JPWO2004033411A1 - Production method of enone ester - Google Patents

Abstract

The present invention provides an industrially advantageous process for producing enone esters as shown below.

Description

  The present invention relates to a novel method for producing an enone ester intermediate which is a raw material for producing a lignan derivative.

The lignan derivative produced according to the present invention is a compound useful for the treatment of arteriosclerosis, particularly atherosclerosis (see Patent Documents 1 and 2). Moreover, the manufacturing method of this lignan derivative and an intermediate body is also reported (refer patent document 3, 4). In Patent Document 3, in Examples 1 to 9, a method for producing a lignan derivative by a Michael addition reaction between a lactone compound and an enone ester is described, and in Reference Example 4, a method for producing an enone ester as an intermediate is described. Moreover, in patent document 4, the manufacturing method of enone ester which is an intermediate body by reaction with a malic acid derivative and a Grignard reagent is reported.
(Patent Document 1) Japanese Patent Laid-Open No. 05-310634 (Patent Document 2) Pamphlet of International Publication No. 93/08155 (Patent Document 3) Japanese Patent Laid-Open No. 06-345695 (Patent Document 4) Pamphlet of International Publication No. 95/33707

で示される化合物（１）と式：

で示される化合物（２）を酢酸エチル中で反応させることを特徴とする式：

で示される化合物（３）の製造方法。
２．上記１記載の方法により化合物（３）を得た後、これをラネーニッケル存在下で還元することを特徴とする式：

で示される化合物（４）の製造方法。
３．還元を酢酸エチル中で行う上記２記載の製造方法。
４．上記２または３記載の方法により化合物（４）を得た後、これを脱水することを特徴とする、式：

で示される化合物（５）の製造方法。
５．上記４で示される化合物（５）をアルコールから結晶化することを特徴とする化合物（５）の結晶の製造方法。
６．上記４で示される化合物（５）の結晶
７．上記４または５記載の方法によりエノンエステルまたはその結晶を得た後、これを式：

で示される化合物（６）と反応させて、式：

で示される化合物（７）を得た後、これを脱水することを特徴とする式：

で示される化合物（８）の製造方法に関する。In Reference Example 4 of Patent Document 3, an oxime compound is first prepared from a bromo compound to obtain an isoxazoline derivative. The reaction from the oxime compound to the isoxazoline derivative is performed in the presence of toluene as a solvent. The reaction yield from the bromo compound to the isoxazoline derivative was 49.5%, which was not a satisfactory production method as an industrial production method. The subsequent reduction reaction of isoxazoline is carried out in the presence of methanol using a palladium catalyst. Palladium is a noble metal, and using this catalyst for industrial production may cause problems in terms of availability and cost when used in large quantities. In addition, since the above two steps (reaction from the oxime compound to the isoxazoline derivative and subsequent reduction reaction of isoxazoline) are performed using toluene and methanol, that is, different solvents, the post-treatment of the reaction becomes complicated. It was not efficient.
The present invention relates to an improvement in the process for producing the enone ester. For example, it has been found that the reaction yield of isoxazoline derivatives from oxime compounds is preferably improved by using ethyl acetate as a result of selecting a solvent. Moreover, when the same ethyl acetate as the previous step was used as a solvent and a reduction reaction was carried out using an inexpensive and readily available Raney nickel catalyst, the yield was almost the same as when a palladium catalyst was used. Furthermore, as a result of various investigations on the crystallization solvent and temperature, the enone ester that was oily at room temperature was found to be crystallized in good yield from an alcohol solvent at low temperatures, and the present invention shown below was completed. .
That is, the present invention
1. formula:

Compound (1) represented by the formula:

A compound represented by the formula (2) is reacted in ethyl acetate:

The manufacturing method of compound (3) shown by these.
2. A compound (3) obtained by the method described in 1 above, is then reduced in the presence of Raney nickel,

The manufacturing method of compound (4) shown by these.
3. 3. The production method according to 2 above, wherein the reduction is carried out in ethyl acetate.
4). A compound (4) obtained by the method described in 2 or 3 above, and then dehydrated, is represented by the formula:

The manufacturing method of compound (5) shown by these.
5). A method for producing a crystal of compound (5), wherein the compound (5) represented by 4 is crystallized from an alcohol.
6). 6. Crystal of compound (5) represented by 4 above After obtaining an enone ester or a crystal thereof by the method described in 4 or 5 above,

Is reacted with a compound (6) represented by the formula:

After obtaining the compound (7) represented by the formula, it is dehydrated:

To a method for producing a compound (8)

第２製法

第１製法のｉ）は、オキシム化合物（１）とアクリル酸エステル（２）とを酸化剤の存在下に反応させてイソオキサゾリン化合物（３）を得た後、生成したイソオキサゾリン化合物（３）をラネーニッケル触媒存在下、水素化分解反応に付してケトアルコール化合物（４）に導き、さらに脱水してエノンエステル（５）を合成するルートである。
ｉｉ）は、種々の溶媒を用い、低温下で（５）の結晶化および精製を行う工程である。
第２製法は、エノンエステル（５）とラクトン化合物（６）とを塩基存在下に反応させて化合物（７）を合成した後、脱水して目的とするリグナン誘導体（８）を得るルートを示している。
反応条件の説明
（第１製法）
原料のオキシム化合物（１）は、文献（例、特開平６−３４５６９５）の方法に従って合成できる。

