JP5193118B2 - Method for producing γ-tyaprisin - Google Patents
Method for producing γ-tyaprisin Download PDFInfo
- Publication number
- JP5193118B2 JP5193118B2 JP2009100155A JP2009100155A JP5193118B2 JP 5193118 B2 JP5193118 B2 JP 5193118B2 JP 2009100155 A JP2009100155 A JP 2009100155A JP 2009100155 A JP2009100155 A JP 2009100155A JP 5193118 B2 JP5193118 B2 JP 5193118B2
- Authority
- JP
- Japan
- Prior art keywords
- mixture
- sodium
- isopropylcyclopentadiene
- solvent
- reaction
- 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 - Fee Related
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/28—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of CHx-moieties
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/79—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/385—Saturated compounds containing a keto group being part of a ring
- C07C49/413—Saturated compounds containing a keto group being part of a ring of a seven- to twelve-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/527—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings
- C07C49/547—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings to a seven- to twelve-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
- C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
- C07C49/717—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups a keto group being part of a seven- to twelve-membered ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
本発明は、医薬の中間体として有用なγ-ツヤプリシンの製造方法に関する。 The present invention relates to a method for producing γ-tjapricin useful as a pharmaceutical intermediate.
γ-ツヤプリシン[5−イソプロピルトロポロン]は、青森ヒバや台湾ヒノキの精油中に含まれる天然物であり、抗菌・抗カビ作用を持つトロポロン類縁体ある。また、抗潰瘍剤であるエグアレンナトリウムの製造中間体である。このγ-ツヤプリシンの製造方法に関しては、次に示すような製造方法が報告されている。すなわち、(1)氷酢酸中、2−クロロ−5−イソプロピルトロポンをリン酸とともに還流してγ-ツヤプリシンを合成する方法が報告され(非特許文献1)、また、この2−クロロ−5−イソプロピルトロポンを、4−イソプロピルアニソールを出発原料にして合成する方法が提案されている(特許文献1)。この方法は、多段階(5工程)であり、超低温反応を含んでいる。更に、危険な試薬を使用するために、操作的に危険を伴う。また、4−イソプロピルアニソールが高価である。 γ-Tyaprisin [5-isopropyltropolone] is a natural product contained in essential oils of Aomori Hiba and Taiwan Hinoki, and is an tropolone analog having antibacterial and antifungal activities. In addition, it is an intermediate for producing eguarene sodium, an anti-ulcer agent. Regarding the method for producing γ-tyaprisin, the following production method has been reported. That is, (1) a method in which 2-chloro-5-isopropyltropone is refluxed with phosphoric acid in glacial acetic acid to synthesize γ-tyaprisin (Non-patent Document 1), and this 2-chloro-5 is reported. A method for synthesizing isopropyl tropone using 4-isopropylanisole as a starting material has been proposed (Patent Document 1). This method is multi-stage (5 steps) and involves ultra-low temperature reactions. Furthermore, the use of dangerous reagents is dangerous in terms of operation. In addition, 4-isopropylanisole is expensive.
更に、(2)シクロペンタジエンとグリニヤル試薬(エチルマグネシウムブロミド)をテトラヒドロフラン溶媒中、溶媒還流温度で反応させた後、イソプロピルトシレートを反応させてイソプロピルシクロペンタジエンを得、これにジクロロケテンを付加反応させてから塩基性条件下で加溶媒分解し、この粗加溶媒分解生成物を酸性にしてトロポロン化合物を析出させ、更にカラムクロマトグラフィーによりγ-ツヤプリシンとその異性体であるβ-ツヤプリシンを分離して、γ-ツヤプリシンを得る方法が報告されている(非特許文献2)。カラムクロマトグラフィーを工業的に実施する上では、生産性及び生産コストに問題が生じる。例えば、大量の溶媒を使用したり、吸着剤の再生、処理等煩雑な操作が必要となる等、精製コストが高くなり、工業的には好ましくない。 Furthermore, (2) cyclopentadiene and Grignard reagent (ethylmagnesium bromide) were reacted in tetrahydrofuran solvent at the solvent reflux temperature, and then isopropyl tosylate was reacted to obtain isopropylcyclopentadiene, which was subjected to addition reaction of dichloroketene. Then, it is solvolyzed under basic conditions, the crude solvolysis product is acidified to precipitate the tropolone compound, and γ-Tyapricin and its isomer β-Tyapricin are separated by column chromatography. A method for obtaining γ-tyaprisin has been reported (Non-patent Document 2). When performing column chromatography industrially, problems arise in productivity and production cost. For example, the purification cost is high, such as using a large amount of solvent or requiring complicated operations such as regeneration and treatment of the adsorbent, which is not industrially preferable.
