JP2006232788A - Method for producing optically active 2-chloro-3-hydroxyl-3,n-diphenyl-propanoic acid amide - Google Patents
Method for producing optically active 2-chloro-3-hydroxyl-3,n-diphenyl-propanoic acid amide Download PDFInfo
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Description
光学活性な２‐クロロ‐３‐ヒドロキシル‐３，Ｎ‐ジフェニル‐プロパン酸アミドの製造法に関する。 The present invention relates to a process for producing optically active 2-chloro-3-hydroxyl-3, N-diphenyl-propanoic acid amide.
光学活性２‐クロロ‐３‐ヒドロキシル‐３‐フェニル‐プロパン酸骨格を持つ化合物は各種医薬化合物の中間体として有用な物質である。 A compound having an optically active 2-chloro-3-hydroxyl-3-phenyl-propanoic acid skeleton is a useful substance as an intermediate for various pharmaceutical compounds.
光学活性２‐クロロ‐３‐ヒドロキシル‐３‐フェニル‐プロパン酸骨格を持つ化合物の合成法としては不斉化学合成法と生化学反応を利用する方法が知られている。不斉化学合成法としては、特許文献１に、光学活性なＮ‐アセチルオキサゾリジノンとベンズアルデヒドとの反応により光学活性な２‐ハロゲノ‐３‐ヒドロキシル‐３‐フェニル‐プロパン酸アミドを合成する方法が記載されている。
また非特許文献１には、光学活性なＮ‐アセチルオキサゾリジンチオンとベンズアルデヒドとの反応により、光学活性な２‐ハロゲノ‐３‐ヒドロキシル‐３‐フェニル‐プロパン酸アミドを合成する方法が記載されている。
特許文献２には、ジホスフィン化合物を配位子とする遷移金属錯体により２‐クロロ‐３‐オキソ‐３‐フェニル‐プロパン酸エステルを不斉水素化し２‐クロロ‐３‐ヒドロキシル‐３‐フェニル‐プロパン酸エステルを得ることが出来る旨が記載されている。
As a method for synthesizing a compound having an optically active 2-chloro-3-hydroxyl-3-phenyl-propanoic acid skeleton, an asymmetric chemical synthesis method and a method utilizing a biochemical reaction are known. As an asymmetric chemical synthesis method, Patent Document 1 describes a method of synthesizing optically active 2-halogeno-3-hydroxyl-3-phenyl-propanoic acid amide by reaction of optically active N-acetyloxazolidinone and benzaldehyde. Has been.
Non-Patent Document 1 describes a method of synthesizing optically active 2-halogeno-3-hydroxyl-3-phenyl-propanoic acid amide by reaction of optically active N-acetyloxazolidinethione with benzaldehyde. .
In Patent Document 2, 2-chloro-3-oxo-3-phenyl-propanoic acid ester is asymmetrically hydrogenated with a transition metal complex having a diphosphine compound as a ligand, and 2-chloro-3-hydroxyl-3-phenyl- It is described that a propanoic acid ester can be obtained.
生化学反応を利用する方法としては酵素法と微生物還元法が知られている。特許文献３には、ｓｙｎ体の２‐クロロ‐３‐ヒドロキシル‐３‐フェニル‐プロパン酸エステルをリパーゼで立体選択的に加水分解し光学活性な２‐クロロ‐３‐ヒドロキシル‐３‐フェニル‐プロパン酸を得ることが出来る旨が記載されている。特許文献４には、２‐クロロ‐３‐オキソ‐３‐フェニル‐プロパン酸エステルを例えばカンジダ属に属する微生物によりに接触させることにより光学活性な２‐クロロ‐３‐ヒドロキシル‐３‐フェニル‐プロパン酸エステルを合成する方法が開示されている。 Enzymatic methods and microbial reduction methods are known as methods utilizing biochemical reactions. Patent Document 3 discloses an optically active 2-chloro-3-hydroxyl-3-phenyl-propane by stereoselective hydrolysis of a syn-form of 2-chloro-3-hydroxyl-3-phenyl-propanoic acid ester with lipase. It is described that an acid can be obtained. In Patent Document 4, optically active 2-chloro-3-hydroxyl-3-phenyl-propane is obtained by contacting 2-chloro-3-oxo-3-phenyl-propanoic acid ester with a microorganism belonging to the genus Candida, for example. A method for synthesizing acid esters is disclosed.
