JPH0548224B2 - - Google Patents
Info
- Publication number
- JPH0548224B2 JPH0548224B2 JP14916585A JP14916585A JPH0548224B2 JP H0548224 B2 JPH0548224 B2 JP H0548224B2 JP 14916585 A JP14916585 A JP 14916585A JP 14916585 A JP14916585 A JP 14916585A JP H0548224 B2 JPH0548224 B2 JP H0548224B2
- Authority
- JP
- Japan
- Prior art keywords
- pyridyl
- added
- reaction
- distilled
- reduced pressure
- 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 - Lifetime
Links
- -1 4-pyridylpimelic acid ester Chemical class 0.000 claims description 15
- RGEJCUIWCMDOOK-UHFFFAOYSA-N 2-pyridin-4-ylcyclohexan-1-one Chemical compound O=C1CCCCC1C1=CC=NC=C1 RGEJCUIWCMDOOK-UHFFFAOYSA-N 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 238000009833 condensation Methods 0.000 claims description 3
- 230000005494 condensation Effects 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 16
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 13
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000000203 mixture Substances 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexyloxide Natural products O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 125000004076 pyridyl group Chemical group 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
- SEIUJHIHBPGGDJ-UHFFFAOYSA-N 2-pyridin-4-ylphenol Chemical class OC1=CC=CC=C1C1=CC=NC=C1 SEIUJHIHBPGGDJ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012450 pharmaceutical intermediate Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- LXSZVOUDYGKZNI-UHFFFAOYSA-N 1-methyl-3-oxo-7-pyridin-4-yl-5,6,7,8-tetrahydro-2h-isoquinoline-4-carbonitrile Chemical compound C1C2=C(C)NC(=O)C(C#N)=C2CCC1C1=CC=NC=C1 LXSZVOUDYGKZNI-UHFFFAOYSA-N 0.000 description 2
- UKVQBONVSSLJBB-UHFFFAOYSA-N 2-pyridin-2-ylacetonitrile Chemical compound N#CCC1=CC=CC=N1 UKVQBONVSSLJBB-UHFFFAOYSA-N 0.000 description 2
- BHIIMPOVZNJDSZ-UHFFFAOYSA-N 4-pyridin-2-ylcyclohexan-1-one Chemical compound C1CC(=O)CCC1C1=CC=CC=N1 BHIIMPOVZNJDSZ-UHFFFAOYSA-N 0.000 description 2
- RSDGRRJTGIGGBP-UHFFFAOYSA-N 4-pyridin-4-ylcyclohexan-1-one Chemical compound C1CC(=O)CCC1C1=CC=NC=C1 RSDGRRJTGIGGBP-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000003177 cardiotonic effect Effects 0.000 description 2
- GBCKMCXGDXVDPG-UHFFFAOYSA-N dimethyl 4-pyridin-4-ylheptanedioate Chemical compound COC(=O)CCC(CCC(=O)OC)C1=CC=NC=C1 GBCKMCXGDXVDPG-UHFFFAOYSA-N 0.000 description 2
- SHWINQXIGSEZAP-UHFFFAOYSA-N dimethyl heptanedioate Chemical compound COC(=O)CCCCCC(=O)OC SHWINQXIGSEZAP-UHFFFAOYSA-N 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 description 1
- DRLVMOAWNVOSPE-UHFFFAOYSA-N 2-phenylcyclohexan-1-one Chemical class O=C1CCCCC1C1=CC=CC=C1 DRLVMOAWNVOSPE-UHFFFAOYSA-N 0.000 description 1
- BMVSAKPRNWZCPG-UHFFFAOYSA-N 2-pyridin-4-ylacetonitrile Chemical compound N#CCC1=CC=NC=C1 BMVSAKPRNWZCPG-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000005396 acrylic acid ester group Chemical group 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- LLEMOWNGBBNAJR-UHFFFAOYSA-N biphenyl-2-ol Chemical class OC1=CC=CC=C1C1=CC=CC=C1 LLEMOWNGBBNAJR-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- HPXRVTGHNJAIIH-PTQBSOBMSA-N cyclohexanol Chemical group O[13CH]1CCCCC1 HPXRVTGHNJAIIH-PTQBSOBMSA-N 0.000 description 1