即ち、１−ブロモ−２−エチルブタン（９）をグリニヤル試薬に調製した後、ホルミル化し、得られたホルミル誘導体（１０）をヒドロキシルアミンと反応させて（１）を得る。
ホルミル化剤としては、Ｎ，Ｎ−ジメチルホルムアミド、１−ホルミルピペリジン、１−ホルミルピロリジン、Ｎ−ホルミルモルホリン、Ｎ−メチル−Ｎ−フェニルホルムアミド、Ｎ−メチル−Ｎ−ピリジン−２−イル−ホルムアミド、Ｎ−メチル−Ｎ−ピリミジン−２−イル−ホルムアミド、Ｎ−（２−ジメチルアミノエチル）−Ｎ−メチルホルムアミド等が例示される。好ましくは、Ｎ，Ｎ−ジメチルホルムアミド、１−ホルミルピペリジン、特に好ましくは、Ｎ，Ｎ−ジメチルホルムアミドである。
オキシム化剤としては、ヒドロキシルアミンおよびその塩（塩酸、硝酸、硫酸、シュウ酸、過塩素酸等）である。
オキシム化合物（１）とアクリル酸エステル（２）の使用割合は特に制限されないが、通常は、（２）を（１）に対してモル換算で等量もしくは小過剰量、好ましくは、１：１〜１：３、さらに好ましくは１：１〜１：１．５で使用する。本反応は、所望によりトリエチルアミン等の塩基存在下で行われても良い。
使用する酸化剤としては、次亜塩素酸ナトリウム、次亜塩素酸カリウム、次亜塩素酸リチウム、次亜塩素酸カルシウム、次亜塩素酸アンモニウム、次亜臭素酸ナトリウム、Ｎ−クロロコハク酸イミド、Ｎ−ブロモコハク酸イミド、クロラミン−Ｔ、１−クロロベンゾトリアゾール、塩素、臭素、第３級ブチルヒポクライト、硝酸セリウムアンモニウム、ジアセトキシヨードベンゼン、ジクロロヨードベンゼン、二酸化マンガン、酢酸水銀（ＩＩ）、酸化水銀（ＩＩ）、ジメチルジオキシラン、塩素酸ナトリウム、亜臭素酸ナトリウム等が例示される。
反応溶媒は、水、テトラヒドロフラン、ジエチルエーテル、ジオキサン等のエーテル類、ｎ−ヘキサン、ｎ−ペンタン等の炭化水素類、アセトン、メチルエチルケトン等のケトン類、ベンゼン、トルエン等の芳香族炭化水素類、塩化メチレン、クロロホルム、ジクロルエタン等のハロゲン化炭化水素類、アセトニトリル等のニトリル類、Ｎ，Ｎ−ジメチルホルムアミド、ヘキサメチルホスホリックトリアミド等のアミド類、メタノール、エタノール、２−プロパノール、第３級ブタノール等のアルコール類、酢酸メチル、酢酸エチル、酢酸プロピル等のエステル類等が例示される。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。中でもエステル類、エーテル類、アルコール類が好ましく、特にエステル類（例、酢酸エチル）が好ましい。酢酸エチルを使用した場合、オキシム化合物（１）からイソオキサゾリン化合物（３）への反応の吸率は、例えば約８４％になる。その結果、原料のブロモ体（化合物９）からの収率は約７６％に達する。
本反応は、通常−２０℃から４０℃、好ましくは、−５℃から室温にて、数分から数時間で完結する。
イソオキサゾリン化合物（３）と接触還元触媒の使用割合は、（３）に対し、０．１〜５０重量％であって、好ましくは１〜１０重量％である。
本接触還元反応は、酸存在下で行われてもよい。酸としては、酢酸、プロピオン酸等の有機酸、塩酸、硼酸等の無機酸である。
接触還元触媒としては、ラネーニッケル、ラネーコバルト、ラネー銅、ラネー鉄等のラネー触媒、パラジウム炭素等の貴金属系触媒である。好ましくは、ラネー触媒、特にラネーニッケル触媒である。
本発明における反応は、好ましくは水素ガス中で行われ、その水素圧は０．１〜１０ＭＰａ、好ましくは０．１〜２ＭＰａである。
溶媒としては、水、メタノール、エタノール等のアルコール系溶媒、トルエン、キシレン等の芳香族炭化水素系溶媒、テトラヒドロフラン、エーテル等のエーテル系溶媒、酢酸エチル、酢酸メチル等のエステル系溶媒等である。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。好ましくは、エステル系溶媒、アルコール系溶媒、特に酢酸エチルである。
反応温度は、１０〜７０℃、好ましくは２０〜４０℃が適当であり、通常１〜数十時間程度で反応は終了する。
還元反応で得たケトアルコール化合物（４）は、好ましくは有機溶媒中で活性化剤を用いて脱水反応を行い、エノンエステル（５）に変換できる。
活性化剤としては、塩化メタンスルホニル、塩化パラトルエンスルホニル、塩化ベンゼンスルホニル、メタンスルホン酸無水物等のスルホニル化剤、塩化アセチル、無水酢酸、塩化ベンゾイル、安息香酸無水物等のアシル化剤、クロロリン酸ジエチル、クロロリン酸ジフェニル等のリン酸化剤、塩化チオニル、オキシ塩化リン、五塩化リン、三臭化リン等のハロゲン化剤である。好ましくは、スルホニル化剤であり、特に好ましくは塩化メタンスルホニルである。
有機溶媒としては、前記の工程と同様の溶媒を使用し得るが、好ましくは酢酸エチルである。
この反応は−１０〜７０℃、好ましくは０〜４０℃で、０．５〜１０時間、好ましくは１〜２時間である。
エノンエステル（５）は、常温においては油状であり、（５）の単離精製は、当業界で慣用されている方法（例えば、蒸留）を利用して行われる。しかし、好ましくは結晶化によって得られる。これによって、エノンエステル（５）を実質的に純粋に得ることができる。
結晶化のために使用する可溶性溶媒としては、テトラヒドロフラン、ジエチルエーテル等のエーテル類、ｎ−ヘキサン、ｎ−ペンタン等の炭化水素類、アセトン、メチルイソブチルケトン等のケトン類、ベンゼン、トルエン等の芳香族炭化水素類、メタノール、エタノール、２−プロパノール、第３級ブタノール等のアルコール類、酢酸メチル、酢酸エチル等のエステル類等である。これらの溶媒は単独で使用しても、２種以上を混合して使用してもよい。また水を混合しても使用できる。中でもエステル類、ケトン類、アルコール類が好ましく、特にアルコール類（例、メタノール）が好ましい。
溶媒の使用量は、化合物（５）に対し総量が０．５〜１００重量部であり、好ましくは１〜５０重量部であり、特に好ましくは１〜１５重量部である。上記結晶化方法において、溶液を冷却すると結晶が析出してくる場合もあるが、析出しない場合には、例えば、冷却下、超音波処理や攪拌等の刺激を与える、種結晶を加える等により結晶を析出させてもよい。結晶化に適切な冷却温度は、−１５０〜４℃であり、好ましくは−８０〜−２０℃である。
（第２製法）
化合物（６）は公知の方法（例、特開平６−３４５６９５）に従って製造できる。
第１工程で使用する化合物（５）および化合物（６）の使用割合は特に制限されないが、通常は、化合物（５）を化合物（６）に対して等量もしくは過剰量、好ましくは１：１〜１：２で使用する。
使用する塩基としては、通常用いられるジアルキル金属アミド類、例えば、リチウムジイソプロピルアミド、ナトリウムジシクロヘキシルアミド等、また、ビス（トリアルキルシリル）金属アミド類、例えば、リチウムビス（トリメチルシリル）アミド類、カリウムビス（トリメチルシリル）アミド、ナトリウムビス（トリエチルシリル）アミド等を用いることができ、好ましくは、リチウムビス（トリメチルシリル）アミドを用いる。
反応溶媒は、例えば、テトラヒドロフラン、ジエチルエーテル、ジオキサン等のエーテル類、ｎ−ヘキサン、ｎ−ペンタン等の炭化水素類、ベンゼン、トルエン等の芳香族炭化水素類、塩化メチレン等のハロゲン化炭化水素類、Ｎ，Ｎ−ジメチルホルムアミド、ヘキサメチルホスホリックトリアミド等のアミド類を単独で、又はそれらを混合して使用できる。好ましい溶媒は、テトラヒドロフラン、塩化メチレン、Ｎ，Ｎ−ジメチルホルムアミド、ヘキサメチルホスホリックトリアミドである。
本工程の反応は、通常−１００℃から１００℃、好ましくは−８０℃から室温にて、数分から数時間で完結する。
第２工程で使用する酸としては無機酸又は有機酸を使用でき、例えば塩酸、硫酸、トリフルオロ酢酸、スルホン酸類（メタンスルホン酸、ｐ−トルエンスルホン酸等）、ルイス酸（三フッ化ホウ素、四塩化チタン等）を用いることができ、好ましくは、三フッ化ホウ素、メタンスルホン酸を用いる。使用量については特に制限はないが、好ましくは１から２当量を用いる。
反応溶媒は、ベンゼン、トルエン等の芳香族炭化水素類、塩化メチレン等のハロゲン化炭化水素類、アセトニトリル等のニトリル類を使用する。
本反応は、通常、−７０℃から１００℃、好ましくは、−２０℃から室温にて数分から数時間で完結する。
以下に実施例及び参考例を記載し、本発明をさらに詳細に説明するが、これらは本発明の限定を意図するものではない。
（略号）
ＤＭＦ＝Ｎ，Ｎ−ジメチルホルムアミド、ＴＨＦ＝テトラヒドロフラン、Ｐａ＝パスカル、ＭＰａ＝メガパスカル、１ｔｏｒｒ＝１．３３３２２ｘ１０^２Ｐａ、ＨＰＬＣ＝高速液体クロマトグラフ、常温＝１５〜２５℃
参考例１

