｒ’＝ Ｒ２−Ｍ
ｅ ） ｒｌ）製造。Elemental analysis value C54,38; H3,55; N11
．． 131 (calculated value C54,55; H3,75; N
11.57) Example 3 1.1-dimethyl-2a-trifluoromethyl-3-oxo-1,2,2a,3-tetrahydro-4H-aceto[1,2-a]-quinoxaline (formula [1] In I-cl,
A=o-7 enylene group, Z=NH, R'= R2-M
e) rl) Manufacture.
３−トリフルオロメチルキノキサリン−２−（ＩＨ）−
オンと大過剰の（約５０倍モル以上、以下同様）イソブ
チンをメタノール中で３０分光照射し、クロマト精製し
目的物を７５％の収率で得た。3-Trifluoromethylquinoxaline-2-(IH)-
A large excess (approximately 50 times the mole or more, the same applies hereinafter) of isobutyne was irradiated with light in methanol for 30 minutes and purified by chromatography to obtain the desired product in a yield of 75%.
融点１４５−１４８℃５
元素分析値 Ｃ５７，７８，Ｈ４，８２； Ｎ １０．
５５（計算値 Ｃ５７，７８； Ｈａ、ａｓ； Ｎ １
０．３７）実施例４
１．１−ジメチル−２ａ−）リフルオロメチル−３−オ
キソ−１，２，２ａ、３−テトラヒドロアセト［２，１
−ｃｌ ［１，４１−ベンズオキサジン（式［ＩＩＩ−
ａ］中、Ａ冨〇−７ｚ ニレ７基、２＝０、Ｒ１−Ｒ２
−Ｈｅ ） （７）製造。Melting point 145-148℃5 Elemental analysis value C57,78, H4,82; N 10.
55 (calculated value C57,78; Ha, as; N 1
0.37) Example 4 1.1-dimethyl-2a-)lifluoromethyl-3-oxo-1,2,2a,3-tetrahydroaceto[2,1
-cl [1,41-benzoxazine (formula [III-
a] Medium, Atomi〇-7z Elm 7 groups, 2=0, R1-R2
-He) (7) Production.
３−トリフルオロメチル−１，４−ベンズオキサジンと
インブテンを実施例３の如く反応させ目的物を３３％の
収率で得た。3-Trifluoromethyl-1,4-benzoxazine and inbutene were reacted as in Example 3 to obtain the desired product in a yield of 33%.
高分解能ＭＳ ［ＩＩＩ／竺）９Ｍ・２７１．０
８２５゜（計算値 ２７１．０８１９）。High-resolution MS [III/Jiku) 9M・271.0
825° (calculated value 271.0819).
実施例５
３−（２−二トキシ−２−メトキシエチル）−３−）リ
フルオロメチル−２−オキソ−１，２，３，４−テトラ
ヒドロキノキサリン（式［ＩＩＩ−ｂ］中、Ａ＝ｏ−フ
ェニレン基、Ｚ ＝ ＮＨ，Ｒ３−Ｈ，Ｒ４＝ＯＥｔ、
Ｒ５禦ＯＭｅ）の製造。Example 5 3-(2-dithoxy-2-methoxyethyl)-3-)lifluoromethyl-2-oxo-1,2,3,4-tetrahydroquinoxaline (in formula [III-b], A=o -phenylene group, Z = NH, R3-H, R4 = OEt,
Production of R5 禦OMe).
３−トリフルオロメチルキノキサリン−２（ＩＨ）−オ
フ （２１４ｍｇ、１．Ｏｍｍｏｌ） メタ／ −ル溶
液（２００ａ＋Ｑ）に大過剰のエチルビニルエーテル（
１０ｍ（２）を加え同様に処理すると目的物が８７％の
収率で得られた。3-Trifluoromethylquinoxaline-2(IH)-off (214mg, 1.Ommol) A large excess of ethyl vinyl ether (
When 10m(2) was added and treated in the same manner, the desired product was obtained with a yield of 87%.