- 125000002243 cyclohexanonyl group Chemical group *C1(*)C(=O)C(*)(*)C(*)(*)C(*)(*)C1(*)* 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- LKKOGZVQGQUVHF-UHFFFAOYSA-N diethyl heptanedioate Chemical compound CCOC(=O)CCCCCC(=O)OCC LKKOGZVQGQUVHF-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010438 heat treatment Methods 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
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Description
【発明の詳細な説明】
産業上の利用分野
本発明は４−ピリジルシクロヘキサノン類の製
造法に関するものであり、これらの４−ピリジル
シクロヘキサノンは、医薬中間体として有用であ
り、特に強心活性を有するイソキノリン誘導体、
例えば次の反応経路によつて得られる
４−シアノ−２，３，５，６，７，８−ヘキサ
ヒドロ−１−メチル−３−オキソ−７−（４−ピ
リジル）イソキノリンの製造中間体として有用で
ある。DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a method for producing 4-pyridylcyclohexanones, which are useful as pharmaceutical intermediates, and are particularly suitable for isoquinolines having cardiotonic activity. derivative,
For example, it can be obtained by the following reaction route. It is useful as an intermediate in the production of 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline.
従来技術
シクロヘキサノンの４位にピリジル基の結合し
た化合物の一般的な製造方法としては、通常なら
４−ピリジルフエノール類の選択的水添とこれに
続くシクロヘキサノール部分の酸化が考えられ
る。Prior Art As a general method for producing a compound having a pyridyl group bonded to the 4-position of cyclohexanone, selective hydrogenation of 4-pyridylphenols and subsequent oxidation of the cyclohexanol moiety can be considered.
発明が解決しようとする問題点
４−ピリジルシクロヘキサノン類の製造方法と
して、通常考えられる４−ピリジルフエノール類
の選択的水添と酸化反応の組み合せによる方法
は、特定の構造の４−ピリジルシクロヘキサノン
を得ようとすると、水添部位の選択性の確保に非
常な困難が予想される。Problems to be Solved by the Invention As a method for producing 4-pyridylcyclohexanones, a method that involves a combination of selective hydrogenation and oxidation reaction of 4-pyridylphenols, which is commonly considered, does not yield 4-pyridylcyclohexanone with a specific structure. If this is attempted, it is expected that it will be extremely difficult to ensure the selectivity of the hydrogenation site.
問題点を解決するための手段
本発明者らは、医薬中間体として有用であり、
特に強心活性を有するイソキノリン誘導体、例え
ば４−シアノ−２，３，５，６，７，８−ヘキサ
ヒドロ−１−メチル−３−オキソ−７−（４−ピ
リジル）イソキノリン製造の中間体として有用な
４−ピリジルシクロヘキサノン類の製造方法につ
いて検討を行つた。Means for Solving the Problems The present inventors have discovered that the present invention is useful as a pharmaceutical intermediate;
Especially useful as an intermediate for the production of isoquinoline derivatives having cardiotonic activity, such as 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline. A method for producing 4-pyridylcyclohexanones was investigated.
４−ピリジルシクロヘキサノン類の一般的製造
方法としては、通常なら例えばフエニルフエノー
ル類の選択的水添と酸化反応の組合せによるフエ
ニルシクロヘキサノン類製造の経路と同じように
次の反応経路に示すような４−ピリジルフエノー
ル類の選択的水添と酸化反応の組合せによる方法
が考えられる。 A general method for producing 4-pyridylcyclohexanones is the same as the route for producing phenylcyclohexanones by a combination of selective hydrogenation and oxidation reaction of phenylphenols, as shown in the following reaction route. A method using a combination of selective hydrogenation and oxidation reaction of 4-pyridylphenols is considered.