不斉化学合成では高価な光学活性試薬や不斉触媒、低温反応装置、高圧反応装置などを使用しなければならない。また、多くの場合、不斉化学合成方法、生化学的方法ともに収率が低いという問題があり、温和な条件下安価に収率良く２‐クロロ‐３‐ヒドロキシル‐３‐フェニル‐プロパン酸骨格を持つ化合物を製造する方法が望まれている。特許文献４では、２‐クロロ‐３‐オキソ‐３‐フェニル‐プロパン酸エステルが微生物のエステラーゼ等により加水分解されそれに引き続き脱炭酸反応が起きてしまうため、収量が低下してしまうという欠点がある。 In asymmetric chemical synthesis, expensive optically active reagents, asymmetric catalysts, low-temperature reactors, high-pressure reactors, etc. must be used. In many cases, there is a problem that the yield is low in both the asymmetric chemical synthesis method and the biochemical method. There is a desire for a method of producing a compound having In Patent Document 4, 2-chloro-3-oxo-3-phenyl-propanoic acid ester is hydrolyzed by microbial esterase and the like, followed by decarboxylation, resulting in a decrease in yield. .
本発明者等は前記課題を解決すべく鋭意研究の結果、２‐クロロ‐３‐オキソ‐３‐フェニル‐プロパン酸アニリドをピキア属の菌体に接触させることにより、光学活性な２‐（Ｓ）‐クロロ‐３‐(Ｒ)‐ヒドロキシル‐３、Ｎ‐ジフェニル‐プロパン酸アミドを得て、さらに、アルコール中で反応させることにより２‐（Ｓ）‐クロロ‐３‐(Ｒ)‐ヒドロキシル‐３‐フェニル‐プロパン酸エステルが得られることを見出し、本発明を完成させるに至った。
即ち、本発明は、
As a result of diligent research to solve the above-mentioned problems, the present inventors contacted 2-chloro-3-oxo-3-phenyl-propanoic acid anilide with Pichia cells to produce optically active 2- (S ) -Chloro-3- (R) -hydroxyl-3, N-diphenyl-propanoic acid amide, and further reacted in alcohol to give 2- (S) -chloro-3- (R) -hydroxyl- The inventors have found that 3-phenyl-propanoic acid ester can be obtained and have completed the present invention.
That is, the present invention
（１）一般式（１） (1) General formula (1)
（式中、Ｒ1、Ｒ2は同一か異なっていてもよく、低級アルキル基、低級アルコキシ基、水酸基、ハロゲン原子または水素原子を表し、２位がＳの配置であり、３位がＲの配置を示す。）で示される光学活性な２‐クロロ‐３‐ヒドロキシル‐３、Ｎ‐ジフェニル‐プロパン酸アミド、
（２）Ｒ1、Ｒ2がともに水素原子である前項（１）に記載の化合物、
（３）一般式（２）
(In the formula, R 1 and R 2 may be the same or different and each represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom or a hydrogen atom, the 2-position is the S configuration, and the 3-position is R. The optically active 2-chloro-3-hydroxyl-3, N-diphenyl-propanoic acid amide represented by
(2) The compound according to the above item (1), wherein R 1 and R 2 are both hydrogen atoms,
(3) General formula (2)
（式中、Ｒ1、Ｒ2は同一か異なっていてもよく、低級アルキル基、低級アルコキシ基、水酸基、ハロゲン原子または水素原子を表わす。）で示される化合物をピキア（Ｐｉｃｈｉａ）属に属す菌体に接触させて還元することを特徴とする前項（１）に記載の化合物の製造法、
（４）使用する微生物がピキア属ミヌタ種（Ｐｉｃｈｉａ ｍｉｎｕｔａ ｖａｒ． ｍｉｎｕｔａ）である前項（３）に記載の製造法、
（５）使用する微生物がピキア属ミヌタ種（Ｐｉｃｈｉａ ｍｉｎｕｔａ ｖａｒ． ｍｉｎｕｔａ）ＮＢＲＣ Ｎｏ．０９７５である前項（４）に記載の製造法、
（６）Ｒ1、Ｒ2がともに水素原子である前項（３）〜（５）のいずれか一項に記載の製造法、
（７）前項（１）に記載の化合物を低級アルコール中で塩化水素ガスを吹き込み反応させて得られる下記一般式（３）で示される光学活性な２‐クロロ‐３‐ヒドロキシル‐３‐フェニル‐プロパン酸エステルの製造法、
(Wherein R 1 and R 2 may be the same or different and each represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom or a hydrogen atom). A bacterium belonging to the genus Pichia A method for producing the compound according to item (1), wherein the compound is reduced by contact with a body,
(4) The production method according to (3) above, wherein the microorganism to be used is Pichia minuta var. Minuta.