また、(3)ヒノキチオール(β−ツヤプリシン)の製造方法として、シクロペンタジエンとアルカリ金属とからシクロペンタジエニル金属を調製する工程、該シクロペンタジエニル金属とイソプロピル化剤とを反応させて、イソプロピルシクロペンタジエンを取得する工程、該イソプロピルシクロペンタジエン中の5−イソプロピルシクロペンタジエンを1−イソプロピルシクロペンタジエンへ選択的に異性化する工程、該1−イソプロピルシクロペンタジエンとジハロケテンとを反応させてケテン付加体を得る工程、該ケテン付加体を分解する工程からなるヒノキチオールの製造方法が提案されている(特許文献2)。 (3) As a method for producing hinokitiol (β-tyaprisin), a step of preparing cyclopentadienyl metal from cyclopentadiene and an alkali metal, reacting the cyclopentadienyl metal with an isopropylating agent, Obtaining cyclopentadiene, selectively isomerizing 5-isopropylcyclopentadiene into 1-isopropylcyclopentadiene in isopropylcyclopentadiene, reacting 1-isopropylcyclopentadiene with dihaloketene to produce a ketene adduct. A method for producing hinokitiol comprising a step of obtaining and a step of decomposing the ketene adduct has been proposed (Patent Document 2).
また、(4)トロポロン化合物特にβ−ツヤプリシンの製造法として、置換もしくは非置換のシクロペンタジエンとジクロロケテンとを付加反応させて、7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン化合物を得、これを塩基の存在下分解しトロポロン化合物を製造するとき、上記化合物を塩基の存在下分解する前に減圧蒸留精製する工程、及び塩基の存在下分解して得た粗トロポロン化合物を蒸留と晶析により精製する工程を行ってトロポロン化合物を製造する方法が提案されている(特許文献3)。更に、シクロペンタジエン類とジクロロケテンとを反応して得たジクロロケテン付加体を加溶媒分解して得られた粗トロポロン化合物を、特定の溶解度パラメーターの溶媒を用いて晶析する粗トロポロン化合物の精製方法が提案されている(特許文献4) (4) As a method for producing a tropolone compound, particularly β-tyaprisin, a substituted or unsubstituted cyclopentadiene and dichloroketene are subjected to an addition reaction to produce 7,7-dichlorobicyclo [3.2.0] -hept-2-ene. -6-one compound was obtained and decomposed in the presence of a base to produce a tropolone compound. The above-mentioned compound was obtained by distillation under reduced pressure before decomposition in the presence of a base, and decomposition in the presence of a base. A method for producing a tropolone compound by performing a process of purifying a crude tropolone compound by distillation and crystallization has been proposed (Patent Document 3). Furthermore, purification of a crude tropolone compound that crystallizes a crude tropolone compound obtained by solvolysis of a dichloroketene adduct obtained by reacting cyclopentadiene with dichloroketene using a solvent having a specific solubility parameter. A method has been proposed (Patent Document 4).
上記の(2)〜(4)の製造方法に見るように、γ-ツヤプリシンが属するトロポロン化合物の製造では、従来、シクロペンタジエンを出発原料とし、これにイソプロピル化剤を反応させてイソプロピルシクロペンタジエンを得、更にジクロロケテンを反応させてケテン付加体を得、これを加溶媒分解して得た粗トロポロン化合物の混合物を精製してトロポロン化合物混合物となし、これから目的のトロポロン化合物を分離している。上記のイソプロピルシクロペンタジエンを得るとき、N,N−ジメチルホルムアミド中で、シクロペンタジエンとナトリウムアミドとを反応させてナトリウムシクロペンタジエニリドを得、これにイソプロピル化剤を反応させることにより、イソプロピルシクロペンタジエンの平衡混合物を収率良く、また再現性よく得ることは知られていない。また、粗トロポロン化合物を蒸留や晶析により精製することは知られているが、この粗トロポロン化合物の混合物から、γ-ツヤプリシンを晶析により分離することは知られていない。 As seen in the production methods (2) to (4) above, in the production of a tropolone compound to which γ-tyaprisin belongs, conventionally, cyclopentadiene is used as a starting material, and this is reacted with an isopropylating agent to produce isopropylcyclopentadiene. Further, the ketene adduct is obtained by further reacting with dichloroketene, and the mixture of the crude tropolone compound obtained by solvolysis is purified into a tropolone compound mixture, from which the desired tropolone compound is separated. When obtaining the isopropylcyclopentadiene described above, cyclopentadiene and sodium amide are reacted in N, N-dimethylformamide to obtain sodium cyclopentadienylide, which is reacted with an isopropylating agent. It is not known that an equilibrium mixture of pentadiene can be obtained with good yield and reproducibility. In addition, it is known to purify a crude tropolone compound by distillation or crystallization, but it is not known to separate γ-tjapricin from this mixture of crude tropolone compounds by crystallization.