しかし、この反応では水添部位の選択性の確保
に非常な困難が予想され、特定の構造の４−ピリ
ジルシクロヘキサノンを高純度で得ることは覚束
ない。 However, in this reaction, it is expected that it will be very difficult to ensure the selectivity of the hydrogenation site, and it is difficult to obtain 4-pyridylcyclohexanone with a specific structure in high purity.
そこで本発明者らはピリジル基の特定位置で置
換された４−ピリジルシクロヘキサノン類を製造
する方法について鋭意検討を続けた結果、特定の
構造の４−ピリジルシクロヘキサノンを容易に製
造できる方法を見出し本発明に到達した。 Therefore, the present inventors continued to conduct intensive studies on methods for producing 4-pyridylcyclohexanones substituted at specific positions of the pyridyl group, and as a result, discovered a method for easily producing 4-pyridylcyclohexanone having a specific structure, and the present invention is presented. reached.
本発明の４−ピリジルシクロヘキサノン類の製
造法は、詳しくは一般式（）
（式中、Ｒはメチルまたはエチル基を表わす）で
示される４−ピリジルピメリン酸エステルをデイ
ークマン縮合したのち、加水分解と脱炭酸を行い
一般式（）
で示される４−ピリジルシクロヘキサノンを製造
する方法に関するものである。 In detail, the method for producing 4-pyridylcyclohexanones of the present invention is expressed by the general formula () (In the formula, R represents a methyl or ethyl group) 4-pyridylpimelic acid ester is subjected to Diekman condensation, and then hydrolyzed and decarboxylated to form the general formula () The present invention relates to a method for producing 4-pyridylcyclohexanone shown in the following.
本発明の方法についてさらに詳しく述べると、
本発明の製造法は次に示す一連の反応経路の一部
として実施される。 To describe the method of the present invention in more detail,
The production method of the present invention is carried out as part of a series of reaction routes shown below.
上記の反応経路におけるＲは前記と同じ置換基
を意味する。 R in the above reaction route means the same substituent as above.
上記において、化合物（）（以下、化合物を
略して呼ぶ）は、（）から（）を経て製造さ
れる。 In the above, the compound () (hereinafter referred to as compound for short) is produced from () through ().
（）から（）を製造する反応では、（）
に対して２当量以上、好ましくは２〜３当量のア
クリル酸エステルをベンゼン、トルエン、クロロ
ホルム、ヘキサン、ジクロルメタン、エチルエー
テル、テトラヒドロフラン、メタノール、エタノ
ールまたは酢酸エチルなどの溶媒中あるいは
（）に対して大過剰のアクリル酸エステルを用
いて無溶媒で、（）に対して0.1〜５モル％の
１，８−ジアザビシクロ（５，４，０）−７−ウ
ンデセンまたはその類縁塩基である１，５−ジア
ザビシクロ（４，３，０）−５−ノネンまたは１，
４−ジアザビシクロ（２，２，２）オクタンなど
を加えて、０〜120℃、好ましくは30〜50℃にお
いて反応させることにより、（）を製造できる。 In the reaction that produces () from (), ()
2 equivalents or more, preferably 2 to 3 equivalents of acrylic acid ester, in a solvent such as benzene, toluene, chloroform, hexane, dichloromethane, ethyl ether, tetrahydrofuran, methanol, ethanol or ethyl acetate, or in a large amount relative to (). 1,8-diazabicyclo(5,4,0)-7-undecene or 1,5-diazabicyclo, which is a related base thereof, in an amount of 0.1 to 5 mol% based on () without solvent using excess acrylic ester. (4,3,0)-5-nonene or 1,
() can be produced by adding 4-diazabicyclo(2,2,2)octane or the like and reacting at 0 to 120°C, preferably 30 to 50°C.