ＤＬ−リンゴ酸（５０．２ｋｇ、３７４ｍｏｌ）に無水酢酸（４０．０ｋｇ、３９２ｍｏｌ）を加え、８０℃で３０分間加熱した。反応溶液を４５℃に冷却した後、塩化アセチル（４８．０ｋｇ、６１１ｍｏｌ）を１８０分かけて加え、同温で３０分間攪拌した。２０℃に冷却後、種晶（１００ｇ）を加え、トルエン（２３０ｋｇ）にて希釈し、１５℃で４０分間、−５℃で６０分間晶析を行った。結晶をろ取した後、−５℃に冷却したトルエン（１７２ｋｇ）で洗浄し、化合物（１１）の未乾結晶（５８．７ｋｇ）を得た。The production method of the compound or crystal according to the present invention will be described in detail below. The production method of the present invention comprises the following two production methods.
First production method

Second manufacturing method

In the first production method i), an isoxazoline compound (3) is obtained by reacting an oxime compound (1) and an acrylic ester (2) in the presence of an oxidizing agent to obtain an isoxazoline compound (3). Is subjected to a hydrocracking reaction in the presence of a Raney nickel catalyst to lead to a ketoalcohol compound (4) and further dehydrated to synthesize enone ester (5).
ii) is a step of performing crystallization and purification of (5) at low temperature using various solvents.
The second production method shows a route in which enone ester (5) and lactone compound (6) are reacted in the presence of a base to synthesize compound (7) and then dehydrated to obtain the desired lignan derivative (8). ing.
Explanation of reaction conditions (1st manufacturing method)
The raw material oxime compound (1) can be synthesized according to literature methods (eg, JP-A-6-345695).