また、ナトリウムシクロペンタジエニリドの調製法としては、(i)液体アンモニア中での金属ナトリウムとシクロペンタジエンとの反応(非特許文献3)、(ii)ジメトキシエタンやジグライム等の有機溶媒中での金属ナトリウムとシクロペンタジエンとの反応(非特許文献4)、(iii)テトラヒドロフラン溶媒中での水素化ナトリウムとシクロペンタジエンとの反応(特許文献5)などが知られている。しかして、シクロペンタジエンとナトリウムアミドとを反応させてナトリウムシクロペンタジエニリドを得ることは知られていないし、この反応をN,N−ジメチルホルムアミド溶媒中で行うことも知られていない。 In addition, sodium cyclopentadienylide can be prepared by (i) reaction of sodium metal with cyclopentadiene in liquid ammonia (Non-patent Document 3), (ii) in an organic solvent such as dimethoxyethane or diglyme. The reaction of sodium metal with cyclopentadiene (Non-patent Document 4), (iii) the reaction of sodium hydride with cyclopentadiene in a tetrahydrofuran solvent (Patent Document 5), and the like are known. Thus, it is not known that cyclopentadiene and sodium amide are reacted to obtain sodium cyclopentadienylide, and this reaction is not known to be performed in an N, N-dimethylformamide solvent.
本発明は、上記の事情に鑑み、γ-ツヤプリシンを、安価かつ簡便に、収率良く製造する方法を提供することを目的とする。 In view of the above circumstances, an object of the present invention is to provide a method for producing γ-tjapricin inexpensively and easily with high yield.
本発明者は、鋭意検討を行った結果、ナトリウムアミドを使用することにより、N,N−ジメチルホルムアミド溶媒中で、シクロペンタジエンからナトリウムシクロペンタジエニリドを円滑に調製できることを見出し、またこの方法で調製したナトリウムシクロペンタジエニリドにイソプロピル化剤を反応させて、収率良くまた再現性良くイソプロピルシクロペンタジエン混合物を得ることができ、更に、この混合物を使用して製造した粗生成物から晶析操作により高純度のγ-ツヤプリシンを分離できることを見出し、本発明を完成した。 As a result of intensive studies, the present inventor has found that sodium cyclopentadienyl can be smoothly prepared from cyclopentadiene in an N, N-dimethylformamide solvent by using sodium amide. An isopropylating agent can be reacted with sodium cyclopentadienylide prepared in step 1 to obtain an isopropylcyclopentadiene mixture with good yield and reproducibility, and further, crystals from a crude product produced using the mixture can be obtained. It was found that high-purity γ-tyaprisin can be separated by an analysis operation, and the present invention has been completed.
すなわち、本発明は、次の(1)〜(3)の工程:
(1)N,N−ジメチルホルムアミド溶媒中で、シクロペンタジエンとナトリウムアミドとを反応させてナトリウムシクロペンタジエニリドを調製し、このナトリウムシクロペンタジエニリドにイソプロピル化剤を反応させてイソプロピルシクロペンタジエンの混合物を得る第1工程、
(2)上記イソプロピルシクロペンタジエンの混合物にジクロロケテンを反応させて、7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン誘導体の混合物を得る第2工程、
(3)上記7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン誘導体の混合物を塩基性条件下で加溶媒分解し、得られる粗生成物から晶析によりγ-ツヤプリシンを分離する第3工程、
からなるγ-ツヤプリシンの製造方法である。
That is, the present invention includes the following steps (1) to (3):
(1) In a N, N-dimethylformamide solvent, cyclopentadiene and sodium amide are reacted to prepare sodium cyclopentadienylide, and this sodium cyclopentadienylide is reacted with an isopropylating agent to produce isopropylcyclohexane. A first step of obtaining a mixture of pentadienes;
(2) a second step of reacting the isopropylcyclopentadiene mixture with dichloroketene to obtain a mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivatives;
(3) Solvent decomposition of the above mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative under basic conditions, and γ- A third step of separating tsuyaprisin,
Is a method for producing γ-tsuyaprisin.