つぎに（）を硫酸または塩酸等の鉱酸中で加
熱して、シアノ基の加水分解および脱炭酸を行つ
たのち、再び硫酸または塩化水素の存在下にメタ
ノールまたはエタノールでカルボキシル基をエス
テル化して（）を導くことができる。（）に
おけるピリジル基の置換位置は（）におけるそ
れがそのまゝ保たれている。得られた（）をテ
トラヒドロフラン溶媒中で、ｔ−ブトキシカリウ
ム、ナトリウムメチラートまたはナトリウムエチ
ラートなどのアルカリの存在下に、30〜80℃でデ
イークマン縮合を行つて（）を製造することが
できる。引続き（）を塩酸または硫酸中で加熱
して加水分解と脱炭酸を行い、本発明にかゝわる
化合物（）を製造することができる。 Next, () is heated in a mineral acid such as sulfuric acid or hydrochloric acid to hydrolyze and decarboxylate the cyano group, and then the carboxyl group is esterified with methanol or ethanol in the presence of sulfuric acid or hydrogen chloride again. () can be derived. The substitution position of the pyridyl group in () is maintained as it is in (). Diekman condensation of the obtained () in a tetrahydrofuran solvent in the presence of an alkali such as t-butoxypotassium, sodium methylate or sodium ethylate at 30 to 80°C can produce (). Subsequently, () is heated in hydrochloric acid or sulfuric acid to perform hydrolysis and decarboxylation to produce the compound () according to the present invention.
発明の効果
本発明により、医薬中間体として有用であり、
特に強心剤として有用なイソキノリン誘導体の製
造中間体である４−ピリジルシクロヘキサノンを
製造できる。Effects of the Invention According to the present invention, it is useful as a pharmaceutical intermediate,
In particular, 4-pyridylcyclohexanone, which is an intermediate for producing isoquinoline derivatives useful as cardiotonic agents, can be produced.
以下に参考例および実施例を示し、本発明をさ
らに詳細に説明する。 The present invention will be explained in further detail with reference to Reference Examples and Examples below.
参考例 １
４−シアノ−４−（４−ピリジル）ピメリン酸
ジメチルエステル
アクリル酸メチル10.4ｇと１，８−ジアザビシ
クロ（５，４，０）−７−ウンデセン0.2ｇを混合
し、30〜40℃で４−ピリジルアセトニトリル14.2
ｇとアクリル酸メチル20.8ｇとの溶液を加えた。Reference example 1 4-cyano-4-(4-pyridyl)pimelic acid dimethyl ester 10.4 g of methyl acrylate and 0.2 g of 1,8-diazabicyclo(5,4,0)-7-undecene were mixed and heated at 30 to 40°C. 4-pyridylacetonitrile 14.2
g and 20.8 g of methyl acrylate were added.
反応終了後、過剰のアクリル酸メチルを減圧下
に留去した。これを酢酸エチルに溶解してシリカ
ゲルカラムを通し、１，８−ジアザビシクロ
（５，４，０）−７−ウンデセンを除き、酢酸エチ
ルを減圧下に留去して、４−シアノ−４−（４−
ピリジル）ピメリン酸ジメチルエステル35ｇを油
状物として得た。IRγNeat naxcm-1：2940、2230、
1730、1590、1430、1200、1170 NMRδCCl4 TMS：1.9
〜2.7（8H，ｍ）、3.58（6H，ｓ）、7.39（2H，ｍ）、
8.62（2H，ｍ）。 After the reaction was completed, excess methyl acrylate was distilled off under reduced pressure. This was dissolved in ethyl acetate and passed through a silica gel column to remove 1,8-diazabicyclo(5,4,0)-7-undecene, and ethyl acetate was distilled off under reduced pressure. 4-
35 g of pyridyl)pimelic acid dimethyl ester were obtained as an oil. IRγ Neat nax cm -1 : 2940, 2230,
1730, 1590, 1430, 1200, 1170 NMRδ CCl4 TMS : 1.9
~2.7 (8H, m), 3.58 (6H, s), 7.39 (2H, m),
8.62 (2H, m).