(5) The microorganism to be used is Pichia minuta var. Minuta NBRC No. The production method according to item (4), which is 0975,
(6) The production method according to any one of (3) to (5), wherein R 1 and R 2 are both hydrogen atoms;
(7) An optically active 2-chloro-3-hydroxyl-3-phenyl- compound represented by the following general formula (3) obtained by reacting the compound described in (1) with hydrogen chloride gas in a lower alcohol. Production method of propanoic acid ester,
（式中、Ｒ1は、低級アルキル基、低級アルコキシ基、水酸基、ハロゲン原子または水素原子を表し、Ｒ3は低級アルキル基を示し、２位がＳの配置であり、３位がＲの配置を示す。）
に関する。
(In the formula, R 1 represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom or a hydrogen atom, R 3 represents a lower alkyl group, the 2-position is an S configuration, and the 3-position is an R configuration. Is shown.)
About.
本発明のピキア属に属す菌体を用いる方法は、温和な条件下、高価な不斉試薬を使用せず収率よく高純度の光学活性な２‐（Ｓ）‐クロロ‐３‐(Ｒ)‐ヒドロキシル‐３、Ｎ‐ジフェニル‐プロパン酸アミドおよび２‐（Ｓ）‐クロロ‐３‐(Ｒ)‐ヒドロキシル‐３‐フェニル‐プロパン酸エステルを製造できる。 The method using the cells belonging to the genus Pichia of the present invention is a highly pure optically active 2- (S) -chloro-3- (R) with a high yield without using an expensive asymmetric reagent under mild conditions. -Hydroxyl-3, N-diphenyl-propanoic acid amide and 2- (S) -chloro-3- (R) -hydroxyl-3-phenyl-propanoic acid ester can be prepared.
式（１）及び式（２）のＲ1およびＲ2は低級アルキル基、低級アルコキシ基、水酸基、ハロゲン原子または水素原子を表す。低級アルキル基とは炭素数１〜４のアルキル基が挙げられ、具体的にはメチル基、エチル基、プロピル基、イソプロピル基、シクロプロピル基、ブチル基、イソブチル基、ターシャリーブチル基などが挙げられる。低級アルコキシ基とは、炭素数１〜４のアルキル基が挙げられ、具体的にはメトキシ基、エトキシ基、プロピルオキシ基、イソプロピルオキシ基、シクロプロポキシ基、ブチルオキシ基、イソブチルオキシ基、ターシャリーブチルオキシ基などが挙げられる。ハロゲン原子としてはフッ素、塩素、臭素が挙げられる。
また、式（３）のＲ3における低級アルキル基とは、炭素数２〜８の直鎖もしくは分岐のアルキル基を表し、例えば、エチル基、プロピル基、ブチル基、イソブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基等が挙げられる。
R 1 and R 2 in Formula (1) and Formula (2) represent a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom, or a hydrogen atom. The lower alkyl group includes an alkyl group having 1 to 4 carbon atoms, and specifically includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, an isobutyl group, a tertiary butyl group, and the like. It is done. The lower alkoxy group includes an alkyl group having 1 to 4 carbon atoms, and specifically includes a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a cyclopropoxy group, a butyloxy group, an isobutyloxy group, and tertiary butyl. An oxy group etc. are mentioned. Examples of the halogen atom include fluorine, chlorine and bromine.
Further, the lower alkyl group in R 3 of the formula (3) represents a linear or branched alkyl group having 2 to 8 carbon atoms, and examples thereof include an ethyl group, a propyl group, a butyl group, an isobutyl group, a pentyl group, and a hexyl group. Group, heptyl group, octyl group and the like.
前記一般式（１）で表される本発明化合物の製造法を下記に示す。
一般式（２）で表される２‐クロロ‐３‐オキソ‐３‐フェニル‐プロパン酸アニリドは、下記一般式（４）で示される２‐ベンゾイル酢酸アニリドを塩化スルフリルやＮ‐クロロフタルイミドなどの塩素化剤でクロル化して得られる（参考例１を参照）。Ｒ1、Ｒ2がともに水素である２‐ベンゾイル酢酸アニリドは東京化成より購入できる。またはそれ以外の式（４）で表される２‐ベンゾイル酢酸アニリドはオーガニック・シンセシス（Ｏｒｇａｎｉｃ Ｓｙｎｔｈｅｓｉｓ）１９６３年４巻４１５頁に記載の製造法で所望の２‐ベンゾイル酢酸エステルを合成し、ジャーナル・オブ・オーガニック・ケミストリー１９９１年５６巻１７１３−１７１８頁に記載の製造法でアニリンと反応させ得ることが出来る。
The production method of the compound of the present invention represented by the general formula (1) is shown below.