That is, 1-bromo-2-ethylbutane (9) is prepared as a Grignard reagent, then formylated, and the resulting formyl derivative (10) is reacted with hydroxylamine to obtain (1).
As the formylating agent, N, N-dimethylformamide, 1-formylpiperidine, 1-formylpyrrolidine, N-formylmorpholine, N-methyl-N-phenylformamide, N-methyl-N-pyridin-2-yl-formamide N-methyl-N-pyrimidin-2-yl-formamide, N- (2-dimethylaminoethyl) -N-methylformamide and the like. N, N-dimethylformamide and 1-formylpiperidine are preferable, and N, N-dimethylformamide is particularly preferable.
Examples of the oximation agent include hydroxylamine and salts thereof (hydrochloric acid, nitric acid, sulfuric acid, oxalic acid, perchloric acid, etc.).
The use ratio of the oxime compound (1) and the acrylate ester (2) is not particularly limited. Usually, however, (2) is equivalent or small excess in terms of mole relative to (1), preferably 1: 1. ˜1: 3, more preferably 1: 1 to 1: 1.5. This reaction may be performed in the presence of a base such as triethylamine, if desired.
The oxidizing agent used is sodium hypochlorite, potassium hypochlorite, lithium hypochlorite, calcium hypochlorite, ammonium hypochlorite, sodium hypobromite, N-chlorosuccinimide, N -Bromosuccinimide, chloramine-T, 1-chlorobenzotriazole, chlorine, bromine, tertiary butyl hypocrite, cerium ammonium nitrate, diacetoxyiodobenzene, dichloroiodobenzene, manganese dioxide, mercury acetate (II), mercury oxide Examples include (II), dimethyldioxirane, sodium chlorate, sodium bromite and the like.
Reaction solvents include water, ethers such as tetrahydrofuran, diethyl ether and dioxane, hydrocarbons such as n-hexane and n-pentane, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene and toluene, chloride Halogenated hydrocarbons such as methylene, chloroform, dichloroethane, nitriles such as acetonitrile, amides such as N, N-dimethylformamide, hexamethylphosphoric triamide, methanol, ethanol, 2-propanol, tertiary butanol, etc. Alcohols, esters such as methyl acetate, ethyl acetate, and propyl acetate. These solvents may be used alone or in combination of two or more. Of these, esters, ethers, and alcohols are preferable, and esters (eg, ethyl acetate) are particularly preferable. When ethyl acetate is used, the absorptivity of the reaction from the oxime compound (1) to the isoxazoline compound (3) is, for example, about 84%. As a result, the yield from the starting bromo compound (Compound 9) reaches about 76%.
This reaction is usually completed within a few minutes to a few hours at −20 ° C. to 40 ° C., preferably −5 ° C. to room temperature.
The use ratio of the isoxazoline compound (3) and the catalytic reduction catalyst is 0.1 to 50% by weight, preferably 1 to 10% by weight, based on (3).
This catalytic reduction reaction may be performed in the presence of an acid. Examples of the acid include organic acids such as acetic acid and propionic acid, and inorganic acids such as hydrochloric acid and boric acid.
Examples of the catalytic reduction catalyst include Raney catalysts such as Raney nickel, Raney cobalt, Raney copper and Raney iron, and noble metal catalysts such as palladium carbon. Raney catalysts, particularly Raney nickel catalysts are preferred.
The reaction in the present invention is preferably carried out in hydrogen gas, and the hydrogen pressure is 0.1 to 10 MPa, preferably 0.1 to 2 MPa.
Examples of the solvent include water, alcohol solvents such as methanol and ethanol, aromatic hydrocarbon solvents such as toluene and xylene, ether solvents such as tetrahydrofuran and ether, and ester solvents such as ethyl acetate and methyl acetate. These solvents may be used alone or in combination of two or more. Preferred are ester solvents, alcohol solvents, particularly ethyl acetate.
The reaction temperature is suitably 10 to 70 ° C., preferably 20 to 40 ° C. The reaction is usually completed in about 1 to several tens of hours.
The keto alcohol compound (4) obtained by the reduction reaction can be converted to the enone ester (5) by performing a dehydration reaction, preferably using an activator in an organic solvent.
Activating agents include sulfonylating agents such as methanesulfonyl chloride, p-toluenesulfonyl chloride, benzenesulfonyl chloride, methanesulfonic anhydride, acylating agents such as acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, chlorophosphorus Phosphorating agents such as diethyl acid and diphenyl chlorophosphate, and halogenating agents such as thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and phosphorus tribromide. Preferred is a sulfonylating agent, and particularly preferred is methanesulfonyl chloride.
As the organic solvent, the same solvent as in the above step can be used, but ethyl acetate is preferable.
This reaction is carried out at −10 to 70 ° C., preferably 0 to 40 ° C., for 0.5 to 10 hours, preferably 1 to 2 hours.
The enone ester (5) is oily at room temperature, and the isolation and purification of (5) is carried out using a method commonly used in the art (for example, distillation). However, it is preferably obtained by crystallization. Thereby, the enone ester (5) can be obtained substantially pure.
Soluble solvents used for crystallization include ethers such as tetrahydrofuran and diethyl ether, hydrocarbons such as n-hexane and n-pentane, ketones such as acetone and methyl isobutyl ketone, and aromatics such as benzene and toluene. Group hydrocarbons, alcohols such as methanol, ethanol, 2-propanol and tertiary butanol, and esters such as methyl acetate and ethyl acetate. These solvents may be used alone or in combination of two or more. It can also be used by mixing water. Of these, esters, ketones, and alcohols are preferable, and alcohols (eg, methanol) are particularly preferable.
The total amount of the solvent used is 0.5 to 100 parts by weight, preferably 1 to 50 parts by weight, particularly preferably 1 to 15 parts by weight, based on the compound (5). In the above crystallization method, crystals may be precipitated when the solution is cooled, but in the case where the solution does not precipitate, for example, the crystal is produced by adding a seed crystal or the like while giving a stimulus such as ultrasonic treatment or stirring under cooling. May be deposited. The cooling temperature suitable for crystallization is −150 to 4 ° C., preferably −80 to −20 ° C.
(Second manufacturing method)
Compound (6) can be produced according to a known method (eg, JP-A-6-345695).
The ratio of the compound (5) and the compound (6) used in the first step is not particularly limited. Usually, the compound (5) is used in an equivalent amount or an excess amount, preferably 1: 1 with respect to the compound (6). Use at ~ 1: 2.
Examples of the base to be used include generally used dialkyl metal amides such as lithium diisopropylamide and sodium dicyclohexylamide, and bis (trialkylsilyl) metal amides such as lithium bis (trimethylsilyl) amide, potassium bis ( Trimethylsilyl) amide, sodium bis (triethylsilyl) amide and the like can be used, and lithium bis (trimethylsilyl) amide is preferably used.
Examples of the reaction solvent include ethers such as tetrahydrofuran, diethyl ether and dioxane, hydrocarbons such as n-hexane and n-pentane, aromatic hydrocarbons such as benzene and toluene, and halogenated hydrocarbons such as methylene chloride. , N, N-dimethylformamide, hexamethylphosphoric triamide and the like can be used alone or as a mixture thereof. Preferred solvents are tetrahydrofuran, methylene chloride, N, N-dimethylformamide, hexamethylphosphoric triamide.
The reaction in this step is usually completed within a few minutes to a few hours at −100 ° C. to 100 ° C., preferably −80 ° C. to room temperature.
As the acid used in the second step, an inorganic acid or an organic acid can be used. For example, hydrochloric acid, sulfuric acid, trifluoroacetic acid, sulfonic acids (methanesulfonic acid, p-toluenesulfonic acid, etc.), Lewis acid (boron trifluoride, Titanium tetrachloride, etc.) can be used, and preferably boron trifluoride or methanesulfonic acid is used. Although there is no restriction | limiting in particular about the usage-amount, Preferably 1 to 2 equivalent is used.
As the reaction solvent, aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as methylene chloride, and nitriles such as acetonitrile are used.
This reaction is usually completed within a few minutes to a few hours at −70 ° C. to 100 ° C., preferably −20 ° C. to room temperature.
EXAMPLES Examples and reference examples will be described below to explain the present invention in more detail, but these are not intended to limit the present invention.
(Abbreviation)
DMF = N, N-dimethylformamide, THF = tetrahydrofuran, Pa = pascal, MPa = megapascal, 1 torr = 1.33322 × 10 ² Pa, HPLC = high performance liquid chromatograph, normal temperature = 15-25 ° C.
Reference example 1