参考例 ２
４−（４−ピリジル）ピメリン酸ジメチルエス
テル
４−シアノ−４−（４−ピリジル）ピメリン酸
ジメチルエステル35ｇを濃塩酸250mlに加え、14
時間加熱還流した。反応終了後、減圧下に塩酸を
留去し、この中へメタノール200mlと濃硫酸１ml
を加えて４時間加熱還流した。Reference example 2 4-(4-pyridyl) pimelic acid dimethyl ester Add 35 g of 4-cyano-4-(4-pyridyl) pimelic acid dimethyl ester to 250 ml of concentrated hydrochloric acid,
The mixture was heated to reflux for an hour. After the reaction is complete, hydrochloric acid is distilled off under reduced pressure, and 200 ml of methanol and 1 ml of concentrated sulfuric acid are added into the solution.
was added and heated under reflux for 4 hours.
反応終了後メタノールを減圧下に留去したの
ち、水150mlと酢酸エチル150mlを加え、撹拌しな
がら重曹を加えてPHを８〜９に調節した。有機層
を分離し、飽和食塩水で洗浄したのち乾燥して溶
媒を留去し、４−（４−ピリジル）ピメリン酸ジ
メチルエステル26ｇを油状物として得た。
IRγNeat naxcm-1：2950、1730、1600、1435、1250、
1200、1170 NMRδCCl4 TMS：1.9〜2.7（8H，ｍ）、3.58
（6H，ｓ）、7.38（2H，ｍ）、8.63（2H，ｍ）。 After the reaction was completed, methanol was distilled off under reduced pressure, 150 ml of water and 150 ml of ethyl acetate were added, and while stirring, sodium bicarbonate was added to adjust the pH to 8-9. The organic layer was separated, washed with saturated brine, dried and the solvent was distilled off to obtain 26 g of 4-(4-pyridyl)pimelic acid dimethyl ester as an oil.
IRγ Neat nax cm -1 : 2950, 1730, 1600, 1435, 1250,
1200, 1170 NMRδ CCl4 TMS : 1.9-2.7 (8H, m), 3.58
(6H, s), 7.38 (2H, m), 8.63 (2H, m).
実施例 １
４−（４−ピリジル）シクロヘキサノン
テトラヒドロフラン100mlにｔ−ブトキシカリ
ウム13ｇを加え、この中へ20〜40℃で４−（４−
ピリジル）ピメリン酸ジメチルエステル26ｇとテ
トラヒドロフラン50mlとの溶液を加え、１時間撹
拌した。Example 1 4-(4-pyridyl)cyclohexanone 13 g of potassium t-butoxy was added to 100 ml of tetrahydrofuran, and 4-(4-
A solution of 26 g of dimethyl pyridyl pimelate and 50 ml of tetrahydrofuran was added and stirred for 1 hour.
反応終了後、水50mlを加え減圧下でテトヒドロ
フランを留去し、２−メトキシカルボニル−４−
（４−ピリジル）シクロヘキサノンを単離するこ
となく、この中へ濃塩酸25mlを加え１時間加熱還
流した。反応終了後、酢酸エチル100mlを加え、
撹拌しながら重曹を加えてPHを８〜９に調節し、
有機層を分離して乾燥した。酢酸エチルを減圧下
に留去して、４−（４−ピリジル）シクロヘキサ
ノン13ｇを得た。mp35〜37℃
IRγNeat naxcm-1：3010、2920、2860、1700、1600、
1400、 NMRδCDl3 TMS：1.7〜2.6（8H，ｍ）、2.8〜3.2
（1H，ｍ）、7.15（2H，ｍ）、8.51（2H，ｍ）。 After the reaction, 50 ml of water was added and tetrahydrofuran was distilled off under reduced pressure to give 2-methoxycarbonyl-4-
Without isolating (4-pyridyl)cyclohexanone, 25 ml of concentrated hydrochloric acid was added thereto and the mixture was heated under reflux for 1 hour. After the reaction is complete, add 100ml of ethyl acetate,
While stirring, add baking soda to adjust the pH to 8-9.