本発明により、医薬等又はその中間体として有用なγ-ツヤプリシンを、安価かつ簡便に、収率良く製造することができる。すなわち、ナトリウムシクロペンタジエニリドは、N,N−ジメチルホルムアミド溶媒中で、ナトリウムアミドとシクロペンタジエンの反応により調製でき、またこれにイソプロピル化剤を反応させることによりイソプロピルシクロペンタジエンの混合物を収率良く、また再現性良く製造でき、更に7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン誘導体の混合物の加溶媒分解粗生成物から晶析によりγ-ツヤプリシンを分離したので、γ-ツヤプリシンを安価かつ簡便に、収率良く製造できる利点がある。 INDUSTRIAL APPLICABILITY According to the present invention, γ-tjapricin useful as a pharmaceutical or the like or an intermediate thereof can be produced inexpensively and easily with a high yield. That is, sodium cyclopentadienyl can be prepared by the reaction of sodium amide and cyclopentadiene in an N, N-dimethylformamide solvent, and by reacting this with an isopropylating agent, a mixture of isopropylcyclopentadiene is obtained in a yield. In addition, it can be produced with good reproducibility, and γ-Tyapricin is separated by crystallization from the solvolysis crude product of a mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivatives. Therefore, there is an advantage that γ-tyapricin can be produced inexpensively and easily with a high yield.
本発明のγ-ツヤプリシンの製造方法を、スキームで示し、また各工程について説明する。 The method for producing γ-tyaprisin of the present invention is shown in a scheme, and each step is described.
第1工程:N,N−ジメチルホルムアミド溶媒中で、シクロペンタジエンとナトリウムアミドとを反応させてナトリウムシクロペンタジエニリドを調製し、このナトリウムシクロペンタジエニリドにイソプロピル化剤(構造式I)を反応させてイソプロピルシクロペンタジエン(構造式II)の混合物(異性体の混合物)を得る工程である。その際、調製したナトリウムシクロペンタジエニリドの反応液に、イソプロピル化剤(構造式I)を添加して反応させることができる。
ここで用いるイソプロピル化剤は、次の一般式:
First step: Sodium cyclopentadienyl is prepared by reacting cyclopentadiene with sodium amide in a N, N-dimethylformamide solvent, and this sodium cyclopentadienyl is converted to an isopropylating agent (structure formula I). Is a step of obtaining a mixture (mixture of isomers) of isopropylcyclopentadiene (structure II). At that time, an isopropylating agent (Structural Formula I) can be added to the prepared reaction solution of sodium cyclopentadienylide for reaction.
The isopropylating agent used here has the following general formula:
で示される化合物である。例えば、2−クロロプロパン、2−ブロモプロパン、2−ヨードプロパン、イソプロピルメタンスルホネート、イソプロピルベンゼンスルホネート、イソプロピルトシレート、イソプロピルトリフルオロメタンスルホネート等が挙げられるが、好ましくは2−ブロモプロパンである。 It is a compound shown by these. Examples thereof include 2-chloropropane, 2-bromopropane, 2-iodopropane, isopropyl methanesulfonate, isopropylbenzene sulfonate, isopropyl tosylate, isopropyl trifluoromethanesulfonate, and the like, and 2-bromopropane is preferable.
前述した特許文献2には、塩基として水酸化カリウム、イソプロピル化剤として2−ブロモプロパンを使用したイソプロピルシクロペンタジエンの製造方法が記載され、反応溶媒にジメチルスルホキシドを使用してカリウムシクロペンタジエニリドと2−ブロモプロパンとを反応させると5−イソプロピルシクロペンタジエンが選択的に生成し、これを選択的に1−イソプロピルシクロペンタジエンへ異性化することが記載され、更にこの反応をN,N−ジメチルホルムアミド溶媒中で行うと、2−イソプロピルシクロペンタジエンが若干優位に生成することが記載されている(1−イソプロピルシクロペンタジエン/2−イソプロピルシクロペンタジエン=41/58)。 Patent Document 2 described above describes a method for producing isopropylcyclopentadiene using potassium hydroxide as a base and 2-bromopropane as an isopropylating agent. Potassium cyclopentadienylide using dimethyl sulfoxide as a reaction solvent. And 2-bromopropane are reacted to selectively produce 5-isopropylcyclopentadiene, which is selectively isomerized to 1-isopropylcyclopentadiene, and this reaction is further described as N, N-dimethyl. It has been described that 2-isopropylcyclopentadiene is formed slightly more favorably in a formamide solvent (1-isopropylcyclopentadiene / 2-isopropylcyclopentadiene = 41/58).