Acetic anhydride (40.0 kg, 392 mol) was added to DL-malic acid (50.2 kg, 374 mol) and heated at 80 ° C. for 30 minutes. After the reaction solution was cooled to 45 ° C., acetyl chloride (48.0 kg, 611 mol) was added over 180 minutes, and the mixture was stirred at the same temperature for 30 minutes. After cooling to 20 ° C., seed crystals (100 g) were added, diluted with toluene (230 kg), and crystallized at 15 ° C. for 40 minutes and at −5 ° C. for 60 minutes. The crystals were collected by filtration and washed with toluene (172 kg) cooled to −5 ° C. to obtain undried crystals (58.7 kg) of compound (11).

マグネシウム（３３１ｇ、１３．６２ｍｏｌ）をＴＨＦ（８．８Ｌ）に懸濁し、窒素置換後６５℃に加熱した。化合物（９）（６６ｇ、０．４０ｍｏｌ）を加え、１５分間加熱を続けた。さらに化合物（９）（２１８２ｇ、１３．２２ｍｏｌ）を８５分かけて加え、１時間加熱還流を続け、反応液を２０℃付近に冷却した。１−ホルミルピペリジン（１４６４ｇ、１２．９４ｍｏｌ）のＴＨＦ（２．２Ｌ）溶液を１００分かけて加え、２０℃付近で１時間攪拌した。上記の操作を繰返し、化合物（１０）の反応溶液を同量得た。ヒドロキシルアミン塩酸塩（２２７１ｇ、３２．６８ｍｏｌ）を水（６．６Ｌ）に溶解し、窒素雰囲気下、１１℃付近に冷却した。化合物（１０）の反応液を合せ、５０分かけて滴下し、２０℃付近で１時間攪拌した。反応液に水（２０Ｌ）および酢酸エチル（１１Ｌ）を加えて分液し、有機層を１０％食塩水（２×１８Ｌ）で洗浄した。それぞれの水層を酢酸エチル（１１Ｌ）で抽出し、有機層を合併後、減圧濃縮して化合物（１）（３２７７ｇ、９３．１％）を得た。

Magnesium (331 g, 13.62 mol) was suspended in THF (8.8 L), purged with nitrogen, and heated to 65 ° C. Compound (9) (66 g, 0.40 mol) was added and heating was continued for 15 minutes. Further, compound (9) (2182 g, 13.22 mol) was added over 85 minutes, followed by heating and refluxing for 1 hour, and the reaction solution was cooled to around 20 ° C. A solution of 1-formylpiperidine (1464 g, 12.94 mol) in THF (2.2 L) was added over 100 minutes, and the mixture was stirred at around 20 ° C. for 1 hour. The above operation was repeated to obtain the same amount of the reaction solution of compound (10). Hydroxylamine hydrochloride (2271 g, 32.68 mol) was dissolved in water (6.6 L) and cooled to around 11 ° C. under a nitrogen atmosphere. The reaction liquid of the compound (10) was combined, added dropwise over 50 minutes, and stirred at around 20 ° C. for 1 hour. Water (20 L) and ethyl acetate (11 L) were added to the reaction solution for liquid separation, and the organic layer was washed with 10% brine (2 × 18 L). Each aqueous layer was extracted with ethyl acetate (11 L), and the organic layers were combined and concentrated under reduced pressure to obtain compound (1) (3277 g, 93.1%).

１４．３％次亜塩素酸ナトリウム水溶液（１７．７ｋｇ、３４．００ｍｏｌ）と酢酸エチル（８Ｌ）の混合溶液を５℃付近に冷却し、化合物（１）（２．０ｋｇ）、アクリル酸メチル（２）（１８１２ｍＬ、２０．１２ｍｏｌ）およびトリエチルアミン（３２４ｍＬ、２．３２ｍｏｌ）の酢酸エチル（８Ｌ）溶液を１００分かけて滴下した。反応液を１０分間攪拌した後に分液し、有機層を水（１５．３Ｌ）、氷冷した３％亜硫酸ナトリウム水溶液（１５．３Ｌ）、水（２×１５．３Ｌ）で順次洗浄した。それぞれの水層を酢酸エチル（８Ｌ）で抽出し、有機層を合併後無水硫酸ナトリウムで乾燥し、減圧濃縮して化合物（３）（２７７８ｇ、８４．１％）を得た。

A mixed solution of 14.3% aqueous sodium hypochlorite solution (17.7 kg, 34.00 mol) and ethyl acetate (8 L) was cooled to around 5 ° C., and compound (1) (2.0 kg), methyl acrylate ( 2) A solution of (1812 mL, 20.12 mol) and triethylamine (324 mL, 2.32 mol) in ethyl acetate (8 L) was added dropwise over 100 minutes. The reaction solution was stirred for 10 minutes and separated, and the organic layer was washed successively with water (15.3 L), ice-cooled 3% aqueous sodium sulfite solution (15.3 L), and water (2 × 15.3 L). Each aqueous layer was extracted with ethyl acetate (8 L), and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound (3) (2778 g, 84.1%).