2-Chloro-3-oxo-3-phenyl-propanoic acid anilide represented by the general formula (2) is obtained by converting 2-benzoyl acetic acid anilide represented by the following general formula (4) to sulfuryl chloride, N-chlorophthalimide and the like. Obtained by chlorination with a chlorinating agent (see Reference Example 1). 2-Benzoyl acetic acid anilide in which R 1 and R 2 are both hydrogen can be purchased from Tokyo Kasei. Alternatively, other 2-benzoylacetate anilides represented by the formula (4) can be synthesized by synthesizing a desired 2-benzoylacetate ester by the production method described in Organic Synthesis, Vol. Of Organic Chemistry 1991, 56, 1713-1718, can be reacted with aniline.
（式中、Ｒ1、Ｒ2は同一か異なっていてもよく、低級アルキル基、低級アルコキシ基、水酸基、ハロゲン原子または水素原子を表す。） (In the formula, R 1 and R 2 may be the same or different and each represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom or a hydrogen atom.)
次いで本発明によれば、一般式（２）で表される２‐クロロ‐３‐オキソ‐３‐フェニル‐プロパン酸アニリドをピキア属に属す微生物の培養液、菌体、菌体処理物を接触させることにより前記式（１）で表される光学活性２‐（Ｓ）‐クロロ‐３‐(Ｒ)‐ヒドロキシル‐３、Ｎ‐ジフェニル‐プロパン酸アミドを製造することができる。本発明において使用される微生物は一般式（２）で表される２‐クロロ‐３‐オキソ‐３‐フェニル‐プロパン酸アニリドを還元するピキア属に属す微生物であれば特に限定されないが、例えばＰｉｃｈｉａ ｍｉｎｕｔａ ｖａｒ． ｍｉｎｕｔａ（ピキア ミヌタ バー ミヌタ） ＮＢＲＣ Ｎｏ．０９７５が挙げられる。該菌株は独立行政法人製品評価技術基盤機構の生物遺伝資源部門から入手することが出来る。また、使用する菌株は、それらの野生株や変異株であってもよく、更にはこれらの微生物から遺伝子組換え、細胞融合などの生物工学的手法により誘導されたものであってもよい。 Next, according to the present invention, 2-chloro-3-oxo-3-phenyl-propanoic acid anilide represented by the general formula (2) is contacted with a culture solution, a microbial cell, and a treated microbial cell of a microorganism belonging to the genus Pichia. Thus, optically active 2- (S) -chloro-3- (R) -hydroxyl-3, N-diphenyl-propanoic acid amide represented by the formula (1) can be produced. The microorganism used in the present invention is not particularly limited as long as it is a microorganism belonging to the genus Pichia that reduces 2-chloro-3-oxo-3-phenyl-propanoic acid anilide represented by the general formula (2). For example, Pichia minuta var. minuta (Pichia Minuta Bar Minuta) NBRC No. 0975. The strain can be obtained from the biological genetic resources section of the National Institute for Product Evaluation Technology. In addition, the strain to be used may be a wild strain or a mutant strain thereof, and further may be derived from these microorganisms by a biotechnological technique such as gene recombination or cell fusion.
微生物の培養手段は増殖可能なら特に限定されず一般的な培養方法を用いればよい。例えば、炭素源としてはグルコース、フラクトース、ラクトース、マルトース、シュークロース等の糖類、グルタミン酸、スレオニン等のアミノ酸類、あるいはフマル酸、リンゴ酸、コハク酸の有機酸、もしくはグリセリンなどが使用できる。窒素源としては硫酸アンモニウム、塩化アンモニウム、尿素などが使用できる。有機栄養源として酵母エキス、トリプトン、肉エキス、コーンスティープリカー、麦芽エキスなどが使用できる。そして無機塩として塩化ナトリウム、硫酸マグネシウム、リン酸水素カリウムなどを含み、ｐＨ３〜８好ましくはｐＨ４〜７に調製した培地に微生物を接種し、常温ないしは加温下、好ましくは２０〜４０℃で培養すればよい。また、かかる微生物菌体の処理物としては凍結乾燥菌体、アセトン乾燥菌体などが挙げられる。さらに微生物菌体あるいは菌体処理物を公知の方法により固定化して使用することもできる。 The microorganism culture means is not particularly limited as long as it can grow, and a general culture method may be used. For example, as the carbon source, saccharides such as glucose, fructose, lactose, maltose and sucrose, amino acids such as glutamic acid and threonine, organic acids such as fumaric acid, malic acid and succinic acid, or glycerin can be used. As the nitrogen source, ammonium sulfate, ammonium chloride, urea and the like can be used. As an organic nutrient source, yeast extract, tryptone, meat extract, corn steep liquor, malt extract and the like can be used. And it inoculates the culture medium which contains sodium chloride, magnesium sulfate, potassium hydrogen phosphate, etc. as inorganic salts, and adjusted to pH 3-8, preferably pH 4-7, and is cultured at room temperature or under heating, preferably at 20-40 ° C. do it. In addition, examples of the processed product of microbial cells include freeze-dried cells and acetone-dried cells. Furthermore, microbial cells or treated cells can be used by immobilizing them by a known method.