The organic layer was separated and dried. Ethyl acetate was distilled off under reduced pressure to obtain 13 g of 4-(4-pyridyl)cyclohexanone. mp35~37℃ IRγ Neat nax cm -1 : 3010, 2920, 2860, 1700, 1600,
1400, NMRδ CDl3 TMS : 1.7-2.6 (8H, m), 2.8-3.2
(1H, m), 7.15 (2H, m), 8.51 (2H, m).
参考例 ３
４−シアノ−４−（２−ピリジル）ピメリン酸
ジメチルエステル
アクリル酸メチル17.2ｇに、１，８−ジアザビ
シクロ（５，４，０）−７−ウンデセン0.1ｇを加
え、30〜40℃で２−ピリジルアセトニトリル11.8
ｇとアクリル酸メチル8.6ｇとの溶液を加えた。Reference Example 3 4-Cyano-4-(2-pyridyl)pimelic acid dimethyl ester 1,8-diazabicyclo(5,4,0)-7-undecene 0.1g was added to 17.2g of methyl acrylate, and the mixture was heated at 30 to 40°C. 2-pyridylacetonitrile 11.8
g and 8.6 g of methyl acrylate were added.
反応終了後、過剰のアクリル酸メチルを減圧下
に留去した。 After the reaction was completed, excess methyl acrylate was distilled off under reduced pressure.
これを酢酸エチルに溶解してシリカゲルカラム
を通し、１，８−ジアザビシクロ（５，４，０）
−７−ウンデセンを除いたのち酢酸エチルを減圧
下に留去して、４−シアノ−４−（２−ピリジル）
ピメリン酸ジメチルエステル26.5ｇを油状物とし
て得た。IRγNeat naxcm-1：2250、1740、1590、1440、
1200、1180 NMRδCCl4 TMS：1.8〜2.6（8H，ｍ）、3.56
（6H，ｓ）、7.3（1H，ｍ）、7.5〜7.9（2H，ｍ）、
8.6（1H，ｍ）。 This was dissolved in ethyl acetate and passed through a silica gel column to form 1,8-diazabicyclo(5,4,0).
After removing -7-undecene, ethyl acetate was distilled off under reduced pressure to produce 4-cyano-4-(2-pyridyl).
26.5 g of pimelic acid dimethyl ester were obtained as an oil. IRγ Neat nax cm -1 : 2250, 1740, 1590, 1440,
1200, 1180 NMRδ CCl4 TMS : 1.8-2.6 (8H, m), 3.56
(6H, s), 7.3 (1H, m), 7.5-7.9 (2H, m),
8.6 (1H, m).
参考例 ４
４−（２−ピリジル）ピメリン酸ジメチルエス
テル
４−シアノ−４−（２−ピリジル）ピメリン酸
ジメチルエステル３ｇと濃塩酸12mlを混合し、８
時間加熱還流した。Reference Example 4 4-(2-pyridyl)pimelic acid dimethyl ester 3 g of 4-cyano-4-(2-pyridyl) pimelic acid dimethyl ester and 12 ml of concentrated hydrochloric acid were mixed, and 8
The mixture was heated to reflux for an hour.
反応終了後、減圧下で塩酸を留去し、この中へ
メタノール40mlと濃硫酸５滴を加えて５時間加熱
還流した。反応終了後、減圧下でメタノールを留
去したのち水を加え重曹でPHを８〜９に調節して
クロロホルムで抽出した。 After the reaction was completed, hydrochloric acid was distilled off under reduced pressure, and 40 ml of methanol and 5 drops of concentrated sulfuric acid were added thereto, followed by heating under reflux for 5 hours. After the reaction was completed, methanol was distilled off under reduced pressure, water was added, the pH was adjusted to 8 to 9 with sodium bicarbonate, and the mixture was extracted with chloroform.