マグネシウム（６．６１ｇ、２７２ｍｍｏｌ）をＴＨＦ（１７０ｍＬ）に懸濁し、触媒量のヨウ素を加えた後に窒素置換、６０℃に加熱した。化合物（９）（１．８０ｇ、１０．９ｍｍｏｌ）を加え、５０分間加熱を続けた。さらに化合物（９）（４３．１０ｇ、２６１．１ｍｍｏｌ）を８０分かけて加え、１時間加熱還流を続け、反応液を２０℃付近に冷却した。ＤＭＦ（１８．８９ｇ、２５８．４ｍｍｏｌ）のＴＨＦ（４０ｍＬ）溶液を７０分かけて加え、２０℃付近で１時間攪拌した。ヒドロキシルアミン塩酸塩（２２．２１ｇ、３１０．１ｍｍｏｌ）を水（６６．６ｍＬ）に溶解し、窒素雰囲気下、１３℃付近に冷却した。先の反応液を７５分かけて滴下し、１７℃付近で１時間攪拌した。反応液に水（１８０ｍＬ）および酢酸エチル（１００ｍＬ）を加えて分液し、有機層を１０％食塩水（２×１８０ｍＬ）で洗浄した。それぞれの水層を酢酸エチル（１００ｍＬ）で抽出し、有機層を合併後、減圧濃縮して化合物（１）（６５．４３ｇ）を得た。

Magnesium (6.61 g, 272 mmol) was suspended in THF (170 mL), and a catalytic amount of iodine was added, followed by nitrogen substitution and heating to 60 ° C. Compound (9) (1.80 g, 10.9 mmol) was added and heating was continued for 50 minutes. Further, compound (9) (43.10 g, 261.1 mmol) was added over 80 minutes, and heating under reflux was continued for 1 hour, and the reaction solution was cooled to around 20 ° C. A solution of DMF (18.89 g, 258.4 mmol) in THF (40 mL) was added over 70 minutes, and the mixture was stirred at around 20 ° C. for 1 hour. Hydroxylamine hydrochloride (22.21 g, 310.1 mmol) was dissolved in water (66.6 mL) and cooled to around 13 ° C. under a nitrogen atmosphere. The previous reaction solution was added dropwise over 75 minutes, and the mixture was stirred at around 17 ° C. for 1 hour. Water (180 mL) and ethyl acetate (100 mL) were added to the reaction solution for liquid separation, and the organic layer was washed with 10% brine (2 × 180 mL). Each aqueous layer was extracted with ethyl acetate (100 mL), and the organic layers were combined and concentrated under reduced pressure to obtain compound (1) (65.43 g).

（Ａ）１２．５６％次亜塩素酸ナトリウム水溶液（２３５ｍＬ、３９６．５ｍｍｏｌ）と酢酸エチル（９３ｍＬ）の混合溶液を１℃付近に冷却し、実施例３で得た化合物（１）（４９．１ｇ）およびアクリル酸メチル（２）（２０．１７ｇ、２３４．３ｍｍｏｌ）の酢酸エチル（６４ｍＬ）溶液を９０分かけて滴下した。反応液を３０分間攪拌した後に分液し、有機層を水（１７５ｍＬ）、氷冷した３％亜硫酸ナトリウム水溶液（１７５ｍＬ）、水（２×１７５ｍＬ）で順次洗浄した。それぞれの水層を酢酸エチル（９４ｍＬ）で抽出し、有機層を合併後、減圧濃縮して化合物（３）（６２．７６ｇ）を得た。
（Ｂ）化合物（１）（８．３５ｇ、６４．６ｍｍｏｌ）およびアクリル酸メチル（７．５６ｍＬ、８４．０ｍｍｏｌ）の酢酸エチル（１６．５ｍＬ）溶液を１℃付近に冷却し、１２．５６％次亜塩素酸ナトリウム水溶液（４４．０ｇ、７１．０ｍｍｏｌ）を５５分かけて滴下した。反応液を３０分間攪拌した後に分液し、有機層を水（３５ｍＬ）、氷冷した３％亜硫酸ナトリウム水溶液（３５ｍＬ）、水（２×３５ｍＬ）で順次洗浄した。それぞれの水層を酢酸エチル（１６．５ｍＬ）で抽出し、有機層を合併した後、減圧濃縮して化合物（３）を得た。

(A) A mixed solution of 12.56% sodium hypochlorite aqueous solution (235 mL, 396.5 mmol) and ethyl acetate (93 mL) was cooled to around 1 ° C., and compound (1) obtained in Example 3 (49. 1 g) and methyl acrylate (2) (20.17 g, 234.3 mmol) in ethyl acetate (64 mL) were added dropwise over 90 minutes. The reaction solution was stirred for 30 minutes and then separated, and the organic layer was washed successively with water (175 mL), ice-cooled 3% aqueous sodium sulfite solution (175 mL), and water (2 × 175 mL). Each aqueous layer was extracted with ethyl acetate (94 mL), and the organic layers were combined and concentrated under reduced pressure to obtain compound (3) (62.76 g).
(B) A solution of compound (1) (8.35 g, 64.6 mmol) and methyl acrylate (7.56 mL, 84.0 mmol) in ethyl acetate (16.5 mL) was cooled to around 1 ° C., and 12.56% Sodium hypochlorite aqueous solution (44.0 g, 71.0 mmol) was added dropwise over 55 minutes. The reaction solution was stirred for 30 minutes and then separated, and the organic layer was washed successively with water (35 mL), ice-cooled 3% aqueous sodium sulfite solution (35 mL), and water (2 × 35 mL). Each aqueous layer was extracted with ethyl acetate (16.5 mL), combined with the organic layer, and then concentrated under reduced pressure to obtain compound (3).