本発明の微生物を用いた不斉還元反応に使用できる反応溶媒は水溶液、もしくは非水溶性の有機溶剤と水溶液の二相系溶媒を用いることが可能である。一般式（２）で表される２‐クロロ‐３‐オキソ‐３‐フェニル‐プロパン酸アニリドは０．０５％〜１０％加えることが可能である。添加方法は一度に加えてもよいし逐次添加をしてもよい。一般式（２）で表される２‐クロロ‐３‐オキソ‐３‐フェニル‐プロパン酸アニリドの溶解補助剤としジメチルホルムアミド、ジメチルスルホキシド、エタノール、メタノールなどの使用も可能である。また、微生物不斉還元反応の副反応である脱クロル化を押さえるために、１‐クロロ‐酢酸エチルなどを加えることも可能である。反応終了後、トルエン、ジクロロメタン、酢酸エチル等の有機溶媒で抽出し、有機溶媒の濃縮、再結晶、クロマトグラフィーなどにより立体選択的に一般式（１）で表される２‐（Ｓ）‐クロロ‐３‐(Ｒ)‐ヒドロキシル‐３、Ｎ‐ジフェニル‐プロパン酸アミドを取得することが出来る。 The reaction solvent that can be used for the asymmetric reduction reaction using the microorganism of the present invention can be an aqueous solution or a two-phase solvent of a water-insoluble organic solvent and an aqueous solution. The 2-chloro-3-oxo-3-phenyl-propanoic acid anilide represented by the general formula (2) can be added in an amount of 0.05% to 10%. The addition method may be added all at once or sequentially. As a solubilizer for 2-chloro-3-oxo-3-phenyl-propanoic acid anilide represented by the general formula (2), dimethylformamide, dimethyl sulfoxide, ethanol, methanol and the like can be used. Also, 1-chloro-ethyl acetate or the like can be added to suppress dechlorination, which is a side reaction of the microbial asymmetric reduction reaction. After completion of the reaction, extraction with an organic solvent such as toluene, dichloromethane, ethyl acetate, etc., and stereoselection of 2- (S) -chloro represented by the general formula (1) by concentration, recrystallization, chromatography, etc. -3- (R) -hydroxyl-3, N-diphenyl-propanoic acid amide can be obtained.
（式中、Ｒ1、Ｒ2は同一か異なっていてもよく、低級アルキル基、低級アルコキシ基、水酸基、ハロゲン原子または水素原子を表し、式（１）において、２位がＳの配置であり、３位がＲの配置を示す。） (In the formula, R 1 and R 2 may be the same or different and each represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom or a hydrogen atom, and in the formula (1), the 2-position is an S configuration. The 3rd position shows the arrangement of R.)
一般式（１）で表される２‐（Ｓ）‐クロロ‐３‐(Ｒ)‐ヒドロキシル‐３、Ｎ‐ジフェニル‐プロパン酸アミドは、低級アルコール中で塩化水素ガス通気下５〜１００時間還流または８５℃〜２４０℃で反応させることで立体構造を保持したままアミド体から下記式（３）で表されるエステル体に変換することが出来る。
低級アルコールとしては、直鎖もしくは分岐の炭素数２〜８のアルコール例えばエタノール、プロパノール、ブタノール、イソブタノール、ペンタノール、ヘキサノール、へプタノール、オクタノールなどが挙げられる。
2- (S) -Chloro-3- (R) -hydroxyl-3, N-diphenyl-propanoic acid amide represented by the general formula (1) is refluxed in a lower alcohol for 5 to 100 hours under hydrogen chloride gas flow. Alternatively, by reacting at 85 ° C. to 240 ° C., the amide form can be converted to the ester form represented by the following formula (3) while maintaining the three-dimensional structure.