そこで、シクロペンタジエンのN,N−ジメチルホルムアミド溶液に水酸化カリウムを加え反応させ、この反応液を2−ブロモプロパン中に滴下してイソプロピルシクロペンタジエンの混合物を製造したところ、水酸化カリウムのN,N−ジメチルホルムアミドへの溶解が影響したためか、カリウムシクロペンタジエニリドの調製に要する反応時間にバラツキが生じ、その結果収率にバラツキが観察された。ところが、本発明によれば、塩基としてナトリウムアミドを用いることにより、ナトリウムシクロペンタジエニリドの調製がスムースに進行し、またその後のイソプロピル化剤(I)との反応によりイソプロピルシクロペンタジエン(II)の平衡混合物を収率良く、また再現性良く得ることができる。また、上記のナトリウムシクロペンタジエニリドとイソプロピル化剤との反応をN,N−ジメチルホルムアミド中で行うには、前述の(i)〜(iii)のナトリウムシクロペンタジエニリド調製法では、それぞれの溶媒をN,N−ジメチルホルムアミドに置換する必要があるため、製造工程が煩雑になる。 Then, potassium hydroxide was added to and reacted with N, N-dimethylformamide solution of cyclopentadiene, and this reaction solution was dropped into 2-bromopropane to produce a mixture of isopropylcyclopentadiene. Due to the influence of dissolution in N-dimethylformamide, the reaction time required for the preparation of potassium cyclopentadienylide varied, and as a result, variation in yield was observed. However, according to the present invention, by using sodium amide as a base, the preparation of sodium cyclopentadienide proceeds smoothly, and the subsequent reaction with the isopropylating agent (I) results in isopropylcyclopentadiene (II). Can be obtained with good yield and reproducibility. In addition, in order to perform the reaction between the sodium cyclopentadienylide and the isopropylating agent in N, N-dimethylformamide, the above-mentioned sodium cyclopentadienide preparation methods (i) to (iii) Since it is necessary to replace each solvent with N, N-dimethylformamide, the production process becomes complicated.
本発明の第1工程において、ナトリウムアミドに対するシクロペンタジエンのモル比は、1〜2の範囲である。ナトリウムアミドに対するイソプロピル化剤のモル比は1〜5であり、好ましくは1〜2の範囲である。ナトリウムアミドに対するN,N−ジメチルホルムアミドのモル比は1〜10であり、好ましくは5〜7の範囲である。反応は−78℃〜溶媒還流温度で行われ、好ましい反応温度は−5℃〜40℃の範囲である。イソプロピルシクロペンタジエン(II)は蒸留精製しても良いが、反応を酸性水溶液でクエンチした後、ヘキサン、へプタン、トルエン等の炭化水素系溶媒で抽出し、その抽出液をそのまま次工程で使用する方が好ましい。 In the first step of the present invention, the molar ratio of cyclopentadiene to sodium amide is in the range of 1-2. The molar ratio of isopropylating agent to sodium amide is 1-5, preferably in the range of 1-2. The molar ratio of N, N-dimethylformamide to sodium amide is 1-10, preferably 5-7. The reaction is carried out at -78 ° C to the solvent reflux temperature, and the preferred reaction temperature is in the range of -5 ° C to 40 ° C. Isopropylcyclopentadiene (II) may be purified by distillation, but after quenching the reaction with an acidic aqueous solution, it is extracted with a hydrocarbon solvent such as hexane, heptane, toluene, etc., and the extract is used as it is in the next step. Is preferred.
第2工程:上記で得たイソプロピルシクロペンタジエン(II)の混合物にジクロロケテンを反応させて、7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン誘導体(構造式III)の混合物を得る工程である。ジクロロケテンは、ジクロロ酢酸クロライドとトリエチルアミンから発生させることができる。第1工程で使用したナトリウムアミドに対するジクロロ酢酸クロライドとトリエチルアミンのモル比は0.5〜2であり、好ましくは0.9〜1.2の範囲である。反応は第1工程の抽出液をそのまま使用し、−78℃〜溶媒還流温度で行われ、好ましい反応温度は−5℃〜20℃の範囲である。得られた粗7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン誘導体(III)は、蒸留精製するのが好ましい。 Second step: The mixture of isopropylcyclopentadiene (II) obtained above is reacted with dichloroketene to produce a 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (structure III ). Dichloroketene can be generated from dichloroacetic acid chloride and triethylamine. The molar ratio of dichloroacetic acid chloride and triethylamine to sodium amide used in the first step is 0.5-2, preferably 0.9-1.2. The reaction is carried out using the extract of the first step as it is, and is carried out at -78 ° C to the solvent reflux temperature, and the preferred reaction temperature is in the range of -5 ° C to 20 ° C. The obtained crude 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) is preferably purified by distillation.