高分解能ＭＳ （！／り、Ｍ◆３１１１１．１１
９５゜（計算値 ３１８．１１９０）。High resolution MS (!/ri, M◆31111.11
95° (calculated value 318.1190).
実施例６
３−（２，２−エトキシ）エチル−３−トリフルオロメ
チル−２−オキソ−１，２，３，４−テトラヒドロキノ
キサリン（式［ＩＩＩ−ｂｌ中、Ａｘｏ−フェニレン基
、Ｚ＝ＮＨ，Ｒ３−Ｈ，Ｒ４−Ｒ５＝ＯＥｔ ） ＋７
）製造。Example 6 3-(2,2-ethoxy)ethyl-3-trifluoromethyl-2-oxo-1,2,3,4-tetrahydroquinoxaline (formula [III-bl, Axo-phenylene group, Z=NH , R3-H, R4-R5=OEt) +7
) Manufacture.
実施例５のメタノールの代りにエタノールを用いると目
的物が８３％の収率で得られた。When ethanol was used in place of methanol in Example 5, the desired product was obtained with a yield of 83%.
融 点 ９８−９９℃高分解能ＭＳ
［ＩＩＩ／竺）２Ｍ・３３２．１３５７゜（計
算値 ３３２．１３４７）。Melting point: 98-99℃ High resolution MS
[III/纺) 2M・332.1357° (calculated value 332.1347).
実施例７
３−（２−オキソエチル） −３−トリフルオロメチル
−２−オキソ−１，２，３，４−テトラヒドロキノキサ
リン（式［ＩＩＩ−ｂ］中、Ａ＝ｏ−フェニレン基、実
施例５のエタノールの代りにアセトニトリルを用いると
表題のアルデヒドが８７％の収率で得られた。Example 7 3-(2-oxoethyl)-3-trifluoromethyl-2-oxo-1,2,3,4-tetrahydroquinoxaline (in formula [III-b], A=o-phenylene group, Example 5 When acetonitrile was used in place of ethanol, the title aldehyde was obtained in 87% yield.
融 点 １２０−１２３℃高分解能
ＭＳ （！／り 、 Ｍ争３３２．１３５７゜（
計算値 ３３２．１３４７） 。Melting point 120-123℃ High resolution MS (!/ri, M 332.1357℃)
Calculated value 332.1347).
実施例８
３−（２−エトキシ−２−メトキシエチル） −３−ト
リフルオロメチル−２−オキソ−１，２，３，４−テト
ラヒドロ−１，４−ベンゾオキサジン（式［ＩＩＩ−ｂ
ｌ中、Ａ ＝ ｏ−）ｚ ニレン基、 Ｚ ＝ＮＨ，Ｒ
３−Ｈ，Ｒ４＝ＯＥｔ 、 Ｒ５＝ＯＭｅ ）の製造。Example 8 3-(2-ethoxy-2-methoxyethyl)-3-trifluoromethyl-2-oxo-1,2,3,4-tetrahydro-1,4-benzoxazine (formula [III-b
In l, A = o-)z nylene group, Z = NH, R
Production of 3-H, R4=OEt, R5=OMe).
実施例５の３−トリフルオロメチルキノキサリン−２−
（ＩＨ）−オンの代りに３−トリフルオロメチル−１，
４−ベンゾオキサジンを用いると目的物が７２％の収率
で得られた。これは２種類のジアステレオマー混合物で
ある。3-Trifluoromethylquinoxaline-2- of Example 5
3-trifluoromethyl-1 instead of (IH)-one,
When 4-benzoxazine was used, the desired product was obtained with a yield of 72%. This is a mixture of two diastereomers.
低極性成分：融点７［１−７７℃。Low polar component: melting point 7 [1-77°C.
高分解能ＭＳ （！／ｅ）、Ｍ◆３１９．１０３
７゜（計算値 ３１９．１０３０）。High resolution MS (!/e), M◆319.103
7° (calculated value 319.1030).