化合物（３）（４１．８４ｇ）に酢酸エチル（６４ｍＬ）、酢酸（２７．１２ｍＬ）、水（１８．８ｍＬ）およびラネーニッケル（１．０４ｇ）を加え、水素雰囲気下（０．４ＭＰａ）、３０℃付近で５．３時間攪拌した。ラネーニッケルをろ別し、酢酸エチル（４×５ｍＬ）で洗浄した。ろ液と洗浄液を合併し、水（８０ｍＬ）を加えて分液した。有機層を７．５％炭酸水素ナトリウム水溶液（３×８０ｍＬ）、１５％食塩水（２×７０ｍＬ）で順次洗浄した。それぞれの水層を酢酸エチル（４０ｍＬ）で抽出し、有機層を合併後、減圧濃縮して化合物（４）（３７．１２ｇ）を得た。

Ethyl acetate (64 mL), acetic acid (27.12 mL), water (18.8 mL) and Raney nickel (1.04 g) were added to compound (3) (41.84 g), and hydrogen atmosphere (0.4 MPa) at 30 ° C. The mixture was stirred for 5.3 hours. Raney nickel was filtered off and washed with ethyl acetate (4 × 5 mL). The filtrate and the washing solution were combined, and water (80 mL) was added for liquid separation. The organic layer was washed sequentially with 7.5% aqueous sodium hydrogen carbonate solution (3 × 80 mL) and 15% brine (2 × 70 mL). Each aqueous layer was extracted with ethyl acetate (40 mL), and the organic layers were combined and concentrated under reduced pressure to obtain compound (4) (37.12 g).

化合物（４）（１８．１６ｇ）に酢酸エチル（３１ｍＬ）を加え、窒素雰囲気下、氷冷下にトリエチルアミン（２５．５０ｇ）および塩化メタンスルホニル（１１．５７ｇ）を加えて２０℃付近で１．５時間攪拌した。反応液に水（７０ｍＬ）および酢酸エチル（５４ｍＬ）を加えて分液した。有機層を水（２×７０ｍＬ）、１Ｎ塩酸水溶液（７０ｍＬ）、水（７０ｍＬ）、７％炭酸水素ナトリウム水溶液（７０ｍＬ）および５％食塩水（７０ｍＬ）で順次洗浄した。それぞれの水層を酢酸エチル（３３ｍＬ）で抽出し、有機層を合併後１９．５４ｇまで減圧濃縮した。濃縮液に酢酸エチル（２０ｍＬ）を加え、１６．９２ｇまで減圧濃縮した。濃縮残渣のうち８．４６ｇを減圧蒸留して淡黄色油状物質の化合物（５）（６．８９ｇ、実施例３から４８．９％）を得た。沸点：９２〜１０６℃（１．６×１０^２Ｐａ）
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，ｐｐｍ）δ：０．８６（ｔ，Ｊ＝７．５Ｈｚ，６Ｈ），１．２２−１．４４（ｍ，４Ｈ），１．８７（ｑｕｉｎｔｅｔ，Ｊ＝６．６Ｈｚ，１Ｈ），２．５４（ｄ，Ｊ＝６．６Ｈｚ，２Ｈ），３．８２（ｓ，３Ｈ），６．６７（ｄ，Ｊ＝１５．９Ｈｚ，１Ｈ），７．０９（ｄ，Ｊ＝１５．９Ｈｚ，１Ｈ）
（化合物（５）の結晶化検討）
常温において油状物質である化合物（５）は４℃以下に冷却すると結晶化することが判明した。各種溶媒中結晶化を検討した結果、メタノール、トルエン、アセトン、酢酸エチル、メチルイソブチルケトン、ヘキサン等から結晶化可能であった。表１は、メタノール、酢酸エチル、アセトン溶媒を用いた時の回収率の結果であり、特にメタノールが好ましい。

Ethyl acetate (31 mL) was added to compound (4) (18.16 g), triethylamine (25.50 g) and methanesulfonyl chloride (11.57 g) were added under a nitrogen atmosphere and ice cooling, and 1. Stir for 5 hours. Water (70 mL) and ethyl acetate (54 mL) were added to the reaction solution to separate the layers. The organic layer was washed successively with water (2 × 70 mL), 1N aqueous hydrochloric acid (70 mL), water (70 mL), 7% aqueous sodium bicarbonate (70 mL) and 5% brine (70 mL). Each aqueous layer was extracted with ethyl acetate (33 mL), and the organic layers were combined and concentrated under reduced pressure to 19.54 g. Ethyl acetate (20 mL) was added to the concentrate, and the mixture was concentrated under reduced pressure to 16.92 g. 8.46 g of the concentrated residue was distilled under reduced pressure to obtain a pale yellow oily compound (5) (6.89 g, 48.9% from Example 3). Boiling point: 92-106 ° C. (1.6 × 10 ² Pa)
¹ H-NMR (CDCl ₃ , ppm) δ: 0.86 (t, J = 7.5 Hz, 6H), 1.22-1.44 (m, 4H), 1.87 (quintet, J = 6. 6 Hz, 1H), 2.54 (d, J = 6.6 Hz, 2H), 3.82 (s, 3H), 6.67 (d, J = 15.9 Hz, 1H), 7.09 (d, J = 15.9Hz, 1H)
(Examination of crystallization of compound (5))
It was found that the compound (5) which is an oily substance at room temperature crystallizes when cooled to 4 ° C. or lower. As a result of examining crystallization in various solvents, it was possible to crystallize from methanol, toluene, acetone, ethyl acetate, methyl isobutyl ketone, hexane and the like. Table 1 shows the results of recovery rates when methanol, ethyl acetate, and acetone solvents were used, and methanol is particularly preferable.