第3工程:上記で得た7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン誘導体(III)の混合物を塩基性条件下で加溶媒分解し、得られる粗生成物から晶析によりγ-ツヤプリシン(構造式IV)を分離する工程である。この分解反応は、アセトン−酢酸−水混合溶媒中で行われ、反応液還流温度で7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン誘導体(III)に対するモル比1〜5の範囲のトリエチルアミンを滴下する。滴下後、溶媒還流温度で1〜10時間攪拌する。反応終了後、通常の後処理を施し、得られた粗生成物にヘキサン、へプタン、含水メタノール、含水エタノールなどの溶媒を添加し溶解し、この溶液に種晶(γ-ツヤプリシン)を加え、0℃〜室温で攪拌した後に、析出したγ-ツヤプリシンを濾取する。晶析に使用する溶媒の量は7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン誘導体(III)の混合物の3〜10倍量である。溶媒を添加した際に不溶物が観察されたときには、デカンテーションにより上澄みを取ってもよい。 Third step: The crude product obtained by solvolysis of the mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) obtained above under basic conditions In this step, γ-tyapricin (Structure IV) is separated from the product by crystallization. This decomposition reaction is carried out in an acetone-acetic acid-water mixed solvent, and the molar ratio to the 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) at the reaction solution reflux temperature. Triethylamine in the range of 1-5 is added dropwise. After the dropwise addition, the mixture is stirred at a solvent reflux temperature for 1 to 10 hours. After completion of the reaction, normal post-treatment is performed, and a solvent such as hexane, heptane, water-containing methanol, water-containing ethanol and the like is added to the obtained crude product to dissolve it. After stirring at 0 ° C. to room temperature, the precipitated γ-tjapricin is collected by filtration. The amount of the solvent used for crystallization is 3 to 10 times the amount of the mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III). When insoluble matter is observed when the solvent is added, the supernatant may be removed by decantation.
(1)イソプロピルシクロペンタジエン(II)の混合物の製造
シクロペンタジエン(14.0g)のN,N−ジメチルホルムアミド(76.3g)溶液に15℃以下でナトリウムアミド(7.3g、92.7%純度)を加えた後、室温で1時間攪拌した。反応液に2−ブロモプロパン(41.7g)を10 ℃以下で滴下した後、1時間攪拌した。反応液に10%塩酸水溶液(30mL)と水(30mL)を加えた後、n−ヘキサン(250mL)にて抽出した。n−ヘキサン抽出液を水(100mLで2回)洗浄した後、無水硫酸ナトリウムにて乾燥した。濾過し、イソプロピルシクロペンタジエン(II)の混合物のn−ヘキサン溶液を得た。
(1) Preparation of a mixture of isopropylcyclopentadiene (II) Sodium amide (7.3 g, 92.7% purity) in a solution of cyclopentadiene (14.0 g) in N, N-dimethylformamide (76.3 g) at 15 ° C. or lower. ) And then stirred at room temperature for 1 hour. 2-Bromopropane (41.7 g) was added dropwise to the reaction solution at 10 ° C. or lower, followed by stirring for 1 hour. A 10% aqueous hydrochloric acid solution (30 mL) and water (30 mL) were added to the reaction solution, and the mixture was extracted with n-hexane (250 mL). The n-hexane extract was washed with water (2 × 100 mL) and then dried over anhydrous sodium sulfate. Filtration gave an n-hexane solution of a mixture of isopropylcyclopentadiene (II).
(2)7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン誘導体(III)の混合物の製造
上記のイソプロピルシクロペンタジエン(II)の混合物のn−ヘキサン溶液に、ジクロロ酢酸クロライド(17.3mL)を加えた。5℃以下でトリエチルアミン(26.5mL)を1時間20分間で滴下した後、1時間30分間攪拌した。反応液に10%塩酸水溶液(50mL)と水(50mL)を加えた後、有機層を分液した。有機層を水(50mLで2回)、飽和炭酸水素ナトリウム水溶液(50mLで1回)、飽和食塩水(50mLで1回)で順次洗浄した後、無水硫酸ナトリウムにて乾燥した。濾過した後、濾液を減圧留去し、得られた残渣を蒸留して、7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン誘導体(III)の混合物(23.8g:沸点105〜107℃/5mmHgの留分)を得た。
(2) Preparation of a mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) To an n-hexane solution of the above mixture of isopropylcyclopentadiene (II), Acetic acid chloride (17.3 mL) was added. Triethylamine (26.5 mL) was added dropwise at 5 ° C. or less over 1 hour and 20 minutes, followed by stirring for 1 hour and 30 minutes. A 10% aqueous hydrochloric acid solution (50 mL) and water (50 mL) were added to the reaction solution, and then the organic layer was separated. The organic layer was washed successively with water (2 × 50 mL), saturated aqueous sodium hydrogen carbonate solution (1 × 50 mL) and saturated brine (1 × 50 mL), and then dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure, and the resulting residue was distilled to obtain a mixture of the 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) (23. 8 g: a fraction having a boiling point of 105 to 107 ° C./5 mmHg).