クロロホルム層を飽和食塩水と水で洗浄して乾
燥した。つぎにクロロホルムを減圧下で留去し
て、４−（２−ピリジル）ピメリン酸ジメチルエ
ステル2.55ｇを油状物として得た。IRγNeat naxcm-1：
3000、2940、1730、1590、1470、1430、1160
NMRδCCl4 TMS：1.8〜2.2（8H，ｍ）、2.7（1H，ｍ）
、
3.5（6H，ｓ）、7.0（2H、ｍ）、7.5（1H，ｍ）、8.45
（1H，ｓ）。 The chloroform layer was washed with saturated brine and water and dried. Next, chloroform was distilled off under reduced pressure to obtain 2.55 g of 4-(2-pyridyl)pimelic acid dimethyl ester as an oil. IRγ Neat nax cm -1 :
3000, 2940, 1730, 1590, 1470, 1430, 1160
NMRδ CCl4 TMS : 1.8-2.2 (8H, m), 2.7 (1H, m)
,
3.5 (6H, s), 7.0 (2H, m), 7.5 (1H, m), 8.45
(1H, s).
実施例 ２
４−（２−ピリジル）シクロヘキサノン
４−（２−ピリジル）ピメリン酸ジメチルエス
テル2.3ｇをテトラヒドロフラン60mlに溶解し、
ナトリウムメチラート2.3ｇを加えて３時間加熱
還流した。反応終了後、水30mlを加え、減圧下で
テトラヒドロフランを留去した。この中へ4N−
塩酸30mlを加えて1.5時間加熱還流した。Example 2 4-(2-pyridyl)cyclohexanone 2.3 g of 4-(2-pyridyl) pimelic acid dimethyl ester was dissolved in 60 ml of tetrahydrofuran,
2.3 g of sodium methylate was added and the mixture was heated under reflux for 3 hours. After the reaction was completed, 30 ml of water was added, and tetrahydrofuran was distilled off under reduced pressure. 4N into this
30 ml of hydrochloric acid was added and the mixture was heated under reflux for 1.5 hours.
反応終了後、酢酸エチル50mlを加え、撹拌しな
がら重曹を加えてPHを８〜９に調節し、酢酸エチ
ル層を分離した。食塩水で洗浄後、乾燥して酢酸
エチルを減圧下で留去し、４−（２−ピリジル）
シクロヘキサノンを0.8ｇ得た。IRγNeat naxcm-1：
1700、1580、1470、1420、1150 NMRδCCl4 TMS：1.8
〜2.6（8H，ｍ）、3.15（1H，ｍ）7.15（2H、ｍ）、
7.6（1H，ｍ）、8.5（1H，ｍ）。 After the reaction was completed, 50 ml of ethyl acetate was added, and while stirring, sodium bicarbonate was added to adjust the pH to 8 to 9, and the ethyl acetate layer was separated. After washing with brine and drying, ethyl acetate was distilled off under reduced pressure to obtain 4-(2-pyridyl).
0.8g of cyclohexanone was obtained. IRγ Neat nax cm -1 :
1700, 1580, 1470, 1420, 1150 NMRδ CCl4 TMS : 1.8
~2.6 (8H, m), 3.15 (1H, m) 7.15 (2H, m),
7.6 (1H, m), 8.5 (1H, m).