Crude product (5) (33.7 kg) was divided into 4 parts, and each was dissolved in methanol (79 kg), and cooled at -40 ° C for 30 minutes and -60 ° C for 60 minutes for crystallization. The obtained crystals were collected by filtration and washed with methanol (123 kg) cooled to −60 ° C., and then crystals of compound (5) were obtained (25.8 kg, 65% in total as compound (5)). HPLC purity: 95.6%, HPLC: HPLC manufactured by SHIMADZU, column; COSMOSIL ODS-MS 4.6 × 250 mm
Example 8 (Measurement of melting point of compound (5))
The crystal of the compound (5) was put in a thermostat adjusted to around 3 ° C., and the temperature was gradually raised to 13 ° C. After showing a constant temperature around 9.6 ° C., the temperature dropped to around 8.7 ° C., and then gradually raised to 13 ° C. The melting point of compound (5) was determined to be 9-10 ° C.
Melting point measuring device: “Andortori TR-71S” manufactured by T and D.
Temperature control device (constant temperature bath): EYELA COOL; ECS-50, THERMO CONTROLLER; THD-50, STIR PUMP; STR-1, WATER BATH; SBC-24

窒素気流下、２５．９重量％リチウムビス（トリメチルシリル）アミド−ＴＨＦ溶液（２９．３ｋｇ、４６．６２ｍｏｌ）をＴＨＦ（１０ｋｇ）で希釈し、−６０℃付近においてラクトン（６）（１４．０ｋｇ、３８．８５ｍｏｌ）のＤＭＦ（３３ｋｇ）−ＴＨＦ（３１ｋｇ）溶液を４．５時間かけて滴下した。更に１０分間攪拌した後、エノンエステル（５）（９．３ｋｇ、４６．９１ｍｏｌ）のＴＨＦ（１９ｋｇ）溶液を２．５時間かけて滴下した。滴下終了後、２５．９重量％リチウムビス（トリメチルシリル）アミド−ＴＨＦ溶液（２０．４ｋｇ、３１．０８ｍｏｌ）を約５０分かけて滴下し、０℃まで昇温して、氷冷下２時間攪拌した。反応液に水（４５ｋｇ）と３５％合成塩酸（１６．０ｋｇ）を加え、酢酸エチルで抽出した。減圧濃縮した残渣をメタノールより結晶化した後、アセトン−メタノールで再結晶し、化合物（７）（１２．１ｋｇ、５５．８％）を得た。

Under a nitrogen stream, 25.9 wt% lithium bis (trimethylsilyl) amide-THF solution (29.3 kg, 46.62 mol) was diluted with THF (10 kg), and lactone (6) (14.0 kg, 38.85 mol) of DMF (33 kg) -THF (31 kg) was added dropwise over 4.5 hours. After further stirring for 10 minutes, a THF (19 kg) solution of enone ester (5) (9.3 kg, 46.91 mol) was added dropwise over 2.5 hours. After completion of the dropwise addition, 25.9 wt% lithium bis (trimethylsilyl) amide-THF solution (20.4 kg, 31.08 mol) was added dropwise over about 50 minutes, the temperature was raised to 0 ° C., and the mixture was stirred for 2 hours under ice cooling. did. Water (45 kg) and 35% synthetic hydrochloric acid (16.0 kg) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The residue concentrated under reduced pressure was crystallized from methanol and then recrystallized from acetone-methanol to obtain Compound (7) (12.1 kg, 55.8%).

化合物（７）（９．００ｋｇ、１６．１１ｍｏｌ）のアセトニトリル（２５．０ｋｇ）懸濁液に、メタンスルホン酸（１．８６ｋｇ）を加え、室温で約１００分間攪拌した。反応液に水（３６．５ｋｇ）を加え、氷冷下、約９０分間攪拌し、析出した結晶を濾取した。アセトン−メタノールより再結晶して化合物（８）（７．３７ｋｇ、８４．７％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３，ｐｐｍ）δ：０．８３（ｔ，Ｊ＝７．０Ｈｚ，６Ｈ），１．２０−１．４２（ｍ，４Ｈ），１．９６−２．１２（ｍ，１Ｈ），２．７３（ｄ，Ｊ＝６．０Ｈｚ，２Ｈ），３．２５（ｓ，３Ｈ），３．４４（ｓ，３Ｈ），３．８６（ｓ，３Ｈ），３．８９（ｓ，３Ｈ），３．９３（ｓ，３Ｈ），４．０４（ｓ，３Ｈ），６．７８−６．９０（ｍ，３Ｈ），７．７３（ｓ，１Ｈ），１４．３８（ｓ，１Ｈ）

Methanesulfonic acid (1.86 kg) was added to a suspension of compound (7) (9.00 kg, 16.11 mol) in acetonitrile (25.0 kg), and the mixture was stirred at room temperature for about 100 minutes. Water (36.5 kg) was added to the reaction solution, the mixture was stirred for about 90 minutes under ice cooling, and the precipitated crystals were collected by filtration. Recrystallization from acetone-methanol gave Compound (8) (7.37 kg, 84.7%).
¹ H-NMR (CDCl ₃ , ppm) δ: 0.83 (t, J = 7.0 Hz, 6H), 1.20-1.42 (m, 4H), 1.96-2.12 (m, 1H), 2.73 (d, J = 6.0 Hz, 2H), 3.25 (s, 3H), 3.44 (s, 3H), 3.86 (s, 3H), 3.89 (s) , 3H), 3.93 (s, 3H), 4.04 (s, 3H), 6.78-6.90 (m, 3H), 7.73 (s, 1H), 14.38 (s, 1H)

  The present invention provides an industrially advantageous process for producing enone esters. By utilizing this invention, a lignan derivative can be industrially efficiently produced.

Claims (7)

formula:

Compound (1) represented by the formula:

A compound represented by the formula (2) is reacted in ethyl acetate:

The manufacturing method of compound (3) shown by these. A compound (3) obtained by the method according to claim 1, which is then reduced in the presence of Raney nickel:

The manufacturing method of compound (4) shown by these. The process according to claim 2, wherein the reduction is carried out in ethyl acetate. A compound (4) obtained by the method according to claim 2 or 3, and then dehydrated, is represented by the formula:

The manufacturing method of compound (5) shown by these. The method for producing a crystal of compound (5) according to claim 4, wherein the crystal is crystallized from alcohol. Crystal of compound (5) according to claim 4 After obtaining the compound (5) or a crystal thereof by the method according to claim 4 or 5, it is represented by the formula:

Is reacted with a compound (6) represented by the formula:

After obtaining the compound (7) represented by the formula, it is dehydrated:

The manufacturing method of compound (8) shown by these.