Examples of the lower alcohol include linear or branched alcohols having 2 to 8 carbon atoms such as ethanol, propanol, butanol, isobutanol, pentanol, hexanol, heptanol, octanol and the like.
（式中、Ｒ1は、低級アルキル基、低級アルコキシ基、水酸基、ハロゲン原子または水素原子を表し、Ｒ3は低級アルキル基を示し、２位がＳの配置であり、３位がＲの配置を示す。） (In the formula, R 1 represents a lower alkyl group, a lower alkoxy group, a hydroxyl group, a halogen atom or a hydrogen atom, R 3 represents a lower alkyl group, the 2-position is an S configuration, and the 3-position is an R configuration. Is shown.)
以下に実施例および参考例を挙げて、本発明をさらに詳細に説明するが、本発明はこれらに限定されるものではない。実施例において部は重量部を、％は重量％をそれぞれ意味する。 EXAMPLES The present invention will be described in more detail below with reference to examples and reference examples, but the present invention is not limited to these. In Examples, “part” means “part by weight” and “%” means “% by weight”.
参考例１
２‐クロロ‐３‐オキソ‐３‐フェニル‐プロパン酸アニリド（式（２）の化合物）の製造
２−ベンゾイル酢酸アニリド１０ｇをテトラヒドロフラン１００ｍｌに溶解し、氷冷下塩化スルフリル５．６４ｇを滴下した。滴下終了後室温に戻し１８時間反応させた。これを減圧濃縮し２‐クロロ‐３‐オキソ‐３‐フェニル‐プロパン酸アニリド（白色結晶） １１．２ｇを得た。
1Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ3、δ）５．８１（１Ｈ，ｓ）、７．１７（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ）７．３５（２Ｈ，ｔ，Ｊ＝７．８Ｈｚ）、７．６６（１Ｈ，ｔ，Ｊ＝７．３Ｈｚ）、８．０８（１Ｈ，ｄ，Ｊ＝７．６Ｈｚ）８．３４（１Ｈ，ｂｓ）
Reference example 1
Preparation of 2-chloro-3-oxo-3-phenyl-propanoic acid anilide (compound of formula (2)) 10 g of 2-benzoylacetic acid anilide was dissolved in 100 ml of tetrahydrofuran, and 5.64 g of sulfuryl chloride was added dropwise under ice cooling. After completion of dropping, the temperature was returned to room temperature and reacted for 18 hours. This was concentrated under reduced pressure to obtain 11.2 g of 2-chloro-3-oxo-3-phenyl-propanoic acid anilide (white crystals).
1H-NMR (300 MHz, CDCl 3, δ) 5.81 (1H, s), 7.17 (1H, t, J = 7.3 Hz) 7.35 (2H, t, J = 7.8 Hz), 7. 66 (1H, t, J = 7.3 Hz), 8.08 (1H, d, J = 7.6 Hz) 8.34 (1H, bs)
実施例１
２‐クロロ‐３‐ヒドロキシル‐３、Ｎ‐ジフェニル‐プロパン酸アミド（式（１）の化合物）の製造
酵母エキス２．５ｇ、大豆ペプトン２．５ｇ、麦芽エキス５ｇ、グルコース１０ｇを水５００ｍｌに溶解し６Ｎ−塩酸水溶液でｐＨ６．０に調製した。これを直径２１ｍｍの試験管１０本に１０ｍｌ分注し、１２０℃で２０分間滅菌した。この培地にＰｉｃｈｉａ ｍｉｎｕｔａ ＮＢＲＣ Ｎｏ．０９７５を１白金耳接種し、２７℃２２０ｒｐｍで４１時間振盪培養した。その培養液にそれぞれ１０％グルコースを１００μＬずつ添加しさらに２時間培養を継続した。その１０本の培養液にそれぞれ１０ｍｇの２‐クロロ‐３‐オキソ‐３‐フェニル‐プロパン酸アニリドを含むジメチルスルホキシド１００μｌを添加し、２７℃２２０ｒｐｍで２４時間振盪反応させた。この反応液を集めて酢酸エチル１２０ｍｌで２回抽出し有機層を合わせて水で３回洗浄、飽和食塩水で１回洗浄した。有機層を無水硫酸マグネシウムで乾燥後、ろ過、減圧濃縮した。得られた結晶を高速液体クロマトグラフィーにより定量した。分析条件は、カラムがジーエルサイエンス株式会社製のＩｎｅｒｔｓｉｌ ＯＤＳ−３（４．６ｍｍ×２５０ｍｍ）、移動相はアセトニトリル：水＝４５：５５を用い、流速０．８ｍｌ／分、カラム温度３５℃で行なった（リテンションタイム：２‐クロロ‐３‐ヒドロキシル‐３、Ｎ‐ジフェニル‐プロパン酸アミド ｓｙｎ体１３．６分、ａｎｔｉ体１７．３分）。２‐クロロ‐３‐ヒドロキシル‐３、Ｎ‐ジフェニル‐プロパン酸アミドの生成量は６６ｍｇ（収率６５．５％）であった。さらに薄層クロマトグラフィー（ヘキサン：酢酸エチル＝３：１）で２‐クロロ‐３‐ヒドロキシル‐３、Ｎ‐ジフェニル‐プロパン酸アミド５８ｍｇ（収率５７．６％）を単離しＮＭＲ測定した。