参考例 ５
４−シアノ−４−（２−ピリジル）ピメリン酸
ジエチルエステル
参考例３と同様にして、２−ピリジルアセトニ
トリル11.8ｇ、アクリル酸エチル30ｇおよび１，
５−ジアザビシクロ（４，３，０）−５−ノネン
0.2ｇから、４−シアノ−４−（２−ピリジル）ピ
メリン酸ジエチルエステル31.9ｇを油状物として
得た。IRγNeat naxcm-1：2250、1740、1590、1440、
1200、1180 NMRδCCl4 TMS：1.2（6H，ｔ）、1.8〜2.6
（8H，ｍ）、4.0（4H，ｑ）、7.3（1H、ｍ）、7.5〜
7.9（2H，ｍ）、8.6（1H，ｍ）。Reference Example 5 4-Cyano-4-(2-pyridyl)pimelic acid diethyl ester In the same manner as in Reference Example 3, 11.8 g of 2-pyridylacetonitrile, 30 g of ethyl acrylate and 1,
5-diazabicyclo(4,3,0)-5-nonene
From 0.2 g, 31.9 g of 4-cyano-4-(2-pyridyl)pimelic acid diethyl ester were obtained as an oil. IRγ Neat nax cm -1 : 2250, 1740, 1590, 1440,
1200, 1180 NMRδ CCl4 TMS : 1.2 (6H, t), 1.8-2.6
(8H, m), 4.0 (4H, q), 7.3 (1H, m), 7.5~
7.9 (2H, m), 8.6 (1H, m).
参考例 ６
４−（２−ピリジル）ピメリン酸ジエチルエス
テル
参考例４と同様にして、４−シアノ−４−（２
−ピリジル）ピメリン酸ジエチルエステル3.2ｇ
から、４−（２−ピリジル）ピメリン酸ジエチル
エステル2.6ｇを油状物として得た。Reference Example 6 4-(2-pyridyl)pimelic acid diethyl ester 4-cyano-4-(2-pyridyl)pimelic acid diethyl ester
-pyridyl) pimelic acid diethyl ester 3.2g
From this, 2.6 g of 4-(2-pyridyl)pimelic acid diethyl ester was obtained as an oil.
IRγNeat naxcm-1：3000、1730、1590、1460、1430、
1180 NMRγCCl4 TMS：1.2（6H，ｔ）、1.8〜2.2（8H，
ｍ）、2.7（1H，ｍ）、4.0（4H，ｑ）、7.1（2H、ｍ）
、
7.6（1H，ｍ）、8.5（1H，ｍ）。IRγ Neat nax cm -1 : 3000, 1730, 1590, 1460, 1430,
1180 NMRγ CCl4 TMS : 1.2 (6H, t), 1.8~2.2 (8H,
m), 2.7 (1H, m), 4.0 (4H, q), 7.1 (2H, m)
,
7.6 (1H, m), 8.5 (1H, m).
実施例 ３
４−（２−ピリジル）シクロヘキサノン
実施例２と同様にして４−（２−ピリジル）ピ
メリン酸ジエチルエステル2.6ｇから、４−（２−
ピリジル）シクロヘキサノンを0.7ｇ得た。Example 3 4-(2-pyridyl)cyclohexanone In the same manner as in Example 2, 4-(2-
0.7 g of cyclohexanone (pyridyl) was obtained.
IRおよびNMRの値は、実施例２−(3)の化合物
と一致した。 The IR and NMR values were consistent with the compound of Example 2-(3).
Claims (1)
示される４−ピリジルピメリン酸エステルをデイ
ークマン縮合したのち、加水分解と脱炭酸を行い
一般式（） で示される４−ピリジルシクロヘキサノンを製造
する方法。[Claims] 1 General formula () (In the formula, R represents a methyl or ethyl group) 4-pyridylpimelic acid ester is subjected to Diekman condensation, and then hydrolyzed and decarboxylated to form the general formula () A method for producing 4-pyridylcyclohexanone shown in
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14916585A JPS6210063A (en) | 1985-07-09 | 1985-07-09 | Production of 4-pyridylcyclohexanone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14916585A JPS6210063A (en) | 1985-07-09 | 1985-07-09 | Production of 4-pyridylcyclohexanone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6210063A JPS6210063A (en) | 1987-01-19 |
| JPH0548224B2 true JPH0548224B2 (en) | 1993-07-20 |
Family
ID=15469216
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP14916585A Granted JPS6210063A (en) | 1985-07-09 | 1985-07-09 | Production of 4-pyridylcyclohexanone |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6210063A (en) |
-
1985
- 1985-07-09 JP JP14916585A patent/JPS6210063A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6210063A (en) | 1987-01-19 |
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