(3)γ-ツヤプリシン(IV)の製造
上記の7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン誘導体(III)の混合物(42.0g)のアセトン(139g)溶液に酢酸(11.3g)と水(22.6g)を加えた後、トリエチルアミン(66.8mL)を還流温度で1時間16分間かけて滴下した後、同温で5時間攪拌した。反応液を放冷し、水(140mL)と10%塩酸水溶液(14mL)を加えた。トルエン(140mLで2回)抽出し、合わせた抽出液を水(70mLで2回)洗浄した後、無水硫酸ナトリウムにて乾燥した。ろ過した後、濾液を減圧留去し、得られた残渣にn−ヘキサン(160mL)を加え、約50℃で攪拌した後、放冷した。溶液部をデカンテーションにて分取した後、種晶(γ-ツヤプリシン)を加えて室温で攪拌した。析出結晶を濾取した後、乾燥してγ-ツヤプリシン(IV)(8.2g、GC純度99%以上)を得た。
(3) Production of γ-Tyaprisin (IV) Acetone (139 g) of a mixture (42.0 g) of the above 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative (III) Acetic acid (11.3 g) and water (22.6 g) were added to the solution, and then triethylamine (66.8 mL) was added dropwise at reflux temperature for 1 hour and 16 minutes, followed by stirring at the same temperature for 5 hours. The reaction mixture was allowed to cool, and water (140 mL) and 10% aqueous hydrochloric acid (14 mL) were added. Toluene (twice with 140 mL) was extracted, and the combined extract was washed with water (twice with 70 mL) and then dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure, n-hexane (160 mL) was added to the resulting residue, and the mixture was stirred at about 50 ° C. and allowed to cool. The solution part was fractionated by decantation, seed crystals (γ-tyaprisin) were added, and the mixture was stirred at room temperature. Precipitated crystals were collected by filtration and dried to obtain γ-tjapricin (IV) (8.2 g, GC purity 99% or more).
Claims (1)
(1)N,N−ジメチルホルムアミド溶媒中で、シクロペンタジエンとナトリウムアミドとを反応させてナトリウムシクロペンタジエニリドを調製し、このナトリウムシクロペンタジエニリドにイソプロピル化剤を反応させてイソプロピルシクロペンタジエンの混合物を得る第1工程、
(2)上記イソプロピルシクロペンタジエンの混合物にジクロロケテンを反応させて、7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン誘導体の混合物を得る第2工程、
(3)上記7,7-ジクロロビシクロ[3.2.0]-ヘプト-2-エン-6-オン誘導体の混合物を塩基性条件下で加溶媒分解し、得られる粗生成物から晶析によりγ-ツヤプリシンを分離する第3工程、
からなるγ-ツヤプリシンの製造方法。 The following steps (1) to (3):
(1) In a N, N-dimethylformamide solvent, cyclopentadiene and sodium amide are reacted to prepare sodium cyclopentadienylide, and this sodium cyclopentadienylide is reacted with an isopropylating agent to produce isopropylcyclohexane. A first step of obtaining a mixture of pentadienes;
(2) a second step of reacting the isopropylcyclopentadiene mixture with dichloroketene to obtain a mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivatives;
(3) Solvent decomposition of the above mixture of 7,7-dichlorobicyclo [3.2.0] -hept-2-en-6-one derivative under basic conditions, and γ- A third step of separating tsuyaprisin,
A method for producing γ-tyaprisin comprising:
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009100155A JP5193118B2 (en) | 2009-04-16 | 2009-04-16 | Method for producing γ-tyaprisin |
KR1020100033584A KR101659624B1 (en) | 2009-04-16 | 2010-04-13 | Method for preparation of -thujaplicin |
CN201010167897.9A CN101863751B (en) | 2009-04-16 | 2010-04-16 | Method for preparation of gamma-thujaplicin |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2009100155A JP5193118B2 (en) | 2009-04-16 | 2009-04-16 | Method for producing γ-tyaprisin |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2010248137A JP2010248137A (en) | 2010-11-04 |
JP5193118B2 true JP5193118B2 (en) | 2013-05-08 |
Family
ID=42955720
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2009100155A Expired - Fee Related JP5193118B2 (en) | 2009-04-16 | 2009-04-16 | Method for producing γ-tyaprisin |
Country Status (3)
Country | Link |
---|---|
JP (1) | JP5193118B2 (en) |
KR (1) | KR101659624B1 (en) |
CN (1) | CN101863751B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108840793B (en) * | 2018-05-28 | 2021-06-15 | 辽宁科技大学 | Method for preparing gamma-thujaplicin by using simulated moving bed chromatography |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2848506A (en) * | 1954-04-29 | 1958-08-19 | Hercules Powder Co Ltd | Preparation of cyclopentadienylsodium |
JPS5133901B1 (en) * | 1970-12-29 | 1976-09-22 | ||
JPS5463063A (en) | 1977-10-28 | 1979-05-21 | Sagami Chem Res Center | Norbornene derivatives and perfume composition consisting of them |