1Ｈ−ＮＭＲ（３００ＭＨｚ，ＣＤＣｌ3、δ）３．４３（１Ｈ，ｄ，Ｊ＝６．１Ｈｚ）、４．６４（１Ｈ，ｄ，Ｊ＝２．８Ｈｚ）、５．４８（１Ｈ，ｄｄ，Ｊ＝２．８Ｈｚ，Ｊ＝６．１Ｈｚ）７．１５（１Ｈ，ｔ，Ｊ＝７．７Ｈｚ）７．２５−７．４８（９Ｈ，ｍ）８．３０（１Ｈ，ｓ）
この単離した２‐クロロ‐３‐ヒドロキシル‐３、Ｎ‐ジフェニル‐プロパン酸アミドを高速液体クロマトグラフィーで光学純度の分析したところ、２Ｓ，３Ｒ体９７．６％ｅｅ、ｓｙｎ体：９０．９％ｄｅであった。ｓｙｎの定義はアンゲバンテ・へミー・インターナショナル・エディション・イン・イングリッシュ（Ａｎｇｅｗ．Ｃｈｅｍ．Ｉｎｔ．Ｅｄ．Ｅｎｇｌ．）１９巻、５５７〜５５８頁（１９８０年）の記載のＳａｔｏｒｕ Ｍａｓａｍｕｎｅらに従った。絶対配置分析条件は、カラムはダイセル化学工業株式会社製のキラルセルＯＤ−Ｈ（４．６ｍｍ×２５０ｍｍ）、移動相はｎ−ヘキサン：イソプロパノール＝９：１を用い、流速１．０ｍｌ／分、カラム温度３５℃で行なった（リテンションタイム：２Ｒ，３Ｒ体７．８分、２Ｓ，３Ｓ体９．１分、２Ｓ，３Ｒ体９．９分、２Ｒ，３Ｓ体１０．９分）。
Example 1
Preparation of 2-chloro-3-hydroxyl-3, N-diphenyl-propanoic acid amide (compound of formula (1)) Yeast extract 2.5 g, soybean peptone 2.5 g, malt extract 5 g, glucose 10 g dissolved in 500 ml water The pH was adjusted to 6.0 with 6N-hydrochloric acid aqueous solution. 10 ml of this was dispensed into 10 test tubes with a diameter of 21 mm and sterilized at 120 ° C. for 20 minutes. In this medium, Pichia minuta NBRC No. One platinum loop of 0975 was inoculated and cultured with shaking at 27 ° C. and 220 rpm for 41 hours. 100 μL of 10% glucose was added to each culture solution, and the culture was further continued for 2 hours. 100 μl of dimethyl sulfoxide containing 10 mg of 2-chloro-3-oxo-3-phenyl-propanoic acid anilide was added to each of the 10 culture solutions, and the mixture was shaken at 27 ° C. and 220 rpm for 24 hours. This reaction solution was collected and extracted twice with 120 ml of ethyl acetate, and the organic layers were combined and washed three times with water and once with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crystals were quantified by high performance liquid chromatography. The analysis conditions were such that the column was Inertsil ODS-3 (4.6 mm × 250 mm) manufactured by GL Sciences, the mobile phase was acetonitrile: water = 45: 55, the flow rate was 0.8 ml / min, and the column temperature was 35 ° C. (Retention time: 2-chloro-3-hydroxyl-3, N-diphenyl-propanoic acid amide syn form 13.6 minutes, anti form 17.3 minutes). The production amount of 2-chloro-3-hydroxyl-3, N-diphenyl-propanoic acid amide was 66 mg (yield 65.5%). Further, 58 mg (yield 57.6%) of 2-chloro-3-hydroxyl-3 and N-diphenyl-propanoic acid amide was isolated and measured by NMR by thin layer chromatography (hexane: ethyl acetate = 3: 1).