Claims (1)
下記式［II］で表わされるオレフィン類とを非反応性溶
媒あるいは反応性溶媒中光の存在下で反応させて下記式
［III−ａ］あるいは［III−ｂ］で表わされる含窒素複
素環系誘導体を製造することを特徴とする含窒素複素環
系誘導体の製造法。 ▲数式、化学式、表等があります▼−−−［ I ］ Ａ：芳香核（ただし、ＮとＺは隣接部位［即ち、σ位に
結合］に結合） Ｚ：−Ｏ−、−Ｎ（Ｒ）−（ただし、Ｒは水素原子ある
いは１価の有機基） ▲数式、化学式、表等があります▼−−−［II］ Ｒ＾１、Ｒ＾２：同一あるいは異なり、それぞれ水素原
子、ハロゲン原子、ニトリル基、またはアルキル基、ア
ルコキシ基、アルコキシカルボニル基、あるいはその他
の価の有機基▲数式、化学式、表等があります▼［III
−ａ］▲数式、化学式、表等があります▼［III−ｂ］ Ａ：上記式［ I ］に同じ、 Ｒ＾１、Ｒ＾２：上記式［II］に同じ、 Ｒ＾３、Ｒ＾４、Ｒ＾５：Ｒ＾１あるいはそれに起因す
る残基、Ｒ＾２あるいはそれに起因する残基、および反
応性溶媒に起因する残基の組み合せ（Ｒ＾３、Ｒ＾４、
Ｒ＾５の内の２つが共同して１つの酸素原子を表わす場
合を含む）[Claims] 1. A nitrogen-containing heterocyclic compound represented by the following formula [I] and an olefin represented by the following formula [II] are reacted in the presence of light in a non-reactive solvent or a reactive solvent. A method for producing a nitrogen-containing heterocyclic derivative, which comprises producing a nitrogen-containing heterocyclic derivative represented by the following formula [III-a] or [III-b]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼---[I] A: Aromatic nucleus (however, N and Z are bonded to adjacent sites [i.e., bonded to the σ position]) Z: -O-, -N(R )-(However, R is a hydrogen atom or a monovalent organic group) ▲There are mathematical formulas, chemical formulas, tables, etc.▼---[II] R^1, R^2: Same or different, hydrogen atom, halogen atom, respectively , nitrile group, or alkyl group, alkoxy group, alkoxycarbonyl group, or other valent organic group ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [III
-a]▲There are mathematical formulas, chemical formulas, tables, etc.▼[III-b] A: Same as the above formula [I], R^1, R^2: Same as the above formula [II], R^3, R^ 4, R^5: A combination of R^1 or a residue derived therefrom, R^2 or a residue derived therefrom, and a residue derived from a reactive solvent (R^3, R^4,
(Including cases where two of R^5 jointly represent one oxygen atom)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61048583A JPS62207264A (en) | 1986-03-07 | 1986-03-07 | Production of nitrogen-containing heterocyclic derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP61048583A JPS62207264A (en) | 1986-03-07 | 1986-03-07 | Production of nitrogen-containing heterocyclic derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS62207264A true JPS62207264A (en) | 1987-09-11 |
Family
ID=12807420
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP61048583A Pending JPS62207264A (en) | 1986-03-07 | 1986-03-07 | Production of nitrogen-containing heterocyclic derivative |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS62207264A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000000478A1 (en) * | 1998-06-26 | 2000-01-06 | Bristol-Myers Squibb Pharma Company | Substituted quinoxalin-2(1h)-ones useful as hiv reverse transcriptase inhibitors |
-
1986
- 1986-03-07 JP JP61048583A patent/JPS62207264A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000000478A1 (en) * | 1998-06-26 | 2000-01-06 | Bristol-Myers Squibb Pharma Company | Substituted quinoxalin-2(1h)-ones useful as hiv reverse transcriptase inhibitors |
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