JPH0753681B2 (en) | 1989-12-25 | 1995-06-07 | 高砂香料工業株式会社 | Method for producing tropone derivative |
MY119945A (en) * | 1998-03-30 | 2005-08-30 | Asahi Chemical Ind | Process for producing hinokitiol. |
JP2001097915A (en) | 1999-09-28 | 2001-04-10 | Asahi Kasei Corp | Production method for tropolone compound |
JP2001097896A (en) * | 1999-09-28 | 2001-04-10 | Asahi Kasei Corp | Method for producing alkylcyclopentadiene compound |
JP2002255887A (en) * | 2001-03-05 | 2002-09-11 | Asahi Kasei Corp | Method for tropolone compound purification |
JP5036111B2 (en) * | 2001-08-20 | 2012-09-26 | 旭化成イーマテリアルズ株式会社 | Process for producing substituted cyclopentadiene |
JP4320197B2 (en) * | 2003-03-25 | 2009-08-26 | 高砂香料工業株式会社 | Process for producing 1-isopropylcyclopentadiene and hinokitiol |
-
2009
- 2009-04-16 JP JP2009100155A patent/JP5193118B2/en not_active Expired - Fee Related
-
2010
- 2010-04-13 KR KR1020100033584A patent/KR101659624B1/en active IP Right Grant
- 2010-04-16 CN CN201010167897.9A patent/CN101863751B/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN101863751A (en) | 2010-10-20 |
CN101863751B (en) | 2014-01-08 |
JP2010248137A (en) | 2010-11-04 |
KR101659624B1 (en) | 2016-09-26 |
KR20100114833A (en) | 2010-10-26 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP2022036968A (en) | Preparation of 3-hydroxy-3,6-dimethylhexahydrobenzofuran-2-one and derivative thereof | |
JP5603169B2 (en) | (E) Process for producing 3-methyl-2-cyclopentadecenone | |
EP1700855B1 (en) | A process for the preparation of tazarotene | |
JP5193118B2 (en) | Method for producing γ-tyaprisin | |
ITBO960289A1 (en) | PROCESS FOR THE PRODUCTION OF 1 - (3-TRIFLUOROMETHYL) PHENYL-PROPAN- 2-ONE INTERMEDIATE IN THE SYNTHESIS OF PHENFLURAMINE | |
JP4320197B2 (en) | Process for producing 1-isopropylcyclopentadiene and hinokitiol | |
WO2023104022A1 (en) | Method for preparing monosubstituted alkynylthiacalix[4]arene | |
JP5039419B2 (en) | Method for producing cross-coupling compound | |
JP4418048B2 (en) | Process for producing 13-cis-retinoic acid | |
JP4258658B2 (en) | Method for producing acetylene compound | |
JP4428086B2 (en) | Method for producing 1-acetoxy-3- (3,4-methylenedioxyphenyl) propene derivative | |
JP2960183B2 (en) | Novel terpene derivative and method for producing the same | |
JP4047040B2 (en) | Method for producing 2-fluorobenzoic acid derivative | |
JP2588783B2 (en) | Preparation of alkynyl ketone derivatives | |
SU1366061A3 (en) | Method of obtaining lineatine | |
EP0153689A2 (en) | Prostaglandin intermediates | |
JP2765575B2 (en) | Process for producing substituted cyclopentenone and substituted cyclohexenone derivatives | |
JP4495670B2 (en) | Method for producing mercaptoalkylphosphonium compounds | |
CN114945547A (en) | Dihydroxylation of olefins using osmate salts (VI) | |
JP2003137835A (en) | Method for producing (r)-3-hydroxy-3-(2-phenyl)hexanoic acid | |
JP5072030B2 (en) | Cyclic α-hydroxy-α, β-unsaturated ketone compound and method for producing cyclopentenone compound | |
JP3340761B2 (en) | Process for producing para-tertiary butoxy-α-methylstyrene | |
JP4490152B2 (en) | 1,1-dialkyl-3- (4-phenanthrenyl) -2-propyn-1-ol derivative | |
JP4075923B2 (en) | 1-acetoxy-3- (substituted phenyl) propene compound | |
JPH03176463A (en) | Pyrrolidinol derivative and its production |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20120207 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20120210 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20120213 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20121225 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20130104 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20130201 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5193118 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20160208 Year of fee payment: 3 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
LAPS | Cancellation because of no payment of annual fees |