1H-NMR (300 MHz, CDCl 3, δ) 3.43 (1H, d, J = 6.1 Hz), 4.64 (1H, d, J = 2.8 Hz), 5.48 (1H, dd, J = 2.8 Hz, J = 6.1 Hz) 7.15 (1 H, t, J = 7.7 Hz) 7.25-7.48 (9 H, m) 8.30 (1 H, s)
This isolated 2-chloro-3-hydroxyl-3, N-diphenyl-propanoic acid amide was analyzed for optical purity by high performance liquid chromatography. As a result, 2S, 3R isomer 97.6% ee, syn isomer: 90.9 % De. The definition of syn was in accordance with Satoru Masamune et al. described in Angew. Chem. Int. Ed. Engl., Vol. 19, pp. 557-558 (1980). The absolute configuration analysis conditions were as follows. The column was Chiralcel OD-H (4.6 mm × 250 mm) manufactured by Daicel Chemical Industries, Ltd., the mobile phase was n-hexane: isopropanol = 9: 1, the flow rate was 1.0 ml / min, the column The temperature was 35 ° C. (retention time: 2R, 3R 7.8 minutes, 2S, 3S 9.1 minutes, 2S, 3R 9.9 minutes, 2R, 3S 10.9 minutes).
実施例２
２‐クロロ‐３‐ヒドロキシル‐３‐フェニル‐プロパン酸ブチルエステル（式（３）の化合物）の合成
実施例１のＰｉｃｈｉａ ｍｉｎｕｔａ ＮＢＲＣ Ｎｏ．０９７５による還元で得られた２‐クロロ‐３‐ヒドロキシル‐３、Ｎ‐ジフェニル‐プロパン酸アミド２５０ｍｇをｎ−ブタノール５０ｍｌに溶解し、塩化水素ガスを吹き込みながら９時間還流した。室温に戻し、酢酸エチルと水を加え分液抽出し、有機層を水洗、飽和食塩水洗浄し、減圧濃縮し褐色オイル２６２ｍｇを得た。これをシリカゲルカラム（ヘキサン：酢酸エチル＝８５：１５）で精製した。２‐クロロ‐３‐ヒドロキシル‐３‐フェニル‐プロパン酸ブチルエステル２１０ｍｇを得た。
Example 2
Synthesis of 2-chloro-3-hydroxyl-3-phenyl-propanoic acid butyl ester (compound of formula (3)) Pichia minuta NBRC No. 1 of Example 1. 250 mg of 2-chloro-3-hydroxyl-3, N-diphenyl-propanoic acid amide obtained by reduction with 0975 was dissolved in 50 ml of n-butanol and refluxed for 9 hours while blowing hydrogen chloride gas. The temperature was returned to room temperature, and ethyl acetate and water were added for separation and extraction. The organic layer was washed with water and saturated brine, and concentrated under reduced pressure to obtain 262 mg of a brown oil. This was purified with a silica gel column (hexane: ethyl acetate = 85: 15). 210 mg of 2-chloro-3-hydroxyl-3-phenyl-propanoic acid butyl ester was obtained.
本発明で得られた２‐クロロ‐３‐ヒドロシキル‐３、Ｎ‐ジフェニル‐プロパン酸アミドは、例えば医薬品であるタキソール側鎖の合成に用いることが出来る。 The 2-chloro-3-hydroxy-3, N-diphenyl-propanoic acid amide obtained in the present invention can be used, for example, for the synthesis of a taxol side chain which is a pharmaceutical product.
Claims (7)
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| WO2018229202A1 (en) | 2017-06-16 | 2018-12-20 | Basf Se | Mesoionic imidazolium compounds and derivatives for combating animal pests |
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| WO2017093214A1 (en) | 2015-12-03 | 2017-06-08 | Bayer Cropscience Aktiengesellschaft | Mesoionic halogenated 3-(acetyl)-1-[(1,3-thiazol-5-yl)methyl]-1h-imidazo[1,2-a]pyridin-4-ium-2-olate derivatives and related compounds as insecticides |
| WO2018229202A1 (en) | 2017-06-16 | 2018-12-20 | Basf Se | Mesoionic imidazolium compounds and derivatives for combating animal pests |
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